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Denosumab for the prevention of skeletal-related events in adults with bone metastases from solid tumours
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Denosumab for the prevention of skeletal-related events in adults with bone metastases from solid tumours
# Guidance
Denosumab is recommended as an option for preventing skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from breast cancer and from solid tumours other than prostate if:
bisphosphonates would otherwise be prescribed and
the manufacturer provides denosumab with the discount agreed in the patient access scheme.
Denosumab is not recommended for preventing skeletal-related events in adults with bone metastases from prostate cancer.
Adults with bone metastases from solid tumours currently receiving denosumab for the prevention of skeletal-related events that is not recommended according to 1.1 and 1.2 should be able to continue treatment until they and their clinician consider it appropriate to stop.# Clinical need and practice
Bone is one of the most common sites for circulating cancer cells to settle and start growing. Metastases can occur in any bones in the body, but the spine is commonly affected, as well as the pelvis, hip, upper leg bones and the skull. Almost any cancer can metastasise to the bone, but cancers of the breast, prostate, lung, bladder, thyroid and kidney spread to the bone most often.
The manufacturer has estimated that there are more than 150,000 people in England and Wales with solid tumours and bone metastases, more than 80% of them with breast and prostate cancer. Approximately 0.5% of women with breast cancer have bone metastases at diagnosis and 4.7% develop bone metastases within 5 years. The manufacturer's submission reported that 11% of people with prostate cancer present with bone metastases at initial staging.
In women with breast cancer, bone metastases are associated with a median reduction in survival of approximately 2 years. In men with prostate cancer, bone metastases are associated with a reduced 5-year survival from 56% to 3%.
Bone metastases are also associated with reduced quality of life and an increased risk of complications from bone weakness or disrupted calcium homeostasis. Complications include pathological fractures (defined as pathological because minimal or no force is needed to cause them), spinal cord compression, radiation to the bone or surgery to the bone. These are collectively defined as skeletal-related events. Mobility may be reduced because of bone pain and other complications. Metastatic bone pain can be intermittent or constant, and people with bone metastases often report inadequate pain relief with analgesics.
The primary aim of treating bone metastases is to manage skeletal morbidity by delaying or preventing skeletal-related events. A second aim is to delay pain and reduce its severity. Current treatments for bone metastases and their complications include radiotherapy, orthopaedic surgery, bone-targeting radio-pharmaceuticals and chemotherapy. Four bisphosphonates have a marketing authorisation for managing bone metastases or preventing skeletal-related events in people with solid tumours: zoledronic acid, disodium pamidronate, sodium clodronate and ibandronic acid. Zoledronic acid is the only bisphosphonate that has a marketing authorisation for the prevention of skeletal-related events in advanced malignancies involving bone without specifying the primary tumour type. Disodium pamidronate and sodium clodronate have a marketing authorisation for breast cancer and multiple myeloma, and ibandronic acid has a marketing authorisation for breast cancer only.
Management of bone metastases varies by primary cancer type. Advanced breast cancer: diagnosis and treatment (NICE clinical guideline 81) recommends offering bisphosphonates to people with newly diagnosed breast cancer and bone metastases to prevent skeletal-related events and reduce pain. Prostate cancer: diagnosis and treatment (NICE clinical guideline 58) does not recommend the use of bisphosphonates to prevent or reduce complications of bone metastases in men with hormone refractory prostate cancer. In this patient group, bisphosphonates for pain relief may be considered when other treatments, including analgesics and palliative radiotherapy, have failed. The oral or intravenous route of administration should be chosen according to convenience, tolerability and cost. In people with lung cancer with bone metastases who need palliation and for whom standard analgesic treatments are inadequate, single-fraction radiotherapy is recommended (Lung cancer: the diagnosis and treatment of lung cancer ). Metastatic spinal cord compression: diagnosis and management of adults at risk of and with metastatic spinal cord compression (NICE clinical guideline 75) recommends bisphosphonates in people with breast cancer or multiple myeloma with vertebral involvement to reduce pain and the risk of vertebral fracture/collapse. In people with vertebral involvement from prostate cancer, bisphosphonates are recommended to reduce pain only if conventional analgesia fails to control pain.# The technology
Denosumab (XGEVA, Amgen) is a fully human monoclonal antibody that reduces osteoclast-mediated bone destruction by inhibiting the receptor activator of nuclear factor kappa-B ligand (RANKL), which is the primary mediator of increased osteoclast activity. Denosumab has a marketing authorisation for the prevention of skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from solid tumours. The recommended dose of denosumab for the prevention of skeletal-related events in bone metastases from solid tumours is 120 mg every 4 weeks. It is administered as a single subcutaneous injection into the thigh, abdomen or upper arm.
The summary of product characteristics lists the following adverse reactions for denosumab: dyspnoea, diarrhoea, osteonecrosis of the jaw, hyperhidrosis, tooth extraction, hypophosphataemia and hypocalcaemia. Denosumab is contraindicated in people with severe, untreated hypocalcaemia. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The cost of a 120 mg vial is £309.86 (excluding VAT; British National Formulary 63). A year of treatment (13 doses) would cost £4028.18 (excluding VAT). Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of denosumab has agreed a patient access scheme with the Department of Health, in which a discount on the list price of denosumab is offered. The size of the discount is commercial-in-confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
# Clinical effectiveness
The Assessment Group identified 8 studies (including 3 of denosumab) reporting outcome data on skeletal-related events – 4 in patients with breast cancer, 2 in patients with prostate cancer and 2 in patients with other solid tumours. The 2 studies in other solid tumours both included patients with non-small cell lung cancer enabling a separate subgroup analysis of non-small cell lung cancer. The Assessment Group undertook a network meta-analysis to compare denosumab with bisphosphonates and with best supportive care.
The definition of skeletal-related event in some instances varied across the trials. In the denosumab trials skeletal-related events was a composite outcome indicator that comprised radiation therapy to alleviate pain or prevent fracture, surgery to bone to treat or prevent fractures, and pathologic fracture or spinal cord compression that can result in paraesthesias, incontinence and paralysis. Some trials also included hypercalcaemia or change in antineo-plastic therapy in the definition of skeletal-related events. However, the definition of a skeletal-related event in the data informing the network meta-analysis was consistent across trials.
## Breast cancer
A double-blind, randomised, controlled trial compared denosumab with zoledronic acid and enrolled patients (n=2046) with confirmed breast cancer and at least 1 bone metastasis. Duration of follow-up was event rate driven and was approximately 34 months. The 3 other studies included in the network meta-analysis compared zoledronic acid with disodium pamidronate (n=1130), zoledronic acid with placebo (n=228) and disodium pamidronate with placebo (n=754).
In the trial comparing denosumab with zoledronic acid, the median time to first skeletal-related event was not reached in the denosumab group and was 26.4 months in the zoledronic acid group (hazard ratio 0.82, 95% confidence interval 0.71 to 0.95, p=0.01 superiority). The study comparing zoledronic acid with placebo reported that median time to first skeletal-related event was not reached in the zoledronic acid group compared with 364 days in the placebo group (p=0.007). Disodium pamidronate was also associated with a statistically significantly longer median time to first skeletal-related event than placebo (12.7 months compared with 7.0 months, p<0.001). The study comparing zoledronic acid with disodium pamidronate reported a statistically significant difference favouring zoledronic acid for time to first skeletal-related event in patients receiving hormone therapy (415 days for zoledronic acid and 370 days for disodium pamidronate, p=0.047), but not for patients receiving chemotherapy (349 days for zoledronic acid and 366 days for disodium pamidronate, p=0.826).
In the trial comparing denosumab with zoledronic acid, the risk of first and subsequent skeletal-related events was reduced in the denosumab group compared with the zoledronic acid group (relative risk 0.77, 95% CI 0.66 to 0.89, p=0.001 superiority). This risk was also reduced with denosumab in the subgroups of patients with or without a history of prior skeletal-related events. The study comparing zoledronic acid with placebo showed a statistically significant effect favouring zoledronic acid (RR 0.59, 95% CI 0.38 to 0.91). The study comparing zoledronic acid and disodium pamidronate showed a statistically significant effect favouring zoledronic acid (RR 0.80, 95% CI 0.66 to 0.97).
In the trial comparing denosumab with zoledronic acid, patients in the denosumab group on average had fewer skeletal-related events (0.45 events per patient per year) than patients in the zoledronic acid group (0.58 events per patient per year, p=0.004). In the other trials included in the network meta-analysis, zoledronic acid was associated with fewer skeletal-related events than placebo (0.63 compared with 1.1, p=0.016). Likewise, disodium pamidronate was associated with fewer skeletal-related events than placebo (2.4 compared with 3.7, p<0.001).
Results of the network meta-analysis showed that denosumab was associated with a statistically significant improvement compared with placebo for time to first on-study skeletal-related event (HR 0.46, 95% CI 0.29 to 0.72), risk of first and subsequent skeletal-related events (RR 0.45, 95% CI 0.28 to 0.72), and skeletal morbidity rate (RR 0.47, 95% CI 0.25 to 0.67). Denosumab was also associated with a statistically significant improvement compared with disodium pamidronate in the time to first skeletal-related event (HR 0.73, 95% CI 0.56 to 0.94) and the risk of first and subsequent skeletal-related events (RR 0.62, 95% CI 0.48 to 0.80). However, the difference in skeletal morbidity rate was not statistically significant. Compared with zoledronic acid, denosumab also improved time to first on-study skeletal-related event (HR 0.82, 95% CI 0.71 to 0.95) and the risk of first and subsequent skeletal-related events (RR 0.77, 95% CI 0.66 to 0.89), although the difference in skeletal morbidity rate was not statistically significant.
The denosumab trial reported no statistically significant difference in median overall survival for the denosumab group compared with the zoledronic acid group (HR 0.95, 95% CI 0.81 to 1.11, p=0.49).
In the same trial, the median time to developing moderate or severe pain in patients with no or mild pain at baseline was statistically significantly longer in the denosumab group than the zoledronic acid group (295 compared with 176 days, HR 0.78, 95% CI 0.67 to 0.92, p=0.0024). There were no differences in EQ-5D scores or analgesic use.
In the trial comparing denosumab with zoledronic acid, the incidence of serious adverse events and adverse events leading to discontinuation were similar in the denosumab and zoledronic acid groups. There was a higher incidence of hypocalcaemia events (5.5% compared with 3.4%) and lower incidence of hypercalcaemia (1.7% compared with 3.5%) in the denosumab group than in the zoledronic acid group respectively. The rate of osteonecrosis of the jaw was similar in the denosumab group and the zoledronic acid group (2.0% and 1.4% respectively). There was a lower rate of adverse events potentially associated with renal impairment in the denosumab group than in the zoledronic acid group (4.9% compared with 8.5% respectively). Acute-phase reactions occurring in the first 3 days after treatment were higher in the zoledronic acid group than in the denosumab group (27.3% compared with 10.4%).
## Prostate cancer
One double-blind, randomised, controlled trial compared denosumab with zoledronic acid and enrolled men aged 18 years or older with confirmed prostate cancer and at least 1 bone metastasis (n=1901). Follow-up was 41 months. A further randomised controlled trial was included in the network meta-analysis that compared zoledronic acid with placebo (n=643).
In the trial comparing denosumab with zoledronic acid, median time to first on-study skeletal-related event was statistically significantly longer with denosumab than zoledronic acid (20.7 compared with 17.1 months, HR 0.82, 95% CI 0.71 to 0.95, p=0.008 superiority). In the study comparing zoledronic acid with placebo, zoledronic acid increased the time to first on-study skeletal-related event (488 days compared with 321 days, p=0.009).
In the trial comparing denosumab with zoledronic acid, the risk of developing first and subsequent on-study skeletal-related events was reduced by denosumab compared with zoledronic acid (RR 0.82, 95% CI 0.71 to 0.94, p=0.008). In the trial comparing zoledronic acid with placebo, zoledronic acid was shown to reduce the risk of first and subsequent skeletal-related events(RR 0.64, 95% CI not reported, p=0.002).
In the trial comparing denosumab with zoledronic acid, skeletal morbidity rate was slightly lower among patients treated with denosumab than patients treated with zoledronic acid (figures provided academic in confidence). In the study comparing zoledronic acid with placebo, zoledronic acid reduced the skeletal morbidity rate from 1.49 in the placebo group to 0.80 in the zoledronic acid group (p=0.006).
The results of the network meta-analysis showed that denosumab was associated with a statistically significant improvement compared with placebo in time to first on-study skeletal-related event (HR 0.56, 95% CI 0.40 to 0.77), risk of first and subsequent skeletal-related events (RR 0.53, 95% CI 0.39 to 0.72) and skeletal morbidity rate (RR 0.52, 95% CI 0.07 to 0.82). Results of the network meta-analysis also showed a statistically significant improvement with denosumab compared with zoledronic acid in time to first on-study skeletal-related event (HR 0.82, 95% CI 0.71 to 0.95) and the risk of first and subsequent skeletal-related events (RR 0.82, 95% CI 0.71 to 0.94). The result for skeletal morbidity rate was not statistically significant.
In the trial comparing denosumab with zoledronic acid, median overall survival was similar in the denosumab group (19.4 months) and the zoledronic acid group (19.8 months, HR 1.03, 95% CI 0.91 to 1.17, p=0.65).
In the same trial, denosumab was associated with an approximately 1 month longer duration to development of moderate or severe pain in patients with no or mild pain at baseline than zoledronic acid (median 5.8 compared with 4.9 months), although the difference was not statistically significant (HR 0.89, 95% CI 0.77 to 1.04, p=0.1416). There were no differences in EQ-5D scores or analgesic use.
In the trial comparing denosumab with zoledronic acid, the incidences of serious adverse events and adverse events leading to discontinuation were similar in the denosumab and zoledronic acid groups (63% compared with 60% and 17% compared with 15% respectively). There were more hypocalcaemia adverse events in the denosumab group than the zoledronic acid group (13% compared with 6% ). A greater number of patients in the denosumab group than the zoledronic acid group experienced osteonecrosis of the jaw (2% compared with 1%). A similar rate of adverse events potentially associated with renal impairment occurred in the denosumab group and the zoledronic acid group (15% and 16% respectively). During the first 3 days of treatment, fewer patients experienced symptoms associated with acute phase reactions in the denosumab group (8%) than the zoledronic acid group (18%).
## Other solid tumours (including non-small cell lung cancer)
A double-blind, randomised, controlled study compared denosumab with zoledronic acid and enrolled patients aged 18 years or older with confirmed solid tumours (except breast and prostate) or multiple myeloma (n=1776). In the study, 40% of patients had non-small cell lung cancer, 10% had multiple myeloma and 50% had other tumours. A post-hoc analysis of data from this study for other solid tumours, excluding multiple myeloma, (n=1597) was provided by the manufacturer as academic-in-confidence and cannot be reported in this document. A summary of the publically available data (that is, data including patients with multiple myeloma) is included in this document. Another study in patients with other solid tumours, excluding breast cancer and prostate cancer, (n=507) that compared zoledronic acid with placebo was included in the network meta-analysis.
In the trial comparing denosumab with zoledronic acid, the median time to first on-study skeletal-related event was longer for denosumab than zoledronic acid (20.6 compared with 16.3 months, HR 0.84, 95% CI 0.71 to 0.98, p=0.0007 non-inferiority). The study comparing zoledronic acid with placebo reported a statistically significant improvement in time to first on-study skeletal-related event (230 days compared with 163 days, p=0.023).
In the trial comparing denosumab with zoledronic acid, denosumab reduced the risk of developing first and subsequent skeletal-related events compared with zoledronic acid (RR 0.90, 95% CI 0.77 to 1.04, p=0.14). In the study comparing zoledronic acid with placebo, zoledronic acid also reduced the risk of developing first and subsequent skeletal-related events compared with placebo (HR 0.732, p=0.017).
The results of the network meta-analysis (using data that excluded patients with multiple myeloma) showed a statistically significant improvement with denosumab compared with placebo in time to first skeletal-related event (HR 0.49, 95% CI 0.30 to 0.78), risk of first and subsequent skeletal-related events (RR 0.62, 95% CI 0.46 to 0.85) and proportion of patients with on-study skeletal-related event (odds ratio 0.58, 95% CI 0.02 to 19.48). Denosumab was also associated with a statistically significant improvement compared with zoledronic acid in time to first skeletal-related event (HR 0.81, 95% CI 0.68 to 0.96). The difference for risk of first or subsequent skeletal-related events, and the proportion of patients with on-study skeletal-related events, was not statistically significant.
In the trial comparing denosumab with zoledronic acid, median overall survival was similar in both groups.
In the same trial, in patients with no or mild pain at baseline, time to development of moderate or severe pain was longer for denosumab than zoledronic acid (median 144 days compared with 112 days (HR 0.81, 95% CI 0.66 to 1.00, p=0.049). There were no differences in EQ-5D scores or analgesic use.
In the study comparing denosumab with zoledronic acid, serious adverse events were reported in 66% of patients treated with zoledronic acid and in 63% of patients treated with denosumab. Other adverse events were similar in both groups. Hypocalcaemia was reported in 10% of patients in the denosumab group and 5.8% of patients in the zoledronic acid group. Rates of osteonecrosis of the jaw were similar in the denosumab (1.3%) and zoledronic acid (1.1%) groups. Renal adverse events occurred more often in the zoledronic acid group (10.9%) than the denosumab group (8.3%). Acute-phase reactions occurred more frequently in the zoledronic acid group (14.5%) than in the denosumab group (6.9%).
## Non-small cell lung cancer
The trial comparing denosumab with zoledronic acid in other solid tumours also reported data on a subgroup of patients with non-small cell lung cancer (n=702). Denosumab was associated with delayed time to first on-study skeletal-related event in patients with non-small cell lung cancer (HR 0.84, 95% CI 0.64 to 1.10, p=0.20). An ad hoc analysis for overall survival reported that denosumab improved overall survival relative to zoledronic acid by 21% in this patient group (HR 0.79, 95% CI 0.65 to 0.95). Skeletal morbidity rate, pain and health-related quality of life, and data on adverse events were not available separately for the non-small cell lung cancer group. Other data were provided as academic-in-confidence by the manufacturer and cannot be included in this document.
The network meta-analysis included another study comparing zoledronic acid with placebo, in patients with solid tumours other than breast and prostate, that reported data separately for a subgroup of patients with non-small cell lung cancer (n=244). Zoledronic acid was not associated with a statistically significant difference in time to first skeletal-related event compared with placebo (171 days and 151 days respectively, p=0.188) nor risk of first and subsequent skeletal-related events (HR 0.73, p=0.061). The incidence of skeletal-related events was lower in the zoledronic acid group (42% with an event), compared with placebo (45% with an event, p=0.557).
The results of the network meta-analysis showed that, compared with placebo, denosumab reduced the risk of first and subsequent skeletal-related events (RR 0.63, 95% CI 0.42 to 0.97). The difference in time to first skeletal-related event, and proportion of patients with a skeletal-related event, was not statistically significant. Compared with zoledronic acid none of the differences for time to first skeletal-related event, risk of first and subsequent skeletal-related event, and proportion of patients with a skeletal-related event was statistically significant.
# Cost effectiveness
The manufacturer identified 21 published studies that contained economic analyses of bisphosphonates. Twelve papers contained economic evaluations that included incremental cost-effectiveness analysis, of which 7 were cost–utility analyses. Of the 12 papers, 8 were in breast cancer, 2 in prostate cancer, 1 in lung cancer and 1 in renal carcinoma. The Assessment Group identified 11 studies, 1 of which included denosumab as an intervention. This study was in patients with prostate cancer and compared denosumab with zoledronic acid. The study used US cost data and reported costs per skeletal-related event avoided.
Of the 11 studies identified by the Assessment Group, 7 were in breast cancer, 3 in prostate cancer and 1 in lung cancer. Three of the breast cancer studies compared disodium pamidronate with best supportive care and reported incremental cost-effectiveness ratios (ICERs) for disodium pamidronate of between £1851 and £276,444 per quality-adjusted life year (QALY) gained. One of the breast cancer studies compared zoledronic acid with best supportive care and reported that zoledronic acid was cost saving. The 3 other breast cancer studies compared different bisphosphonates, 2 reported that oral ibandronate was cost saving compared with zoledronic acid and disodium pamidronate, while the third reported that disodium pamidronate was cost saving compared with zoledronic acid. Of the 3 studies in prostate cancer, 1 compared zoledronic acid with best supportive care and reported ICERs for zoledronic acid of between £2124 and £31,476 per QALY gained depending on the country of the cost data. The second reported that zoledronic acid was associated with £11,137 in additional costs per skeletal-related event avoided and had an ICER of £105,976 per QALY gained. The third compared denosumab and zoledronic acid and reported a cost per skeletal-related event avoided for denosumab of £31,532 using a 3-year time horizon. The lung cancer study reported that, using UK cost data, zoledronic acid was cost saving compared with best supportive care.
The manufacturer of denosumab submitted a Markov economic model that assessed the cost effectiveness of denosumab in 3 patient groups: breast cancer, prostate cancer and other solid tumours (excluding breast and prostate). The model had 5 health states: no prior skeletal-related event on treatment, prior skeletal-related event on treatment, no prior skeletal-related event off treatment, prior skeletal-related event off treatment, and death. The model had a 4-week cycle length and a half-cycle correction was applied. Patients were followed for 10 years.
The model compared the cost effectiveness of denosumab with zoledronic acid, disodium pamidronate, ibandronic acid and best supportive care. Zoledronic acid was the primary comparator in patients with breast cancer, with disodium pamidronate and ibandronic acid as secondary comparators. In prostate cancer, for patients with no pain or pain with no prior skeletal-related event, the comparator was best supportive care and, in patients with pain and a prior skeletal-related event, the comparator was zoledronic acid. In other solid tumours, for patients with no pain or pain with no prior skeletal-related event, the comparator was best supportive care. In patients with pain and a prior skeletal-related event, the comparators were zoledronic acid and disodium pamidronate.
The selection of the comparator in the analyses (that is best supportive care or a bisphosphonate) was informed by a chart review of patients in the UK. This showed that 87%, 49% and 37% of patients with bone metastases from breast, prostate and solid tumours other than breast and prostate were being treated or had been treated with bisphosphonates respectively. The choice of bisphosphonate in the analyses was informed by data from the IMS Oncology Analyzer. This reported that, for breast cancer, prostate cancer and other solid tumours, zoledronic acid was used in 50%, 92% and 80% of patients respectively. For disodium pamidronate, the proportions were 18%, 4% and 20% and, for ibandronic acid, the proportions were 31%, 4% and 0%.
The same model structure was used for each tumour type, but the absolute and relative risks of skeletal-related events, adverse events and cancer mortality were modelled to reflect the differences between tumour types. The skeletal-related event risk and event rates were derived from the individual denosumab clinical trials. Data from the zoledronic acid arm of each of the trials were used to estimate the baseline absolute risk of skeletal-related events. Treatment effects were estimated from the trial data for denosumab compared with zoledronic acid and from the network meta-analysis for the other comparators. Within each tumour type, all patients were assumed to have the same survival risk regardless of treatment. Five adverse events (osteonecrosis of the jaw, renal toxicity, hypercalcaemia, hypocalcaemia and skin infections) were included in the model based on their impact on cost and/or health-related quality of life. Adverse event data for denosumab and zoledronic acid were taken from the denosumab clinical trials and, for disodium pamidronate and ibandronic acid, from published clinical trials. Discontinuation from treatment was based on the manufacturer's phase III trial data and included discontinuation because of adverse effects, withdrawal of consent, treatment refusal, protocol violation, other illnesses and other reasons. Discontinuation rates for other comparators were taken from the literature.
The utility values used in the model were derived from the denosumab clinical trials, which included the administration of the EQ-5D questionnaire every 4 weeks. For each skeletal-related event, it was assumed that the utility decrement started 5 months before identification and resolved 5 months afterwards. All utility values were calculated separately for different tumour types. Utility values were provided academic-in-confidence by the manufacturer and cannot be reported in this document.
Drug costs were taken from BNF 61. Bisphosphonate and denosumab administration costs were derived from a structured questionnaire conducted among UK healthcare professionals and a subsequent costing study. It was assumed that bisphosphonates were administered every 4 weeks. Skeletal-related event costs were derived from a prospective observational study in the UK, and cost estimation using NHS reference costs and personal social services costs. Monitoring and adverse events costs were based on NHS reference costs. In the base-case analysis, it was assumed that vertebral fractures were asymptomatic and incurred no costs.
The manufacturer of denosumab has agreed a patient access scheme with the Department of Health, in which a discount on the list price of denosumab is offered. The size of the discount is commercial-in-confidence. The base-case results for the incremental cost per QALY gained without the patient access scheme and with the patient access scheme are presented.
## Analyses without the patient access scheme
For breast cancer, in the manufacturer's base-case analysis without the patient access scheme, denosumab when compared with zoledronic acid was associated with an incremental cost of £1484 and an incremental QALY gain of 0.07 leading to an ICER of £203,387 per QALY gained. Denosumab was associated with an ICER of £13,835 per QALY gained when compared with ibandronic acid and dominated (that is, was less costly and more effective than) disodium pamidronate.
For prostate cancer, in the manufacturer's base-case analysis without the patient access scheme, in the subgroup of patients with painful bone metastases and who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £922 and an incremental QALY gain of 0.006 leading to an ICER of £157,276 per QALY gained. In the subgroup of patients with no pain, or pain and no history of a prior skeletal-related event, denosumab when compared with best supportive care was associated with an incremental cost of £3993 and an incremental QALY gain of 0.039 leading to an ICER of £102,067 per QALY gained.
For other solid tumours including non-small cell lung cancer, in the manufacturer's base-case analysis without the patient access scheme, in the subgroup of patients with painful bone metastases and who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £757 and an incremental QALY gain of 0.004 leading to an ICER of £205,580 per QALY gained. Denosumab dominated disodium pamidronate. In the subgroup of patients with no pain or pain and no history of a prior skeletal-related event, denosumab when compared with best supportive care was associated with an incremental cost of £2530 and an incremental QALY gain of 0.021 leading to an ICER of £122,499 per QALY gained.
## Analyses with the patient access scheme
For breast cancer, in the manufacturer's analysis with the patient access scheme, denosumab when compared with zoledronic acid was associated with a cost saving of £483 and an incremental QALY gain of 0.07. When compared with ibandronic acid and disodium pamidronate denosumab was associated with cost savings of £1895 and £3453 and incremental QALYs of 0.005 and 0.013 respectively. Denosumab therefore dominated each comparator.
For prostate cancer, in the manufacturer's analysis with the patient access scheme, in the subgroup of patients with painful bone metastases and who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid was associated with a cost saving of £281 and an incremental QALY gain of 0.006. Denosumab therefore dominated zoledronic acid. In the subgroup of patients with no pain or pain and no history of a prior skeletal-related event, denosumab when compared with best supportive care was associated with an incremental cost of £2790 and an incremental QALY gain of 0.039 with an ICER of £71,320 per QALY gained.
For other solid tumours including non-small cell lung cancer, in the manufacturer's analysis with the patient access scheme, in the subgroup of patients with painful bone metastases and who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid and disodium pamidronate was associated with cost savings of £43 and £2918 and incremental QALY gains of 0.004 and 0.006 respectively. Denosumab therefore dominated zoledronic acid and disodium pamidronate. In the subgroup of patients with no pain, or pain and no history of a prior skeletal-related event, denosumab when compared with best supportive care was associated with an incremental cost of £1730 and an incremental QALY of 0.021 leading to an ICER of £83,763 per QALY gained.
The manufacturer undertook sensitivity analyses to assess the impact of parameters and assumptions on the cost per QALY gained. The ICER was sensitive to skeletal-related event utilities, alternative dosing frequency and administration of bisphosphonates, application of skeletal-related event rates without the 21-day window, and assuming no discontinuation rate.
In the Assessment Group's view the manufacturer's model was of good quality and structure but noted that:
Treatment-specific effects data for the subgroups based on prior skeletal-related event experience were not applied.
The rates of adverse events for best supportive care were assumed to be zero.
Costs for zoledronic acid used in the model were 5% higher than those listed in BNF 62.
The manufacturer used median values rather than means from the costing study because of the skewed nature of the replies.
The manufacturer used 2008/09 reference costs for radiotherapy planning and administration rather than the 2009/10 costs that were used for all other skeletal-related events.
There was no detail about the functional forms that were tested during the EQ-5D data analysis.
## Assessment Group model
The Assessment Group rebuilt the manufacturer's model using the same basic structure. The Assessment Group included the same analyses as the manufacturer: breast cancer, prostate cancer and other solid tumours (including non-small cell lung cancer), but also included a separate analysis based on the subgroup data for patients with non-small cell lung cancer. Analyses were completed including all patients, and separately for patients who had not had a skeletal-related event and those who had. There were no data to allow separation of non-small cell lung cancer outcomes by skeletal-related event history, therefore only an analysis of all patients is presented for this subgroup.
In the base-case analysis, the Assessment Group applied the results of its network meta-analysis for time to first skeletal-related event and risk of subsequent skeletal-related event. In addition, the Assessment Group made amendments to the resource data, using the zoledronic acid price and the disodium pamidronate price based on BNF 62. It recalculated the costs associated with skeletal-related events, excluding excess bed days (except for spinal cord compression). The costs for serious adverse events were also amended to allow for some serious adverse events such as osteonecrosis of the jaw and renal toxicity to include some costs associated with outpatient care as well as inpatient care.
## Analyses without the patient access scheme
The results of the Assessment Group's base-case cost-effectiveness analysis without the patient access scheme showed that, for breast cancer (analysis of all patients, regardless of skeletal-related event history), denosumab when compared with zoledronic acid was associated with an incremental cost of £1707 and an incremental QALY gain of 0.007 leading to an ICER of £245,264 per QALY gained. Denosumab was associated with an incremental cost of £6242 and incremental QALY gain of 0.027 giving an ICER of £229,547 per QALY gained when compared with best supportive care. When compared with disodium pamidronate, denosumab was dominant with a cost saving of £1355 and incremental QALY gain of 0.012.
For prostate cancer, in the Assessment Group's base-case analysis without the patient access scheme, in the subgroup of patients who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £1053 and an incremental QALY gain of 0.006 leading to an ICER of £170,854 per QALY gained. When compared with best supportive care, denosumab was associated with an incremental cost of £3897 and incremental QALY gain of 0.025 leading to an ICER of £152,916 per QALY gained. In the subgroup of patients with no prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £1061 and an incremental QALY gain of 0.011 giving an ICER of £99,561 per QALY gained. When compared with best supportive care, denosumab was associated with an incremental cost of £3969 and an incremental QALY gain of 0.039 leading to an ICER of £103,003 per QALY gained.
For other solid tumours including non-small cell lung cancer, in the Assessment Group's base-case analysis without the patient access scheme, in the subgroup of patients who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £848 and an incremental QALY gain of 0.004 leading to an ICER of £196,114 per QALY gained. When compared with best supportive care, denosumab was associated with an incremental cost of £2620 and an incremental QALY gain of 0.011 giving an ICER of £238,840 per QALY gained. In the subgroup of patients with no prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £823 and an incremental QALY gain of 0.008 leading to an ICER of £106,812 per QALY gained. When compared with best supportive care, denosumab was associated with an incremental cost of £2473 and an incremental QALY gain of 0.024 giving an ICER of £103,350 per QALY gained.
For the subgroup data for non-small cell lung cancer (including both patients with and without a prior skeletal-related event), without the patient access scheme, denosumab when compared with zoledronic acid was associated with an incremental cost of £708 and an incremental QALY gain of 0.005 leading to an ICER of £149,878 per QALY gained. When compared with best supportive care, denosumab was associated with an incremental cost of £2262 and an incremental QALY gain of 0.012 giving an ICER of £191,412 per QALY gained.
## Analyses with the patient access scheme
For breast cancer, the Assessment Group's analysis with the patient access scheme showed that denosumab when compared with zoledronic acid and disodium pamidronate was associated with cost savings of £243 and £3305 and an incremental QALY gain of 0.007 and 0.012 respectively. Denosumab dominated zoledronic acid and disodium pamidronate. Compared with best supportive care, denosumab was associated with an incremental cost of £4292 and an incremental QALY of 0.027 leading to an ICER of £157,829 per QALY gained.
For prostate cancer, with the patient access scheme, in the subgroup of patients who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid was associated with a cost saving of £131 and an incremental QALY gain of 0.006. Denosumab was therefore dominant. Compared with best supportive care, the incremental cost was £2713 and incremental QALY gain 0.025 leading to an ICER for denosumab of £106,446 per QALY gained. In the subgroup of patients with no prior skeletal-related event, denosumab when compared with zoledronic acid was associated with a cost saving of £123 and an incremental QALY gain of 0.011. Denosumab was therefore dominant. Compared with best supportive care the incremental cost was £2785 and incremental QALY gain 0.039 leading to an ICER for denosumab of £72,269 per QALY gained.
For other solid tumours including non-small cell lung cancer and including the patient access scheme, in the subgroup of patients who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £66 and an incremental QALY gain of 0.004 leading to an ICER of £15,282 per QALY gained. When compared with best supportive care denosumab was associated with an incremental cost of £1839 and an incremental QALY gain of 0.011 leading to an ICER of £167,587 per QALY gained. In the subgroup of patients who have no prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £41 and an incremental QALY gain of 0.008 leading to an ICER of £5337 per QALY gained. Compared with best supportive care, denosumab was associated with an additional cost of £1691 and an incremental QALY of 0.024 leading to an ICER of £70,679 per QALY gained.
For non-small cell lung cancer with the patient access scheme, denosumab was associated with an incremental cost of £28 and an incremental QALY gain of 0.005 leading to an ICER of £5972. Compared with best supportive care, denosumab was associated with incremental costs of £1583 and an incremental QALY gain of 0.012 leading to an ICER of £133,926 per QALY gained.
The Assessment Group performed univariate sensitivity analyses to assess the impact of using some of the manufacturer's costs and estimates within the model, alternative rates of discontinuation assumed for active treatments, alternative assumptions about the change in utility for a patient who has never had a skeletal-related event having a skeletal-related event, applying utility multipliers for those nearing death, limiting or excluding the effects of serious adverse events, altering the time horizon to 5 years and 2 years, excluding general mortality, and extending the effect of spinal cord compression to beyond 5 months from diagnosis. Analyses were also completed assuming alternative costs for zoledronic acid. Sensitivity analyses included the patient access scheme. The results of these analyses generally supported the conclusions in the base-case cost-effectiveness analysis.
After the consultation, additional information was provided about the use of bisphosphonates in patients with bone metastases from prostate cancer. The patient chart review (see section 4.2.5) included 1161 patients with bone metastases from prostate cancer. In patients who were receiving or had received bisphosphonate treatment (49%), the reasons for treatment (not mutually exclusive) were: to prevent skeletal-related events (56%), to treat or prevent bone pain (42%), to treat bone metastases or lesions at the original site (27%), to prevent new bone metastases or lesions (21%), or because the patient had high-risk disease (18%). A survey of UK specialists who treat genito-urinary cancer as a special or main interest was also submitted from the British Uro-Oncology Group. The survey was sent to 200 specialists, of whom 61 responded. Of those responding, 87% prescribed zoledronic acid, of whom 36% used it only in patients who had previously had a skeletal-related event. In patients who had had a prior skeletal-related event, 47% of specialists prescribed it mostly for bone pain, 32% prescribed it mostly for delaying further skeletal-related events and 17% prescribed it for both.
# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of denosumab, having considered evidence on the nature of skeletal-related events in adults with bone metastases from solid tumours and the value placed on the benefits of denosumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
## Clinical effectiveness
The Committee considered the nature of the condition, and noted evidence submitted and presented by the patient experts and clinical specialists on the impact of bone metastases on people. The Committee heard from the clinical specialists and patient experts that complications from bone metastases can affect mobility so people can be housebound, unable to participate socially and have difficulties with employment. The Committee also heard that pain from bone metastases can be significant and managing pain is an important part of treatment. Pain can be continuous and excruciating and sometimes means the person needs hospitalisation. Pain treatment can include high-dose opioids that can have undesirable effects such as sleepiness and constipation, which can severely affect some people. The clinical specialists and patient experts considered that treatments delaying skeletal-related events and reducing pain enabled people to enjoy family life for longer. The Committee recognised the impact on people of bone metastases and the value placed by them on minimising the effects of bone metastases.
The Committee discussed the existing clinical options for preventing skeletal-related events in people with bone metastases from breast cancer, noting that the guideline on advanced breast cancer (NICE clinical guideline 81) recommends using bisphosphonates. The Committee heard from clinical specialists that bisphosphonates are commonly used in this patient group, and that, of the available bisphosphonates, oral ibandronate may be preferred because it can be administered in the community. However, the Committee heard that, if there are concerns about adherence or if people have acute pain, zoledronic acid or intravenous ibandronate are used. The Committee also heard that, of the intravenous treatments, zoledronic acid is normally used in people with bone metastases from breast cancer. The Committee heard from the patient expert that not everyone with metastatic breast cancer prefers oral bisphosphonates over intravenous bisphosphonates because the administration requirements for oral treatment are complex and sometimes people prefer the more frequent clinical contact that is necessary with an intravenous drug. The Committee concluded that, for people with bone metastases from breast cancer, bisphosphonates were the appropriate comparator, specifically zoledronic acid and ibandronate.
The Committee then discussed the appropriate comparator for the group of people with bone metastases from prostate cancer. It discussed the recommendations in the guideline on prostate cancer (NICE clinical guideline 58) and noted that bisphosphonates are not recommended for the prevention of skeletal-related events. However, for a subgroup of people with prostate cancer, bisphosphonates are recommended for use as pain relief when other treatments have failed. The Committee heard from a representative of the Guideline Development Group that the group evaluated bisphosphonates both for preventing skeletal-related events and for pain relief from bone metastases in hormone-refractory metastatic prostate cancer. The Committee understood that the group considered evidence from a systematic review and meta-analysis and, based on that evidence, did not recommend bisphosphonates for preventing skeletal-related events in prostate cancer. However, the evidence did suggest a trend favouring bisphosphonates over placebo for relieving pain from bone metastases in prostate cancer. The Committee noted comments received during consultation that the systematic review informing the clinical guideline was 'flawed' because it assumed a class effect for bisphosphonates and included studies that were not relevant to the aim of preventing skeletal-related events. The Committee was aware that it was not within the remit of this appraisal to review the clinical guideline recommendations, and that the analysis by both the manufacturer and the Assessment Group for this appraisal of denosumab had not assumed a class effect and had focused on studies with skeletal-related event outcomes. The Committee understood that, based on the clinical guideline recommendations, bisphosphonates may be used in people with hormone-refractory (castration-resistant) prostate cancer. However, this use is restricted to pain relief when other treatments have failed.
The Committee noted that neither denosumab nor any of the bisphosphonates has marketing authorisation specifically for pain relief in people with prostate cancer. The Committee also noted the testimony from patient experts about the importance of pain relief (section 4.3.2). It discussed comments received during consultation that pain relief is an implicit part of preventing skeletal-related events because one of the events included in the skeletal-related event outcome is time to radiotherapy to the bone; an intervention given as pain relief. The Committee considered that there were differences between treatment aims to relieve pain, prevent pain and delay worsening pain, but understood that both were important to patients. However, the Committee was only able to make a recommendation in accordance with the wording of the marketing authorisation about the use of denosumab for the prevention of skeletal-related events. It was unable to make recommendations specifically for the use of denosumab for pain relief in people with prostate cancer.
The Committee then discussed the evidence about the use of bisphosphonates in UK clinical practice. The Committee heard from clinical specialists at the first Committee meeting that bisphosphonate use in people with bone metastases from prostate cancer is not uniform across the NHS. If zoledronic acid is used, it is used in people with castration-resistant (previously known as hormone-refractory) prostate cancer with painful bone metastases for whom other treatments, including analgesics and palliative radiotherapy, have failed. The Committee discussed the survey data and chart review data submitted by consultees. The Committee noted that these showed that bisphosphonates were being used in clinical practice, but that there was variation in reasons for their use. The Committee noted that the survey data had a high non-response rate that could affect the reliability of the data and overestimate the use of bisphosphonates. The Committee also noted that the evidence identified by the Assessment Group for the effectiveness of bisphosphonates in comparison with standard care was the same randomised controlled trial as had been identified by the Guideline Development Group. In the absence of new data on the clinical effectiveness of bisphosphonates, the Committee was not persuaded that these data on use should be relied on over the recommendations in the clinical guideline. The Committee concluded that, because bisphosphonates are recommended for pain relief when other treatments have failed in the guideline on prostate cancer (NICE clinical guideline 58), and not for the prevention of skeletal-related events, the appropriate comparator in this appraisal for people with bone metastases from prostate cancer is best supportive care.
The Committee discussed the existing clinical options for preventing skeletal-related events in people with bone metastases from solid tumours other than breast and prostate tumours. The Committee noted that no NICE guidelines or other guidelines had been identified about using bisphosphonates in this patient group, and so guideline recommendations could not be used to inform the decision about the appropriate comparator. The Committee noted that a patient chart review by the manufacturer estimated that, in 50% of people with bone metastases from other solid tumours, bisphosphonates were prescribed or planned for future use, and zoledronic acid (80%) and disodium pamidronate (20%) are the bisphosphonates generally used in these patients (see section 4.2.5). The Committee heard from the Assessment Group that it had been advised that oral bisphosphonates are not used in people with bone metastases from lung cancer, and the clinical specialists advised that, in renal cell carcinoma, zoledronic acid may be used. The Committee concluded that there was uncertainty about the treatments in routine use for people with bone metastases from solid tumours other than breast and prostate. It accepted that intravenous bisphosphonates, namely zoledronic acid and disodium pamidronate, would be used for some people and that, based on the manufacturer's evidence, it was unlikely that bisphosphonates would be used as a first-line treatment. The Committee concluded that the appropriate comparators for people with bone metastases from solid tumours other than breast or prostate were best supportive care in general, and bisphosphonates, specifically zoledronic acid or disodium pamidronate for some patients for whom they are prescribed in clinical practice.
The Committee discussed the benefits of denosumab as a technology. It considered whether the subcutaneous route of administration offered advantages to patients or the NHS in terms of resource use compared with intravenous, though not oral, bisphosphonates. The Committee heard from the clinical specialists that, in theory, denosumab could be given at GP surgeries and could free up resources from chemotherapy suites. It also heard that, compared with zoledronic acid, denosumab was considered to offer some benefits in terms of reduced nephrotoxicity and acute phase reactions (for example, fever, muscle and bone pain, and arthralgia). It also heard that people having denosumab did not need blood test monitoring each month except those with severe renal impairment (creatinine clearance less than 30 ml/min or receiving dialysis) to monitor hypocalcaemia, which would potentially make it more convenient for people.
The Committee noted that the primary outcome measure in the denosumab trials was time to first on-study skeletal-related event. The Committee noted that skeletal-related event was a composite outcome indicator that included treatments as well as complications of bone metastases. The Committee discussed whether using a composite outcome was clinically meaningful. The Committee heard from the clinical specialists that each component of the composite outcome was important but that, to interpret the data, it is helpful if different skeletal-related events are reported separately. However, clinical trials in bone metastases have historically reported composite outcomes and there is no validated method to assign different weights to different events in the composite indicator. The Committee noted comments received during consultation about the uncertain clinical significance of using composite skeletal-related event outcomes, but concluded that it was appropriate to use skeletal-related events as defined in the clinical trials as the basis of its decision.
The Committee discussed the outcomes of the denosumab trials in the context of the other trials identified by the Assessment Group in its network meta-analysis. The Committee noted that the trials consistently showed that denosumab improved skeletal-related event outcomes compared with zoledronic acid, and that zoledronic acid improved skeletal-related event outcomes compared with placebo. The Committee discussed the other outcome data from the denosumab trials, noting that there were no benefits to overall survival for denosumab compared with zoledronic acid and that the outcomes for pain, although all favoured denosumab, were not all statistically significant. The Committee concluded that the evidence directly comparing denosumab with zoledronic acid for skeletal-related event outcomes suggested that denosumab was clinically more effective than zoledronic acid. However, the data for other outcomes such as pain, survival and quality of life did not show such a consistent benefit over zoledronic acid.
The Committee discussed the result of the Assessment Group's network meta-analysis to compare denosumab with other bisphosphonates and best supportive care. The Committee noted that the Assessment Group had first completed a random effects model, but subsequently preferred a fixed effects model. The Committee was aware that a fixed effects model is appropriate when it is believed that each study is estimating the same treatment effect or that inferences are to be made based on the available studies. The Committee discussed whether a random effects model would have been more appropriate for the network meta-analysis to account for heterogeneity among the included studies. The Committee heard from the Assessment Group that there were not enough studies included in the network meta-analysis for the between-study standard deviation to be properly calculated. It heard that an analysis that included an assumption of mild-to-moderate heterogeneity, although affecting the estimates of effect, would not have affected the outcomes of the economic modelling. The Committee further noted consultation comments received from the manufacturer about the appropriateness and reliability of the indirect method used to estimate the effect of zoledronic acid compared with disodium pamidronate, when direct estimation was possible. It noted that the Assessment Group accepted the comment made by the manufacturer and that it had revised its network meta-analysis in light of the manufacturer's comment. The Committee noted the revised analysis and accepted this amendment considering that it did not materially affect the estimates produced. The Committee agreed that the estimates of the effects were consistent across the evidence sources submitted, and that it could consider the analyses of cost effectiveness that had used the estimates from the Assessment Group's network meta-analysis using the fixed effects model.
The Committee discussed the adverse events data from the denosumab trials. The Committee noted that fewer incidents of renal toxicities and acute phase reactions were reported in the denosumab group than in the zoledronic acid group. However, there was a higher incidence of hypocalcaemia and osteonecrosis of the jaw in the denosumab group than in the zoledronic acid group. The Committee heard from the clinical specialists that they considered that denosumab could be given to people with mild-to-moderate renal failure and that this could be particularly valuable for people with metastatic prostate cancer, many of whom have reduced renal function. The Committee noted comments from consultation that recommendations should be based on the intention to treat with zoledronic acid, rather than the ability to treat with zoledronic acid. This was so that denosumab would be available to people for whom zoledronic acid would otherwise be appropriate, but who could not be treated with it because it was contraindicated because of impaired renal function. The Committee understood from clinical specialists that such people had not been able to be enrolled in the denosumab trials because zoledronic acid was used as a comparator. The Committee understood that denosumab may have a specific role in preventing skeletal-related events for people who cannot be treated with bisphosphonates because of reduced renal function. The Committee agreed that the recommendations should be based on the intention to treat with bisphosphonates.
The Committee discussed the Assessment Group's subgroup analysis of the data for patients with non-small cell lung cancer. The Committee heard from the clinical specialists that they considered that this was an appropriate subgroup clinically because different primary tumour types responded to treatment in different ways. However, the Committee also recognised the comments from the manufacturer that these data were from a post-hoc analysis that was not powered to show a difference in effect. The Committee concluded that it was appropriate to consider subgroups based on primary tumour type. However, it was aware of the limitations of the data available to inform such analysis.
The Committee noted that, in accordance with the final scope for the appraisal, both the manufacturer and the Assessment Group had provided subgroup analyses based on patient history of prior skeletal-related event. The Committee discussed the analyses, noting that the evidence was generally consistent with the analysis that included all patients but that, in some cases, the effect was no longer statistically significant. The Committee heard from the Assessment Group that this subgroup analysis was potentially important in the economic analysis because prior history influenced the baseline utility in the model, as well as the likelihood of having skeletal-related events. The Committee heard from the clinical specialists that they considered that history of a prior skeletal-related event reflected a continuation of disease progression rather than a separate subgroup. The Committee took account of these views when it considered the cost-effectiveness analysis. Based on the clinical evidence the Committee considered that the data were consistent regardless of prior skeletal-related event history.
## Cost effectiveness
The Committee discussed the economic models provided by the manufacturer and the Assessment Group, noting that the Assessment Group had based its model on the basic structure of the manufacturer's model. The Committee discussed the model structure and the parameter values used, noting where the Assessment Group had updated or amended inputs used by the manufacturer. It noted the similarities in the outputs of the modelling completed by the manufacturer and the Assessment Group, but it also noted the considerable differences in these outputs compared with those of the existing cost-effectiveness literature (sections 4.2.1 and 4.2.2). The Committee concluded that the structure of the Assessment Group model was appropriate to inform its deliberations, but given the differences in outputs it was appropriate to also consider the wider economic evidence available.
The Committee discussed whether the assumption of a reduction in utility starting 5 months before the skeletal-related event is recorded is a valid assumption in reflecting the clinical development of a skeletal-related event. The Committee heard from the clinical specialists that they would expect a gradual deterioration in the patient's condition before a skeletal-related event happened, for example, pain would start worsening before a patient would be considered for palliative radiotherapy or bone surgery. The Committee concluded that it was appropriate to assume reduced quality of life before the skeletal-related event happened and accepted the 5-month utility reduction as plausible.
The Committee noted that analyses had been completed for all patients and separately using treatment-specific data for patients with and without a prior skeletal-related event. The Committee had heard from the clinical specialists that this was not a distinction they made (see section 4.3.14), and noted that the outputs of the modelling were consistent across these analyses regardless of the data used. The Committee concluded that issues about the use in the modelling of subgroup-specific effects data based on prior skeletal-related event experience was not an important driver for decision-making.
The Committee discussed the assumptions about the cost and adverse events modelled for best supportive care in the manufacturer's and the Assessment Group's models, noting that both of the models assumed there were no adverse events for best supportive care. The Committee discussed the nature of best supportive care for people with bone metastases. The Committee heard from clinical specialists that opioid analgesia is the main form of pain control for people with bone metastases. It heard that opioids have many adverse reactions including altered consciousness, sleepiness and constipation. The Committee also heard from the clinical specialists that radioactive isotopes are also increasingly used for pain control for people with bone metastases from prostate cancer. The Committee noted that no evidence had been provided that enabled it to quantify the impact of this on cost effectiveness. The Committee concluded that the costs of best supportive care may have been underestimated, and that there could be additional disutilities resulting from adverse events that were not accounted for in the model.
The Committee discussed the results of the Assessment Group analyses. The Committee noted that depending on tumour type and skeletal related event history, the base-case analyses predicted a small incremental QALY gain (range from 0.004 to 0.011) favouring denosumab when compared with zoledronic acid. It also noted the slightly larger, but still small, increments when denosumab was compared with best supportive care (range from 0.011 to 0.039). The Committee recognised that a similar QALY gain for both denosumab and zoledronic acid was calculated from the manufacturer's modelling, and that these small QALY gains meant that the ICERs were sensitive to small changes in costs.
The Committee discussed the estimates of cost effectiveness from the Assessment Group analyses without the patient access scheme. It noted that the ICER for denosumab when compared with zoledronic acid was more than £200,000 per QALY gained for the metastatic breast cancer population, more than £100,000 per QALY gained for the metastatic prostate cancer population, and £100,000 per QALY gained for people with bone metastases from solid tumours other than breast and prostate. For denosumab compared with best supportive care, the ICERs were all more than £100,000 per QALY gained. The Committee recognised that the ICERs provided by the manufacturer for denosumab compared with zoledronic acid and denosumab compared with best supportive care were of a similar magnitude. The Committee concluded that without the patient access scheme denosumab could not be recommended as a cost-effective use of NHS resources.
The Committee discussed the implications of the analyses in both the Assessment Group and the manufacturer models, that is, when the interventions (that is denosumab, zoledronic acid and best supportive care) were considered simultaneously in an incremental analysis, the small gains in QALYs and relatively larger increases in costs meant that zoledronic acid was not a cost-effective use of NHS resources. The Committee discussed whether this changed its conclusions (see sections 4.3.3 and 4.3.7) on the appropriateness of using zoledronic acid as a comparator against which to assess the cost effectiveness of denosumab in people with breast cancer and for the subgroup of people with solid tumours other than breast and prostate cancer for whom bisphosphonates are used.
The Committee noted that in the systematic literature review of cost-effectiveness studies reported by the Assessment Group, the studies of the bisphosphonates reported a range of ICERs, most of which were relatively favourable to the bisphosphonates in general and to zoledronic acid in particular. However, none of these studies was based on utility measurement consistent with NICE's methods guide. The Committee particularly examined the results of the Health Technology Assessment (HTA) monograph that informed the guideline on advanced breast cancer (NICE clinical guideline 81) and produced an ICER of £1850 per QALY gained. The Committee heard from the Assessment Group that there were differences between its model and the HTA monograph in the cost estimates used and that the HTA monograph included additional costs specific to pain and its management that weren't included in the Assessment Group model. The incidence of skeletal-related events was also higher in the HTA monograph and the utility decrement associated with each skeletal-related event was considerably greater. The Committee heard from the clinical specialists that the management of bone metastases has changed over time as treatments have improved, which could partly explain the lower event rates in the denosumab trials and Assessment Group modelling in the current appraisal. The Committee agreed there was transparency in the modelling completed by the Assessment Group. The Committee expressed concern that both the Assessment Group model and the manufacturer's model suggested that zoledronic acid was not cost effective compared with best supportive care. However, the Committee recognised that the scope of this appraisal was limited to appraising the cost effectiveness of denosumab compared with zoledronic acid or best supportive care. It considered that the cost effectiveness of zoledronic acid compared with best supportive care would need to be subject to an appropriate review before definitive conclusions could be drawn.
The Committee then discussed the analyses in patients with breast cancer and solid tumours other than breast and prostate, comparing denosumab with zoledronic acid, including the patient access scheme. It noted that, for breast cancer, the patient access scheme reduced the cost of denosumab so that it became less costly and more effective than zoledronic acid. The Committee also noted that, in people with bone metastases from solid tumours other than in the breast and prostate, including the patient access scheme reduced the ICER for denosumab compared with zoledronic acid to less than £16,000 per QALY gained and to less than £6000 per QALY gained in the non-small cell lung cancer subgroup. The Committee recognised that the submitted cost-effectiveness analyses suggested that zoledronic acid was not cost effective when compared with best supportive care. However, in view of the contradictory results from the published economic evaluations, and the recommendations about bisphosphonates in the guideline on advanced breast cancer (NICE clinical guideline 81), the Committee was persuaded that zoledronic acid was an appropriate comparator against which to appraise denosumab for people with breast cancer and the subgroup of people with solid tumours other than breast and prostate for whom zoledronic acid is indicated. On balance, the Committee, while recognising the uncertainties over the cost effectiveness of zoledronic acid, concluded that denosumab, based on current prices and with the patient access scheme, was shown to be cost effective compared with zoledronic acid (or other bisphosphonates in the case of metastatic breast cancer). Therefore, denosumab should be an additional option when zoledronic acid (or other bisphosphonates in the case of metastatic breast cancer) is used. For breast cancer, this should be in accordance with the recommendations in the guideline on advanced breast cancer (NICE clinical guideline 81).
The Committee discussed the Assessment Group's analyses of denosumab compared with best supportive care, noting that these were consistent with the manufacturer's analyses. The Committee noted that even with the patient access scheme, denosumab was associated with high ICERs, the lowest of which in the Assessment Group's analyses remained above £70,000 per QALY gained. The Committee concluded that denosumab could not be recommended as a cost-effective use of NHS resources for preventing skeletal-related events for those groups for whom best supportive care is the appropriate comparator (see sections 4.3.6 and 4.3.7), that is, people with bone metastases from prostate cancer and in the general population of people with bone metastases from solid tumours other than breast and prostate.
The Committee noted comments received during consultation that, compared with zoledronic acid, denosumab was shown to be more effective and less costly, and therefore in instances in which zoledronic acid was currently used, denosumab may be a more efficient use of NHS resources. The Committee also recognised that denosumab may offer some benefits in terms of administration over intravenous bisphosphonates and have a role in the treatment of people with reduced renal function (see section 4.3.8). The Committee considered the clinical guideline recommendation for the use of bisphosphonates for pain relief on one hand and the constraints on the appraisal to make recommendations about the use of denosumab for the prevention of skeletal-related events on the other hand. The Committee did not consider that a recommendation about denosumab for the prevention of skeletal-related events would lead to a more efficient use of NHS resources if existing NICE guidance recommended the use of bisphosphonates for pain relief only because the populations, although overlapping, were not necessarily the same. The Committee was not persuaded that the results of the analyses in section 4.2.25 (which suggested that denosumab may be associated with lower costs than zoledronic acid) should change its decisions that the appropriate comparator for people with bone metastases from prostate cancer was best supportive care and that for this patient group denosumab had not been shown to be a cost-effective use of NHS resources.
The Committee noted comments received at consultation which stated that zoledronic acid was not the only bisphosphonate used in solid tumours other than breast and prostate, and that disodium pamidronate was also used. It discussed whether denosumab should be recommended as an alternative to disodium pamidronate. The Committee was aware that although zoledronic acid is the only bisphosphonate that has marketing authorisation in this patient group, the data provided by the manufacturer indicated that disodium pamidronate is being prescribed for approximately 20% of the people who are being treated or have been treated with a bisphosphonate (see section 4.2.5). The Committee took into consideration the price of disodium pamidronate, which is higher than zoledronic acid. It was aware that there is no estimate of clinical effectiveness for denosumab compared with disodium pamidronate in this patient group, but noted the availability of evidence from people with breast cancer (see section 4.1.7). The Committee concluded that denosumab should also be considered as an alternative where disodium pamidronate was used. In people with bone metastases from solid tumours other than breast and prostate cancers, denosumab was recommended as an alternative option if bisphosphonates would otherwise be prescribed.
The Committee considered comments received during the consultation on the appraisal consultation document that the fact that denosumab is recommended for the treatment of breast cancer but not for the treatment of prostate cancer could be interpreted as indirect sex discrimination. This is because the vast majority of people with breast cancer are women, and prostate cancer can only occur in biological men. The recommendations therefore mean that people with prostate cancer, that is, men and transgender women, cannot access treatment with denosumab for preventing skeletal-related events. The Committee agreed that the reason denosumab was not recommended for preventing skeletal-related events in prostate cancer was not because prostate cancer occurs in men and transgender women, nor was it related in any way to the different gender profile of the patients. Instead, the Committee considered that the evidence indicates that current clinical management and disease course varies between breast, prostate and other solid tumours. The Committee noted that separate clinical trials have been carried out in these different cancer types, and that the trials showed different efficacy profiles for denosumab between the cancer types. The choice of comparator for denosumab in the different cancer types was informed by its marketing authorisation and the published clinical guidelines. The ICER for using denosumab in prostate cancer compared with best supportive care is high (more than £70,000 per QALY gained and therefore beyond the threshold at which NICE would normally recommend a treatment). The Committee considered that the evidence on different cost-effectiveness profiles for the different types of disease means that it is doubtful whether the Committee's recommendations can be regarded as treating patients with prostate cancer less favourably than patients with breast cancer. Bearing in mind NICE's duties and functions and the requirement for the Committee's recommendations to be based on the clinical and cost effectiveness of treatments, the Committee considered that the recommendation for prostate cancer was a means of achieving a legitimate aim. Given the high level of the ICER for using denosumab in prostate cancer, the Committee was satisfied that the recommendation is a proportionate means of achieving that aim and that its recommendations do not lead to unlawful discrimination. Therefore it concluded that it did not need to add to or change its recommendations in light of the consultation comments.
# Summary of Appraisal Committee's key conclusions
TA265
Appraisal title: Denosumab for the prevention of skeletal-related events in adults with bone metastases from solid tumours
Section
Key conclusion
Denosumab is recommended as an option for preventing skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from breast cancer and from solid tumours other than prostate if bisphosphonates would otherwise be prescribed and the manufacturer provides denosumab with the discount agreed in the patient access scheme.
In people with bone metastases from breast cancer, the patient access scheme reduced the cost of denosumab so that it became less costly and more effective than zoledronic acid.
In people with bone metastases from solid tumours other than breast and prostate, the patient access scheme reduced the ICER for denosumab compared with zoledronic acid to less than £16,000 per QALY gained and to less than £6000 per QALY gained in the non-small cell lung cancer subgroup. For this patient group, the Committee also discussed the off-label use of disodium pamidronate in clinical practice, although it recognised that no estimate of clinical effectiveness was available for disodium pamidronate in this group. It also noted that the cost of disodium pamidronate was higher than that of zoledronic acid. The Committee concluded that denosumab should also be considered as an alternative where disodium pamidronate was used. In people with bone metastases from solid tumours other than breast and prostate cancers, denosumab was recommended as an alternative option where bisphosphonates would otherwise be prescribed.
Denosumab is not recommended for preventing skeletal-related events in adults with bone metastases from prostate cancer.
Compared with best supportive care, denosumab was associated with high incremental cost-effectiveness ratios (ICERs), even with the patient access scheme, the lowest of which remained above £70,000 per quality-adjusted life year (QALY) gained.
Current practice
Clinical need of patients, including the availability of alternative treatments
For people with bone metastases from breast cancer, bisphosphonates are the appropriate comparator, specifically zoledronic acid and ibandronate.
The appropriate comparator for denosumab in people with metastatic prostate cancer in an appraisal considering the prevention of skeletal-related events is best supportive care.
The appropriate comparators for people with bone metastases from solid tumours other than breast or prostate were best supportive care in general, and bisphosphonates, specifically zoledronic acid or disodium pamidronate for a proportion of people in whom they are prescribed in clinical practice.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee heard from the clinical specialist that, in theory, denosumab could be given at GP surgeries and could free up resources from chemotherapy suites. It also heard that, compared with zoledronic acid, denosumab was considered to offer some benefits in terms of reduced nephrotoxicity and acute phase reactions. It also heard that denosumab did not need blood test monitoring each month except in people with severe renal impairment (creatinine clearance less than 30 ml/min or receiving dialysis) to monitor hypocalcaemia, which would potentially make it more convenient for people.
What is the position of the treatment in the pathway of care for the condition?
The Committee considered denosumab as an alternative to bisphosphonates and as an alternative to best supportive care when bisphosphonates are not used.
Adverse effects
The Committee noted that, in the denosumab trials, fewer incidents of renal toxicities and acute phase reactions were reported in the denosumab group than in the zoledronic acid group. However, there was a higher incidence of hypocalcaemia and osteonecrosis of jaw in the denosumab group than in the zoledronic acid group.
The Committee understood that denosumab may have a specific role in preventing skeletal-related events for people who cannot be treated with bisphosphonates because of reduced renal function.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The primary end point in the clinical trials (time to first on-study skeletal-related event) was based on a composite outcome indicator (that is skeletal-related events) that included both treatments and complications of bone metastases. The clinical specialists considered that each component of the outcome was important but that, to interpret the results, it is helpful if different skeletal-related events are reported separately. The Committee concluded that it was appropriate to use skeletal-related events as the basis of the decision.
Relevance to general clinical practice in the NHS
The generalisability of the trial data to general clinical practice in the NHS was not an issue in this appraisal.
N/A
Uncertainties generated by the evidence
A number of network meta-analyses were submitted. The Committee agreed that there was consistency across the evidence sources submitted and that it could consider the estimates of cost effectiveness that had used the estimates from the Assessment Group's network meta-analysis using a fixed effects model.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee concluded that it was appropriate to consider subgroups based on primary tumour type. However, it was aware of the limitations of the data available to inform such analysis.
The Committee heard from the clinical specialists that they considered that history of a prior skeletal-related event reflected a continuation of disease progression rather than a separate subgroup. Based on the clinical evidence, the Committee considered that the data were consistent regardless of prior skeletal-related event history.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that the evidence directly comparing denosumab with zoledronic acid suggested that denosumab was more clinically effective than zoledronic acid in all 3 cancer groups for which there was trial evidence. However, the data for other outcomes such as pain, survival and quality of life did not show such a consistent benefit over zoledronic acid.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee discussed the economic models provided by the manufacturer and the Assessment Group, noting that the Assessment Group had based its model on the basic structure of the manufacturer's model. The Committee concluded that the structure of the Assessment Group model was appropriate to inform its deliberations, but that it was appropriate to also consider the wider economic evidence available.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted the similarities in the outputs of the modelling completed by the manufacturer and the Assessment Group, but it also noted the considerable differences in these outputs compared with those of the existing cost-effectiveness literature.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee discussed whether the assumption of a reduction in utility starting 5 months before the skeletal-related event is recorded is a valid assumption. It concluded that it was appropriate to assume reduced quality of life before the skeletal-related event happened.
The Committee discussed the differences between the Assessment Group modelling and the published economic analysis that had informed the guideline on advanced breast cancer (NICE clinical guideline 81). It noted that the utility decrement associated with each skeletal-related event was considerably greater than that assumed in the Assessment Group modelling.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee concluded that denosumab, based on current prices and with the patient access scheme, was shown to be cost effective compared with zoledronic acid (or other bisphosphonates in the case of metastatic breast cancer). Therefore, denosumab would be an additional option when zoledronic acid (or other bisphosphonates in the case of metastatic breast cancer) would be used.
For this patient group, the Committee also discussed the off-label use of disodium pamidronate in clinical practice, although it recognised that no estimate of clinical effectiveness was available for disodium pamidronate in this group. It also noted that the cost of disodium pamidronate was higher than that of zoledronic acid. The Committee concluded that denosumab should also be considered as an alternative where disodium pamidronate was used. In people with bone metastases from solid tumours other than breast and prostate cancers, denosumab was recommended as an alternative option if bisphosphonates would otherwise be prescribed.
What are the key drivers of cost effectiveness?
The Committee discussed the univariate sensitivity analysis conducted by the Assessment Group. It noted that the ICER was sensitive to reductions in the price of zoledronic acid.
Most likely cost-effectiveness estimate (given as an ICER)
Without the patient access scheme, denosumab could not be recommended as a cost-effective use of NHS resources.
For breast cancer, the patient access scheme reduced the cost of denosumab so that it became less costly and more effective than zoledronic acid.
For people with bone metastases from solid tumours other than breast and prostate, the patient access scheme reduced the ICER for denosumab compared with zoledronic acid to less than £16,000 per QALY gained and to less than £6000 per QALY gained in the non-small cell lung cancer subgroup.
For all 3 patient groups, compared with best supportive care, denosumab was associated with high ICERs even with the patient access scheme in the Assessment Group's analyses. The lowest of these remained above £70,000 per QALY gained.
Additional factors taken into account
Patient access schemes (PPRS)
The manufacturer of denosumab has agreed a patient access scheme with the Department of Health, in which a discount on the list price of denosumab is offered. The size of the discount is commercial-in-confidence.
End-of-life considerations
End-of-life considerations were not addressed in this appraisal.
N/A
Equalities considerations and social value judgements
The Committee considered comments received during the consultation on the appraisal consultation document that the fact that denosumab is recommended for the treatment of breast cancer but not for the treatment of prostate cancer could be interpreted as indirect sex discrimination. The Committee agreed that the reason denosumab was not recommended for preventing skeletal related events in prostate cancer was not because prostate cancer occurs in men and transgender women, nor was it related in any way to the different gender profile of the patients. Instead, the Committee considered that the evidence indicates that current clinical management and disease course varies between breast, prostate and other solid tumours. The Committee noted that separate clinical trials have been carried out in these different cancer types, and that the trials showed different efficacy profiles for denosumab between the cancer types. The choice of comparator for denosumab in the different cancer types was informed by its marketing authorisation and the published clinical guidelines. The ICER for using denosumab in prostate cancer compared with best supportive care is high and beyond the threshold at which NICE would normally recommend a treatment. The Committee therefore concluded that it did not need to add to or change its recommendations in light of the consultation comments.
# Related NICE guidance
Published
Opioids in palliative care: safe and effective prescribing of strong opioids for pain in palliative care of adults. NICE clinical guideline 140 (2012).
Lung cancer: the diagnosis and treatment of lung cancer. NICE clinical guideline 121 (2011).
Advanced breast cancer: diagnosis and treatment. NICE clinical guideline 81 (2009).
Metastatic spinal cord compression: diagnosis and management of adults at risk of and with metastatic spinal cord compression. NICE clinical guideline 75 (2008).
Prostate cancer: diagnosis and treatment. NICE clinical guideline 58 (2008).
Under development
NICE is developing the following guidance (details available from the NICE website):
Denosumab for prolonging bone metastasis-free survival in hormone-refractory prostate cancer. NICE technology appraisal guidance in development (publication expected November 2013).
Prostate cancer: diagnosis and treatment (update). NICE clinical guideline in development (publication expected November 2013).# Review of guidance
The guidance on this technology will be considered for review by the Guidance Executive in July 2013. The Appraisal Committee noted that the ICER was sensitive to reductions in the price of zoledronic acid, and was aware that zoledronic acid is due to come off patent in 2013 and that this may result in a reduction in the price of zoledronic acid because of the availability of cheaper generic versions. In that scenario, the cost-effective analysis that it based its decision on would need to be revised.
Andrew DillonChief ExecutiveOctober 2012# Changes after publication
February 2014: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE multiple technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Denosumab is recommended as an option for preventing skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from breast cancer and from solid tumours other than prostate if:\n\nbisphosphonates would otherwise be prescribed and\n\nthe manufacturer provides denosumab with the discount agreed in the patient access scheme.\n\nDenosumab is not recommended for preventing skeletal-related events in adults with bone metastases from prostate cancer.\n\nAdults with bone metastases from solid tumours currently receiving denosumab for the prevention of skeletal-related events that is not recommended according to 1.1 and 1.2 should be able to continue treatment until they and their clinician consider it appropriate to stop.', 'Clinical need and practice': "Bone is one of the most common sites for circulating cancer cells to settle and start growing. Metastases can occur in any bones in the body, but the spine is commonly affected, as well as the pelvis, hip, upper leg bones and the skull. Almost any cancer can metastasise to the bone, but cancers of the breast, prostate, lung, bladder, thyroid and kidney spread to the bone most often.\n\nThe manufacturer has estimated that there are more than 150,000\xa0people in England and Wales with solid tumours and bone metastases, more than 80% of them with breast and prostate cancer. Approximately 0.5% of women with breast cancer have bone metastases at diagnosis and 4.7% develop bone metastases within 5\xa0years. The manufacturer's submission reported that 11% of people with prostate cancer present with bone metastases at initial staging.\n\nIn women with breast cancer, bone metastases are associated with a median reduction in survival of approximately 2\xa0years. In men with prostate cancer, bone metastases are associated with a reduced 5-year survival from 56% to 3%.\n\nBone metastases are also associated with reduced quality of life and an increased risk of complications from bone weakness or disrupted calcium homeostasis. Complications include pathological fractures (defined as pathological because minimal or no force is needed to cause them), spinal cord compression, radiation to the bone or surgery to the bone. These are collectively defined as skeletal-related events. Mobility may be reduced because of bone pain and other complications. Metastatic bone pain can be intermittent or constant, and people with bone metastases often report inadequate pain relief with analgesics.\n\nThe primary aim of treating bone metastases is to manage skeletal morbidity by delaying or preventing skeletal-related events. A second aim is to delay pain and reduce its severity. Current treatments for bone metastases and their complications include radiotherapy, orthopaedic surgery, bone-targeting radio-pharmaceuticals and chemotherapy. Four bisphosphonates have a marketing authorisation for managing bone metastases or preventing skeletal-related events in people with solid tumours: zoledronic acid, disodium pamidronate, sodium clodronate and ibandronic acid. Zoledronic acid is the only bisphosphonate that has a marketing authorisation for the prevention of skeletal-related events in advanced malignancies involving bone without specifying the primary tumour type. Disodium pamidronate and sodium clodronate have a marketing authorisation for breast cancer and multiple myeloma, and ibandronic acid has a marketing authorisation for breast cancer only.\n\nManagement of bone metastases varies by primary cancer type. Advanced breast cancer: diagnosis and treatment (NICE clinical guideline 81) recommends offering bisphosphonates to people with newly diagnosed breast cancer and bone metastases to prevent skeletal-related events and reduce pain. Prostate cancer: diagnosis and treatment (NICE clinical guideline\xa058) does not recommend the use of bisphosphonates to prevent or reduce complications of bone metastases in men with hormone refractory prostate cancer. In this patient group, bisphosphonates for pain relief may be considered when other treatments, including analgesics and palliative radiotherapy, have failed. The oral or intravenous route of administration should be chosen according to convenience, tolerability and cost. In people with lung cancer with bone metastases who need palliation and for whom standard analgesic treatments are inadequate, single-fraction radiotherapy is recommended (Lung cancer: the diagnosis and treatment of lung cancer [NICE clinical guideline\xa0121]). Metastatic spinal cord compression: diagnosis and management of adults at risk of and with metastatic spinal cord compression (NICE clinical guideline\xa075) recommends bisphosphonates in people with breast cancer or multiple myeloma with vertebral involvement to reduce pain and the risk of vertebral fracture/collapse. In people with vertebral involvement from prostate cancer, bisphosphonates are recommended to reduce pain only if conventional analgesia fails to control pain.", 'The technology': 'Denosumab (XGEVA, Amgen) is a fully human monoclonal antibody that reduces osteoclast-mediated bone destruction by inhibiting the receptor activator of nuclear factor kappa-B ligand (RANKL), which is the primary mediator of increased osteoclast activity. Denosumab has a marketing authorisation for the prevention of skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from solid tumours. The recommended dose of denosumab for the prevention of skeletal-related events in bone metastases from solid tumours is 120\xa0mg every 4\xa0weeks. It is administered as a single subcutaneous injection into the thigh, abdomen or upper arm.\n\nThe summary of product characteristics lists the following adverse reactions for denosumab: dyspnoea, diarrhoea, osteonecrosis of the jaw, hyperhidrosis, tooth extraction, hypophosphataemia and hypocalcaemia. Denosumab is contraindicated in people with severe, untreated hypocalcaemia. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe cost of a 120\xa0mg vial is £309.86 (excluding VAT; British National Formulary [BNF] 63). A year of treatment (13\xa0doses) would cost £4028.18 (excluding VAT). Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of denosumab has agreed a patient access scheme with the Department of Health, in which a discount on the list price of denosumab is offered. The size of the discount is commercial-in-confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.', 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nThe Assessment Group identified 8 studies (including 3 of denosumab) reporting outcome data on skeletal-related events – 4\xa0in patients with breast cancer, 2\xa0in patients with prostate cancer and 2\xa0in patients with other solid tumours. The 2\xa0studies in other solid tumours both included patients with non-small cell lung cancer enabling a separate subgroup analysis of non-small cell lung cancer. The Assessment Group undertook a network meta-analysis to compare denosumab with bisphosphonates and with best supportive care.\n\nThe definition of skeletal-related event in some instances varied across the trials. In the denosumab trials skeletal-related events was a composite outcome indicator that comprised radiation therapy to alleviate pain or prevent fracture, surgery to bone to treat or prevent fractures, and pathologic fracture or spinal cord compression that can result in paraesthesias, incontinence and paralysis. Some trials also included hypercalcaemia or change in antineo-plastic therapy in the definition of skeletal-related events. However, the definition of a skeletal-related event in the data informing the network meta-analysis was consistent across trials.\n\n## Breast cancer\n\nA double-blind, randomised, controlled trial compared denosumab with zoledronic acid and enrolled patients (n=2046) with confirmed breast cancer and at least 1 bone metastasis. Duration of follow-up was event rate driven and was approximately 34\xa0months. The 3\xa0other studies included in the network meta-analysis compared zoledronic acid with disodium pamidronate (n=1130), zoledronic acid with placebo (n=228) and disodium pamidronate with placebo (n=754).\n\nIn the trial comparing denosumab with zoledronic acid, the median time to first skeletal-related event was not reached in the denosumab group and was 26.4\xa0months in the zoledronic acid group (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.71 to 0.95, p=0.01 superiority). The study comparing zoledronic acid with placebo reported that median time to first skeletal-related event was not reached in the zoledronic acid group compared with 364\xa0days in the placebo group (p=0.007). Disodium pamidronate was also associated with a statistically significantly longer median time to first skeletal-related event than placebo (12.7\xa0months compared with 7.0\xa0months, p<0.001). The study comparing zoledronic acid with disodium pamidronate reported a statistically significant difference favouring zoledronic acid for time to first skeletal-related event in patients receiving hormone therapy (415\xa0days for zoledronic acid and 370\xa0days for disodium pamidronate, p=0.047), but not for patients receiving chemotherapy (349\xa0days for zoledronic acid and 366\xa0days for disodium pamidronate, p=0.826).\n\nIn the trial comparing denosumab with zoledronic acid, the risk of first and subsequent skeletal-related events was reduced in the denosumab group compared with the zoledronic acid group (relative risk [RR] 0.77, 95% CI\xa00.66 to 0.89, p=0.001 superiority). This risk was also reduced with denosumab in the subgroups of patients with or without a history of prior skeletal-related events. The study comparing zoledronic acid with placebo showed a statistically significant effect favouring zoledronic acid (RR\xa00.59, 95% CI\xa00.38 to 0.91). The study comparing zoledronic acid and disodium pamidronate showed a statistically significant effect favouring zoledronic acid (RR\xa00.80, 95% CI\xa00.66 to 0.97).\n\nIn the trial comparing denosumab with zoledronic acid, patients in the denosumab group on average had fewer skeletal-related events (0.45\xa0events per patient per year) than patients in the zoledronic acid group (0.58\xa0events per patient per year, p=0.004). In the other trials included in the network meta-analysis, zoledronic acid was associated with fewer skeletal-related events than placebo (0.63 compared with 1.1, p=0.016). Likewise, disodium pamidronate was associated with fewer skeletal-related events than placebo (2.4 compared with 3.7, p<0.001).\n\nResults of the network meta-analysis showed that denosumab was associated with a statistically significant improvement compared with placebo for time to first on-study skeletal-related event (HR\xa00.46, 95% CI\xa00.29 to 0.72), risk of first and subsequent skeletal-related events (RR\xa00.45, 95% CI\xa00.28 to 0.72), and skeletal morbidity rate (RR\xa00.47, 95% CI\xa00.25 to 0.67). Denosumab was also associated with a statistically significant improvement compared with disodium pamidronate in the time to first skeletal-related event (HR 0.73, 95% CI\xa00.56 to 0.94) and the risk of first and subsequent skeletal-related events (RR\xa00.62, 95% CI\xa00.48 to 0.80). However, the difference in skeletal morbidity rate was not statistically significant. Compared with zoledronic acid, denosumab also improved time to first on-study skeletal-related event (HR\xa00.82, 95% CI\xa00.71 to 0.95) and the risk of first and subsequent skeletal-related events (RR\xa00.77, 95% CI\xa00.66 to 0.89), although the difference in skeletal morbidity rate was not statistically significant.\n\nThe denosumab trial reported no statistically significant difference in median overall survival for the denosumab group compared with the zoledronic acid group (HR\xa00.95, 95% CI\xa00.81 to 1.11, p=0.49).\n\nIn the same trial, the median time to developing moderate or severe pain in patients with no or mild pain at baseline was statistically significantly longer in the denosumab group than the zoledronic acid group (295 compared with 176\xa0days, HR\xa00.78, 95% CI\xa00.67 to 0.92, p=0.0024). There were no differences in EQ-5D scores or analgesic use.\n\nIn the trial comparing denosumab with zoledronic acid, the incidence of serious adverse events and adverse events leading to discontinuation were similar in the denosumab and zoledronic acid groups. There was a higher incidence of hypocalcaemia events (5.5% compared with 3.4%) and lower incidence of hypercalcaemia (1.7% compared with 3.5%) in the denosumab group than in the zoledronic acid group respectively. The rate of osteonecrosis of the jaw was similar in the denosumab group and the zoledronic acid group (2.0% and 1.4% respectively). There was a lower rate of adverse events potentially associated with renal impairment in the denosumab group than in the zoledronic acid group (4.9% compared with 8.5% respectively). Acute-phase reactions occurring in the first 3\xa0days after treatment were higher in the zoledronic acid group than in the denosumab group (27.3% compared with 10.4%).\n\n## Prostate cancer\n\nOne double-blind, randomised, controlled trial compared denosumab with zoledronic acid and enrolled men aged 18\xa0years or older with confirmed prostate cancer and at least 1 bone metastasis (n=1901). Follow-up was 41\xa0months. A further randomised controlled trial was included in the network meta-analysis that compared zoledronic acid with placebo (n=643).\n\nIn the trial comparing denosumab with zoledronic acid, median time to first on-study skeletal-related event was statistically significantly longer with denosumab than zoledronic acid (20.7 compared with 17.1\xa0months, HR\xa00.82, 95%\xa0CI 0.71 to 0.95, p=0.008 superiority). In the study comparing zoledronic acid with placebo, zoledronic acid increased the time to first on-study skeletal-related event (488\xa0days compared with 321\xa0days, p=0.009).\n\nIn the trial comparing denosumab with zoledronic acid, the risk of developing first and subsequent on-study skeletal-related events was reduced by denosumab compared with zoledronic acid (RR\xa00.82, 95%\xa0CI 0.71 to 0.94, p=0.008). In the trial comparing zoledronic acid with placebo, zoledronic acid was shown to reduce the risk of first and subsequent skeletal-related events(RR\xa00.64, 95% CI not reported, p=0.002).\n\nIn the trial comparing denosumab with zoledronic acid, skeletal morbidity rate was slightly lower among patients treated with denosumab than patients treated with zoledronic acid (figures provided academic in confidence). In the study comparing zoledronic acid with placebo, zoledronic acid reduced the skeletal morbidity rate from 1.49 in the placebo group to 0.80 in the zoledronic acid group (p=0.006).\n\nThe results of the network meta-analysis showed that denosumab was associated with a statistically significant improvement compared with placebo in time to first on-study skeletal-related event (HR\xa00.56, 95% CI\xa00.40 to 0.77), risk of first and subsequent skeletal-related events (RR\xa00.53, 95% CI\xa00.39 to 0.72) and skeletal morbidity rate (RR\xa00.52, 95%\xa0CI 0.07 to 0.82). Results of the network meta-analysis also showed a statistically significant improvement with denosumab compared with zoledronic acid in time to first on-study skeletal-related event (HR\xa00.82, 95% CI\xa00.71 to 0.95) and the risk of first and subsequent skeletal-related events (RR\xa00.82, 95% CI\xa00.71 to 0.94). The result for skeletal morbidity rate was not statistically significant.\n\nIn the trial comparing denosumab with zoledronic acid, median overall survival was similar in the denosumab group (19.4\xa0months) and the zoledronic acid group (19.8\xa0months, HR\xa01.03, 95% CI\xa00.91 to 1.17, p=0.65).\n\nIn the same trial, denosumab was associated with an approximately 1\xa0month longer duration to development of moderate or severe pain in patients with no or mild pain at baseline than zoledronic acid (median 5.8 compared with 4.9\xa0months), although the difference was not statistically significant (HR\xa00.89, 95% CI\xa00.77 to 1.04, p=0.1416). There were no differences in EQ-5D scores or analgesic use.\n\nIn the trial comparing denosumab with zoledronic acid, the incidences of serious adverse events and adverse events leading to discontinuation were similar in the denosumab and zoledronic acid groups (63% compared with 60% and 17% compared with 15% respectively). There were more hypocalcaemia adverse events in the denosumab group than the zoledronic acid group (13% [121/943] compared with 6% [55/945]). A greater number of patients in the denosumab group than the zoledronic acid group experienced osteonecrosis of the jaw (2% compared with 1%). A similar rate of adverse events potentially associated with renal impairment occurred in the denosumab group and the zoledronic acid group (15% and 16% respectively). During the first 3\xa0days of treatment, fewer patients experienced symptoms associated with acute phase reactions in the denosumab group (8%) than the zoledronic acid group (18%).\n\n## Other solid tumours (including non-small cell lung cancer)\n\nA double-blind, randomised, controlled study compared denosumab with zoledronic acid and enrolled patients aged 18\xa0years or older with confirmed solid tumours (except breast and prostate) or multiple myeloma (n=1776). In the study, 40% of patients had non-small cell lung cancer, 10% had multiple myeloma and 50% had other tumours. A post-hoc analysis of data from this study for other solid tumours, excluding multiple myeloma, (n=1597) was provided by the manufacturer as academic-in-confidence and cannot be reported in this document. A summary of the publically available data (that is, data including patients with multiple myeloma) is included in this document. Another study in patients with other solid tumours, excluding breast cancer and prostate cancer, (n=507) that compared zoledronic acid with placebo was included in the network meta-analysis.\n\nIn the trial comparing denosumab with zoledronic acid, the median time to first on-study skeletal-related event was longer for denosumab than zoledronic acid (20.6 compared with 16.3\xa0months, HR\xa00.84, 95% CI\xa00.71 to 0.98, p=0.0007 non-inferiority). The study comparing zoledronic acid with placebo reported a statistically significant improvement in time to first on-study skeletal-related event (230\xa0days compared with 163\xa0days, p=0.023).\n\nIn the trial comparing denosumab with zoledronic acid, denosumab reduced the risk of developing first and subsequent skeletal-related events compared with zoledronic acid (RR 0.90, 95% CI\xa00.77 to 1.04, p=0.14). In the study comparing zoledronic acid with placebo, zoledronic acid also reduced the risk of developing first and subsequent skeletal-related events compared with placebo (HR\xa00.732, p=0.017).\n\nThe results of the network meta-analysis (using data that excluded patients with multiple myeloma) showed a statistically significant improvement with denosumab compared with placebo in time to first skeletal-related event (HR\xa00.49, 95% CI\xa00.30 to 0.78), risk of first and subsequent skeletal-related events (RR\xa00.62, 95% CI\xa00.46 to 0.85) and proportion of patients with on-study skeletal-related event (odds ratio [OR] 0.58, 95%\xa0CI 0.02 to 19.48). Denosumab was also associated with a statistically significant improvement compared with zoledronic acid in time to first skeletal-related event (HR\xa00.81, 95% CI 0.68 to 0.96). The difference for risk of first or subsequent skeletal-related events, and the proportion of patients with on-study skeletal-related events, was not statistically significant.\n\nIn the trial comparing denosumab with zoledronic acid, median overall survival was similar in both groups.\n\nIn the same trial, in patients with no or mild pain at baseline, time to development of moderate or severe pain was longer for denosumab than zoledronic acid (median 144\xa0days compared with 112\xa0days (HR\xa00.81, 95% CI 0.66 to 1.00, p=0.049). There were no differences in EQ-5D scores or analgesic use.\n\nIn the study comparing denosumab with zoledronic acid, serious adverse events were reported in 66% of patients treated with zoledronic acid and in 63% of patients treated with denosumab. Other adverse events were similar in both groups. Hypocalcaemia was reported in 10% of patients in the denosumab group and 5.8% of patients in the zoledronic acid group. Rates of osteonecrosis of the jaw were similar in the denosumab (1.3%) and zoledronic acid (1.1%) groups. Renal adverse events occurred more often in the zoledronic acid group (10.9%) than the denosumab group (8.3%). Acute-phase reactions occurred more frequently in the zoledronic acid group (14.5%) than in the denosumab group (6.9%).\n\n## Non-small cell lung cancer\n\nThe trial comparing denosumab with zoledronic acid in other solid tumours also reported data on a subgroup of patients with non-small cell lung cancer (n=702). Denosumab was associated with delayed time to first on-study skeletal-related event in patients with non-small cell lung cancer (HR\xa00.84, 95% CI 0.64 to 1.10, p=0.20). An ad hoc analysis for overall survival reported that denosumab improved overall survival relative to zoledronic acid by 21% in this patient group (HR\xa00.79, 95% CI 0.65 to 0.95). Skeletal morbidity rate, pain and health-related quality of life, and data on adverse events were not available separately for the non-small cell lung cancer group. Other data were provided as academic-in-confidence by the manufacturer and cannot be included in this document.\n\nThe network meta-analysis included another study comparing zoledronic acid with placebo, in patients with solid tumours other than breast and prostate, that reported data separately for a subgroup of patients with non-small cell lung cancer (n=244). Zoledronic acid was not associated with a statistically significant difference in time to first skeletal-related event compared with placebo (171\xa0days and 151\xa0days respectively, p=0.188) nor risk of first and subsequent skeletal-related events (HR\xa00.73, p=0.061). The incidence of skeletal-related events was lower in the zoledronic acid group (42% with an event), compared with placebo (45% with an event, p=0.557).\n\nThe results of the network meta-analysis showed that, compared with placebo, denosumab reduced the risk of first and subsequent skeletal-related events (RR\xa00.63, 95% CI 0.42 to 0.97). The difference in time to first skeletal-related event, and proportion of patients with a skeletal-related event, was not statistically significant. Compared with zoledronic acid none of the differences for time to first skeletal-related event, risk of first and subsequent skeletal-related event, and proportion of patients with a skeletal-related event was statistically significant.\n\n# Cost effectiveness\n\nThe manufacturer identified 21 published studies that contained economic analyses of bisphosphonates. Twelve papers contained economic evaluations that included incremental cost-effectiveness analysis, of which 7 were cost–utility analyses. Of the 12\xa0papers, 8\xa0were in breast cancer, 2 in prostate cancer, 1 in lung cancer and 1\xa0in renal carcinoma. The Assessment Group identified 11\xa0studies, 1\xa0of which included denosumab as an intervention. This study was in patients with prostate cancer and compared denosumab with zoledronic acid. The study used US cost data and reported costs per skeletal-related event avoided.\n\nOf the 11 studies identified by the Assessment Group, 7 were in breast cancer, 3 in prostate cancer and 1 in lung cancer. Three of the breast cancer studies compared disodium pamidronate with best supportive care and reported incremental cost-effectiveness ratios (ICERs) for disodium pamidronate of between £1851 and £276,444 per quality-adjusted life year (QALY) gained. One of the breast cancer studies compared zoledronic acid with best supportive care and reported that zoledronic acid was cost saving. The 3\xa0other breast cancer studies compared different bisphosphonates, 2 reported that oral ibandronate was cost saving compared with zoledronic acid and disodium pamidronate, while the third reported that disodium pamidronate was cost saving compared with zoledronic acid. Of the 3 studies in prostate cancer, 1\xa0compared zoledronic acid with best supportive care and reported ICERs for zoledronic acid of between £2124 and £31,476 per QALY gained depending on the country of the cost data. The second reported that zoledronic acid was associated with £11,137 in additional costs per skeletal-related event avoided and had an ICER of £105,976 per QALY gained. The third compared denosumab and zoledronic acid and reported a cost per skeletal-related event avoided for denosumab of £31,532 using a 3-year time horizon. The lung cancer study reported that, using UK cost data, zoledronic acid was cost saving compared with best supportive care.\n\nThe manufacturer of denosumab submitted a Markov economic model that assessed the cost effectiveness of denosumab in 3\xa0patient groups: breast cancer, prostate cancer and other solid tumours (excluding breast and prostate). The model had 5\xa0health states: no prior skeletal-related event on treatment, prior skeletal-related event on treatment, no prior skeletal-related event off treatment, prior skeletal-related event off treatment, and death. The model had a 4-week cycle length and a half-cycle correction was applied. Patients were followed for 10\xa0years.\n\nThe model compared the cost effectiveness of denosumab with zoledronic acid, disodium pamidronate, ibandronic acid and best supportive care. Zoledronic acid was the primary comparator in patients with breast cancer, with disodium pamidronate and ibandronic acid as secondary comparators. In prostate cancer, for patients with no pain or pain with no prior skeletal-related event, the comparator was best supportive care and, in patients with pain and a prior skeletal-related event, the comparator was zoledronic acid. In other solid tumours, for patients with no pain or pain with no prior skeletal-related event, the comparator was best supportive care. In patients with pain and a prior skeletal-related event, the comparators were zoledronic acid and disodium pamidronate.\n\nThe selection of the comparator in the analyses (that is best supportive care or a bisphosphonate) was informed by a chart review of patients in the UK. This showed that 87%, 49% and 37% of patients with bone metastases from breast, prostate and solid tumours other than breast and prostate were being treated or had been treated with bisphosphonates respectively. The choice of bisphosphonate in the analyses was informed by data from the IMS Oncology Analyzer. This reported that, for breast cancer, prostate cancer and other solid tumours, zoledronic acid was used in 50%, 92% and 80% of patients respectively. For disodium pamidronate, the proportions were 18%, 4% and 20% and, for ibandronic acid, the proportions were 31%, 4% and 0%.\n\nThe same model structure was used for each tumour type, but the absolute and relative risks of skeletal-related events, adverse events and cancer mortality were modelled to reflect the differences between tumour types. The skeletal-related event risk and event rates were derived from the individual denosumab clinical trials. Data from the zoledronic acid arm of each of the trials were used to estimate the baseline absolute risk of skeletal-related events. Treatment effects were estimated from the trial data for denosumab compared with zoledronic acid and from the network meta-analysis for the other comparators. Within each tumour type, all patients were assumed to have the same survival risk regardless of treatment. Five adverse events (osteonecrosis of the jaw, renal toxicity, hypercalcaemia, hypocalcaemia and skin infections) were included in the model based on their impact on cost and/or health-related quality of life. Adverse event data for denosumab and zoledronic acid were taken from the denosumab clinical trials and, for disodium pamidronate and ibandronic acid, from published clinical trials. Discontinuation from treatment was based on the manufacturer's phase III trial data and included discontinuation because of adverse effects, withdrawal of consent, treatment refusal, protocol violation, other illnesses and other reasons. Discontinuation rates for other comparators were taken from the literature.\n\nThe utility values used in the model were derived from the denosumab clinical trials, which included the administration of the EQ-5D questionnaire every 4\xa0weeks. For each skeletal-related event, it was assumed that the utility decrement started 5\xa0months before identification and resolved 5\xa0months afterwards. All utility values were calculated separately for different tumour types. Utility values were provided academic-in-confidence by the manufacturer and cannot be reported in this document.\n\nDrug costs were taken from BNF 61. Bisphosphonate and denosumab administration costs were derived from a structured questionnaire conducted among UK healthcare professionals and a subsequent costing study. It was assumed that bisphosphonates were administered every 4\xa0weeks. Skeletal-related event costs were derived from a prospective observational study in the UK, and cost estimation using NHS reference costs and personal social services costs. Monitoring and adverse events costs were based on NHS reference costs. In the base-case analysis, it was assumed that vertebral fractures were asymptomatic and incurred no costs.\n\nThe manufacturer of denosumab has agreed a patient access scheme with the Department of Health, in which a discount on the list price of denosumab is offered. The size of the discount is commercial-in-confidence. The base-case results for the incremental cost per QALY gained without the patient access scheme and with the patient access scheme are presented.\n\n## Analyses without the patient access scheme\n\nFor breast cancer, in the manufacturer's base-case analysis without the patient access scheme, denosumab when compared with zoledronic acid was associated with an incremental cost of £1484 and an incremental QALY gain of 0.07 leading to an ICER of £203,387 per QALY gained. Denosumab was associated with an ICER of £13,835 per QALY gained when compared with ibandronic acid and dominated (that is, was less costly and more effective than) disodium pamidronate.\n\nFor prostate cancer, in the manufacturer's base-case analysis without the patient access scheme, in the subgroup of patients with painful bone metastases and who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £922 and an incremental QALY gain of 0.006 leading to an ICER of £157,276 per QALY gained. In the subgroup of patients with no pain, or pain and no history of a prior skeletal-related event, denosumab when compared with best supportive care was associated with an incremental cost of £3993 and an incremental QALY gain of 0.039 leading to an ICER of £102,067 per QALY gained.\n\nFor other solid tumours including non-small cell lung cancer, in the manufacturer's base-case analysis without the patient access scheme, in the subgroup of patients with painful bone metastases and who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £757 and an incremental QALY gain of 0.004 leading to an ICER of £205,580 per QALY gained. Denosumab dominated disodium pamidronate. In the subgroup of patients with no pain or pain and no history of a prior skeletal-related event, denosumab when compared with best supportive care was associated with an incremental cost of £2530 and an incremental QALY gain of 0.021 leading to an ICER of £122,499 per QALY gained.\n\n## Analyses with the patient access scheme\n\nFor breast cancer, in the manufacturer's analysis with the patient access scheme, denosumab when compared with zoledronic acid was associated with a cost saving of £483 and an incremental QALY gain of 0.07. When compared with ibandronic acid and disodium pamidronate denosumab was associated with cost savings of £1895 and £3453 and incremental QALYs of 0.005 and 0.013 respectively. Denosumab therefore dominated each comparator.\n\nFor prostate cancer, in the manufacturer's analysis with the patient access scheme, in the subgroup of patients with painful bone metastases and who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid was associated with a cost saving of £281 and an incremental QALY gain of 0.006. Denosumab therefore dominated zoledronic acid. In the subgroup of patients with no pain or pain and no history of a prior skeletal-related event, denosumab when compared with best supportive care was associated with an incremental cost of £2790 and an incremental QALY gain of 0.039 with an ICER of £71,320 per QALY gained.\n\nFor other solid tumours including non-small cell lung cancer, in the manufacturer's analysis with the patient access scheme, in the subgroup of patients with painful bone metastases and who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid and disodium pamidronate was associated with cost savings of £43 and £2918 and incremental QALY gains of 0.004 and 0.006 respectively. Denosumab therefore dominated zoledronic acid and disodium pamidronate. In the subgroup of patients with no pain, or pain and no history of a prior skeletal-related event, denosumab when compared with best supportive care was associated with an incremental cost of £1730 and an incremental QALY of 0.021 leading to an ICER of £83,763 per QALY gained.\n\nThe manufacturer undertook sensitivity analyses to assess the impact of parameters and assumptions on the cost per QALY gained. The ICER was sensitive to skeletal-related event utilities, alternative dosing frequency and administration of bisphosphonates, application of skeletal-related event rates without the 21-day window, and assuming no discontinuation rate.\n\nIn the Assessment Group's view the manufacturer's model was of good quality and structure but noted that:\n\nTreatment-specific effects data for the subgroups based on prior skeletal-related event experience were not applied.\n\nThe rates of adverse events for best supportive care were assumed to be zero.\n\nCosts for zoledronic acid used in the model were 5% higher than those listed in BNF 62.\n\nThe manufacturer used median values rather than means from the costing study because of the skewed nature of the replies.\n\nThe manufacturer used 2008/09 reference costs for radiotherapy planning and administration rather than the 2009/10 costs that were used for all other skeletal-related events.\n\nThere was no detail about the functional forms that were tested during the EQ-5D data analysis.\n\n## Assessment Group model\n\nThe Assessment Group rebuilt the manufacturer's model using the same basic structure. The Assessment Group included the same analyses as the manufacturer: breast cancer, prostate cancer and other solid tumours (including non-small cell lung cancer), but also included a separate analysis based on the subgroup data for patients with non-small cell lung cancer. Analyses were completed including all patients, and separately for patients who had not had a skeletal-related event and those who had. There were no data to allow separation of non-small cell lung cancer outcomes by skeletal-related event history, therefore only an analysis of all patients is presented for this subgroup.\n\nIn the base-case analysis, the Assessment Group applied the results of its network meta-analysis for time to first skeletal-related event and risk of subsequent skeletal-related event. In addition, the Assessment Group made amendments to the resource data, using the zoledronic acid price and the disodium pamidronate price based on BNF 62. It recalculated the costs associated with skeletal-related events, excluding excess bed days (except for spinal cord compression). The costs for serious adverse events were also amended to allow for some serious adverse events such as osteonecrosis of the jaw and renal toxicity to include some costs associated with outpatient care as well as inpatient care.\n\n## Analyses without the patient access scheme\n\nThe results of the Assessment Group's base-case cost-effectiveness analysis without the patient access scheme showed that, for breast cancer (analysis of all patients, regardless of skeletal-related event history), denosumab when compared with zoledronic acid was associated with an incremental cost of £1707 and an incremental QALY gain of 0.007 leading to an ICER of £245,264 per QALY gained. Denosumab was associated with an incremental cost of £6242 and incremental QALY gain of 0.027 giving an ICER of £229,547 per QALY gained when compared with best supportive care. When compared with disodium pamidronate, denosumab was dominant with a cost saving of £1355 and incremental QALY gain of 0.012.\n\nFor prostate cancer, in the Assessment Group's base-case analysis without the patient access scheme, in the subgroup of patients who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £1053 and an incremental QALY gain of 0.006 leading to an ICER of £170,854 per QALY gained. When compared with best supportive care, denosumab was associated with an incremental cost of £3897 and incremental QALY gain of 0.025 leading to an ICER of £152,916 per QALY gained. In the subgroup of patients with no prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £1061 and an incremental QALY gain of 0.011 giving an ICER of £99,561 per QALY gained. When compared with best supportive care, denosumab was associated with an incremental cost of £3969 and an incremental QALY gain of 0.039 leading to an ICER of £103,003 per QALY gained.\n\nFor other solid tumours including non-small cell lung cancer, in the Assessment Group's base-case analysis without the patient access scheme, in the subgroup of patients who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £848 and an incremental QALY gain of 0.004 leading to an ICER of £196,114 per QALY gained. When compared with best supportive care, denosumab was associated with an incremental cost of £2620 and an incremental QALY gain of 0.011 giving an ICER of £238,840 per QALY gained. In the subgroup of patients with no prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £823 and an incremental QALY gain of 0.008 leading to an ICER of £106,812 per QALY gained. When compared with best supportive care, denosumab was associated with an incremental cost of £2473 and an incremental QALY gain of 0.024 giving an ICER of £103,350 per QALY gained.\n\nFor the subgroup data for non-small cell lung cancer (including both patients with and without a prior skeletal-related event), without the patient access scheme, denosumab when compared with zoledronic acid was associated with an incremental cost of £708 and an incremental QALY gain of 0.005 leading to an ICER of £149,878 per QALY gained. When compared with best supportive care, denosumab was associated with an incremental cost of £2262 and an incremental QALY gain of 0.012 giving an ICER of £191,412 per QALY gained.\n\n## Analyses with the patient access scheme\n\nFor breast cancer, the Assessment Group's analysis with the patient access scheme showed that denosumab when compared with zoledronic acid and disodium pamidronate was associated with cost savings of £243 and £3305 and an incremental QALY gain of 0.007 and 0.012 respectively. Denosumab dominated zoledronic acid and disodium pamidronate. Compared with best supportive care, denosumab was associated with an incremental cost of £4292 and an incremental QALY of 0.027 leading to an ICER of £157,829 per QALY gained.\n\nFor prostate cancer, with the patient access scheme, in the subgroup of patients who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid was associated with a cost saving of £131 and an incremental QALY gain of 0.006. Denosumab was therefore dominant. Compared with best supportive care, the incremental cost was £2713 and incremental QALY gain 0.025 leading to an ICER for denosumab of £106,446 per QALY gained. In the subgroup of patients with no prior skeletal-related event, denosumab when compared with zoledronic acid was associated with a cost saving of £123 and an incremental QALY gain of 0.011. Denosumab was therefore dominant. Compared with best supportive care the incremental cost was £2785 and incremental QALY gain 0.039 leading to an ICER for denosumab of £72,269 per QALY gained.\n\nFor other solid tumours including non-small cell lung cancer and including the patient access scheme, in the subgroup of patients who have experienced a prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £66 and an incremental QALY gain of 0.004 leading to an ICER of £15,282 per QALY gained. When compared with best supportive care denosumab was associated with an incremental cost of £1839 and an incremental QALY gain of 0.011 leading to an ICER of £167,587 per QALY gained. In the subgroup of patients who have no prior skeletal-related event, denosumab when compared with zoledronic acid was associated with an incremental cost of £41 and an incremental QALY gain of 0.008 leading to an ICER of £5337 per QALY gained. Compared with best supportive care, denosumab was associated with an additional cost of £1691 and an incremental QALY of 0.024 leading to an ICER of £70,679 per QALY gained.\n\nFor non-small cell lung cancer with the patient access scheme, denosumab was associated with an incremental cost of £28 and an incremental QALY gain of 0.005 leading to an ICER of £5972. Compared with best supportive care, denosumab was associated with incremental costs of £1583 and an incremental QALY gain of 0.012 leading to an ICER of £133,926 per QALY gained.\n\nThe Assessment Group performed univariate sensitivity analyses to assess the impact of using some of the manufacturer's costs and estimates within the model, alternative rates of discontinuation assumed for active treatments, alternative assumptions about the change in utility for a patient who has never had a skeletal-related event having a skeletal-related event, applying utility multipliers for those nearing death, limiting or excluding the effects of serious adverse events, altering the time horizon to 5\xa0years and 2\xa0years, excluding general mortality, and extending the effect of spinal cord compression to beyond 5\xa0months from diagnosis. Analyses were also completed assuming alternative costs for zoledronic acid. Sensitivity analyses included the patient access scheme. The results of these analyses generally supported the conclusions in the base-case cost-effectiveness analysis.\n\nAfter the consultation, additional information was provided about the use of bisphosphonates in patients with bone metastases from prostate cancer. The patient chart review (see section 4.2.5) included 1161 patients with bone metastases from prostate cancer. In patients who were receiving or had received bisphosphonate treatment (49%), the reasons for treatment (not mutually exclusive) were: to prevent skeletal-related events (56%), to treat or prevent bone pain (42%), to treat bone metastases or lesions at the original site (27%), to prevent new bone metastases or lesions (21%), or because the patient had high-risk disease (18%). A survey of UK specialists who treat genito-urinary cancer as a special or main interest was also submitted from the British Uro-Oncology Group. The survey was sent to 200 specialists, of whom 61 responded. Of those responding, 87% prescribed zoledronic acid, of whom 36% used it only in patients who had previously had a skeletal-related event. In patients who had had a prior skeletal-related event, 47% of specialists prescribed it mostly for bone pain, 32% prescribed it mostly for delaying further skeletal-related events and 17% prescribed it for both.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of denosumab, having considered evidence on the nature of skeletal-related events in adults with bone metastases from solid tumours and the value placed on the benefits of denosumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n## Clinical effectiveness\n\nThe Committee considered the nature of the condition, and noted evidence submitted and presented by the patient experts and clinical specialists on the impact of bone metastases on people. The Committee heard from the clinical specialists and patient experts that complications from bone metastases can affect mobility so people can be housebound, unable to participate socially and have difficulties with employment. The Committee also heard that pain from bone metastases can be significant and managing pain is an important part of treatment. Pain can be continuous and excruciating and sometimes means the person needs hospitalisation. Pain treatment can include high-dose opioids that can have undesirable effects such as sleepiness and constipation, which can severely affect some people. The clinical specialists and patient experts considered that treatments delaying skeletal-related events and reducing pain enabled people to enjoy family life for longer. The Committee recognised the impact on people of bone metastases and the value placed by them on minimising the effects of bone metastases.\n\nThe Committee discussed the existing clinical options for preventing skeletal-related events in people with bone metastases from breast cancer, noting that the guideline on advanced breast cancer (NICE clinical guideline 81) recommends using bisphosphonates. The Committee heard from clinical specialists that bisphosphonates are commonly used in this patient group, and that, of the available bisphosphonates, oral ibandronate may be preferred because it can be administered in the community. However, the Committee heard that, if there are concerns about adherence or if people have acute pain, zoledronic acid or intravenous ibandronate are used. The Committee also heard that, of the intravenous treatments, zoledronic acid is normally used in people with bone metastases from breast cancer. The Committee heard from the patient expert that not everyone with metastatic breast cancer prefers oral bisphosphonates over intravenous bisphosphonates because the administration requirements for oral treatment are complex and sometimes people prefer the more frequent clinical contact that is necessary with an intravenous drug. The Committee concluded that, for people with bone metastases from breast cancer, bisphosphonates were the appropriate comparator, specifically zoledronic acid and ibandronate.\n\nThe Committee then discussed the appropriate comparator for the group of people with bone metastases from prostate cancer. It discussed the recommendations in the guideline on prostate cancer (NICE clinical guideline 58) and noted that bisphosphonates are not recommended for the prevention of skeletal-related events. However, for a subgroup of people with prostate cancer, bisphosphonates are recommended for use as pain relief when other treatments have failed. The Committee heard from a representative of the Guideline Development Group that the group evaluated bisphosphonates both for preventing skeletal-related events and for pain relief from bone metastases in hormone-refractory metastatic prostate cancer. The Committee understood that the group considered evidence from a systematic review and meta-analysis and, based on that evidence, did not recommend bisphosphonates for preventing skeletal-related events in prostate cancer. However, the evidence did suggest a trend favouring bisphosphonates over placebo for relieving pain from bone metastases in prostate cancer. The Committee noted comments received during consultation that the systematic review informing the clinical guideline was 'flawed' because it assumed a class effect for bisphosphonates and included studies that were not relevant to the aim of preventing skeletal-related events. The Committee was aware that it was not within the remit of this appraisal to review the clinical guideline recommendations, and that the analysis by both the manufacturer and the Assessment Group for this appraisal of denosumab had not assumed a class effect and had focused on studies with skeletal-related event outcomes. The Committee understood that, based on the clinical guideline recommendations, bisphosphonates may be used in people with hormone-refractory (castration-resistant) prostate cancer. However, this use is restricted to pain relief when other treatments have failed.\n\nThe Committee noted that neither denosumab nor any of the bisphosphonates has marketing authorisation specifically for pain relief in people with prostate cancer. The Committee also noted the testimony from patient experts about the importance of pain relief (section 4.3.2). It discussed comments received during consultation that pain relief is an implicit part of preventing skeletal-related events because one of the events included in the skeletal-related event outcome is time to radiotherapy to the bone; an intervention given as pain relief. The Committee considered that there were differences between treatment aims to relieve pain, prevent pain and delay worsening pain, but understood that both were important to patients. However, the Committee was only able to make a recommendation in accordance with the wording of the marketing authorisation about the use of denosumab for the prevention of skeletal-related events. It was unable to make recommendations specifically for the use of denosumab for pain relief in people with prostate cancer.\n\nThe Committee then discussed the evidence about the use of bisphosphonates in UK clinical practice. The Committee heard from clinical specialists at the first Committee meeting that bisphosphonate use in people with bone metastases from prostate cancer is not uniform across the NHS. If zoledronic acid is used, it is used in people with castration-resistant (previously known as hormone-refractory) prostate cancer with painful bone metastases for whom other treatments, including analgesics and palliative radiotherapy, have failed. The Committee discussed the survey data and chart review data submitted by consultees. The Committee noted that these showed that bisphosphonates were being used in clinical practice, but that there was variation in reasons for their use. The Committee noted that the survey data had a high non-response rate that could affect the reliability of the data and overestimate the use of bisphosphonates. The Committee also noted that the evidence identified by the Assessment Group for the effectiveness of bisphosphonates in comparison with standard care was the same randomised controlled trial as had been identified by the Guideline Development Group. In the absence of new data on the clinical effectiveness of bisphosphonates, the Committee was not persuaded that these data on use should be relied on over the recommendations in the clinical guideline. The Committee concluded that, because bisphosphonates are recommended for pain relief when other treatments have failed in the guideline on prostate cancer (NICE clinical guideline 58), and not for the prevention of skeletal-related events, the appropriate comparator in this appraisal for people with bone metastases from prostate cancer is best supportive care.\n\nThe Committee discussed the existing clinical options for preventing skeletal-related events in people with bone metastases from solid tumours other than breast and prostate tumours. The Committee noted that no NICE guidelines or other guidelines had been identified about using bisphosphonates in this patient group, and so guideline recommendations could not be used to inform the decision about the appropriate comparator. The Committee noted that a patient chart review by the manufacturer estimated that, in 50% of people with bone metastases from other solid tumours, bisphosphonates were prescribed or planned for future use, and zoledronic acid (80%) and disodium pamidronate (20%) are the bisphosphonates generally used in these patients (see section 4.2.5). The Committee heard from the Assessment Group that it had been advised that oral bisphosphonates are not used in people with bone metastases from lung cancer, and the clinical specialists advised that, in renal cell carcinoma, zoledronic acid may be used. The Committee concluded that there was uncertainty about the treatments in routine use for people with bone metastases from solid tumours other than breast and prostate. It accepted that intravenous bisphosphonates, namely zoledronic acid and disodium pamidronate, would be used for some people and that, based on the manufacturer's evidence, it was unlikely that bisphosphonates would be used as a first-line treatment. The Committee concluded that the appropriate comparators for people with bone metastases from solid tumours other than breast or prostate were best supportive care in general, and bisphosphonates, specifically zoledronic acid or disodium pamidronate for some patients for whom they are prescribed in clinical practice.\n\nThe Committee discussed the benefits of denosumab as a technology. It considered whether the subcutaneous route of administration offered advantages to patients or the NHS in terms of resource use compared with intravenous, though not oral, bisphosphonates. The Committee heard from the clinical specialists that, in theory, denosumab could be given at GP surgeries and could free up resources from chemotherapy suites. It also heard that, compared with zoledronic acid, denosumab was considered to offer some benefits in terms of reduced nephrotoxicity and acute phase reactions (for example, fever, muscle and bone pain, and arthralgia). It also heard that people having denosumab did not need blood test monitoring each month except those with severe renal impairment (creatinine clearance less than\xa030\xa0ml/min or receiving dialysis) to monitor hypocalcaemia, which would potentially make it more convenient for people.\n\nThe Committee noted that the primary outcome measure in the denosumab trials was time to first on-study skeletal-related event. The Committee noted that skeletal-related event was a composite outcome indicator that included treatments as well as complications of bone metastases. The Committee discussed whether using a composite outcome was clinically meaningful. The Committee heard from the clinical specialists that each component of the composite outcome was important but that, to interpret the data, it is helpful if different skeletal-related events are reported separately. However, clinical trials in bone metastases have historically reported composite outcomes and there is no validated method to assign different weights to different events in the composite indicator. The Committee noted comments received during consultation about the uncertain clinical significance of using composite skeletal-related event outcomes, but concluded that it was appropriate to use skeletal-related events as defined in the clinical trials as the basis of its decision.\n\nThe Committee discussed the outcomes of the denosumab trials in the context of the other trials identified by the Assessment Group in its network meta-analysis. The Committee noted that the trials consistently showed that denosumab improved skeletal-related event outcomes compared with zoledronic acid, and that zoledronic acid improved skeletal-related event outcomes compared with placebo. The Committee discussed the other outcome data from the denosumab trials, noting that there were no benefits to overall survival for denosumab compared with zoledronic acid and that the outcomes for pain, although all favoured denosumab, were not all statistically significant. The Committee concluded that the evidence directly comparing denosumab with zoledronic acid for skeletal-related event outcomes suggested that denosumab was clinically more effective than zoledronic acid. However, the data for other outcomes such as pain, survival and quality of life did not show such a consistent benefit over zoledronic acid.\n\nThe Committee discussed the result of the Assessment Group's network meta-analysis to compare denosumab with other bisphosphonates and best supportive care. The Committee noted that the Assessment Group had first completed a random effects model, but subsequently preferred a fixed effects model. The Committee was aware that a fixed effects model is appropriate when it is believed that each study is estimating the same treatment effect or that inferences are to be made based on the available studies. The Committee discussed whether a random effects model would have been more appropriate for the network meta-analysis to account for heterogeneity among the included studies. The Committee heard from the Assessment Group that there were not enough studies included in the network meta-analysis for the between-study standard deviation to be properly calculated. It heard that an analysis that included an assumption of mild-to-moderate heterogeneity, although affecting the estimates of effect, would not have affected the outcomes of the economic modelling. The Committee further noted consultation comments received from the manufacturer about the appropriateness and reliability of the indirect method used to estimate the effect of zoledronic acid compared with disodium pamidronate, when direct estimation was possible. It noted that the Assessment Group accepted the comment made by the manufacturer and that it had revised its network meta-analysis in light of the manufacturer's comment. The Committee noted the revised analysis and accepted this amendment considering that it did not materially affect the estimates produced. The Committee agreed that the estimates of the effects were consistent across the evidence sources submitted, and that it could consider the analyses of cost effectiveness that had used the estimates from the Assessment Group's network meta-analysis using the fixed effects model.\n\nThe Committee discussed the adverse events data from the denosumab trials. The Committee noted that fewer incidents of renal toxicities and acute phase reactions were reported in the denosumab group than in the zoledronic acid group. However, there was a higher incidence of hypocalcaemia and osteonecrosis of the jaw in the denosumab group than in the zoledronic acid group. The Committee heard from the clinical specialists that they considered that denosumab could be given to people with mild-to-moderate renal failure and that this could be particularly valuable for people with metastatic prostate cancer, many of whom have reduced renal function. The Committee noted comments from consultation that recommendations should be based on the intention to treat with zoledronic acid, rather than the ability to treat with zoledronic acid. This was so that denosumab would be available to people for whom zoledronic acid would otherwise be appropriate, but who could not be treated with it because it was contraindicated because of impaired renal function. The Committee understood from clinical specialists that such people had not been able to be enrolled in the denosumab trials because zoledronic acid was used as a comparator. The Committee understood that denosumab may have a specific role in preventing skeletal-related events for people who cannot be treated with bisphosphonates because of reduced renal function. The Committee agreed that the recommendations should be based on the intention to treat with bisphosphonates.\n\nThe Committee discussed the Assessment Group's subgroup analysis of the data for patients with non-small cell lung cancer. The Committee heard from the clinical specialists that they considered that this was an appropriate subgroup clinically because different primary tumour types responded to treatment in different ways. However, the Committee also recognised the comments from the manufacturer that these data were from a post-hoc analysis that was not powered to show a difference in effect. The Committee concluded that it was appropriate to consider subgroups based on primary tumour type. However, it was aware of the limitations of the data available to inform such analysis.\n\nThe Committee noted that, in accordance with the final scope for the appraisal, both the manufacturer and the Assessment Group had provided subgroup analyses based on patient history of prior skeletal-related event. The Committee discussed the analyses, noting that the evidence was generally consistent with the analysis that included all patients but that, in some cases, the effect was no longer statistically significant. The Committee heard from the Assessment Group that this subgroup analysis was potentially important in the economic analysis because prior history influenced the baseline utility in the model, as well as the likelihood of having skeletal-related events. The Committee heard from the clinical specialists that they considered that history of a prior skeletal-related event reflected a continuation of disease progression rather than a separate subgroup. The Committee took account of these views when it considered the cost-effectiveness analysis. Based on the clinical evidence the Committee considered that the data were consistent regardless of prior skeletal-related event history.\n\n## Cost effectiveness\n\nThe Committee discussed the economic models provided by the manufacturer and the Assessment Group, noting that the Assessment Group had based its model on the basic structure of the manufacturer's model. The Committee discussed the model structure and the parameter values used, noting where the Assessment Group had updated or amended inputs used by the manufacturer. It noted the similarities in the outputs of the modelling completed by the manufacturer and the Assessment Group, but it also noted the considerable differences in these outputs compared with those of the existing cost-effectiveness literature (sections 4.2.1 and 4.2.2). The Committee concluded that the structure of the Assessment Group model was appropriate to inform its deliberations, but given the differences in outputs it was appropriate to also consider the wider economic evidence available.\n\nThe Committee discussed whether the assumption of a reduction in utility starting 5\xa0months before the skeletal-related event is recorded is a valid assumption in reflecting the clinical development of a skeletal-related event. The Committee heard from the clinical specialists that they would expect a gradual deterioration in the patient's condition before a skeletal-related event happened, for example, pain would start worsening before a patient would be considered for palliative radiotherapy or bone surgery. The Committee concluded that it was appropriate to assume reduced quality of life before the skeletal-related event happened and accepted the 5-month utility reduction as plausible.\n\nThe Committee noted that analyses had been completed for all patients and separately using treatment-specific data for patients with and without a prior skeletal-related event. The Committee had heard from the clinical specialists that this was not a distinction they made (see section 4.3.14), and noted that the outputs of the modelling were consistent across these analyses regardless of the data used. The Committee concluded that issues about the use in the modelling of subgroup-specific effects data based on prior skeletal-related event experience was not an important driver for decision-making.\n\nThe Committee discussed the assumptions about the cost and adverse events modelled for best supportive care in the manufacturer's and the Assessment Group's models, noting that both of the models assumed there were no adverse events for best supportive care. The Committee discussed the nature of best supportive care for people with bone metastases. The Committee heard from clinical specialists that opioid analgesia is the main form of pain control for people with bone metastases. It heard that opioids have many adverse reactions including altered consciousness, sleepiness and constipation. The Committee also heard from the clinical specialists that radioactive isotopes are also increasingly used for pain control for people with bone metastases from prostate cancer. The Committee noted that no evidence had been provided that enabled it to quantify the impact of this on cost effectiveness. The Committee concluded that the costs of best supportive care may have been underestimated, and that there could be additional disutilities resulting from adverse events that were not accounted for in the model.\n\nThe Committee discussed the results of the Assessment Group analyses. The Committee noted that depending on tumour type and skeletal related event history, the base-case analyses predicted a small incremental QALY gain (range from 0.004 to 0.011) favouring denosumab when compared with zoledronic acid. It also noted the slightly larger, but still small, increments when denosumab was compared with best supportive care (range from 0.011 to 0.039). The Committee recognised that a similar QALY gain for both denosumab and zoledronic acid was calculated from the manufacturer's modelling, and that these small QALY gains meant that the ICERs were sensitive to small changes in costs.\n\nThe Committee discussed the estimates of cost effectiveness from the Assessment Group analyses without the patient access scheme. It noted that the ICER for denosumab when compared with zoledronic acid was more than £200,000 per QALY gained for the metastatic breast cancer population, more than £100,000 per QALY gained for the metastatic prostate cancer population, and £100,000 per QALY gained for people with bone metastases from solid tumours other than breast and prostate. For denosumab compared with best supportive care, the ICERs were all more than £100,000 per QALY gained. The Committee recognised that the ICERs provided by the manufacturer for denosumab compared with zoledronic acid and denosumab compared with best supportive care were of a similar magnitude. The Committee concluded that without the patient access scheme denosumab could not be recommended as a cost-effective use of NHS resources.\n\nThe Committee discussed the implications of the analyses in both the Assessment Group and the manufacturer models, that is, when the interventions (that is denosumab, zoledronic acid and best supportive care) were considered simultaneously in an incremental analysis, the small gains in QALYs and relatively larger increases in costs meant that zoledronic acid was not a cost-effective use of NHS resources. The Committee discussed whether this changed its conclusions (see sections 4.3.3 and 4.3.7) on the appropriateness of using zoledronic acid as a comparator against which to assess the cost effectiveness of denosumab in people with breast cancer and for the subgroup of people with solid tumours other than breast and prostate cancer for whom bisphosphonates are used.\n\nThe Committee noted that in the systematic literature review of cost-effectiveness studies reported by the Assessment Group, the studies of the bisphosphonates reported a range of ICERs, most of which were relatively favourable to the bisphosphonates in general and to zoledronic acid in particular. However, none of these studies was based on utility measurement consistent with NICE's methods guide. The Committee particularly examined the results of the Health Technology Assessment (HTA) monograph that informed the guideline on advanced breast cancer (NICE clinical guideline\xa081) and produced an ICER of £1850 per QALY gained. The Committee heard from the Assessment Group that there were differences between its model and the HTA monograph in the cost estimates used and that the HTA monograph included additional costs specific to pain and its management that weren't included in the Assessment Group model. The incidence of skeletal-related events was also higher in the HTA monograph and the utility decrement associated with each skeletal-related event was considerably greater. The Committee heard from the clinical specialists that the management of bone metastases has changed over time as treatments have improved, which could partly explain the lower event rates in the denosumab trials and Assessment Group modelling in the current appraisal. The Committee agreed there was transparency in the modelling completed by the Assessment Group. The Committee expressed concern that both the Assessment Group model and the manufacturer's model suggested that zoledronic acid was not cost effective compared with best supportive care. However, the Committee recognised that the scope of this appraisal was limited to appraising the cost effectiveness of denosumab compared with zoledronic acid or best supportive care. It considered that the cost effectiveness of zoledronic acid compared with best supportive care would need to be subject to an appropriate review before definitive conclusions could be drawn.\n\nThe Committee then discussed the analyses in patients with breast cancer and solid tumours other than breast and prostate, comparing denosumab with zoledronic acid, including the patient access scheme. It noted that, for breast cancer, the patient access scheme reduced the cost of denosumab so that it became less costly and more effective than zoledronic acid. The Committee also noted that, in people with bone metastases from solid tumours other than in the breast and prostate, including the patient access scheme reduced the ICER for denosumab compared with zoledronic acid to less than £16,000 per QALY gained and to less than £6000 per QALY gained in the non-small cell lung cancer subgroup. The Committee recognised that the submitted cost-effectiveness analyses suggested that zoledronic acid was not cost effective when compared with best supportive care. However, in view of the contradictory results from the published economic evaluations, and the recommendations about bisphosphonates in the guideline on advanced breast cancer (NICE clinical guideline\xa081), the Committee was persuaded that zoledronic acid was an appropriate comparator against which to appraise denosumab for people with breast cancer and the subgroup of people with solid tumours other than breast and prostate for whom zoledronic acid is indicated. On balance, the Committee, while recognising the uncertainties over the cost effectiveness of zoledronic acid, concluded that denosumab, based on current prices and with the patient access scheme, was shown to be cost effective compared with zoledronic acid (or other bisphosphonates in the case of metastatic breast cancer). Therefore, denosumab should be an additional option when zoledronic acid (or other bisphosphonates in the case of metastatic breast cancer) is used. For breast cancer, this should be in accordance with the recommendations in the guideline on advanced breast cancer (NICE clinical guideline 81).\n\nThe Committee discussed the Assessment Group's analyses of denosumab compared with best supportive care, noting that these were consistent with the manufacturer's analyses. The Committee noted that even with the patient access scheme, denosumab was associated with high ICERs, the lowest of which in the Assessment Group's analyses remained above £70,000 per QALY gained. The Committee concluded that denosumab could not be recommended as a cost-effective use of NHS resources for preventing skeletal-related events for those groups for whom best supportive care is the appropriate comparator (see sections 4.3.6 and 4.3.7), that is, people with bone metastases from prostate cancer and in the general population of people with bone metastases from solid tumours other than breast and prostate.\n\nThe Committee noted comments received during consultation that, compared with zoledronic acid, denosumab was shown to be more effective and less costly, and therefore in instances in which zoledronic acid was currently used, denosumab may be a more efficient use of NHS resources. The Committee also recognised that denosumab may offer some benefits in terms of administration over intravenous bisphosphonates and have a role in the treatment of people with reduced renal function (see section 4.3.8). The Committee considered the clinical guideline recommendation for the use of bisphosphonates for pain relief on one hand and the constraints on the appraisal to make recommendations about the use of denosumab for the prevention of skeletal-related events on the other hand. The Committee did not consider that a recommendation about denosumab for the prevention of skeletal-related events would lead to a more efficient use of NHS resources if existing NICE guidance recommended the use of bisphosphonates for pain relief only because the populations, although overlapping, were not necessarily the same. The Committee was not persuaded that the results of the analyses in section 4.2.25 (which suggested that denosumab may be associated with lower costs than zoledronic acid) should change its decisions that the appropriate comparator for people with bone metastases from prostate cancer was best supportive care and that for this patient group denosumab had not been shown to be a cost-effective use of NHS resources.\n\nThe Committee noted comments received at consultation which stated that zoledronic acid was not the only bisphosphonate used in solid tumours other than breast and prostate, and that disodium pamidronate was also used. It discussed whether denosumab should be recommended as an alternative to disodium pamidronate. The Committee was aware that although zoledronic acid is the only bisphosphonate that has marketing authorisation in this patient group, the data provided by the manufacturer indicated that disodium pamidronate is being prescribed for approximately 20% of the people who are being treated or have been treated with a bisphosphonate (see section 4.2.5). The Committee took into consideration the price of disodium pamidronate, which is higher than zoledronic acid. It was aware that there is no estimate of clinical effectiveness for denosumab compared with disodium pamidronate in this patient group, but noted the availability of evidence from people with breast cancer (see section 4.1.7). The Committee concluded that denosumab should also be considered as an alternative where disodium pamidronate was used. In people with bone metastases from solid tumours other than breast and prostate cancers, denosumab was recommended as an alternative option if bisphosphonates would otherwise be prescribed.\n\nThe Committee considered comments received during the consultation on the appraisal consultation document that the fact that denosumab is recommended for the treatment of breast cancer but not for the treatment of prostate cancer could be interpreted as indirect sex discrimination. This is because the vast majority of people with breast cancer are women, and prostate cancer can only occur in biological men. The recommendations therefore mean that people with prostate cancer, that is, men and transgender women, cannot access treatment with denosumab for preventing skeletal-related events. The Committee agreed that the reason denosumab was not recommended for preventing skeletal-related events in prostate cancer was not because prostate cancer occurs in men and transgender women, nor was it related in any way to the different gender profile of the patients. Instead, the Committee considered that the evidence indicates that current clinical management and disease course varies between breast, prostate and other solid tumours. The Committee noted that separate clinical trials have been carried out in these different cancer types, and that the trials showed different efficacy profiles for denosumab between the cancer types. The choice of comparator for denosumab in the different cancer types was informed by its marketing authorisation and the published clinical guidelines. The ICER for using denosumab in prostate cancer compared with best supportive care is high (more than £70,000 per QALY gained and therefore beyond the threshold at which NICE would normally recommend a treatment). The Committee considered that the evidence on different cost-effectiveness profiles for the different types of disease means that it is doubtful whether the Committee's recommendations can be regarded as treating patients with prostate cancer less favourably than patients with breast cancer. Bearing in mind NICE's duties and functions and the requirement for the Committee's recommendations to be based on the clinical and cost effectiveness of treatments, the Committee considered that the recommendation for prostate cancer was a means of achieving a legitimate aim. Given the high level of the ICER for using denosumab in prostate cancer, the Committee was satisfied that the recommendation is a proportionate means of achieving that aim and that its recommendations do not lead to unlawful discrimination. Therefore it concluded that it did not need to add to or change its recommendations in light of the consultation comments.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA265\n\nAppraisal title: Denosumab for the prevention of skeletal-related events in adults with bone metastases from solid tumours\n\nSection\n\nKey conclusion\n\nDenosumab is recommended as an option for preventing skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from breast cancer and from solid tumours other than prostate if bisphosphonates would otherwise be prescribed and the manufacturer provides denosumab with the discount agreed in the patient access scheme.\n\n\n\n\n\nIn people with bone metastases from breast cancer, the patient access scheme reduced the cost of denosumab so that it became less costly and more effective than zoledronic acid.\n\n\n\n\n\nIn people with bone metastases from solid tumours other than breast and prostate, the patient access scheme reduced the ICER for denosumab compared with zoledronic acid to less than £16,000 per QALY gained and to less than £6000 per QALY gained in the non-small cell lung cancer subgroup. For this patient group, the Committee also discussed the off-label use of disodium pamidronate in clinical practice, although it recognised that no estimate of clinical effectiveness was available for disodium pamidronate in this group. It also noted that the cost of disodium pamidronate was higher than that of zoledronic acid. The Committee concluded that denosumab should also be considered as an alternative where disodium pamidronate was used. In people with bone metastases from solid tumours other than breast and prostate cancers, denosumab was recommended as an alternative option where bisphosphonates would otherwise be prescribed.\n\n, 4.3.26\n\nDenosumab is not recommended for preventing skeletal-related events in adults with bone metastases from prostate cancer.\n\n\n\n\n\nCompared with best supportive care, denosumab was associated with high incremental cost-effectiveness ratios (ICERs), even with the patient access scheme, the lowest of which remained above £70,000 per quality-adjusted life year (QALY) gained.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nFor people with bone metastases from breast cancer, bisphosphonates are the appropriate comparator, specifically zoledronic acid and ibandronate.\n\n\n\n\n\nThe appropriate comparator for denosumab in people with metastatic prostate cancer in an appraisal considering the prevention of skeletal-related events is best supportive care.\n\n\n\n\n\nThe appropriate comparators for people with bone metastases from solid tumours other than breast or prostate were best supportive care in general, and bisphosphonates, specifically zoledronic acid or disodium pamidronate for a proportion of people in whom they are prescribed in clinical practice.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee heard from the clinical specialist that, in theory, denosumab could be given at GP surgeries and could free up resources from chemotherapy suites. It also heard that, compared with zoledronic acid, denosumab was considered to offer some benefits in terms of reduced nephrotoxicity and acute phase reactions. It also heard that denosumab did not need blood test monitoring each month except in people with severe renal impairment (creatinine clearance\xa0less than 30\xa0ml/min or receiving dialysis) to monitor hypocalcaemia, which would potentially make it more convenient for people.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee considered denosumab as an alternative to bisphosphonates and as an alternative to best supportive care when bisphosphonates are not used.\n\n\n\n\n\n\n\nAdverse effects\n\nThe Committee noted that, in the denosumab trials, fewer incidents of renal toxicities and acute phase reactions were reported in the denosumab group than in the zoledronic acid group. However, there was a higher incidence of hypocalcaemia and osteonecrosis of jaw in the denosumab group than in the zoledronic acid group.\n\nThe Committee understood that denosumab may have a specific role in preventing skeletal-related events for people who cannot be treated with bisphosphonates because of reduced renal function.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe primary end point in the clinical trials (time to first on-study skeletal-related event) was based on a composite outcome indicator (that is skeletal-related events) that included both treatments and complications of bone metastases. The clinical specialists considered that each component of the outcome was important but that, to interpret the results, it is helpful if different skeletal-related events are reported separately. The Committee concluded that it was appropriate to use skeletal-related events as the basis of the decision.\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe generalisability of the trial data to general clinical practice in the NHS was not an issue in this appraisal.\n\nN/A\n\nUncertainties generated by the evidence\n\nA number of network meta-analyses were submitted. The Committee agreed that there was consistency across the evidence sources submitted and that it could consider the estimates of cost effectiveness that had used the estimates from the Assessment Group's network meta-analysis using a fixed effects model.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee concluded that it was appropriate to consider subgroups based on primary tumour type. However, it was aware of the limitations of the data available to inform such analysis.\n\n\n\n\n\nThe Committee heard from the clinical specialists that they considered that history of a prior skeletal-related event reflected a continuation of disease progression rather than a separate subgroup. Based on the clinical evidence, the Committee considered that the data were consistent regardless of prior skeletal-related event history.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that the evidence directly comparing denosumab with zoledronic acid suggested that denosumab was more clinically effective than zoledronic acid in all 3 cancer groups for which there was trial evidence. However, the data for other outcomes such as pain, survival and quality of life did not show such a consistent benefit over zoledronic acid.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee discussed the economic models provided by the manufacturer and the Assessment Group, noting that the Assessment Group had based its model on the basic structure of the manufacturer's model. The Committee concluded that the structure of the Assessment Group model was appropriate to inform its deliberations, but that it was appropriate to also consider the wider economic evidence available.\n\n\n\n\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted the similarities in the outputs of the modelling completed by the manufacturer and the Assessment Group, but it also noted the considerable differences in these outputs compared with those of the existing cost-effectiveness literature.\n\n\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee discussed whether the assumption of a reduction in utility starting 5\xa0months before the skeletal-related event is recorded is a valid assumption. It concluded that it was appropriate to assume reduced quality of life before the skeletal-related event happened.\n\n\n\nThe Committee discussed the differences between the Assessment Group modelling and the published economic analysis that had informed the guideline on advanced breast cancer (NICE clinical guideline 81). It noted that the utility decrement associated with each skeletal-related event was considerably greater than that assumed in the Assessment Group modelling.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee concluded that denosumab, based on current prices and with the patient access scheme, was shown to be cost effective compared with zoledronic acid (or other bisphosphonates in the case of metastatic breast cancer). Therefore, denosumab would be an additional option when zoledronic acid (or other bisphosphonates in the case of metastatic breast cancer) would be used.\n\n\n\n\n\nFor this patient group, the Committee also discussed the off-label use of disodium pamidronate in clinical practice, although it recognised that no estimate of clinical effectiveness was available for disodium pamidronate in this group. It also noted that the cost of disodium pamidronate was higher than that of zoledronic acid. The Committee concluded that denosumab should also be considered as an alternative where disodium pamidronate was used. In people with bone metastases from solid tumours other than breast and prostate cancers, denosumab was recommended as an alternative option if bisphosphonates would otherwise be prescribed.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee discussed the univariate sensitivity analysis conducted by the Assessment Group. It noted that the ICER was sensitive to reductions in the price of zoledronic acid.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nWithout the patient access scheme, denosumab could not be recommended as a cost-effective use of NHS resources.\n\n\n\n\n\nFor breast cancer, the patient access scheme reduced the cost of denosumab so that it became less costly and more effective than zoledronic acid.\n\n\n\n\n\nFor people with bone metastases from solid tumours other than breast and prostate, the patient access scheme reduced the ICER for denosumab compared with zoledronic acid to less than £16,000 per QALY gained and to less than £6000 per QALY gained in the non-small cell lung cancer subgroup.\n\n\n\n\n\nFor all 3 patient groups, compared with best supportive care, denosumab was associated with high ICERs even with the patient access scheme in the Assessment Group's analyses. The lowest of these remained above £70,000 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe manufacturer of denosumab has agreed a patient access scheme with the Department of Health, in which a discount on the list price of denosumab is offered. The size of the discount is commercial-in-confidence.\n\n\n\nEnd-of-life considerations\n\nEnd-of-life considerations were not addressed in this appraisal.\n\nN/A\n\nEqualities considerations and social value judgements\n\nThe Committee considered comments received during the consultation on the appraisal consultation document that the fact that denosumab is recommended for the treatment of breast cancer but not for the treatment of prostate cancer could be interpreted as indirect sex discrimination. The Committee agreed that the reason denosumab was not recommended for preventing skeletal related events in prostate cancer was not because prostate cancer occurs in men and transgender women, nor was it related in any way to the different gender profile of the patients. Instead, the Committee considered that the evidence indicates that current clinical management and disease course varies between breast, prostate and other solid tumours. The Committee noted that separate clinical trials have been carried out in these different cancer types, and that the trials showed different efficacy profiles for denosumab between the cancer types. The choice of comparator for denosumab in the different cancer types was informed by its marketing authorisation and the published clinical guidelines. The ICER for using denosumab in prostate cancer compared with best supportive care is high and beyond the threshold at which NICE would normally recommend a treatment. The Committee therefore concluded that it did not need to add to or change its recommendations in light of the consultation comments.\n\n", 'Related NICE guidance': 'Published\n\nOpioids in palliative care: safe and effective prescribing of strong opioids for pain in palliative care of adults. NICE clinical guideline 140 (2012).\n\nLung cancer: the diagnosis and treatment of lung cancer. NICE clinical guideline 121 (2011).\n\nAdvanced breast cancer: diagnosis and treatment. NICE clinical guideline 81 (2009).\n\nMetastatic spinal cord compression: diagnosis and management of adults at risk of and with metastatic spinal cord compression. NICE clinical guideline 75 (2008).\n\nProstate cancer: diagnosis and treatment. NICE clinical guideline 58 (2008).\n\nUnder development\n\nNICE is developing the following guidance (details available from the NICE\xa0website):\n\nDenosumab for prolonging bone metastasis-free survival in hormone-refractory prostate cancer. NICE technology appraisal guidance in development (publication expected November 2013).\n\nProstate cancer: diagnosis and treatment (update). NICE clinical guideline in development (publication expected November 2013).', 'Review of guidance': 'The guidance on this technology will be considered for review by the Guidance Executive in July 2013. The Appraisal Committee noted that the ICER was sensitive to reductions in the price of zoledronic acid, and was aware that zoledronic acid is due to come off patent in 2013 and that this may result in a reduction in the price of zoledronic acid because of the availability of cheaper generic versions. In that scenario, the cost-effective analysis that it based its decision on would need to be revised.\n\nAndrew DillonChief ExecutiveOctober 2012', 'Changes after publication': 'February 2014: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta265
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Alteplase for treating acute ischaemic stroke
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Alteplase for treating acute ischaemic stroke
Evidence-based recommendations on alteplase (Actilyse) for treating acute ischaemic stroke in adults.
# Guidance
This guidance replaces NICE technology appraisal guidance 122 (published in June 2007). For details see About this guidance.
Alteplase is recommended within its marketing authorisation for treating acute ischaemic stroke in adults if:
treatment is started as early as possible within 4.5 hours of onset of stroke symptoms, and
intracranial haemorrhage has been excluded by appropriate imaging techniques.# The technology
Alteplase (Actilyse, Boehringer Ingelheim) is a tissue plasminogen activator manufactured by recombinant DNA technology. It activates the production of plasmin from its precursor plasminogen. Plasmin is an enzyme that degrades fibrin clots. The aim of treatment is to reduce the impact of ischaemia by restoring blood flow through the occluded (blocked) artery. A UK marketing authorisation for alteplase to treat acute ischaemic stroke within 3 hours of the onset of symptoms was granted in September 2002. On 14 March 2012 the manufacturer received approval from the Medicines and Healthcare products Regulatory Agency extending the use of alteplase to within 4.5 hours of the onset of symptoms. The current marketing authorisation states that treatment must be started as early as possible within 4.5 hours after onset of stroke symptoms and after exclusion of intracranial haemorrhage by appropriate imaging techniques.
The summary of product characteristics lists the following adverse reactions for alteplase: haemorrhage (intracranial and gastrointestinal), recurrent ischaemia or angina, hypotension, heart failure, pulmonary oedema and reperfusion arrhythmias. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The cost of alteplase is £135 per 10-mg pack, £180 per 20-mg pack and £300 per 50-mg pack (excluding VAT; 'British national formulary' edition 63). The cost per course of treatment depends on the body weight of the patient, and can range from £300 to £600 based on a recommended dose of 0.9 mg per kilogram of body weight. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of alteplase and a review of this submission by the Evidence Review Group (ERG; appendix B). The decision problem addressed by the manufacturer considered whether treatment with alteplase was clinically effective compared with standard medical care (standard medical and supportive management that does not include alteplase) for treating acute ischaemic stroke in adults within 4.5 hours of symptom onset, and whether alteplase treatment was a cost-effective use of NHS resources.
The manufacturer carried out a systematic literature search, which was based on a previously published Cochrane review ('Thrombolysis for acute ischaemic stroke'), but restricted the search to randomised controlled trials of alteplase. For the 0 to 3-hour treatment window, the manufacturer identified no trials other than those included in the previous guidance on alteplase in acute ischaemic stroke (NICE technology appraisal guidance 122) from 2007. The trials in technology appraisal guidance 122 included NINDS (National Institute of Neurological Disorders and Stroke) I and II, ATLANTIS ('Thrombolysis for acute noninterventional therapy in ischaemic stroke') A and B, and ECASS (the 'European Cooperative Acute Stroke Study') II. All these trials were multicentre, double-blinded, placebo-controlled randomised controlled trials of alteplase administered at its licensed dose of 0.9 mg/kg. Treatment with alteplase was administered within 3 hours (NINDS I and II), 5 hours (ATLANTIS B) or 6 hours (ATLANTIS A, ECASS II) of onset of stroke symptoms. Patients were followed up for outcomes for 90 days. The NINDS and ATLANTIS trials were conducted in North America and the ECASS trial in multiple sites in Europe (including the UK), Australia and New Zealand.
The clinical-effectiveness evidence in the manufacturer's submission focused on the extended 3 to 4.5-hour treatment window for which the only directly relevant trial identified by the manufacturer was ECASS III. Other trials with data indirectly relevant to this treatment window were ATLANTIS A and B and ECASS II, from which subgroup data specifically for the 3 to 4.5-hour window were used by the manufacturer in sensitivity analyses. The manufacturer noted that this involved stratifying data into subgroups that had not been specified before randomisation. The manufacturer also identified the third International Stroke Trial (IST-3), a randomised open-label blinded endpoint trial in which alteplase was administered within 6 hours of symptom onset. However, the manufacturer commented that this trial was not placebo controlled and therefore did not meet its trial selection criteria, and that no published results were available at the time of submission.
ECASS III was a placebo-controlled multicentre trial carried out across 130 sites in 19 European countries. Of the 821 patients 22 were from the UK. Patients were eligible for inclusion if aged between 18 and 80 years, diagnosed with acute ischaemic stroke and able to receive treatment within 3 to 4.5 hours of the onset of stroke symptoms. Before randomisation, brain imaging was used to exclude intracranial haemorrhage. The trial randomly assigned eligible patients to receive 0.9 mg/kg of intravenous alteplase (n=418) or placebo (n=403). Patients were followed up for 90 days for outcomes. Baseline demographic and disease characteristics were similar between participants in the 2 treatment arms, but the initial severity of the stroke (as assessed by the National Institutes of Health stroke scale ) and the proportion of patients with a history of previous stroke were both significantly higher in the placebo arm.
The primary outcome in ECASS III was the presence or absence of disability at 90 days as assessed by the modified Rankin scale, which measures the degree of disability or dependence in people who have had a stroke and ranges from 0 (symptom free) to 6 (dead). From intention-to-treat analyses, 52.4% of patients randomised to the alteplase treatment arm had a favourable outcome at 90 days (a score of 0 or 1 ) compared with 45.2% of patients randomised to placebo (odds ratio 1.34, 95% confidence interval 1.02 to 1.76, p=0.04). After adjustment for confounding baseline variables (identified as being statistically significant at p<0.10) including treatment arm, NIHSS score, smoking, time from onset of stroke to treatment, and presence or absence of previous hypertension, alteplase remained statistically significantly associated with a favourable outcome (OR 1.42, 95% CI 1.02 to 1.98, p=0.04).
ECASS III also reported the composite outcome of death or dependence (defined as a score of 3–6 on the modified Rankin scale) at 90 days. There were no statistically significant differences in the number of patients who were dead or dependent between the alteplase and placebo treatment arms (33.5% compared with 38.5%, relative risk 0.87, 95% CI 0.73 to 1.05).
The ECASS III trial also reported as a secondary endpoint a global outcome score at 90 days, which combined a score of 0–1 on the modified Rankin scale, a score of 1 on the Glasgow outcome scale (a 5-point measure of brain injury, with 1 indicating independence and 5 death), a score of 95–100 on the Barthel index (a 10-item measure of a person's daily function, with higher scores reflecting higher function), and a score of 0–1 on the NIHSS. Randomisation to alteplase was associated with a statistically significantly higher probability of achieving a favourable global outcome score (OR 1.28, 95% CI 1.00 to 1.65, p=0.05).
The manufacturer presented a summary of adverse reactions based on intention-to-treat analyses in the ECASS III trial at 90 days. Fatal adverse reactions were reported for 7.7% of patients in the alteplase arm and 8.4% of those in the placebo arm. A statistically significantly higher proportion of patients in the alteplase arm had an intracranial haemorrhage (27.0% compared with 17.6%, p=0.001) or a symptomatic intracranial haemorrhage (2.4% compared with 0.3%, p=0.008) compared with the placebo arm. Three patients (0.7%) randomised to the alteplase arm had a fatal intracranial haemorrhage. Investigator-defined drug-related adverse reactions were reported for 23.9% of patients in the alteplase treatment arm and 6.9% of patients in the placebo arm. Other serious adverse reactions were reported for 25.1% of patients in the alteplase arm and 24.6% of those in the placebo arm.
The manufacturer conducted meta-analyses to calculate the relative risks associated with alteplase for all-cause mortality within 90 days, death or dependence within 90 days, and symptomatic intracranial haemorrhage within 10 days for each of the 3 treatment windows (0 to 3 hours, 3 to 4.5 hours, and 0 to 4.5 hours). The manufacturer presented results from both fixed and random-effects models. For the 0 to 3-hour window, the manufacturer used data from ECASS II and NINDS and used the relative risks from ECASS III for the 3 to 4.5-hour window. For the 0 to 4.5-hour window, the manufacturer used data from ECASS II (0 to 3 hours), ECASS III (3 to 4.5 hours) and NINDS (0 to 3 hours). Heterogeneity between the 3 studies was low for the outcomes of all-cause mortality and death or dependence, but moderate for the outcome of symptomatic intracranial haemorrhage.
The manufacturer compared all-cause mortality at 90 days for the 2 treatment arms. No statistically significant difference was observed between alteplase and placebo for the 3 to 4.5-hour (RR 0.82, 95% CI 0.50 to 1.33, p=0.42), the 0 to 3-hour (RR 1.05, 95% CI 0.55 to 2.03, p=0.88) or the 0 to 4.5-hour (RR 0.89, 95% CI 0.67 to 1.18, p=0.41) treatment windows. For the outcome of death or dependence at 90 days, the manufacturer reported no statistically significant difference between alteplase and placebo for the 3 to 4.5-hour window (RR 0.87, 95% CI 0.73 to 1.05, p=0.14). However, a statistically significant difference in favour of alteplase was reported for both the 0 to 3-hour window (RR 0.81, 95% CI 0.72 to 0.92, p=0.002) and the 0 to 4.5-hour window (RR 0.83, 95% CI 0.75 to 0.92, p<0.001). For the outcome of symptomatic intracranial haemorrhage occurring within 10 days, patients randomised to receive alteplase within the 3 to 4.5-hour window had a statistically significant higher risk (RR 4.82, 95% CI 1.06 to 21.87, p=0.04), with similar results for the 0 to 4.5-hour treatment window (RR 4.18, 95% CI 1.39 to 12.53, p=0.01). For the 0 to 3-hour window, the manufacturer reported a higher risk of symptomatic intracranial haemorrhage among patients randomised to alteplase that was not statistically significant (RR 3.94, 95% CI 0.61 to 25.47, p=0.15).
The manufacturer conducted a systematic review of published cost-effectiveness analyses but did not identify any studies that evaluated the cost effectiveness of alteplase for the treatment of acute ischaemic stroke within 3 to 4.5 hours of onset of symptoms. Instead, the manufacturer adapted a published cost-effectiveness analysis (Sandercock et al., 2002) relevant to the decision problem from the previous guidance on alteplase in acute ischaemic stroke (NICE technology appraisal guidance 122) and used this as part of its submission.
The manufacturer developed a Markov model simulating patients with acute ischaemic stroke who do or do not receive alteplase within 4.5 hours of onset of symptoms. Patients were modelled through 3 possible health states: independent, dependent and dead. The independent state was defined by a modified Rankin scale score of 0–2 and the dependent state by a modified Rankin scale score of 3–5. The model had 3 time phases: from 0 to 6 months when the model assumed the treatment effect of alteplase was complete at 90 days and maintained at 6 months; from 6 to 12 months when the model assumed no further treatment effect; and beyond 12 months when the model also assumed no further treatment effect from alteplase. However, beyond 12 months the model assumed that people in the dependent or independent states could have a recurrent stroke. The model also assumed that people in the dependent state at 12 months and beyond do not move to an independent state, and that people in the independent state at 12 months and beyond do not move to a dependent state unless they survive a recurrent stroke. The model assumed a lifetime horizon with a cycle length of 6 months for the first 12 months, followed by cycles of 12 months thereafter.
The manufacturer chose a population for the model based on SITS-MOST ('Safe implementation of thrombolysis in stroke-monitoring study'), a European observational study of patients receiving alteplase. The manufacturer considered that this study population represented the mean age (68 years) and gender distribution (39.8% female) of patients who would receive alteplase in clinical practice in England and Wales.
For the first phase (0 to 6 months) of the manufacturer's economic model, the size of the effect of treatment with alteplase was informed by the manufacturer's meta-analyses for the 3 treatment windows as described in section 3.8. For the standard treatment arm, the proportion of people in each health state (39.53% independent, 32.56% dependent and 27.91% dead) was informed by the Lothian stroke registry, a registry in Edinburgh, Scotland, of 1779 inpatients with suspected or confirmed stroke from 1989 to 2000. The manufacturer also provided an alternative distribution of the proportion of people who received standard treatment in each health state from the placebo arm of the ECASS III trial at 90 days. This alternative distribution (61.54% independent, 30.27% dependent and 8.19% dead) was used by the ERG in exploratory sensitivity analyses. The manufacturer then used the relative risks of death and death or dependence to calculate the distribution of people in the alteplase arm across the independent, dependent and dead states at the end of the first phase (6 months). The manufacturer used the relative risk of death to estimate the proportion of people who would die and therefore enter the dead state during the first phase. The proportion of people in the dependent state at 6 months was calculated as the difference between the estimated proportion of people who were dead or dependent, and the estimated proportion who were dead. The manufacturer assumed in the model that a symptomatic intracranial haemorrhage had a cost impact (because it required a further diagnostic computed tomography scan), with the health consequences being captured in the outcome of death or dependence from the clinical trials.
For the second phase of the model (6 to 12 months), the manufacturer assumed that people could move from the independent or dependent state to any other health state with equal probabilities for both treatment arms. These transition probabilities were based on the Lothian stroke registry. For the third phase of the model (beyond 12 months), the annual risk of a recurrent stroke (0.05), and the associated risk of mortality (0.25), were taken from the Lothian stroke registry. To estimate the mortality risk for people who did not have another stroke, the manufacturer took data from the Office for National Statistics life tables for England and Wales and adjusted them upward by a factor of 2.3 (taken from the Perth Community Stroke Study) to reflect the higher mortality rates among people who have had a stroke compared with the general UK population.
The manufacturer conducted a literature review to identify appropriate utility values for the independent and dependent states in the model. The manufacturer did not identify any relevant utility values additional to those used in NICE technology appraisal guidance 122 on alteplase in acute ischaemic stroke within the first 3 hours after symptom onset. The manufacturer's submission for this appraisal identified 1 trial (Dorman et al., 1997) that collected EQ-5D utility values in a sample of 147 patients from the Lothian stroke registry. This trial provided utility values of 0.74 (95% CI 0.69 to 0.79) for the independent state and 0.38 (95% CI 0.29 to 0.47) for the dependent state. The model assumed that these utility values remained fixed over time unless a person had a recurrent stroke which resulted in dependence, and thus a move from the independent to the dependent state.
The model included drug acquisition and administration costs as well as the costs of acute and long-term stroke care. The cost of alteplase was based on the mean body weight (76 kg) of patients in the 3 to 4.5-hour cohort from the SITS-MOST trial. Based on the recommended dose of 0.9 mg/kg, the average dose was 68.4 mg, resulting in a total estimated cost of £480 (£300 per 50-mg pack and £180 per 20-mg pack). Administration costs associated with alteplase of £1316 per patient were based on estimates of extra staff time in the trial by Sandercock et al. (2002). For people in either treatment arm who had a symptomatic intracranial haemorrhage, the model included a one-off cost of £100 for an additional CT scan. For all health states in the model, the manufacturer applied annual costs specific to the state (adjusted for inflation to 2012/13 prices) adapted from a study by Youman et al. (2003), which calculated the costs of acute events and long-term stroke care.
The manufacturer's base-case deterministic cost-effectiveness analysis for the 0 to 4.5-hour window estimated an incremental cost-effectiveness ratio (ICER) of £2441 per quality-adjusted life year (QALY) gained for alteplase compared with standard care (incremental costs £811; incremental QALYs 0.333). The probabilistic cost-effectiveness analysis resulted in an ICER of £2296 per QALY gained.
The manufacturer conducted a number of one-way sensitivity analyses on various parameters in the model, including the relative risks associated with alteplase of death or of death or dependence, the risk of recurrent stroke and mortality irrespective of previous treatment, the dose of alteplase treatment, the annual costs of care in the dependent and independent states, the cost of a fatal stroke, and the utility values. The results of these one-way sensitivity analyses indicated that the ICERs were robust to changes in most input parameters, except for the relative risks of death and death or dependence for treatment with alteplase applied in the first phase of the model. When the manufacturer used the upper limit of the 95% confidence interval for the relative risks of death (1.18) and death or dependence (0.92), alteplase treatment led to a very small loss in QALYs at a decreased cost compared with standard care, resulting in £44,342 saved per QALY lost. The manufacturer also conducted additional deterministic sensitivity analyses, which included different scenarios using additional clinical efficacy data from unplanned subgroup analyses of the ATLANTIS A and B and ECASS II trials for 3 to 4.5 hours, and weighted the results based on the assumption that in UK clinical practice a higher proportion of patients are treated during the 0 to 3-hour window (76%) than during the 3 to 4.5-hour window (24%). Using these analyses, alteplase either dominated placebo (that is, was both less costly and more effective) or had an ICER below £2000 per QALY gained. Results of the probabilistic sensitivity analysis showed that alteplase had a high probability (above 90%) of being cost effective at a level of £20,000 to £30,000 per QALY gained.
The manufacturer's base-case deterministic cost-effectiveness analysis for the 3 to 4.5-hour window resulted in an ICER of £6272 per QALY gained for alteplase compared with standard care (incremental costs £2068; incremental QALYs 0.33). The probabilistic cost-effectiveness analysis resulted in an ICER of £6169 per QALY gained. The results of the one-way sensitivity analyses were similar to those for the 0 to 4.5-hour window, indicating that the ICERs were robust to changes in most input parameters, except for changes in the relative risks of death and death or dependence for treatment with alteplase. In an additional sensitivity analysis, the manufacturer pooled 3 to 4.5-hour efficacy data from the ECASS II and ATLANTIS trials with the ECASS III data. This sensitivity analysis resulted in an ICER of £5631 per QALY gained for alteplase compared with standard care.
For the 0 to 3-hour treatment window, the manufacturer presented cost-effectiveness results similar to those presented in the previous guidance on alteplase in acute ischaemic stroke (NICE technology appraisal guidance 122); that is, alteplase dominated standard care, resulting in lower costs and more QALYs for both the deterministic and the probabilistic analyses.
The ERG considered that the clinical-effectiveness evidence submitted by the manufacturer was of good quality. The ERG noted that the patients randomised to the alteplase arm of both the NINDS trial (which provided clinical evidence for the 0 to 3-hour window) and the ECASS III trial had strokes that were less severe on average, which in turn may have biased the results in favour of alteplase. However, the manufacturer also presented adjusted analyses for the primary outcome (disability at 90 days) from the ECASS III trial. The ERG considered that the meta-analytical approach by the manufacturer was appropriate. The ERG agreed with the manufacturer that data derived from unplanned subgroup analyses from the ATLANTIS A and B and ECASS II trials, in which treatment with alteplase was administered up to 6 hours from onset of symptoms, should not be included in the base-case meta-analyses. The ERG also noted that heterogeneity between the studies included in the base-case meta-analyses for the 0 to 4.5-hour window for the outcomes of death and death or dependence was low and not statistically significant.
The ERG commented that the manufacturer submitted an economic model that was in line with the decision problem defined in the scope and closely adhered to the NICE reference case requirements for economic analysis. The ERG commented that the manufacturer provided a reasonable strategy for searching the literature for existing cost-effectiveness studies, although it did not explicitly state its exclusion criteria. The ERG stated that it was appropriate for the manufacturer to conduct separate analyses for patients eligible for treatment within the 0 to 3-hour window and the 3 to 4.5-hour window. The ERG noted that the utility values for the dependent and independent states did not allow for any decreases in health-related quality of life over time, which may have overestimated the lifetime QALYs accrued in the independent state. The ERG stated that, although this may have biased the QALY gains in favour of alteplase, the manufacturer's economic model was not sensitive to changes in the utility values, and so the effect of adjusting these values over time in the model was likely to be small. The ERG noted that in the probabilistic sensitivity analysis, the manufacturer sampled independently the relative risks for death and death or dependence associated with treatment with alteplase, which had a marked impact on the ICERs in the one-way sensitivity analyses. The ERG noted that this did not take into account the likely correlation between the outcomes of death and death or dependence, and that the probabilistic sensitivity analysis might not provide an accurate description of the uncertainty around the mean costs and QALYs, although the ERG did not expect it to have a large impact on the ICER.
The ERG conducted an exploratory sensitivity analysis by replacing the proportion of people in the 3 health states (dependent, independent and dead) at the end of the first phase (0 to 6 months) taken from the Lothian stroke registry with those observed in the ECASS III trial population. Because mortality rates were lower in the ECASS III trial, a higher proportion of patients were in the independent state (61.54%) and a lower proportion in the dead state (8.19%). This sensitivity analysis resulted in an ICER of £4451 per QALY gained for alteplase compared with standard care for the 0 to 4.5-hour window (incremental costs £698; incremental QALYs 0.157).
Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from # Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of alteplase, having considered evidence on the nature of acute ischaemic stroke and the value placed on the benefits of alteplase by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee discussed the place of alteplase in the clinical pathway for people who have had an acute ischaemic stroke. The Committee heard from the clinical specialists that alteplase is routinely used in the NHS in England and Wales in patients aged 18–80 years within 4.5 hours of onset of symptoms. The Committee was aware of the recently published third International Stroke Trial (IST-3), an open-label trial comparing alteplase with standard care. However, the Committee noted that the manufacturer had excluded this trial from its submission because it provided data that were not restricted to alteplase within its current UK marketing authorisation; specifically, the trial included patients aged above 80 years and patients who were treated up to 6 hours after the onset of symptoms.
The Committee heard from clinical specialists that alteplase is more effective the earlier it is given to patients. The clinical specialists commented that, while extending the treatment window to 4.5 hours would enable more patients to be treated with alteplase, this might result in some patients who present early receiving delayed treatment and therefore not benefiting from alteplase to the extent that they might otherwise have. The clinical specialists and patient experts emphasised the importance of treating patients with acute ischaemic stroke as early as possible.
The Committee heard from the patient experts that an important benefit of alteplase was its potential to reduce long-term disability caused by stroke, which can affect the quality of life of the patient and their families, carers and friends, and can also increase the need to adjust the patient's lifestyle and living conditions. The Committee was aware that brain imaging must be carried out to confirm the absence of intracranial bleeding before treatment with alteplase can be started. However, the Committee heard from 1 patient expert that some people with acute ischaemic stroke may not have immediate access to brain-imaging facilities. The Committee recognised the importance of this issue, and noted the NICE Quality Standard for Stroke, which recommends that patients with acute stroke receive brain imaging within 1 hour of arrival at hospital. The Committee also heard from clinical specialists that Accident and Emergency departments of all acute-care hospitals in England and Wales should have access to 24-hour, 7 days a week brain-imaging facilities. The Committee recognised that patients outside the licensed indication for alteplase (under 18 years and over 80 years of age) in England and Wales may have the potential to benefit from treatment with the technology. However, consistent with NICE methods, the Committee was aware that it can only make recommendations based on the current marketing authorisation for alteplase.
The Committee considered the evidence submitted by the manufacturer on the clinical effectiveness of alteplase. The Committee noted that no clinical-effectiveness data for the 0 to 3-hour treatment window additional to those included in NICE technology appraisal guidance 122 were available, and that clinical-effectiveness data for the 3 to 4.5-hour treatment window were derived primarily from the ECASS III trial. The Committee heard from clinical specialists that, although the trial included only a small proportion of patients from the UK, the results of the trial were generalisable to patients receiving alteplase treatment in England and Wales. The Committee also heard from the clinical specialists that it was reasonable for the manufacturer to measure the effectiveness of alteplase from analyses that adjusted for baseline differences in potential confounding variables between the 2 treatment groups. In addition, the clinical specialists noted that the modified Rankin scale was widely used as a measure of disability in stroke patients in England and Wales. The Committee concluded that the ECASS III trial was of good methodological quality and provided robust evidence of the clinical efficacy of alteplase for the 3 to 4.5-hour treatment window.
The Committee considered the clinical effectiveness of alteplase for the 3 to 4.5-hour treatment window. The Committee noted that no statistically significant differences in mortality, or in the composite outcome of death or dependence, between patients randomised to alteplase or standard care were observed at 90-day follow-up. However, the Committee also noted that a statistically significantly higher proportion of patients in the alteplase treatment arm achieved a favourable outcome without significant disability (modified Rankin scale score of 0 or 1) at 90-day follow-up. The Committee therefore concluded that alteplase administered between 3 and 4.5 hours after onset of stroke symptoms was an effective treatment for acute ischaemic stroke because it decreased the probability of disability.
The Committee considered the manufacturer's meta-analyses, which generated alternative estimates of alteplase's effect on all-cause mortality and also on death or dependence (modified Rankin scale score of 3 to 6) at 90 days for each of the 3 treatment windows (0 to 3 hours, 3 to 4.5 hours, and 0 to 4.5 hours), and which were used for the clinical-effectiveness parameters in the manufacturer's economic model. The Committee noted that the trials included in the meta-analyses for the 0 to 4.5-hour treatment window were of good methodological quality and were sufficiently similar in terms of study design and results. The Committee noted that there were no statistically significant differences in all-cause mortality reported at 90 days between alteplase and placebo for any of the 3 treatment windows. Therefore, the Committee agreed that an effect of alteplase on improving survival has currently not been proven. The Committee noted that a statistically significant difference in favour of alteplase was reported for the composite outcome of death or dependence for the 0 to 3-hour and 0 to 4.5-hour treatment windows in the manufacturer's meta-analyses. The Committee therefore concluded that alteplase administered between 0 and 4.5 hours after onset of stroke symptoms was an effective treatment for acute ischaemic stroke because it decreased the probability of death or dependence.
The Committee considered the evidence on adverse reactions associated with alteplase. The Committee noted that a significantly higher proportion of patients in the alteplase arm had symptomatic intracranial haemorrhage within 10 days compared with the placebo arm for the 3 to 4.5-hour window in the ECASS III trial and for the 0 to 4.5-hour window in the manufacturer's meta-analyses. However, the Committee noted that while alteplase increased the risk of symptomatic intracranial haemorrhage, the absolute number of patients in the ECASS III trial who had a symptomatic intracranial haemorrhage was small. The Committee heard from the clinical specialists that symptomatic intracranial haemorrhage is the primary cause of death within 7 days for patients receiving alteplase treatment, and that clinicians have difficulty predicting which patients are at high risk. The Committee also noted that the proportion of other reported serious adverse reactions and fatal adverse reactions in the ECASS III trial up to 90 days was similar across the 2 treatment arms. The Committee concluded that, although the increased risk of symptomatic intracranial haemorrhage associated with alteplase is offset by significant improvements in favourable outcomes at 90 days, symptomatic intracranial haemorrhage is an adverse event that needs to be included in modelling of the cost effectiveness of alteplase.
The Committee considered the manufacturer's economic model, the assumptions on which the parameters were based, and the critique and exploratory analyses conducted by the ERG. The Committee noted that the model structure and many of the input parameters were identical to those used in the economic model for NICE technology appraisal guidance 122 (0 to 3-hour window) and agreed that this approach was appropriate. With regard to the clinical-effectiveness parameters used in the model, the Committee acknowledged that the survival benefit associated with alteplase compared with standard care, which resulted from a point estimate for the relative risk for alteplase treatment and death of less than 1, was appropriately reflected in the economic model. However, the Committee noted that the manufacturer had assumed that the relative treatment effect of alteplase was maintained beyond 90 days up to 6 months in the model with no longer-term survival benefit beyond this point. The Committee considered that this may have been a conservative approach if alteplase offers a survival advantage compared with placebo beyond 6 months, a proposition the Committee found plausible, although not currently proven statistically, given that alteplase was associated with a reduction in death or dependence at 90 days. The Committee was aware that the utility values were not adjusted over time in the model, which may have overestimated the QALYs accrued by people in the independent health state and therefore biased the results in favour of alteplase. However, the Committee considered that this was not a crucial limitation of the model because the ICERs were not sensitive to changes in the utility values in the manufacturer's sensitivity analyses, and therefore any downward adjustment over time would have had a small impact on the ICERs. The Committee was also aware that the manufacturer assumed that people who had a symptomatic intracranial haemorrhage in the economic model incurred the additional one-off cost of a CT scan but experienced no further disutility beyond that captured in the dependent or independent health states. The Committee heard from the clinical specialists that this assumption was reasonable. Overall, the Committee concluded that the economic model adhered to the NICE reference case for economic analysis and the modelling approach was reasonable.
The Committee considered the most plausible ICERs presented by the manufacturer and also by the ERG in its exploratory analyses. It agreed that alteplase either dominated standard care or had an ICER below £10,000 per QALY gained depending on the time-to-treatment window considered. The Committee noted that the results were robust for most of the deterministic sensitivity analyses conducted by the manufacturer. The Committee also noted that none of the additional exploratory analyses undertaken by the ERG resulted in ICERs that varied substantially from those presented in the manufacturer's submission. The Committee considered that patients with acute ischaemic stroke who are admitted to hospital later (beyond 3 hours after onset of symptoms) may have less severe stroke and so any absolute benefit of treatment with alteplase compared with standard care may be diminished, resulting in a higher ICER. However, the Committee noted that the ICER for the 3 to 4.5-hour treatment window was low and therefore concluded that treating acute ischaemic stroke with alteplase within 0 to 4.5 hours of onset of stroke symptoms was a cost-effective use of NHS resources. The Committee also agreed with the clinical specialists that extending the time window for treatment should not diminish the urgency with which people suspected of having an acute ischaemic stroke should be treated.
The Committee discussed whether any equality issues required consideration in this appraisal. The Committee was aware that extension of the licence to 4.5 hours after symptom onset may enable increased access to treatment with alteplase for patients in remote or rural locations.
# Summary of Appraisal Committee's key conclusions
TA264
Appraisal title: Alteplase for treating acute ischaemic stroke (review of technology appraisal guidance 122)
Section
Key conclusion
Alteplase is recommended within its marketing authorisation for treating acute ischaemic stroke in adults if:
treatment is started as early as possible within 4.5 hours of onset of stroke symptoms, and
intracranial haemorrhage has been excluded by appropriate imaging techniques.
The Committee concluded that alteplase administered between 3 and 4.5 hours after onset of stroke symptoms was an effective treatment for acute ischaemic stroke because it decreased the probability of disability.
The Committee concluded that alteplase administered between 0 and 4.5 hours after onset of stroke symptoms was an effective treatment for acute ischaemic stroke because it decreased the probability of death or dependence.
The Committee agreed that alteplase either dominated standard care or had an ICER below £10,000 per QALY gained depending on the time-to-treatment window considered. The Committee concluded that treating acute ischaemic stroke with alteplase within 0 to 4.5 hours of onset of stroke symptoms was a cost-effective use of NHS resources.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee heard from the clinical specialists that alteplase is routinely used for the treatment of acute ischaemic stroke in the NHS in England and Wales in patients aged 18–80 years within 4.5 hours of onset of symptoms.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee heard from the patient experts that an important benefit of alteplase was its potential to reduce long-term disability caused by stroke, which can affect the quality of life of the patient and their families, carers and friends, and can also increase the need to adjust the patient's lifestyle and living conditions.
What is the position of the treatment in the pathway of care for the condition?
A UK marketing authorisation for alteplase to treat acute ischaemic stroke within 3 hours of the onset of symptoms was granted in September 2002. On 14 March 2012 the manufacturer received approval from the Medicines and Healthcare products Regulatory Agency extending the use of alteplase to within 4.5 hours of the onset of symptoms. The current marketing authorisation states that treatment must be started as early as possible within 4.5 hours after onset of stroke symptoms and after exclusion of intracranial haemorrhage by appropriate imaging techniques.
Adverse reactions
The Committee noted that a significantly higher proportion of patients in the alteplase arm had symptomatic intracranial haemorrhage within 10 days compared with the placebo arm for the 3 to 4.5-hour window in the ECASS III trial and for the 0 to 4.5-hour window in the manufacturer's meta-analyses. However, the Committee noted that while alteplase increased the risk of symptomatic intracranial haemorrhage, the absolute number of patients in the ECASS III trial who had a symptomatic intracranial haemorrhage was small. The Committee concluded that, although the increased risk of symptomatic intracranial haemorrhage associated with alteplase is offset by significant improvements in favourable outcomes at 90 days, symptomatic intracranial haemorrhage is an adverse event that needs to be included in modelling of the cost effectiveness of alteplase.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee noted that no clinical-effectiveness data for the 0 to 3-hour treatment window additional to those included in NICE technology appraisal guidance 122 were available, and that clinical-effectiveness data for the 3 to 4.5-hour treatment window were derived primarily from the ECASS III trial. The Committee concluded that the ECASS III trial was of good methodological quality and provided robust evidence of the clinical efficacy of alteplase for the 3 to 4.5-hour treatment window.
The Committee noted that the trials included in the meta-analyses for the 0 to 4.5-hour treatment window were of good methodological quality and were sufficiently similar in terms of study design and results.
Relevance to general clinical practice in the NHS
The Committee recognised that patients outside the licensed indication for alteplase (under 18 years and over 80 years of age) in England and Wales may have the potential to benefit from treatment with the technology. However, consistent with NICE methods, the Committee was aware that it can only make recommendations based on the current marketing authorisation for alteplase.
Uncertainties generated by the evidence
The Committee noted that there were no statistically significant differences in all-cause mortality reported at 90 days between alteplase and placebo for any of the 3 treatment windows. Therefore, the Committee agreed that an effect of alteplase on improving survival has currently not been proven.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
Not applicable
Estimate of the size of the clinical effectiveness including strength of supporting evidence
From intention-to-treat analyses in the ECASS III trial, 52.4% of patients randomised to the alteplase treatment arm had a favourable outcome at 90 days (a modified Rankin score of 0 or 1 ) compared with 45.2% of patients randomised to placebo (OR 1.34, 95% CI 1.02 to 1.76, p=0.04).
The Committee concluded that alteplase administered between 3 and 4.5 hours after onset of stroke symptoms was an effective treatment for acute ischaemic stroke because it decreased the probability of disability.
The Committee noted that a statistically significant difference in favour of alteplase was reported for the composite outcome of death or dependence for the 0 to 3-hour and 0 to 4.5-hour treatment windows in the manufacturer's meta-analyses. The Committee therefore concluded that alteplase administered between 0 and 4.5 hours after onset of stroke symptoms was an effective treatment for acute ischaemic stroke because it decreased the probability of death or dependence.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee noted that the model structure and many of the input parameters were identical to those used in the economic model for NICE technology appraisal guidance 122 (0 to 3-hour window) and agreed that this approach was appropriate. The Committee concluded that the economic model adhered to the NICE reference case for economic analysis and the modelling approach was reasonable.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted that the manufacturer had assumed that the relative treatment effect of alteplase was maintained beyond 90 days up to 6 months in the model with no longer-term survival benefit beyond this point. The Committee considered that this may have been a conservative approach if alteplase offers a survival advantage compared with placebo beyond 6 months, a proposition the Committee found plausible, although not currently proven statistically, given that alteplase was associated with a reduction in death or dependence at 90 days.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee was aware that the utility values were not adjusted over time in the model, which may have overestimated the QALYs accrued by people in the independent health state and therefore biased the results in favour of alteplase. However, the Committee considered that this was not a crucial limitation of the model because the ICERs were not sensitive to changes in the utility values in the manufacturer's sensitivity analyses, and therefore any downward adjustment over time would have had a small impact on the ICERs. The Committee was also aware that the manufacturer assumed that people who had a symptomatic intracranial haemorrhage in the economic model incurred the additional one-off cost of a CT scan but experienced no further disutility beyond that captured in the dependent or independent health states. The Committee heard from the clinical specialists that this assumption was reasonable.
Are there specific groups of people for whom the technology is particularly cost effective?
Not applicable
What are the key drivers of cost effectiveness?
The ICERs were robust to changes in most input parameters, except for the relative risks of death and death or dependence for treatment with alteplase applied in the first phase of the model.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee agreed that alteplase either dominated standard care or had an ICER below £10,000 per QALY gained depending on the time-to-treatment window considered.
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable
End-of-life considerations
Not applicable
Equalities considerations and social value judgements
The Committee was aware that extension of the licence to 4.5 hours after symptom onset may enable increased access to treatment with alteplase for patients in remote or rural locations.
# Recommendations for further research
The clinical efficacy and safety of thrombolysis with alteplase for acute ischaemic stroke is being assessed outside of its current marketing authorisation, specifically in patients aged up to 80 years and up to 6 hours from onset of stroke symptoms (the third International Stroke Trial ).# Related NICE guidance
Published
Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of technology appraisal guidance 90). NICE technology appraisal guidance 210 (2010).
Prevention of cardiovascular disease. NICE public heath guidance 25 (2010).
Stroke: diagnosis and initial management of acute stroke and transient ischaemic attack (TIA). NICE clinical guideline 68 (2008).
Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. NICE clinical guideline 67 (2008).# Review of guidance
The guidance on this technology will be considered for review in September 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveSeptember 2012# Changes after publication
February 2014:
minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
It replaces NICE technology appraisal guidance 122 (published in June 2007).
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'This guidance replaces NICE technology appraisal guidance 122 (published in June 2007). For details see About this guidance.\n\nAlteplase is recommended within its marketing authorisation for treating acute ischaemic stroke in adults if:\n\ntreatment is started as early as possible within 4.5\xa0hours of onset of stroke symptoms, and\n\nintracranial haemorrhage has been excluded by appropriate imaging techniques.', 'The technology ': "Alteplase (Actilyse, Boehringer Ingelheim) is a tissue plasminogen activator manufactured by recombinant DNA technology. It activates the production of plasmin from its precursor plasminogen. Plasmin is an enzyme that degrades fibrin clots. The aim of treatment is to reduce the impact of ischaemia by restoring blood flow through the occluded (blocked) artery. A UK marketing authorisation for alteplase to treat acute ischaemic stroke within 3\xa0hours of the onset of symptoms was granted in September 2002. On 14 March 2012 the manufacturer received approval from the Medicines and Healthcare products Regulatory Agency extending the use of alteplase to within 4.5\xa0hours of the onset of symptoms. The current marketing authorisation states that treatment must be started as early as possible within 4.5 hours after onset of stroke symptoms and after exclusion of intracranial haemorrhage by appropriate imaging techniques.\n\nThe summary of product characteristics lists the following adverse reactions for alteplase: haemorrhage (intracranial and gastrointestinal), recurrent ischaemia or angina, hypotension, heart failure, pulmonary oedema and reperfusion arrhythmias. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe cost of alteplase is £135 per 10-mg pack, £180 per 20-mg pack and £300 per 50-mg pack (excluding VAT; 'British national formulary' [BNF] edition 63). The cost per course of treatment depends on the body weight of the patient, and can range from £300 to £600 based on a recommended dose of 0.9\xa0mg per kilogram of body weight. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of alteplase and a review of this submission by the Evidence Review Group (ERG; appendix B). The decision problem addressed by the manufacturer considered whether treatment with alteplase was clinically effective compared with standard medical care (standard medical and supportive management that does not include alteplase) for treating acute ischaemic stroke in adults within 4.5\xa0hours of symptom onset, and whether alteplase treatment was a cost-effective use of NHS resources.\n\nThe manufacturer carried out a systematic literature search, which was based on a previously published Cochrane review ('Thrombolysis for acute ischaemic stroke'), but restricted the search to randomised controlled trials of alteplase. For the 0 to 3-hour treatment window, the manufacturer identified no trials other than those included in the previous guidance on alteplase in acute ischaemic stroke (NICE technology appraisal guidance 122) from 2007. The trials in technology appraisal guidance 122 included NINDS (National Institute of Neurological Disorders and Stroke) I and II, ATLANTIS ('Thrombolysis for acute noninterventional therapy in ischaemic stroke') A and B, and ECASS (the 'European Cooperative Acute Stroke Study') II. All these trials were multicentre, double-blinded, placebo-controlled randomised controlled trials of alteplase administered at its licensed dose of 0.9\xa0mg/kg. Treatment with alteplase was administered within 3\xa0hours (NINDS I and II), 5\xa0hours (ATLANTIS B) or 6\xa0hours (ATLANTIS A, ECASS\xa0II) of onset of stroke symptoms. Patients were followed up for outcomes for 90\xa0days. The NINDS and ATLANTIS trials were conducted in North America and the ECASS trial in multiple sites in Europe (including the UK), Australia and New Zealand.\n\nThe clinical-effectiveness evidence in the manufacturer's submission focused on the extended 3 to 4.5-hour treatment window for which the only directly relevant trial identified by the manufacturer was ECASS\xa0III. Other trials with data indirectly relevant to this treatment window were ATLANTIS A and B and ECASS\xa0II, from which subgroup data specifically for the 3 to 4.5-hour window were used by the manufacturer in sensitivity analyses. The manufacturer noted that this involved stratifying data into subgroups that had not been specified before randomisation. The manufacturer also identified the third International Stroke Trial (IST-3), a randomised open-label blinded endpoint trial in which alteplase was administered within 6\xa0hours of symptom onset. However, the manufacturer commented that this trial was not placebo controlled and therefore did not meet its trial selection criteria, and that no published results were available at the time of submission.\n\nECASS\xa0III was a placebo-controlled multicentre trial carried out across 130\xa0sites in 19\xa0European countries. Of the 821 patients 22 were from the UK. Patients were eligible for inclusion if aged between 18 and 80\xa0years, diagnosed with acute ischaemic stroke and able to receive treatment within 3 to 4.5\xa0hours of the onset of stroke symptoms. Before randomisation, brain imaging was used to exclude intracranial haemorrhage. The trial randomly assigned eligible patients to receive 0.9\xa0mg/kg of intravenous alteplase (n=418) or placebo (n=403). Patients were followed up for 90\xa0days for outcomes. Baseline demographic and disease characteristics were similar between participants in the 2 treatment arms, but the initial severity of the stroke (as assessed by the National Institutes of Health stroke scale [NIHSS; a 15-item quantitative measure of stroke-related neurological impairment]) and the proportion of patients with a history of previous stroke were both significantly higher in the placebo arm.\n\nThe primary outcome in ECASS\xa0III was the presence or absence of disability at 90\xa0days as assessed by the modified Rankin scale, which measures the degree of disability or dependence in people who have had a stroke and ranges from 0 (symptom free) to 6 (dead). From intention-to-treat analyses, 52.4% of patients randomised to the alteplase treatment arm had a favourable outcome at 90\xa0days (a score of 0 or 1 [no significant disability]) compared with 45.2% of patients randomised to placebo (odds ratio [OR] 1.34, 95% confidence interval [CI] 1.02 to 1.76, p=0.04). After adjustment for confounding baseline variables (identified as being statistically significant at p<0.10) including treatment arm, NIHSS score, smoking, time from onset of stroke to treatment, and presence or absence of previous hypertension, alteplase remained statistically significantly associated with a favourable outcome (OR 1.42, 95% CI 1.02 to 1.98, p=0.04).\n\nECASS\xa0III also reported the composite outcome of death or dependence (defined as a score of 3–6 on the modified Rankin scale) at 90\xa0days. There were no statistically significant differences in the number of patients who were dead or dependent between the alteplase and placebo treatment arms (33.5% compared with 38.5%, relative risk [RR] 0.87, 95% CI 0.73 to 1.05).\n\nThe ECASS\xa0III trial also reported as a secondary endpoint a global outcome score at 90\xa0days, which combined a score of 0–1 on the modified Rankin scale, a score of 1 on the Glasgow outcome scale (a 5-point measure of brain injury, with 1 indicating independence and 5 death), a score of 95–100 on the Barthel index (a 10-item measure of a person's daily function, with higher scores reflecting higher function), and a score of 0–1 on the NIHSS. Randomisation to alteplase was associated with a statistically significantly higher probability of achieving a favourable global outcome score (OR\xa01.28, 95% CI 1.00 to 1.65, p=0.05).\n\nThe manufacturer presented a summary of adverse reactions based on intention-to-treat analyses in the ECASS\xa0III trial at 90\xa0days. Fatal adverse reactions were reported for 7.7% of patients in the alteplase arm and 8.4% of those in the placebo arm. A statistically significantly higher proportion of patients in the alteplase arm had an intracranial haemorrhage (27.0% compared with 17.6%, p=0.001) or a symptomatic intracranial haemorrhage (2.4% compared with 0.3%, p=0.008) compared with the placebo arm. Three patients (0.7%) randomised to the alteplase arm had a fatal intracranial haemorrhage. Investigator-defined drug-related adverse reactions were reported for 23.9% of patients in the alteplase treatment arm and 6.9% of patients in the placebo arm. Other serious adverse reactions were reported for 25.1% of patients in the alteplase arm and 24.6% of those in the placebo arm.\n\nThe manufacturer conducted meta-analyses to calculate the relative risks associated with alteplase for all-cause mortality within 90\xa0days, death or dependence within 90\xa0days, and symptomatic intracranial haemorrhage within 10\xa0days for each of the 3 treatment windows (0 to 3\xa0hours, 3 to 4.5\xa0hours, and 0 to 4.5\xa0hours). The manufacturer presented results from both fixed and random-effects models. For the 0 to 3-hour window, the manufacturer used data from ECASS\xa0II and NINDS and used the relative risks from ECASS\xa0III for the 3 to 4.5-hour window. For the 0 to 4.5-hour window, the manufacturer used data from ECASS\xa0II (0 to 3\xa0hours), ECASS\xa0III (3 to 4.5\xa0hours) and NINDS (0 to 3\xa0hours). Heterogeneity between the 3\xa0studies was low for the outcomes of all-cause mortality and death or dependence, but moderate for the outcome of symptomatic intracranial haemorrhage.\n\nThe manufacturer compared all-cause mortality at 90\xa0days for the 2\xa0treatment arms. No statistically significant difference was observed between alteplase and placebo for the 3 to 4.5-hour (RR 0.82, 95% CI 0.50 to 1.33, p=0.42), the 0 to 3-hour (RR 1.05, 95% CI 0.55 to 2.03, p=0.88) or the 0 to 4.5-hour (RR 0.89, 95% CI 0.67 to 1.18, p=0.41) treatment windows. For the outcome of death or dependence at 90\xa0days, the manufacturer reported no statistically significant difference between alteplase and placebo for the 3 to 4.5-hour window (RR 0.87, 95% CI 0.73 to 1.05, p=0.14). However, a statistically significant difference in favour of alteplase was reported for both the 0 to 3-hour window (RR 0.81, 95% CI 0.72 to 0.92, p=0.002) and the 0 to 4.5-hour window (RR 0.83, 95% CI 0.75 to 0.92, p<0.001). For the outcome of symptomatic intracranial haemorrhage occurring within 10\xa0days, patients randomised to receive alteplase within the 3 to 4.5-hour window had a statistically significant higher risk (RR 4.82, 95% CI 1.06 to 21.87, p=0.04), with similar results for the 0 to 4.5-hour treatment window (RR 4.18, 95% CI 1.39 to 12.53, p=0.01). For the 0 to 3-hour window, the manufacturer reported a higher risk of symptomatic intracranial haemorrhage among patients randomised to alteplase that was not statistically significant (RR 3.94, 95% CI 0.61 to 25.47, p=0.15).\n\nThe manufacturer conducted a systematic review of published cost-effectiveness analyses but did not identify any studies that evaluated the cost effectiveness of alteplase for the treatment of acute ischaemic stroke within 3 to 4.5\xa0hours of onset of symptoms. Instead, the manufacturer adapted a published cost-effectiveness analysis (Sandercock et al., 2002) relevant to the decision problem from the previous guidance on alteplase in acute ischaemic stroke (NICE technology appraisal guidance 122) and used this as part of its submission.\n\nThe manufacturer developed a Markov model simulating patients with acute ischaemic stroke who do or do not receive alteplase within 4.5\xa0hours of onset of symptoms. Patients were modelled through 3 possible health states: independent, dependent and dead. The independent state was defined by a modified Rankin scale score of 0–2 and the dependent state by a modified Rankin scale score of 3–5. The model had 3 time phases: from 0 to 6\xa0months when the model assumed the treatment effect of alteplase was complete at 90\xa0days and maintained at 6\xa0months; from 6 to 12\xa0months when the model assumed no further treatment effect; and beyond 12\xa0months when the model also assumed no further treatment effect from alteplase. However, beyond 12\xa0months the model assumed that people in the dependent or independent states could have a recurrent stroke. The model also assumed that people in the dependent state at 12\xa0months and beyond do not move to an independent state, and that people in the independent state at 12\xa0months and beyond do not move to a dependent state unless they survive a recurrent stroke. The model assumed a lifetime horizon with a cycle length of 6\xa0months for the first 12\xa0months, followed by cycles of 12\xa0months thereafter.\n\nThe manufacturer chose a population for the model based on SITS-MOST ('Safe implementation of thrombolysis in stroke-monitoring study'), a European observational study of patients receiving alteplase. The manufacturer considered that this study population represented the mean age (68\xa0years) and gender distribution (39.8% female) of patients who would receive alteplase in clinical practice in England and Wales.\n\nFor the first phase (0 to 6\xa0months) of the manufacturer's economic model, the size of the effect of treatment with alteplase was informed by the manufacturer's meta-analyses for the 3 treatment windows as described in section 3.8. For the standard treatment arm, the proportion of people in each health state (39.53% independent, 32.56% dependent and 27.91% dead) was informed by the Lothian stroke registry, a registry in Edinburgh, Scotland, of 1779\xa0inpatients with suspected or confirmed stroke from 1989 to 2000. The manufacturer also provided an alternative distribution of the proportion of people who received standard treatment in each health state from the placebo arm of the ECASS\xa0III trial at 90\xa0days. This alternative distribution (61.54% independent, 30.27% dependent and 8.19% dead) was used by the ERG in exploratory sensitivity analyses. The manufacturer then used the relative risks of death and death or dependence to calculate the distribution of people in the alteplase arm across the independent, dependent and dead states at the end of the first phase (6\xa0months). The manufacturer used the relative risk of death to estimate the proportion of people who would die and therefore enter the dead state during the first phase. The proportion of people in the dependent state at 6\xa0months was calculated as the difference between the estimated proportion of people who were dead or dependent, and the estimated proportion who were dead. The manufacturer assumed in the model that a symptomatic intracranial haemorrhage had a cost impact (because it required a further diagnostic computed tomography [CT] scan), with the health consequences being captured in the outcome of death or dependence from the clinical trials.\n\nFor the second phase of the model (6 to 12\xa0months), the manufacturer assumed that people could move from the independent or dependent state to any other health state with equal probabilities for both treatment arms. These transition probabilities were based on the Lothian stroke registry. For the third phase of the model (beyond 12\xa0months), the annual risk of a recurrent stroke (0.05), and the associated risk of mortality (0.25), were taken from the Lothian stroke registry. To estimate the mortality risk for people who did not have another stroke, the manufacturer took data from the Office for National Statistics life tables for England and Wales and adjusted them upward by a factor of 2.3 (taken from the Perth Community Stroke Study) to reflect the higher mortality rates among people who have had a stroke compared with the general UK population.\n\nThe manufacturer conducted a literature review to identify appropriate utility values for the independent and dependent states in the model. The manufacturer did not identify any relevant utility values additional to those used in NICE technology appraisal guidance 122 on alteplase in acute ischaemic stroke within the first 3\xa0hours after symptom onset. The manufacturer's submission for this appraisal identified 1 trial (Dorman et al., 1997) that collected EQ-5D utility values in a sample of 147 patients from the Lothian stroke registry. This trial provided utility values of 0.74 (95% CI 0.69 to 0.79) for the independent state and 0.38 (95% CI 0.29 to 0.47) for the dependent state. The model assumed that these utility values remained fixed over time unless a person had a recurrent stroke which resulted in dependence, and thus a move from the independent to the dependent state.\n\nThe model included drug acquisition and administration costs as well as the costs of acute and long-term stroke care. The cost of alteplase was based on the mean body weight (76\xa0kg) of patients in the 3 to 4.5-hour cohort from the SITS-MOST trial. Based on the recommended dose of 0.9\xa0mg/kg, the average dose was 68.4\xa0mg, resulting in a total estimated cost of £480 (£300 per 50-mg pack and £180 per 20-mg pack). Administration costs associated with alteplase of £1316 per patient were based on estimates of extra staff time in the trial by Sandercock et al. (2002). For people in either treatment arm who had a symptomatic intracranial haemorrhage, the model included a one-off cost of £100 for an additional CT scan. For all health states in the model, the manufacturer applied annual costs specific to the state (adjusted for inflation to 2012/13 prices) adapted from a study by Youman et al. (2003), which calculated the costs of acute events and long-term stroke care.\n\nThe manufacturer's base-case deterministic cost-effectiveness analysis for the 0 to 4.5-hour window estimated an incremental cost-effectiveness ratio (ICER) of £2441 per quality-adjusted life year (QALY) gained for alteplase compared with standard care (incremental costs £811; incremental QALYs 0.333). The probabilistic cost-effectiveness analysis resulted in an ICER of £2296 per QALY gained.\n\nThe manufacturer conducted a number of one-way sensitivity analyses on various parameters in the model, including the relative risks associated with alteplase of death or of death or dependence, the risk of recurrent stroke and mortality irrespective of previous treatment, the dose of alteplase treatment, the annual costs of care in the dependent and independent states, the cost of a fatal stroke, and the utility values. The results of these one-way sensitivity analyses indicated that the ICERs were robust to changes in most input parameters, except for the relative risks of death and death or dependence for treatment with alteplase applied in the first phase of the model. When the manufacturer used the upper limit of the 95% confidence interval for the relative risks of death (1.18) and death or dependence (0.92), alteplase treatment led to a very small loss in QALYs at a decreased cost compared with standard care, resulting in £44,342 saved per QALY lost. The manufacturer also conducted additional deterministic sensitivity analyses, which included different scenarios using additional clinical efficacy data from unplanned subgroup analyses of the ATLANTIS A and B and ECASS\xa0II trials for 3 to 4.5\xa0hours, and weighted the results based on the assumption that in UK clinical practice a higher proportion of patients are treated during the 0 to 3-hour window (76%) than during the 3 to 4.5-hour window (24%). Using these analyses, alteplase either dominated placebo (that is, was both less costly and more effective) or had an ICER below £2000 per QALY gained. Results of the probabilistic sensitivity analysis showed that alteplase had a high probability (above 90%) of being cost effective at a level of £20,000 to £30,000 per QALY gained.\n\nThe manufacturer's base-case deterministic cost-effectiveness analysis for the 3 to 4.5-hour window resulted in an ICER of £6272 per QALY gained for alteplase compared with standard care (incremental costs £2068; incremental QALYs 0.33). The probabilistic cost-effectiveness analysis resulted in an ICER of £6169 per QALY gained. The results of the one-way sensitivity analyses were similar to those for the 0 to 4.5-hour window, indicating that the ICERs were robust to changes in most input parameters, except for changes in the relative risks of death and death or dependence for treatment with alteplase. In an additional sensitivity analysis, the manufacturer pooled 3 to 4.5-hour efficacy data from the ECASS\xa0II and ATLANTIS trials with the ECASS\xa0III data. This sensitivity analysis resulted in an ICER of £5631 per QALY gained for alteplase compared with standard care.\n\nFor the 0 to 3-hour treatment window, the manufacturer presented cost-effectiveness results similar to those presented in the previous guidance on alteplase in acute ischaemic stroke (NICE technology appraisal guidance 122); that is, alteplase dominated standard care, resulting in lower costs and more QALYs for both the deterministic and the probabilistic analyses.\n\nThe ERG considered that the clinical-effectiveness evidence submitted by the manufacturer was of good quality. The ERG noted that the patients randomised to the alteplase arm of both the NINDS trial (which provided clinical evidence for the 0 to 3-hour window) and the ECASS\xa0III trial had strokes that were less severe on average, which in turn may have biased the results in favour of alteplase. However, the manufacturer also presented adjusted analyses for the primary outcome (disability at 90\xa0days) from the ECASS\xa0III trial. The ERG considered that the meta-analytical approach by the manufacturer was appropriate. The ERG agreed with the manufacturer that data derived from unplanned subgroup analyses from the ATLANTIS A and B and ECASS\xa0II trials, in which treatment with alteplase was administered up to 6\xa0hours from onset of symptoms, should not be included in the base-case meta-analyses. The ERG also noted that heterogeneity between the studies included in the base-case meta-analyses for the 0 to 4.5-hour window for the outcomes of death and death or dependence was low and not statistically significant.\n\nThe ERG commented that the manufacturer submitted an economic model that was in line with the decision problem defined in the scope and closely adhered to the NICE reference case requirements for economic analysis. The ERG commented that the manufacturer provided a reasonable strategy for searching the literature for existing cost-effectiveness studies, although it did not explicitly state its exclusion criteria. The ERG stated that it was appropriate for the manufacturer to conduct separate analyses for patients eligible for treatment within the 0 to 3-hour window and the 3 to 4.5-hour window. The ERG noted that the utility values for the dependent and independent states did not allow for any decreases in health-related quality of life over time, which may have overestimated the lifetime QALYs accrued in the independent state. The ERG stated that, although this may have biased the QALY gains in favour of alteplase, the manufacturer's economic model was not sensitive to changes in the utility values, and so the effect of adjusting these values over time in the model was likely to be small. The ERG noted that in the probabilistic sensitivity analysis, the manufacturer sampled independently the relative risks for death and death or dependence associated with treatment with alteplase, which had a marked impact on the ICERs in the one-way sensitivity analyses. The ERG noted that this did not take into account the likely correlation between the outcomes of death and death or dependence, and that the probabilistic sensitivity analysis might not provide an accurate description of the uncertainty around the mean costs and QALYs, although the ERG did not expect it to have a large impact on the ICER.\n\nThe ERG conducted an exploratory sensitivity analysis by replacing the proportion of people in the 3\xa0health states (dependent, independent and dead) at the end of the first phase (0 to 6 months) taken from the Lothian stroke registry with those observed in the ECASS\xa0III trial population. Because mortality rates were lower in the ECASS\xa0III trial, a higher proportion of patients were in the independent state (61.54%) and a lower proportion in the dead state (8.19%). This sensitivity analysis resulted in an ICER of £4451 per QALY gained for alteplase compared with standard care for the 0 to 4.5-hour window (incremental costs £698; incremental QALYs 0.157).\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report, which are available from http://guidance.nice.org.uk/TA264", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of alteplase, having considered evidence on the nature of acute ischaemic stroke and the value placed on the benefits of alteplase by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the place of alteplase in the clinical pathway for people who have had an acute ischaemic stroke. The Committee heard from the clinical specialists that alteplase is routinely used in the NHS in England and Wales in patients aged 18–80\xa0years within 4.5\xa0hours of onset of symptoms. The Committee was aware of the recently published third International Stroke Trial (IST-3), an open-label trial comparing alteplase with standard care. However, the Committee noted that the manufacturer had excluded this trial from its submission because it provided data that were not restricted to alteplase within its current UK marketing authorisation; specifically, the trial included patients aged above 80\xa0years and patients who were treated up to 6\xa0hours after the onset of symptoms.\n\nThe Committee heard from clinical specialists that alteplase is more effective the earlier it is given to patients. The clinical specialists commented that, while extending the treatment window to 4.5\xa0hours would enable more patients to be treated with alteplase, this might result in some patients who present early receiving delayed treatment and therefore not benefiting from alteplase to the extent that they might otherwise have. The clinical specialists and patient experts emphasised the importance of treating patients with acute ischaemic stroke as early as possible.\n\nThe Committee heard from the patient experts that an important benefit of alteplase was its potential to reduce long-term disability caused by stroke, which can affect the quality of life of the patient and their families, carers and friends, and can also increase the need to adjust the patient's lifestyle and living conditions. The Committee was aware that brain imaging must be carried out to confirm the absence of intracranial bleeding before treatment with alteplase can be started. However, the Committee heard from 1 patient expert that some people with acute ischaemic stroke may not have immediate access to brain-imaging facilities. The Committee recognised the importance of this issue, and noted the NICE Quality Standard for Stroke, which recommends that patients with acute stroke receive brain imaging within 1\xa0hour of arrival at hospital. The Committee also heard from clinical specialists that Accident and Emergency departments of all acute-care hospitals in England and Wales should have access to 24-hour, 7 days a week brain-imaging facilities. The Committee recognised that patients outside the licensed indication for alteplase (under 18\xa0years and over 80\xa0years of age) in England and Wales may have the potential to benefit from treatment with the technology. However, consistent with NICE methods, the Committee was aware that it can only make recommendations based on the current marketing authorisation for alteplase.\n\nThe Committee considered the evidence submitted by the manufacturer on the clinical effectiveness of alteplase. The Committee noted that no clinical-effectiveness data for the 0 to 3-hour treatment window additional to those included in NICE technology appraisal guidance 122 were available, and that clinical-effectiveness data for the 3 to 4.5-hour treatment window were derived primarily from the ECASS\xa0III trial. The Committee heard from clinical specialists that, although the trial included only a small proportion of patients from the UK, the results of the trial were generalisable to patients receiving alteplase treatment in England and Wales. The Committee also heard from the clinical specialists that it was reasonable for the manufacturer to measure the effectiveness of alteplase from analyses that adjusted for baseline differences in potential confounding variables between the 2\xa0treatment groups. In addition, the clinical specialists noted that the modified Rankin scale was widely used as a measure of disability in stroke patients in England and Wales. The Committee concluded that the ECASS III trial was of good methodological quality and provided robust evidence of the clinical efficacy of alteplase for the 3 to 4.5-hour treatment window.\n\nThe Committee considered the clinical effectiveness of alteplase for the 3 to 4.5-hour treatment window. The Committee noted that no statistically significant differences in mortality, or in the composite outcome of death or dependence, between patients randomised to alteplase or standard care were observed at 90-day follow-up. However, the Committee also noted that a statistically significantly higher proportion of patients in the alteplase treatment arm achieved a favourable outcome without significant disability (modified Rankin scale score of 0 or 1) at 90-day follow-up. The Committee therefore concluded that alteplase administered between 3 and 4.5\xa0hours after onset of stroke symptoms was an effective treatment for acute ischaemic stroke because it decreased the probability of disability.\n\nThe Committee considered the manufacturer's meta-analyses, which generated alternative estimates of alteplase's effect on all-cause mortality and also on death or dependence (modified Rankin scale score of 3 to 6) at 90\xa0days for each of the 3\xa0treatment windows (0 to 3\xa0hours, 3 to 4.5\xa0hours, and 0 to 4.5\xa0hours), and which were used for the clinical-effectiveness parameters in the manufacturer's economic model. The Committee noted that the trials included in the meta-analyses for the 0 to 4.5-hour treatment window were of good methodological quality and were sufficiently similar in terms of study design and results. The Committee noted that there were no statistically significant differences in all-cause mortality reported at 90 days between alteplase and placebo for any of the 3 treatment windows. Therefore, the Committee agreed that an effect of alteplase on improving survival has currently not been proven. The Committee noted that a statistically significant difference in favour of alteplase was reported for the composite outcome of death or dependence for the 0 to 3-hour and 0 to 4.5-hour treatment windows in the manufacturer's meta-analyses. The Committee therefore concluded that alteplase administered between 0 and 4.5\xa0hours after onset of stroke symptoms was an effective treatment for acute ischaemic stroke because it decreased the probability of death or dependence.\n\nThe Committee considered the evidence on adverse reactions associated with alteplase. The Committee noted that a significantly higher proportion of patients in the alteplase arm had symptomatic intracranial haemorrhage within 10\xa0days compared with the placebo arm for the 3 to 4.5-hour window in the ECASS\xa0III trial and for the 0 to 4.5-hour window in the manufacturer's meta-analyses. However, the Committee noted that while alteplase increased the risk of symptomatic intracranial haemorrhage, the absolute number of patients in the ECASS\xa0III trial who had a symptomatic intracranial haemorrhage was small. The Committee heard from the clinical specialists that symptomatic intracranial haemorrhage is the primary cause of death within 7\xa0days for patients receiving alteplase treatment, and that clinicians have difficulty predicting which patients are at high risk. The Committee also noted that the proportion of other reported serious adverse reactions and fatal adverse reactions in the ECASS\xa0III trial up to 90\xa0days was similar across the 2\xa0treatment arms. The Committee concluded that, although the increased risk of symptomatic intracranial haemorrhage associated with alteplase is offset by significant improvements in favourable outcomes at 90\xa0days, symptomatic intracranial haemorrhage is an adverse event that needs to be included in modelling of the cost effectiveness of alteplase.\n\nThe Committee considered the manufacturer's economic model, the assumptions on which the parameters were based, and the critique and exploratory analyses conducted by the ERG. The Committee noted that the model structure and many of the input parameters were identical to those used in the economic model for NICE technology appraisal guidance 122 (0 to 3-hour window) and agreed that this approach was appropriate. With regard to the clinical-effectiveness parameters used in the model, the Committee acknowledged that the survival benefit associated with alteplase compared with standard care, which resulted from a point estimate for the relative risk for alteplase treatment and death of less than 1, was appropriately reflected in the economic model. However, the Committee noted that the manufacturer had assumed that the relative treatment effect of alteplase was maintained beyond 90\xa0days up to 6\xa0months in the model with no longer-term survival benefit beyond this point. The Committee considered that this may have been a conservative approach if alteplase offers a survival advantage compared with placebo beyond 6\xa0months, a proposition the Committee found plausible, although not currently proven statistically, given that alteplase was associated with a reduction in death or dependence at 90\xa0days. The Committee was aware that the utility values were not adjusted over time in the model, which may have overestimated the QALYs accrued by people in the independent health state and therefore biased the results in favour of alteplase. However, the Committee considered that this was not a crucial limitation of the model because the ICERs were not sensitive to changes in the utility values in the manufacturer's sensitivity analyses, and therefore any downward adjustment over time would have had a small impact on the ICERs. The Committee was also aware that the manufacturer assumed that people who had a symptomatic intracranial haemorrhage in the economic model incurred the additional one-off cost of a CT scan but experienced no further disutility beyond that captured in the dependent or independent health states. The Committee heard from the clinical specialists that this assumption was reasonable. Overall, the Committee concluded that the economic model adhered to the NICE reference case for economic analysis and the modelling approach was reasonable.\n\nThe Committee considered the most plausible ICERs presented by the manufacturer and also by the ERG in its exploratory analyses. It agreed that alteplase either dominated standard care or had an ICER below £10,000 per QALY gained depending on the time-to-treatment window considered. The Committee noted that the results were robust for most of the deterministic sensitivity analyses conducted by the manufacturer. The Committee also noted that none of the additional exploratory analyses undertaken by the ERG resulted in ICERs that varied substantially from those presented in the manufacturer's submission. The Committee considered that patients with acute ischaemic stroke who are admitted to hospital later (beyond 3\xa0hours after onset of symptoms) may have less severe stroke and so any absolute benefit of treatment with alteplase compared with standard care may be diminished, resulting in a higher ICER. However, the Committee noted that the ICER for the 3 to 4.5-hour treatment window was low and therefore concluded that treating acute ischaemic stroke with alteplase within 0 to 4.5\xa0hours of onset of stroke symptoms was a cost-effective use of NHS resources. The Committee also agreed with the clinical specialists that extending the time window for treatment should not diminish the urgency with which people suspected of having an acute ischaemic stroke should be treated.\n\nThe Committee discussed whether any equality issues required consideration in this appraisal. The Committee was aware that extension of the licence to 4.5\xa0hours after symptom onset may enable increased access to treatment with alteplase for patients in remote or rural locations.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA264\n\nAppraisal title: Alteplase for treating acute ischaemic stroke (review of technology appraisal guidance 122)\n\n\n\nSection\n\nKey conclusion\n\nAlteplase is recommended within its marketing authorisation for treating acute ischaemic stroke in adults if:\n\ntreatment is started as early as possible within 4.5\xa0hours of onset of stroke symptoms, and\n\nintracranial haemorrhage has been excluded by appropriate imaging techniques.\n\n\n\n\n\nThe Committee concluded that alteplase administered between 3 and 4.5\xa0hours after onset of stroke symptoms was an effective treatment for acute ischaemic stroke because it decreased the probability of disability.\n\n\n\n\n\nThe Committee concluded that alteplase administered between 0 and 4.5\xa0hours after onset of stroke symptoms was an effective treatment for acute ischaemic stroke because it decreased the probability of death or dependence.\n\n\n\nThe Committee agreed that alteplase either dominated standard care or had an ICER below £10,000 per QALY gained depending on the time-to-treatment window considered. The Committee concluded that treating acute ischaemic stroke with alteplase within 0 to 4.5\xa0hours of onset of stroke symptoms was a cost-effective use of NHS resources.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard from the clinical specialists that alteplase is routinely used for the treatment of acute ischaemic stroke in the NHS in England and Wales in patients aged 18–80\xa0years within 4.5\xa0hours of onset of symptoms.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\n\n\nThe Committee heard from the patient experts that an important benefit of alteplase was its potential to reduce long-term disability caused by stroke, which can affect the quality of life of the patient and their families, carers and friends, and can also increase the need to adjust the patient's lifestyle and living conditions.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nA UK marketing authorisation for alteplase to treat acute ischaemic stroke within 3\xa0hours of the onset of symptoms was granted in September 2002. On 14 March 2012 the manufacturer received approval from the Medicines and Healthcare products Regulatory Agency extending the use of alteplase to within 4.5\xa0hours of the onset of symptoms. The current marketing authorisation states that treatment must be started as early as possible within 4.5 hours after onset of stroke symptoms and after exclusion of intracranial haemorrhage by appropriate imaging techniques.\n\n\n\nAdverse reactions\n\nThe Committee noted that a significantly higher proportion of patients in the alteplase arm had symptomatic intracranial haemorrhage within 10\xa0days compared with the placebo arm for the 3 to 4.5-hour window in the ECASS\xa0III trial and for the 0 to 4.5-hour window in the manufacturer's meta-analyses. However, the Committee noted that while alteplase increased the risk of symptomatic intracranial haemorrhage, the absolute number of patients in the ECASS\xa0III trial who had a symptomatic intracranial haemorrhage was small. The Committee concluded that, although the increased risk of symptomatic intracranial haemorrhage associated with alteplase is offset by significant improvements in favourable outcomes at 90\xa0days, symptomatic intracranial haemorrhage is an adverse event that needs to be included in modelling of the cost effectiveness of alteplase.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee noted that no clinical-effectiveness data for the 0 to 3-hour treatment window additional to those included in NICE technology appraisal guidance 122 were available, and that clinical-effectiveness data for the 3 to 4.5-hour treatment window were derived primarily from the ECASS\xa0III trial. The Committee concluded that the ECASS III trial was of good methodological quality and provided robust evidence of the clinical efficacy of alteplase for the 3 to 4.5-hour treatment window.\n\nThe Committee noted that the trials included in the meta-analyses for the 0 to 4.5-hour treatment window were of good methodological quality and were sufficiently similar in terms of study design and results.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee recognised that patients outside the licensed indication for alteplase (under 18\xa0years and over 80\xa0years of age) in England and Wales may have the potential to benefit from treatment with the technology. However, consistent with NICE methods, the Committee was aware that it can only make recommendations based on the current marketing authorisation for alteplase.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee noted that there were no statistically significant differences in all-cause mortality reported at 90 days between alteplase and placebo for any of the 3 treatment windows. Therefore, the Committee agreed that an effect of alteplase on improving survival has currently not been proven.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNot applicable\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nFrom intention-to-treat analyses in the ECASS\xa0III trial, 52.4% of patients randomised to the alteplase treatment arm had a favourable outcome at 90\xa0days (a modified Rankin score of 0 or 1 [no significant disability]) compared with 45.2% of patients randomised to placebo (OR 1.34, 95% CI 1.02 to 1.76, p=0.04).\n\nThe Committee concluded that alteplase administered between 3 and 4.5\xa0hours after onset of stroke symptoms was an effective treatment for acute ischaemic stroke because it decreased the probability of disability.\n\nThe Committee noted that a statistically significant difference in favour of alteplase was reported for the composite outcome of death or dependence for the 0 to 3-hour and 0 to 4.5-hour treatment windows in the manufacturer's meta-analyses. The Committee therefore concluded that alteplase administered between 0 and 4.5\xa0hours after onset of stroke symptoms was an effective treatment for acute ischaemic stroke because it decreased the probability of death or dependence.\n\n\n\n\n\n, 4.6, 4.7\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee noted that the model structure and many of the input parameters were identical to those used in the economic model for NICE technology appraisal guidance 122 (0 to 3-hour window) and agreed that this approach was appropriate. The Committee concluded that the economic model adhered to the NICE reference case for economic analysis and the modelling approach was reasonable.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that the manufacturer had assumed that the relative treatment effect of alteplase was maintained beyond 90\xa0days up to 6\xa0months in the model with no longer-term survival benefit beyond this point. The Committee considered that this may have been a conservative approach if alteplase offers a survival advantage compared with placebo beyond 6\xa0months, a proposition the Committee found plausible, although not currently proven statistically, given that alteplase was associated with a reduction in death or dependence at 90\xa0days.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee was aware that the utility values were not adjusted over time in the model, which may have overestimated the QALYs accrued by people in the independent health state and therefore biased the results in favour of alteplase. However, the Committee considered that this was not a crucial limitation of the model because the ICERs were not sensitive to changes in the utility values in the manufacturer's sensitivity analyses, and therefore any downward adjustment over time would have had a small impact on the ICERs. The Committee was also aware that the manufacturer assumed that people who had a symptomatic intracranial haemorrhage in the economic model incurred the additional one-off cost of a CT scan but experienced no further disutility beyond that captured in the dependent or independent health states. The Committee heard from the clinical specialists that this assumption was reasonable.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe ICERs were robust to changes in most input parameters, except for the relative risks of death and death or dependence for treatment with alteplase applied in the first phase of the model.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee agreed that alteplase either dominated standard care or had an ICER below £10,000 per QALY gained depending on the time-to-treatment window considered.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable\n\n–\n\nEnd-of-life considerations\n\nNot applicable\n\n–\n\nEqualities considerations and social value judgements\n\nThe Committee was aware that extension of the licence to 4.5\xa0hours after symptom onset may enable increased access to treatment with alteplase for patients in remote or rural locations.\n\n", 'Recommendations for further research ': 'The clinical efficacy and safety of thrombolysis with alteplase for acute ischaemic stroke is being assessed outside of its current marketing authorisation, specifically in patients aged up to 80\xa0years and up to 6\xa0hours from onset of stroke symptoms (the third International Stroke Trial [IST-3]).', 'Related NICE guidance': 'Published\n\nClopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of technology appraisal guidance 90). NICE technology appraisal guidance 210 (2010).\n\nPrevention of cardiovascular disease. NICE public heath guidance 25 (2010).\n\nStroke: diagnosis and initial management of acute stroke and transient ischaemic attack (TIA). NICE clinical guideline 68 (2008).\n\nLipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. NICE clinical guideline 67 (2008).', 'Review of guidance': 'The guidance on this technology will be considered for review in September 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveSeptember 2012', 'Changes after publication': 'February 2014:\n minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nIt replaces NICE technology appraisal guidance 122 (published in June 2007).\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta264
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Evidence-based recommendations on alteplase (Actilyse) for treating acute ischaemic stroke in adults.
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e5d079b6907f03d1e4aa6fad408b6c01442e1b1b
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nice
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Neutropenic sepsis: prevention and management in people with cancer
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Neutropenic sepsis: prevention and management in people with cancer
This guideline covers preventing, identifying and managing neutropenic sepsis in children, young people and adults receiving treatment for cancer in the community and in secondary and tertiary care. It aims to reduce the risk of infection in people with neutropenia (low number of white blood cells) who are receiving anticancer treatment and improve management of neutropenic sepsis.
# Introduction
Neutropenic sepsis is a potentially fatal complication of anticancer treatment (particularly chemotherapy). Mortality rates ranging between 2% and 21% have been reported in adults. Aggressive use of inpatient intravenous antibiotic therapy has reduced morbidity and mortality rates and intensive care management is now needed in fewer than 5% of cases in England.
Systemic therapies to treat cancer can suppress the ability of bone marrow to respond to infection. This is particularly the case with systemic chemotherapy, although radiotherapy can also cause such suppression.
Chemotherapy is most commonly given in a day-case or outpatient setting so most episodes of obvious sepsis, and fever in a person with potential sepsis, present in the community. People receiving chemotherapy and their carers need to be told about the risk of neutropenic sepsis and the warning signs and symptoms. Neutropenic sepsis is a medical emergency that requires immediate hospital investigation and treatment.
A report by the National Confidential Enquiry into Patient Outcome and Death (Systemic anti-cancer therapy: for better for worse? ) and a follow-up report by the National Chemotherapy Advisory Group (Chemotherapy services in England: ensuring quality and safety ) highlighted problems in the management of neutropenic sepsis in adults receiving chemotherapy. These problems included inadequate management of neutropenic fever leading to avoidable deaths, and a need for systems for urgent assessment and organisation-level policies for dealing with neutropenic fever. The reports also noted variation in the provision of information on the treatment of side effects and on access to 24-hour telephone advice.
In addition, there is national variation in the use of:
primary and secondary prophylaxis
risk stratification in episodes of febrile neutropenia
-ral or intravenous antibiotics
growth factors
inpatient or outpatient management policies.
This guideline aims to improve outcomes by providing evidence-based recommendations on the prevention, identification and management of this life-threatening complication of cancer treatment.
The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.
This guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or their parent or carer) should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing medicines – guidance for doctors and the prescribing advice provided by the Joint Standing Committee on Medicines (a joint committee of the Royal College of Paediatrics and Child Health and the Neonatal and Paediatric Pharmacists Group) for further information. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations.# Recommendations
The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.
The recommendations in this guideline were developed after discussion of the relevance of the evidence to children, young people and adults with cancer. The recommendations are intended for use in patients of any age. Where age-limited or disease-specific recommendations are made they are clearly indicated as such.
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Information, support and training
## Information and support for patients and carers
Provide patients having anticancer treatment and their carers with written and oral information, both before starting and throughout their anticancer treatment, on:
neutropenic sepsis
how and when to contact 24-hour specialist oncology advice
how and when to seek emergency care.
## Training for healthcare professionals
Healthcare professionals and staff who come into contact with patients having anticancer treatment should be provided with training on neutropenic sepsis. The training should be tailored according to the type of contact.
# Reducing the risk of septic complications of anticancer treatment
For adult patients (aged 18 years and older) with acute leukaemias, stem cell transplants or solid tumours in whom significant neutropenia (neutrophil count 0.5×109 per litre or lower) is an anticipated consequence of chemotherapy, offer prophylaxis with a fluoroquinolone during the expected period of neutropenia only. Follow the MHRA safety advice on fluoroquinolone antibiotics.
Rates of antibiotic resistance and infection patterns should be monitored in treatment facilities where patients are having fluoroquinolones for the prophylaxis of neutropenic sepsis.
Do not routinely offer G-CSF for the prevention of neutropenic sepsis in adults receiving chemotherapy unless they are receiving G-CSF as an integral part of the chemotherapy regimen or in order to maintain dose intensity.
# When to refer patients in the community for suspected neutropenic sepsis
Suspect neutropenic sepsis in patients having anticancer treatment who become unwell.
Refer patients with suspected neutropenic sepsis immediately for assessment in secondary or tertiary care.
# Managing suspected neutropenic sepsis in secondary and tertiary care
## Emergency treatment and assessment
Treat suspected neutropenic sepsis as an acute medical emergency and offer empiric antibiotic therapy immediately.
Include in the initial clinical assessment of patients with suspected neutropenic sepsis:
history and examination
full blood count, kidney and liver function tests (including albumin), C-reactive protein, lactate and blood culture.
## Further assessment
After completing the initial clinical assessment (see recommendation 1.4.1.2) try to identify the underlying cause of the sepsis by carrying out:
additional peripheral blood culture in patients with a central venous access device if clinically feasible
urinalysis in all children aged under 5 years.
Do not perform a chest X-ray unless clinically indicated.
## Starting antibiotic therapy
Offer beta lactam monotherapy with piperacillin with tazobactam as initial empiric antibiotic therapy to patients with suspected neutropenic sepsis who need intravenous treatment unless there are patient-specific or local microbiological contraindications.
Do not offer an aminoglycoside, either as monotherapy or in dual therapy, for the initial empiric treatment of suspected neutropenic sepsis unless there are patient-specific or local microbiological indications.
Do not offer empiric glycopeptide antibiotics to patients with suspected neutropenic sepsis who have central venous access devices unless there are patient-specific or local microbiological indications.
Do not remove central venous access devices as part of the initial empiric management of suspected neutropenic sepsis.
## Confirming a diagnosis of neutropenic sepsis
Diagnose neutropenic sepsis in patients having anticancer treatment whose neutrophil count is 0.5×109 per litre or lower and who have either:
a temperature higher than 38oC or
-ther signs or symptoms consistent with clinically significant sepsis.
# Managing confirmed neutropenic sepsis
## Assessing the patient's risk of septic complications
A healthcare professional with competence in managing complications of anticancer treatment should assess the patient's risk of septic complications within 24 hours of presentation to secondary or tertiary care, basing the risk assessment on presentation features and using a validated risk scoring system.
## Patients at low risk of septic complications
Consider outpatient antibiotic therapy for patients with confirmed neutropenic sepsis and a low risk of developing septic complications, taking into account the patient's social and clinical circumstances and discussing with them the need to return to hospital promptly if a problem develops.
## Patients at high risk of septic complications
For patients with confirmed neutropenic sepsis and a high risk of developing septic complications, a healthcare professional with competence in managing complications of anticancer treatment should daily:
review the patient's clinical status
reassess the patient's risk of septic complications, using a validated risk scoring system.
Do not switch initial empiric antibiotics in patients with unresponsive fever unless there is clinical deterioration or a microbiological indication.
Switch from intravenous to oral antibiotic therapy after 48 hours of treatment in patients whose risk of developing septic complications has been reassessed as low by a healthcare professional with competence in managing complications of anticancer treatment using a validated risk scoring system.
Offer discharge to patients having empiric antibiotic therapy for neutropenic sepsis only after:
the patient's risk of developing septic complications has been reassessed as low by a healthcare professional with competence in managing complications of anticancer treatment using a validated risk scoring systemand
taking into account the patient's social and clinical circumstances and discussing with them the need to return to hospital promptly if a problem develops.
## Duration of empiric antibiotic treatment
Continue inpatient empiric antibiotic therapy in all patients who have unresponsive fever unless an alternative cause of fever is likely.
Discontinue empiric antibiotic therapy in patients whose neutropenic sepsis has responded to treatment, irrespective of neutrophil count.
At the time of review (November 2019), fluoroquinolone antibiotics did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Prescribing guidance: prescribing unlicensed medicines for further information.
For more information see the Department of Health's Updated guidance on the diagnosis and reporting of Clostridium difficile and guidance from the Health Protection Agency and the Department of Health on Clostridium difficile infection: how to deal with the problem.
At the time of publication (September 2012) piperacillin with tazobactam did not have a UK marketing authorisation for use in children aged under 2 years. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The child's parent or carer should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing medicines – guidance for doctors and the prescribing advice provided by the Joint Standing Committee on Medicines (a joint committee of the Royal College of Paediatrics and Child Health and the Neonatal and Paediatric Pharmacists Group) for further information.
Examples of risk scoring systems include the Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients (Journal of Clinical Oncology 2000; 18: 3038–51) and the modified Alexander rule for children (aged under 18) (European Journal of Cancer 2009; 45: 2843–9).
# Terms used in this guideline
Anticancer treatment Treatment that is given with the intent to reduce the level of cancer cells in a patient. It includes, but is not limited to, chemotherapy and radiotherapy.
Empiric An action undertaken prior to determination of the underlying cause of a problem.
Empiric antibiotic An antibiotic given to a person before a specific microorganism or source of the potential infection is known. It is usually a broad-spectrum antibiotic and the treatment may change if the microorganism or source is confirmed.
G-CSF (granulocyte-colony stimulating factor) A type of protein that stimulates the bone marrow to make white blood cells (granulocytes).# Research recommendations
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.
# Service provision for neutropenic sepsis in patients with cancer
A prospective national cohort study should be carried out to assess the incidence of suspected and proven neutropenic sepsis in patients having anticancer treatment.
Why this is important
The incidence of suspected neutropenic sepsis in England and Wales is difficult to determine. A national cohort study of patients referred for suspected neutropenic sepsis, including diagnoses and clinical outcomes, should be undertaken to improve service planning and delivery. Such a study may also generate hypotheses concerning more and less efficient methods of delivering services for neutropenic sepsis, which could then be formally tested.
# Patient support and information
A descriptive study involving patients who have had neutropenic sepsis and their carers should be undertaken to find out what types of support and information patients and carers were given, which of these they found helpful or unhelpful, and whether they think additional or different types of support or information are needed.
Why this is important
There is a lack of research on the experience of patients who have had neutropenic sepsis and their carers. Better knowledge of the support and information patients and carers are given, how helpful they find it and how they think it could be improved will allow the development of different approaches to providing information and support and test these in practice. This research could improve the experience of patients, and potentially their clinical outcomes. It may also highlight important inequities and suggest ways of addressing them.
# Signs and symptoms that predict neutropenic sepsis in the community
A prospective study should be carried out to determine which signs and symptoms experienced by patients in the community predict neutropenic sepsis and the outcomes of these episodes.
Why this is important
The initial decision to refer to secondary or tertiary care for investigation for suspected neutropenic sepsis is an important step that has both risks and benefits. An overly inclusive approach will inconvenience many patients and carers, expose patients to unnecessary invasive testing and increase resource use by the health service. Referral criteria that are too narrow will delay the emergency treatment of infection and may lead to death, increased need for intensive or critical care facilities, and reduced overall quality of life for patients with cancer and their carers. The current research base in this area is weak and largely extrapolated from selected populations in hospitals. A clearer, quantitative understanding of how the features of neutropenic sepsis appear in patients may lead to more accurate referral criteria for suspected neutropenic sepsis.
# Reducing the risk of complications of anticancer treatment in children and young people, and in adults diagnosed with lymphoma
Randomised studies should investigate primary prophylaxis of neutropenic sepsis in 2 populations: children and young people (aged under 18) having treatment for solid tumours or haematological malignancies, or stem cell transplantation; and adults (aged 18 and older) diagnosed with lymphoma. The studies should compare the effectiveness of fluoroquinolone antibiotics given alone, fluoroquinolone antibiotics given together with G-CSF preparations, and G-CSF preparations given alone. Outcome measures should include overall mortality, infectious episodes and adverse events. In addition, quality of life should be determined using quantitative and qualitative methods. The resulting data should be used to develop a cost-effectiveness analysis comparing these 3 forms of prophylaxis in children and young people having anticancer treatment, and in adults diagnosed with lymphoma.
Why this is important
Data from studies of adults with leukaemia, stem cell transplantation and many solid tumours suggest that prophylaxis with fluoroquinolone antibiotics reduces the risk of neutropenic sepsis. However, the benefit of fluoroquinolone antibiotics in adults diagnosed with lymphoma is unclear. Children and young people having anticancer treatment are a distinct population and differ from adults in a number of ways, including the types of cancer they have, the anticancer treatment they are given, their reactions to fluoroquinolones and subcutaneous injections, and the ease with which they can adhere to daily medication. The effects of these differences are not known, but it is known that death rates from neutropenic sepsis are higher in children and young people than in adults. Studies of primary prophylaxis of neutropenic sepsis in children and young adults, and in adults with lymphoma, could be of great value in helping to reduce the risk of neutropenic sepsis in these 2 patient populations.
# Switching from inpatient intravenous to outpatient oral antibiotic therapy in patients with neutropenic sepsis
A randomised controlled trial should be undertaken to evaluate the clinical and cost effectiveness of stopping intravenous antibiotic therapy and switching to oral therapy within the first 24 hours of treatment in patients with neutropenic sepsis who are having treatment with intravenous antibiotics. The outcomes to be measured are overtreatment, death, need for critical care, length of hospital stay, duration of fever and quality of life.
Why this is important
Moderately strong evidence was found to support the use of outpatient therapies for patients with neutropenic sepsis who are at low risk of severe infection. These studies switched from inpatient to outpatient treatment at a variety of time points. A meta-regression undertaken by the Guideline Development Group suggested that very early (before 24 hours) discharge is associated with a greater risk of readmission and need to change treatments, but the evidence was sparse. If a short period of hospital admission was found to be safe and effective for selected patients with neutropenic sepsis, it could provide considerable improvements in their quality of life and reduce the resource burden on hospitals.# Finding more information and resources
You can see everything NICE says on this topic in the NICE Pathways on neutropenic sepsis and sepsis.
To find out what NICE has said on topics related to this guideline, see our web page on blood conditions.
For full details of the evidence and the guideline committee's discussions, see the full version of the guideline. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.
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{'Introduction': "Neutropenic sepsis is a potentially fatal complication of anticancer treatment (particularly chemotherapy). Mortality rates ranging between 2% and 21% have been reported in adults. Aggressive use of inpatient intravenous antibiotic therapy has reduced morbidity and mortality rates and intensive care management is now needed in fewer than 5% of cases in England.\n\nSystemic therapies to treat cancer can suppress the ability of bone marrow to respond to infection. This is particularly the case with systemic chemotherapy, although radiotherapy can also cause such suppression.\n\nChemotherapy is most commonly given in a day-case or outpatient setting so most episodes of obvious sepsis, and fever in a person with potential sepsis, present in the community. People receiving chemotherapy and their carers need to be told about the risk of neutropenic sepsis and the warning signs and symptoms. Neutropenic sepsis is a medical emergency that requires immediate hospital investigation and treatment.\n\nA report by the National Confidential Enquiry into Patient Outcome and Death (Systemic anti-cancer therapy: for better for worse? ) and a follow-up report by the National Chemotherapy Advisory Group (Chemotherapy services in England: ensuring quality and safety ) highlighted problems in the management of neutropenic sepsis in adults receiving chemotherapy. These problems included inadequate management of neutropenic fever leading to avoidable deaths, and a need for systems for urgent assessment and organisation-level policies for dealing with neutropenic fever. The reports also noted variation in the provision of information on the treatment of side effects and on access to 24-hour telephone advice.\n\nIn addition, there is national variation in the use of:\n\nprimary and secondary prophylaxis\n\nrisk stratification in episodes of febrile neutropenia\n\noral or intravenous antibiotics\n\ngrowth factors\n\ninpatient or outpatient management policies.\n\nThis guideline aims to improve outcomes by providing evidence-based recommendations on the prevention, identification and management of this life-threatening complication of cancer treatment.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.\n\nThis guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or their parent or carer) should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing medicines – guidance for doctors and the prescribing advice provided by the Joint Standing Committee on Medicines (a joint committee of the Royal College of Paediatrics and Child Health and the Neonatal and Paediatric Pharmacists Group) for further information. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations.", 'Recommendations': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nThe recommendations in this guideline were developed after discussion of the relevance of the evidence to children, young people and adults with cancer. The recommendations are intended for use in patients of any age. Where age-limited or disease-specific recommendations are made they are clearly indicated as such.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Information, support and training\n\n## Information and support for patients and carers\n\nProvide patients having anticancer treatment and their carers with written and oral information, both before starting and throughout their anticancer treatment, on:\n\nneutropenic sepsis\n\nhow and when to contact 24-hour specialist oncology advice\n\nhow and when to seek emergency care.\n\n## Training for healthcare professionals\n\nHealthcare professionals and staff who come into contact with patients having anticancer treatment should be provided with training on neutropenic sepsis. The training should be tailored according to the type of contact.\n\n# Reducing the risk of septic complications of anticancer treatment\n\nFor adult patients (aged 18\xa0years and older) with acute leukaemias, stem cell transplants or solid tumours in whom significant neutropenia (neutrophil count 0.5×109 per litre or lower) is an anticipated consequence of chemotherapy, offer prophylaxis with a fluoroquinolone during the expected period of neutropenia only. Follow the MHRA safety advice on fluoroquinolone antibiotics.\n\nRates of antibiotic resistance and infection patterns should be monitored in treatment facilities where patients are having fluoroquinolones for the prophylaxis of neutropenic sepsis.\n\nDo not routinely offer G-CSF for the prevention of neutropenic sepsis in adults receiving chemotherapy unless they are receiving G-CSF as an integral part of the chemotherapy regimen or in order to maintain dose intensity.\n\n# When to refer patients in the community for suspected neutropenic sepsis\n\nSuspect neutropenic sepsis in patients having anticancer treatment who become unwell.\n\nRefer patients with suspected neutropenic sepsis immediately for assessment in secondary or tertiary care.\n\n# Managing suspected neutropenic sepsis in secondary and tertiary care\n\n## Emergency treatment and assessment\n\nTreat suspected neutropenic sepsis as an acute medical emergency and offer empiric antibiotic therapy immediately.\n\nInclude in the initial clinical assessment of patients with suspected neutropenic sepsis:\n\nhistory and examination\n\nfull blood count, kidney and liver function tests (including albumin), C-reactive protein, lactate and blood culture.\n\n## Further assessment\n\nAfter completing the initial clinical assessment (see recommendation 1.4.1.2) try to identify the underlying cause of the sepsis by carrying out:\n\nadditional peripheral blood culture in patients with a central venous access device if clinically feasible\n\nurinalysis in all children aged under 5\xa0years.\n\nDo not perform a chest X-ray unless clinically indicated.\n\n## Starting antibiotic therapy\n\nOffer beta lactam monotherapy with piperacillin with tazobactam as initial empiric antibiotic therapy to patients with suspected neutropenic sepsis who need intravenous treatment unless there are patient-specific or local microbiological contraindications.\n\nDo not offer an aminoglycoside, either as monotherapy or in dual therapy, for the initial empiric treatment of suspected neutropenic sepsis unless there are patient-specific or local microbiological indications.\n\nDo not offer empiric glycopeptide antibiotics to patients with suspected neutropenic sepsis who have central venous access devices unless there are patient-specific or local microbiological indications.\n\nDo not remove central venous access devices as part of the initial empiric management of suspected neutropenic sepsis.\n\n## Confirming a diagnosis of neutropenic sepsis\n\nDiagnose neutropenic sepsis in patients having anticancer treatment whose neutrophil count is 0.5×109 per litre or lower and who have either:\n\na temperature higher than 38oC or\n\nother signs or symptoms consistent with clinically significant sepsis.\n\n# Managing confirmed neutropenic sepsis\n\n## Assessing the patient's risk of septic complications\n\nA healthcare professional with competence in managing complications of anticancer treatment should assess the patient's risk of septic complications within 24\xa0hours of presentation to secondary or tertiary care, basing the risk assessment on presentation features and using a validated risk scoring system.\n\n## Patients at low risk of septic complications\n\nConsider outpatient antibiotic therapy for patients with confirmed neutropenic sepsis and a low risk of developing septic complications, taking into account the patient's social and clinical circumstances and discussing with them the need to return to hospital promptly if a problem develops.\n\n## Patients at high risk of septic complications\n\nFor patients with confirmed neutropenic sepsis and a high risk of developing septic complications, a healthcare professional with competence in managing complications of anticancer treatment should daily:\n\nreview the patient's clinical status\n\nreassess the patient's risk of septic complications, using a validated risk scoring system.\n\nDo not switch initial empiric antibiotics in patients with unresponsive fever unless there is clinical deterioration or a microbiological indication.\n\nSwitch from intravenous to oral antibiotic therapy after 48\xa0hours of treatment in patients whose risk of developing septic complications has been reassessed as low by a healthcare professional with competence in managing complications of anticancer treatment using a validated risk scoring system.\n\nOffer discharge to patients having empiric antibiotic therapy for neutropenic sepsis only after:\n\nthe patient's risk of developing septic complications has been reassessed as low by a healthcare professional with competence in managing complications of anticancer treatment using a validated risk scoring systemand\n\ntaking into account the patient's social and clinical circumstances and discussing with them the need to return to hospital promptly if a problem develops.\n\n## Duration of empiric antibiotic treatment\n\nContinue inpatient empiric antibiotic therapy in all patients who have unresponsive fever unless an alternative cause of fever is likely.\n\nDiscontinue empiric antibiotic therapy in patients whose neutropenic sepsis has responded to treatment, irrespective of neutrophil count.\n\n At the time of review (November 2019), fluoroquinolone antibiotics did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Prescribing guidance: prescribing unlicensed medicines for further information.\n\n For more information see the Department of Health's Updated guidance on the diagnosis and reporting of Clostridium difficile and guidance from the Health Protection Agency and the Department of Health on Clostridium difficile infection: how to deal with the problem.\n\n At the time of publication (September 2012) piperacillin with tazobactam did not have a UK marketing authorisation for use in children aged under 2\xa0years. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The child's parent or carer should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing medicines – guidance for doctors and the prescribing advice provided by the Joint Standing Committee on Medicines (a joint committee of the Royal College of Paediatrics and Child Health and the Neonatal and Paediatric Pharmacists Group) for further information.\n\n\n\n Examples of risk scoring systems include the Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients (Journal of Clinical Oncology 2000; 18: 3038–51) and the modified Alexander rule for children (aged under 18) (European Journal of Cancer 2009; 45: 2843–9).\n\n\n\n", 'Terms used in this guideline': 'Anticancer treatment Treatment that is given with the intent to reduce the level of cancer cells in a patient. It includes, but is not limited to, chemotherapy and radiotherapy.\n\nEmpiric An action undertaken prior to determination of the underlying cause of a problem.\n\nEmpiric antibiotic An antibiotic given to a person before a specific microorganism or source of the potential infection is known. It is usually a broad-spectrum antibiotic and the treatment may change if the microorganism or source is confirmed.\n\nG-CSF (granulocyte-colony stimulating factor) A type of protein that stimulates the bone marrow to make white blood cells (granulocytes).', 'Research recommendations': 'The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Service provision for neutropenic sepsis in patients with cancer\n\nA prospective national cohort study should be carried out to assess the incidence of suspected and proven neutropenic sepsis in patients having anticancer treatment.\n\nWhy this is important\n\nThe incidence of suspected neutropenic sepsis in England and Wales is difficult to determine. A national cohort study of patients referred for suspected neutropenic sepsis, including diagnoses and clinical outcomes, should be undertaken to improve service planning and delivery. Such a study may also generate hypotheses concerning more and less efficient methods of delivering services for neutropenic sepsis, which could then be formally tested.\n\n# Patient support and information\n\nA descriptive study involving patients who have had neutropenic sepsis and their carers should be undertaken to find out what types of support and information patients and carers were given, which of these they found helpful or unhelpful, and whether they think additional or different types of support or information are needed.\n\nWhy this is important\n\nThere is a lack of research on the experience of patients who have had neutropenic sepsis and their carers. Better knowledge of the support and information patients and carers are given, how helpful they find it and how they think it could be improved will allow the development of different approaches to providing information and support and test these in practice. This research could improve the experience of patients, and potentially their clinical outcomes. It may also highlight important inequities and suggest ways of addressing them.\n\n# Signs and symptoms that predict neutropenic sepsis in the community\n\nA prospective study should be carried out to determine which signs and symptoms experienced by patients in the community predict neutropenic sepsis and the outcomes of these episodes.\n\nWhy this is important\n\nThe initial decision to refer to secondary or tertiary care for investigation for suspected neutropenic sepsis is an important step that has both risks and benefits. An overly inclusive approach will inconvenience many patients and carers, expose patients to unnecessary invasive testing and increase resource use by the health service. Referral criteria that are too narrow will delay the emergency treatment of infection and may lead to death, increased need for intensive or critical care facilities, and reduced overall quality of life for patients with cancer and their carers. The current research base in this area is weak and largely extrapolated from selected populations in hospitals. A clearer, quantitative understanding of how the features of neutropenic sepsis appear in patients may lead to more accurate referral criteria for suspected neutropenic sepsis.\n\n# Reducing the risk of complications of anticancer treatment in children and young people, and in adults diagnosed with lymphoma\n\nRandomised studies should investigate primary prophylaxis of neutropenic sepsis in 2\xa0populations: children and young people (aged under 18) having treatment for solid tumours or haematological malignancies, or stem cell transplantation; and adults (aged 18 and older) diagnosed with lymphoma. The studies should compare the effectiveness of fluoroquinolone antibiotics given alone, fluoroquinolone antibiotics given together with G-CSF preparations, and G-CSF preparations given alone. Outcome measures should include overall mortality, infectious episodes and adverse events. In addition, quality of life should be determined using quantitative and qualitative methods. The resulting data should be used to develop a cost-effectiveness analysis comparing these 3\xa0forms of prophylaxis in children and young people having anticancer treatment, and in adults diagnosed with lymphoma.\n\nWhy this is important\n\nData from studies of adults with leukaemia, stem cell transplantation and many solid tumours suggest that prophylaxis with fluoroquinolone antibiotics reduces the risk of neutropenic sepsis. However, the benefit of fluoroquinolone antibiotics in adults diagnosed with lymphoma is unclear. Children and young people having anticancer treatment are a distinct population and differ from adults in a number of ways, including the types of cancer they have, the anticancer treatment they are given, their reactions to fluoroquinolones and subcutaneous injections, and the ease with which they can adhere to daily medication. The effects of these differences are not known, but it is known that death rates from neutropenic sepsis are higher in children and young people than in adults. Studies of primary prophylaxis of neutropenic sepsis in children and young adults, and in adults with lymphoma, could be of great value in helping to reduce the risk of neutropenic sepsis in these 2\xa0patient populations.\n\n# Switching from inpatient intravenous to outpatient oral antibiotic therapy in patients with neutropenic sepsis\n\nA randomised controlled trial should be undertaken to evaluate the clinical and cost effectiveness of stopping intravenous antibiotic therapy and switching to oral therapy within the first 24\xa0hours of treatment in patients with neutropenic sepsis who are having treatment with intravenous antibiotics. The outcomes to be measured are overtreatment, death, need for critical care, length of hospital stay, duration of fever and quality of life.\n\nWhy this is important\n\nModerately strong evidence was found to support the use of outpatient therapies for patients with neutropenic sepsis who are at low risk of severe infection. These studies switched from inpatient to outpatient treatment at a variety of time points. A meta-regression undertaken by the Guideline Development Group suggested that very early (before 24\xa0hours) discharge is associated with a greater risk of readmission and need to change treatments, but the evidence was sparse. If a short period of hospital admission was found to be safe and effective for selected patients with neutropenic sepsis, it could provide considerable improvements in their quality of life and reduce the resource burden on hospitals.', 'Finding more information and resources': "You can see everything NICE says on this topic in the NICE Pathways on neutropenic sepsis and sepsis.\n\nTo find out what NICE has said on topics related to this guideline, see our web page on blood conditions.\n\nFor full details of the evidence and the guideline committee's discussions, see the full version of the guideline. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice."}
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https://www.nice.org.uk/guidance/cg151
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This guideline covers preventing, identifying and managing neutropenic sepsis in children, young people and adults receiving treatment for cancer in the community and in secondary and tertiary care. It aims to reduce the risk of infection in people with neutropenia (low number of white blood cells) who are receiving anticancer treatment and improve management of neutropenic sepsis.
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5a21148561f0d13bd482492b479dbf70a821cb33
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nice
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SonoVue (sulphur hexafluoride microbubbles) – contrast agent for contrast-enhanced ultrasound imaging of the liver
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SonoVue (sulphur hexafluoride microbubbles) – contrast agent for contrast-enhanced ultrasound imaging of the liver
Evidence-based recommendations on SonoVue (sulphur hexafluoride microbubbles) for contrast-enhanced ultrasound imaging of the liver.
# Recommendations
Contrast-enhanced ultrasound with SonoVue is recommended for characterising incidentally detected focal liver lesions in adults in whom an unenhanced ultrasound scan is inconclusive. An unenhanced ultrasound scan in which a focal liver lesion is detected, but not characterised, is defined as inconclusive.
Contrast-enhanced ultrasound with SonoVue is recommended for investigating potential liver metastases in adults:
if contrast-enhanced computed tomography (CT) is not clinically appropriate, is not accessible or is not acceptable to the person, and
in whom an unenhanced ultrasound scan is unsatisfactory and contrast is needed for further diagnosis.
Contrast-enhanced ultrasound with SonoVue is recommended for characterising focal liver lesions in adults whose cirrhosis is being monitored:
if contrast-enhanced magnetic resonance imaging (MRI) is not clinically appropriate, is not accessible or is not acceptable to the person, and
when unenhanced ultrasound scan is inconclusive.# The technology
SonoVue (Bracco UK), a pharmaceutical agent for diagnostic use only, is a contrast agent involving sulphur hexafluoride microbubbles. It is indicated for contrast-enhanced ultrasound imaging in adults when unenhanced imaging has been inconclusive. SonoVue has a European marketing authorisation for use in echocardiography, doppler imaging of macrovasculature (for example, cerebral arteries) and of microvasculature (for example, breast and liver lesions). Following input during the scoping phase of the evaluation, this evaluation focuses on the use of SonoVue for liver imaging. Additional details of the clinical condition and the technology are provided in sections 3 and 4 respectively.# Clinical need and practice
# Current practice and the problem addressed
Ultrasound scanning, along with other imaging technologies such as CT and MRI, is important in diagnosing and planning treatment for many people with liver disease. Liver imaging sometimes identifies focal abnormalities that cannot be characterised initially and another test may be needed to further explore the abnormality. The main aim of subsequent liver imaging is to distinguish between cancer and benign abnormalities that are not likely to need further treatment. Liver lesions are commonly found at an initial unenhanced ultrasound scan. If the abnormality is not characterised by an unenhanced ultrasound scan, the person is usually referred for either MRI and/or CT. The definition of the term 'inconclusive' in this evaluation is an unenhanced ultrasound scan in which a focal liver lesion is detected but not characterised. The aim of this evaluation was to compare the clinical and cost effectiveness of contrast-enhanced ultrasound using the contrast agent SonoVue with contrast-enhanced CT and contrast-enhanced MRI for investigating and characterising focal liver lesions in adults, in whom previous liver imaging has been inconclusive. Three specific clinical indications were assessed:
characterising focal liver lesions identified through monitoring of people with cirrhosis
investigating potential liver metastases in people with colorectal cancer
characterising incidentally detected focal liver lesions unrelated to the clinical indication for which the imaging was requested.
## The condition
In the context of this evaluation, the term focal liver lesion refers to any focal area of perceived difference seen on imaging that occurs in 1 specific area of the liver. Focal liver lesions can be broadly classified as benign (for example, haemangioma, focal nodular hyperplasia, focal fatty infiltration or sparing, and adenoma) or malignant (for example, primary hepatocellular carcinoma, cholangiocarcinoma and liver metastases). Identifying or excluding malignancy is the primary aim of diagnostic imaging.
The distinction between benign and malignant lesions helps to determine the prognosis and subsequent treatment strategy. Benign asymptomatic liver lesions, which comprise as many as 70–75% of the focal liver lesions assessed in the UK, usually do not need treatment. Depending on the type of lesion, the person may be discharged or their condition may be monitored and the lesion rescanned in 6–12 months. If a malignant lesion is identified it is important to distinguish between primary and secondary cancers because this is likely to affect how the condition is managed. Malignant lesions may be treated with a range of interventions, including chemotherapy, surgery and local ablative therapy.
There are 2 main types of liver cancer. A cancer that starts in the liver is known as a primary liver cancer and a cancer that spreads to the liver from another part of the body is known as metastatic cancer. Approximately 3200 people in the UK are diagnosed with primary liver cancer each year, whereas approximately 90,000 people are diagnosed with liver metastases.
Most people with a diagnosis of primary liver cancer (approximately 85%) have a hepatocellular carcinoma. A major risk factor for developing hepatocellular carcinoma is underlying cirrhosis (scarring of liver tissue). Cirrhosis commonly results from alcoholism, hepatitis B and C, and fatty liver disease. Primary liver cancer is the second most rapidly increasing cancer in men and the third in women (increases of 38% and 28% respectively in the past decade).
Primary liver cancer in adults has a poor prognosis because it tends to be diagnosed in the advanced stages. Only a minority of cases of primary liver cancer are diagnosed in the early stages when surgery may help. The prognosis of primary liver cancer depends on the extent of disease and underlying liver function. About 20% of people with primary liver cancer live for at least 1 year after diagnosis. Around 5% live for at least 5 years.
The primary cancers most commonly leading to metastases in the liver originate in the breast, lung and bowel (colorectal). The origin of the primary cancer is important because the cells of the liver metastases are the same as those of the primary cancer, and liver metastases are likely to be treated according to the cell type of the primary cancer. The prognosis of liver metastases depends on the extent of the disease and comorbidities. For example, 40–60% of people with stage 4 colorectal cancer with resectable liver metastases will live for 5 years after surgery.
## The diagnostic and care pathways
Contrast-enhanced ultrasound could be included in the diagnostic pathway as a replacement for contrast-enhanced CT/contrast-enhanced MRI (figure 1), or as a triage step to reduce the use of contrast-enhanced CT/contrast-enhanced MRI. The available data only allowed contrast-enhanced ultrasound with SonoVue as a replacement for contrast-enhanced CT/contrast-enhanced MRI to be included in the economic analysis.
Figure 1 Diagnostic pathway for liver imaging with contrast-enhanced ultrasound as a replacement for contrast-enhanced CT/contrast-enhanced MRI
Abbreviations: CEUS, contrast-enhanced ultrasound; US, ultrasound.
In general, care pathways for people with liver cancer are guided by prognosis. Prognosis depends on both the extent of the tumour and on comorbidity. Improvements in survival as a result of treatment largely depend on the disease stage at diagnosis: the earlier the diagnosis is made, the greater the chance for successful treatment. Detailed care pathways for the 3 indications considered in this assessment can be found in section 3.4 of the diagnostics assessment report.
The European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) produced guidelines and good clinical practice recommendations for contrast-enhanced ultrasound in 2004. The latest version was published in 2008 and is currently being updated.
The 2008 EFSUMB guidelines recommend the use of contrast-enhanced ultrasound for the characterisation of focal liver lesions in a range of indications. The guidelines also provide information on the typical enhancement patterns associated with various types of benign and malignant liver lesions.
The treatment of primary hepatocellular carcinoma has been addressed in published technology appraisals guidance, and NICE has issued interventional procedure guidance on a number of individual interventions for primary hepatocellular carcinoma and liver metastases (see the NICE website for details). NICE clinical guideline on colorectal cancer recommends the use of CT in staging of colorectal cancer, which includes the identification of liver metastases. Expert opinion suggests that there may be significant regional variation within the NHS in the characterisation of focal liver lesions.# The diagnostic tests
# SonoVue
SonoVue is a second-generation contrast agent that uses sulphur hexafluoride microbubbles for contrast-enhanced ultrasound imaging in adults. SonoVue is a low solubility gas contrast agent that allows imaging at low mechanical index, which leads to effective suppression of the tissue signal. It is used to enhance the echogenicity of the blood and can thus improve the signal to noise ratio in ultrasound. SonoVue has a UK marketing authorisation for diagnostic use only. The summary of product characteristics states that SonoVue improves display of the blood vessels in liver lesions during doppler sonography, allowing more specific characterisation of lesions. The summary of product characteristics also states that SonoVue should only be used in people in whom unenhanced ultrasound is inconclusive.
SonoVue consists of a kit containing a vial of sulphur hexafluoride gas and phospholipid powder, a prefilled syringe of solvent (sodium chloride solution) and a transfer and ventilation system (mini spike). The saline is introduced into the vial by the mini spike delivery system and once reconstituted, microbubbles are formed. These microbubbles are the contrast agent which is injected into a peripheral vein at the antecubital fossa. When the ultrasound probe is placed on the abdomen, ultrasound waves cause the microbubbles to resonate so that a signal is picked up by a transducer and an image is formed on a screen.
SonoVue remains within the blood vessels and, depending on the type of lesion, it shows a pattern of uptake similar to that of contrast agents used for imaging blood vessels in CT or MRI. The contrast agent is broken down by the body after a few minutes. The sulphur hexafluoride gas is exhaled through the lungs and the phospholipid component of the microbubble shell is metabolised (re-entering the endogenous phospholipid metabolic pathway).
# Comparator
People with inconclusive unenhanced ultrasound are currently referred for contrast-enhanced CT and/or contrast-enhanced MRI. These are the comparators for this assessment. Contrast-enhanced MRI generally uses gadolinium-based vascular contrast agents. These can differentiate between benign and malignant focal liver lesions by vascular enhancement patterns in a similar way to contrast agents used for contrast-enhanced CT and contrast-enhanced ultrasound. However, contrast-enhanced MRI of the liver can also use hepatocyte-specific contrast agents. These include superparamagnetic iron oxide (SPIO) and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA).
Expert opinion indicated that biopsy would not be performed as the next test when unenhanced ultrasound was inconclusive. Therefore, biopsy was not considered a relevant comparator in this assessment.
The comparators used in the model were:
contrast-enhanced CT
contrast-enhanced MRI using gadolinium as the contrast agent
contrast-enhanced MRI using SPIO as the contrast agent.# Outcomes
The Diagnostics Advisory Committee (section 10) considered evidence from a number of sources.
# How outcomes were assessed
A systematic review of the effectiveness of contrast-enhanced ultrasound using SonoVue compared with contrast-enhanced CT and contrast-enhanced MRI was undertaken by the External Assessment Group. The outcome measures included:
the effect of testing on the treatment plan (for example, surgical or medical management, or palliative care)
the effect of pre-treatment testing on clinical outcome (for example, overall survival, progression-free survival)
prognosis – the ability of the test result to predict clinical outcome (for example, overall survival, progression-free survival, response to treatment)
test accuracy and number of people or lesions for which no conclusive diagnostic information could be obtained with contrast-enhanced ultrasound using SonoVue.
Radiation exposure was not considered a relevant outcome because the population is mostly older adults in whom additional incident cancers as a result of imaging are likely to be minimal.
A systematic review of the evidence on cost effectiveness for SonoVue was undertaken by the External Assessment Group. The External Assessment Group constructed multiple de novo models. The outcomes of interest for the modelling were costs and the morbidity and mortality associated with the investigation and characterisation of focal liver lesions and their treatment. These included survival and health-related quality of life, including the impact of adverse events associated with treatment (such as chemotherapy).
Diagnostic technologies themselves do not usually have direct evidence for health-related quality of life, and the de novo models therefore followed a linked evidence approach in which intermediate outcomes (results of the test/s) were linked to the care pathway to estimate clinical outcomes and hence quality-adjusted life year (QALY) gains. Costs and QALYs were assigned to SonoVue and the comparators.
# Clinical effectiveness
A total of 17 studies in 18 publications were included in the assessment. All of the included studies were test accuracy studies:
concerned the use of contrast-enhanced ultrasound with SonoVue for characterising focal liver lesions identified during routine monitoring of people with cirrhosis
assessed the performance of contrast-enhanced ultrasound with SonoVue for investigating potential liver metastases in people with known primary cancers (mostly colorectal cancer)
concerned the use of contrast-enhanced ultrasound with SonoVue for characterising incidentally detected focal liver lesions.
Only 1 of the studies of test accuracy included in this assessment reported information on adverse events related to testing. In this study there were no adverse events associated with contrast-enhanced ultrasound with SonoVue. There was no information about the comparator (contrast-enhanced MRI with gadolinium). A large, retrospective safety study of contrast-enhanced ultrasound with SonoVue in abdominal imaging did not meet the inclusion criteria for this assessment but reported data from 23,188 investigations in 29 centres in Italy. This study found 29 incidents of adverse events, of which 2 were graded as serious, 1 as severe, 3 as moderate and 23 as mild. There were no fatal adverse events. Most non-serious adverse events resolved without intervention.
All included studies were published in 2006 or later. Most were conducted in Europe (most in Italy or Spain). Two studies reported funding from the manufacturer of SonoVue.
## Results by clinical indication
Test accuracy data in relation to each clinical indication assessed are summarised below.
Studies conducted in people with cirrhosis during routine monitoring all concerned the differentiation of hepatocellular carcinoma from other lesion types in small to medium (<30 mm) focal liver lesions. The definition of a positive test for hepatocellular carcinoma varied across studies. Studies assessing contrast-enhanced MRI used 3 contrast agents: gadolinium (a vascular contrast agent), SPIO (a hepatocyte-specific contrast agent) and Gd-EOB-DTPA (a 'combined' vascular and hepatocyte-specific contrast agent). There was no consistent evidence for any significant difference in test performance between the 3 imaging modalities (contrast-enhanced ultrasound, contrast-enhanced CT and contrast-enhanced MRI) and the 3 MRI contrast media assessed. When the definition of hepatocellular carcinoma given in the EFSUMB guidelines (arterial phase enhancement followed by portal-venous washout) was used, estimates of the sensitivity and specificity of each of the imaging modalities varied across studies. There was some evidence, from 1 study comparing contrast-enhanced ultrasound and contrast-enhanced MRI using gadolinium, that these imaging techniques may be better at ruling out hepatocellular carcinoma in focal liver lesions between 11 and 30 mm (sensitivities were 92% and 95% respectively) than in small focal liver lesions 10 mm or less (sensitivities 27% and 73% respectively). However, this study did not use the EFSUMB definition of hepatocellular carcinoma. It is therefore possible that some of the variation in sensitivity estimates in studies of focal liver lesions smaller than 30 mm may be a result of differences in the size distribution of focal liver lesions included. The evidence suggested that contrast-enhanced ultrasound alone may be adequate to rule out hepatocellular carcinoma for focal liver lesions between 11 and 30 mm.
Studies of the diagnosis of liver metastases using imaging with vascular contrast media (contrast-enhanced ultrasound, contrast-enhanced CT and contrast-enhanced MRI with gadolinium), in which definitions of a positive imaging test were reported, gave various descriptions of peripheral rim enhancement as the criteria for liver metastases. Two studies also reported data for contrast-enhanced MRI with SPIO. There was no evidence of any consistent difference in test performance between the 3 imaging modalities and the different contrast media assessed. Per patient sensitivity estimates, from 2 studies, were generally high: 83% for all imaging modalities and both MRI contrast agents in 1 study of people with colorectal cancer and more than 95% for both contrast-enhanced ultrasound and contrast-enhanced CT in a second study of people with various primary cancers (mostly colorectal cancer). The only previous systematic review of contrast-enhanced ultrasound with SonoVue for the diagnosis of liver metastases did not include any comparator tests and reported sensitivities ranging from 79% to 100%. The limited data available indicate that contrast-enhanced ultrasound alone may be adequate to rule out liver metastases in people with known primary malignancies.
The primary outcome measure reported by studies conducted in people with incidentally detected focal liver lesions was test accuracy for the differentiation of malignant from benign liver lesions. Studies consistently used definitions of the imaging criteria for hepatocellular carcinoma and liver metastases which were similar to those reported in the EFSUMB guidelines on the use of contrast-enhanced ultrasound. All studies reported no significant difference in the accuracy of contrast-enhanced ultrasound, contrast-enhanced CT and contrast-enhanced MRI for characterising focal liver lesions. The pooled estimates of sensitivity for the detection of 'any liver malignancy' were approximately 95% for both contrast-enhanced ultrasound and contrast-enhanced CT. The pooled estimates of specificity were 94% and 93% respectively, based on data from 4 studies. The single study comparing contrast-enhanced ultrasound with contrast-enhanced MRI used gadolinium for MRI in all people, with the addition of SPIO in an unspecified number. This study reported sensitivity estimates of 91% and 82% respectively, and corresponding specificity estimates of 67% and 63%. Data from 1 study indicated that combined imaging using both contrast-enhanced ultrasound and contrast-enhanced CT did not increase sensitivity when a positive result on either modality was treated as 'test positive'. This, combined with the high estimates of sensitivity, indicates that contrast-enhanced ultrasound alone may be adequate to rule out liver malignancy in people with incidentally detected focal liver lesions.
# Economic analysis
Four studies were identified that met the inclusion criteria for an economic analysis of the use of SonoVue in contrast-enhanced ultrasound.
Although all the studies were of reasonably good quality, they did not fully address the cost effectiveness of SonoVue as defined in this assessment. Limitations included restricted information about disease management and progression, choice of equipment and administrative procedures in different settings, inclusion of costing elements in the calculation, and health outcomes. Zaim et al. (2011) was the only study that modelled disease management and reported health outcomes relevant to this assessment, but the follow-up was only 24 months.
The External Assessment Group performed a de novo analysis to address specifically the decision problem for this evaluation and to estimate the cost effectiveness of SonoVue in England.
The External Assessment Group conducted an analysis of contrast-enhanced ultrasound using SonoVue for assessing focal liver lesions in adults, in whom unenhanced ultrasound or other liver imaging has been inconclusive. Three separate models were used for 3 clinical applications for which the most data on test performance were available and experts suggested there was most likely to be clinical benefit:
cirrhosis surveillance (for characterising focal liver lesions identified through monitoring of people with cirrhosis)
investigating potential liver metastases in colorectal cancer
characterising incidentally detected focal liver lesions.
In each model, contrast-enhanced ultrasound with SonoVue was compared with contrast-enhanced CT, contrast-enhanced MRI using gadolinium and/or contrast-enhanced MRI using SPIO. Average costs, expected life years and expected QALYs per person were calculated for the above technologies.
## Costs
Costs of contrast-enhanced and unenhanced ultrasound were informed by expert clinical opinion and cost information provided the manufacturer of SonoVue. The costs of using the contrast agent, including cannulation, were assumed to be £48.70 (estimate supplied by the manufacturer and agreed by clinicians). In addition, contrast-enhanced ultrasound was expected to take longer than unenhanced ultrasound. Therefore, the External Assessment Group used the difference between the reference costs of an ultrasound taking less than 20 minutes (£55) and an ultrasound taking more than 20 minutes (£71) as the additional time costs of contrast-enhanced ultrasound. The total additional cost was therefore estimated to be £65. This assumed that contrast-enhanced ultrasound is performed in the same appointment as the unenhanced scan. Costs of the other diagnostic tests were based on 2011 NHS reference costs.
## Cost effectiveness
A model description, test accuracy data and results of the base-case and additional analyses are provided below for each of the 3 models.
Model description
The model was a modified version of a model produced by the Peninsula Technology Assessment Group (the PenTAG cirrhosis surveillance model). The population consisted of people with a diagnosis of compensated cirrhosis entering a surveillance programme (aged 70 years or younger with no pre-existing medical conditions that would preclude treatment with liver transplant or hepatic resection ). The time horizon was a lifetime and the cycle duration was 1 month. Patients in the model can develop hepatocellular carcinoma. In the base-case analysis monitoring takes place every 6 months, and stops when people reach 70 years.
Test accuracy data used in the model
It was assumed that the first test used for monitoring was unenhanced ultrasound. The test performance of unenhanced ultrasound used in the model is shown in table 1 and was based on the study by Bennett et al. (2002) as used in the health technology assessment report by Thompson Coon et al. (2007). This study was preferred over other studies because it distinguished between small, medium and large tumours, and had a reasonable sample size (n=200).
Tumour size
Sensitivity
Small
Medium
Large
*The false-positive rate was 0.04.
Additional imaging takes place when unenhanced ultrasound is inconclusive. About 43% of unenhanced ultrasounds were estimated to be inconclusive, based on information provided by the manufacturer of SonoVue. In the base-case analysis, the probability of identifying hepatocellular carcinoma and the proportion of people with a false-positive test result were taken from Leoni et al. (2010). Data from this study were used because diagnostic criteria matched the EFSUMB guidance on the use of contrast-enhanced ultrasound and the performance of contrast-enhanced ultrasound, contrast-enhanced CT and contrast-enhanced MRI with gadolinium was reported in the same population. The study included people with liver lesions between 1 and 3 cm. In the base-case analysis the External Assessment Group used these results to model the diagnostic accuracy for both small (<2 cm) and medium (2–5 cm) tumours (table 2). The sensitivity for identifying large hepatocellular carcinomas was assumed to be 100% for all confirmatory imaging tests, and this assumption was agreed by the clinical experts.
Test
Sensitivity for identifying small and medium tumours
Contrast-enhanced ultrasound
Contrast-enhanced CT
Contrast-enhanced MRI with gadolinium
*False-positive rates were 0.03, 0.03 and 0.01 for contrast-enhanced ultrasound, contrast-enhanced CT and contrast-enhanced MRI with gadolinium respectively.
Base-case cost effectiveness results
Contrast-enhanced ultrasound had the lowest discounted lifetime costs per person (£35,744), followed by contrast-enhanced CT (£36,124) and contrast-enhanced MRI with gadolinium (£36,807). Compared with contrast-enhanced ultrasound, contrast-enhanced CT was as effective but more costly, and was thus considered to be dominated by contrast-enhanced ultrasound. Contrast-enhanced MRI with gadolinium cost £1063 more per person than contrast-enhanced ultrasound, but also yielded 0.022 more QALYs, giving an incremental cost-effectiveness ratio (ICER) of £48,454 per QALY gained. Contrast-enhanced ultrasound is more cost-effective than contrast-enhanced MRI at £20,000 per QALY gained because although less effective it costs less and the ICER for contrast-enhanced MRI compared with contrast-enhanced ultrasound is above this value.
Additional analyses
A range of additional analyses were performed by the External Assessment Group. Compared with contrast-enhanced MRI with gadolinium (and contrast-enhanced CT), contrast-enhanced ultrasound was the most cost effective option in many of the additional analyses, except when it was assumed that all positive (true and false) unenhanced ultrasound examinations were subject to confirmatory testing instead of only the inconclusive results, and when the proportion of people estimated to have an inconclusive unenhanced ultrasound was considerably lower (20% instead of 43%). These 2 analyses resulted in ICERs for contrast-enhanced MRI with gadolinium compared with contrast-enhanced ultrasound of £12,806 and £16,121 per QALY gained respectively (contrast-enhanced CT was dominated by contrast-enhanced ultrasound in both cases).
In probabilistic sensitivity analysis with over 5000 replications, at £20,000 per QALY gained the probability that contrast-enhanced ultrasound, contrast-enhanced CT or contrast-enhanced MRI with gadolinium was most cost effective was 99%, 0% and 1% respectively.
Model description
The model was a modified version of the model developed by Brush et al. (2011). The population consisted of people who had previously had surgery for primary colorectal cancer and who, during routine follow-up, were identified as potentially having a metastatic recurrence. The time horizon was a lifetime and the cycle duration was 1 year.
Test accuracy data used in the model
The test performance used in the base case was from Mainenti et al. (2010) because this study compared all 3 alternative tests (contrast-enhanced CT, contrast-enhanced MRI with gadolinium, contrast-enhanced MRI with SPIO) with contrast-enhanced ultrasound (table 3).
Test
Sensitivity
Specificity
Contrast-enhanced ultrasound
Contrast-enhanced CT
Contrast-enhanced MRI with gadolinium
Contrast-enhanced MRI with SPIO
Base-case cost effectiveness results
In the base-case analysis, using the different imaging techniques to investigate potential liver metastases from colorectal cancer resulted in equal expected lifetime QALYs (8.364). Contrast-enhanced ultrasound and contrast-enhanced CT were the least costly tests, with expected lifetime costs of approximately £7510 per person. Contrast-enhanced MRI with gadolinium (£7688) and contrast-enhanced MRI with SPIO (£7722) were both more costly than, and thus dominated by, contrast-enhanced CT and contrast-enhanced ultrasound. Contrast-enhanced ultrasound and contrast-enhanced CT were cost-effective technologies, with equal expected costs and effectiveness.
Additional analyses
A range of additional analyses were performed by the External Assessment Group. Analyses that had an impact on the results of the base-case analysis are summarised here. In the base-case analysis it was assumed that people who were incorrectly diagnosed with liver metastases would have a biopsy and the incorrect diagnosis would be discovered before treatment. If this is not assumed, and people could receive unnecessary treatment, the lower specificity of contrast-enhanced ultrasound had larger consequences. This led to contrast-enhanced ultrasound being both the most costly and the least effective option, and contrast-enhanced MRI with gadolinium dominating all other tests. When alternative sources of test performance were used, from Jones et al. (2011) and Clevert et al. (2009), contrast-enhanced ultrasound was the cost-effective option in both scenarios.
In probabilistic sensitivity analysis with 5000 replications, at £20,000 per QALY gained contrast-enhanced CT had the highest probability of being cost effective (48%), followed by contrast-enhanced ultrasound (47%), contrast-enhanced MRI with gadolinium (3%) and contrast-enhanced MRI with SPIO (2%).
Model description
People with incidentally detected focal liver lesions can have a variety of conditions, ranging from malignant lesions such as hepatocellular carcinoma and metastases to different types of benign lesions. The prognosis and costs for people diagnosed with hepatocellular carcinoma were modelled using the cirrhosis surveillance model, whereas the prognosis and costs for people with liver metastases were modelled using the liver metastases model. The model took a lifetime time horizon. The costs, life years and QALYs for people with a malignancy other than hepatocellular carcinoma or metastases were assumed to be equal to those in people with hepatocellular carcinoma. However, it was known in advance of the modelling that the costs and QALYs for these people would have a limited effect on the cost effectiveness of contrast-enhanced ultrasound, because its sensitivity was very similar to that of the comparators and the prior probability of other malignancies was small.
Test accuracy data used in the model
The approach used in the base case was to take the results from the meta-analysis of 4 studies that compared contrast-enhanced ultrasound with contrast-enhanced CT for the differentiation of malignant and benign lesions. Table 4 illustrates the similar performance of the 2 tests.
Estimate
% confidence interval (exact method)
Sensitivity of contrast-enhanced ultrasound
% to 96.6%
Sensitivity of contrast-enhanced CT
% to 96.1%
Specificity of contrast-enhanced ultrasound
% to 96.3%
Specificity of contrast-enhanced CT
% to 95.8%
Only 1 study, Seitz (2010), compared the test accuracy of contrast-enhanced ultrasound with MRI (a sensitivity of 77.3% and 63.6% and a specificity of 75.0 and 76.7, respectively, were used in the base case). This study reported that all people in a subgroup had contrast-enhanced MRI with gadolinium, and that a subset of these people also had MRI with a SPIO contrast agent. It was difficult to determine the different accuracies of MRI with the 2 different contrast agents from the study, and therefore sections relating to the use of MRI in the characterisation of incidentally detected focal liver lesions refer to contrast-enhanced MRI overall.
Base-case cost-effectiveness results
The lower costs of contrast-enhanced ultrasound combined with slightly better test performance meant that contrast-enhanced ultrasound dominated both contrast-enhanced CT (contrast-enhanced ultrasound cost £52 less and yielded 0.0002 additional QALYs) and contrast-enhanced MRI (contrast-enhanced ultrasound cost £131 less and yielded 0.0026 additional QALYs).
Additional analyses
A range of additional analyses were performed by the External Assessment Group. Although these analyses changed the absolute costs and effectiveness of the different strategies, they did not lead to any significant changes in the incremental costs and effectiveness of contrast-enhanced ultrasound compared with contrast-enhanced CT or contrast-enhanced MRI. The cost of the tests was the most critical factor in the analyses. The impact of other factors (for example, prior probabilities of a particular diagnosis and costs of treatment) was minimal because the accuracy of the tests was so similar.
Probabilistic sensitivity analyses showed that the probability of contrast-enhanced ultrasound being cost effective compared with contrast-enhanced CT and contrast-enhanced MRI was greater than 95% at £20,000 per QALY gained.# Considerations
The Diagnostics Advisory Committee reviewed the evidence on the clinical and cost effectiveness of contrast-enhanced ultrasound with SonoVue and noted that the technology was assessed in 3 clinical indications, in adults, when unenhanced ultrasound is inconclusive:
characterising incidentally detected focal liver unrelated to the clinical indication for which the imaging was requested
investigating potential liver metastases in people with colorectal cancer
characterising focal liver lesions identified through monitoring of people with cirrhosis.
In general, the committee noted that most of the studies identified in the systematic review of clinical effectiveness were of diagnostic test accuracy and that the quality assessment of these studies, using QUADAS 2, highlighted significant limitations in the data. In particular, there was a 'high' risk of bias rating for the 'patient selection' domain from the use of a retrospective study design or from inappropriate exclusions of particular patient groups (for example, exclusion of people with a low probability of malignancy).
The committee thought that the large retrospective safety study of contrast-enhanced ultrasound with SonoVue in abdominal imaging showed that the safety profile of SonoVue was comparable to, if not better than, contrast-enhanced CT and contrast enhanced MRI.
The committee also considered the impact of the use of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), as a newer 'combined' vascular and hepatocyte-specific contrast agent for MRI. The External Assessment Group noted that, although most of the evidence for MRI was based on older contrast agents (such as SPIO), a study of people with cirrhosis by Blondin et al. (2011) did not suggest that the accuracy of Gd-EOB-DTPA was significantly different to that of contrast-enhanced ultrasound. Blondin et al. showed that sensitivity estimates were similar and high (>90%) for both contrast-enhanced ultrasound and Gd-EOB-DTPA contrast-enhanced MRI. Specificity appeared lower for contrast-enhanced ultrasound than for Gd-EOB-DTPA contrast-enhanced MRI, but the small number of people with benign lesions in this study resulted in high imprecision in specificity estimates: 50% (95% confidence interval 42 to 88%) for contrast-enhanced ultrasound and 83% (95% CI 36 to 100%) for Gd-EOB-DTPA contrast-enhanced MRI.
The committee considered contrast-enhanced ultrasound with SonoVue for characterising incidentally detected focal liver lesions and noted that, in liver imaging, this clinical indication would likely be the most common application of the technology. The committee noted that the base-case analysis showed clinically insignificant increases in effectiveness for contrast-enhanced ultrasound compared with contrast-enhanced CT and MRI (incremental QALYs for contrast-enhanced ultrasound compared with contrast-enhanced CT were 0.00016, and for contrast-enhanced ultrasound compared with contrast-enhanced MRI, 0.0026). Moreover, there were cost decreases with contrast-enhanced ultrasound (£52 compared with contrast-enhanced CT, and £131 compared with contrast-enhanced MRI). Thus contrast-enhanced ultrasound with SonoVue dominated the comparators. Probabilistic sensitivity analysis revealed that there was little uncertainty about the cost effectiveness of contrast-enhanced ultrasound compared with the other 2 imaging techniques. Additional analyses did not lead to significant changes in the incremental costs and effectiveness of contrast-enhanced ultrasound compared with contrast-enhanced CT or contrast-enhanced MRI. Therefore, the committee concluded that it could recommend contrast-enhanced ultrasound with SonoVue for characterising incidentally detected focal liver lesions.
The committee considered contrast-enhanced ultrasound with SonoVue for investigating potential liver metastases in people with colorectal cancer and noted that the NICE clinical guideline on colorectal cancer recommends the use of CT in staging of colorectal cancer, which includes the identification of liver metastases. Therefore, the use of contrast-enhanced ultrasound with SonoVue would only be applicable in a small number of cases (for example, if contrast-enhanced CT is not clinically appropriate, is not accessible, is not acceptable to the person, or is inconclusive). The committee considered the economic analysis performed by the External Assessment Group and noted that the base-case analysis showed that contrast-enhanced CT was cost effective; however, contrast-enhanced ultrasound with SonoVue generated equal benefits and was only £1 more costly. The committee considered a range of additional analyses performed by the External Assessment Group. In the base-case analysis it was assumed that people who were incorrectly diagnosed with liver metastases (false-positives) would receive biopsy and the incorrect diagnosis would be discovered before treatment. If this is not assumed, then people could receive unnecessary treatment and the lower specificity of contrast-enhanced ultrasound resulted in increased costs and reduced effectiveness. Contrast-enhanced MRI with gadolinium dominates all other tests under this assumption. The committee discussed that although the diagnostic pathway varies depending on the clinical scenario, most people would be unlikely to receive unnecessary treatment. This is because the multidisciplinary team would probably seek assurance (from further imaging or a watch and wait strategy) before starting treatment. Direct biopsies of liver metastases may make the metastases inoperable, so they are unlikely to be performed. Therefore, the committee recommended the use of contrast-enhanced ultrasound with SonoVue for investigating potential liver metastases from colorectal cancer, when contrast-enhanced CT is not clinically appropriate, is not accessible or is not acceptable to the person.
The committee considered the applicability of the colorectal cancer analysis to metastases from other primary cancers. It concluded that the data for diagnostic accuracy are equally applicable to liver metastases from other primary cancers (because the liver is being imaged in all cases). Although the treatment of metastases may vary by type of primary cancer, the committee did not consider that this would affect the cost effectiveness of SonoVue sufficiently for it to modify its decision not to limit its recommendations to potential liver metastases from colorectal cancer.
The committee considered contrast-enhanced ultrasound with SonoVue for characterising focal liver lesions identified through monitoring people with cirrhosis. The committee considered the economic analysis performed by the External Assessment Group and noted that the base-case analysis showed that contrast-enhanced ultrasound with SonoVue was cost effective. The committee felt that the clinical evidence base was weaker for this indication, as noted in the diagnostics assessment report.
The committee considered several circumstances that would result in contrast-enhanced ultrasound being less cost effective. First, the modelling assumed that all people with diagnoses of hepatocellular carcinoma on characterisation scans, regardless of modality, would have subsequent scans with CT or MRI for treatment planning. The committee heard from experts that although lesions characterised with contrast-enhanced ultrasound would need subsequent CT or MRI scans, focal liver lesions characterised with CT or MRI would not usually need a second scan. The External Assessment Group determined that the extra scans did not add significantly to the overall cost and would not affect the overall cost effectiveness.
The committee also noted that in the base case, a high proportion of people who had an initial unenhanced ultrasound were assumed to have inconclusive scans (43%, from data supplied by the manufacturer of SonoVue). The committee noted that it was difficult for the External Assessment Group to ascertain accurate estimates for this parameter in people with cirrhosis because of variation in the definition of 'inconclusive' in the studies and clinical practice. The committee heard from clinical experts that this estimate did not reflect clinical practice and that inconclusive scans normally occur in a much lower proportion of people (10–15%) who then need further imaging to characterise their lesion(s). The External Assessment Group reviewed data submitted by the manufacturer and concluded that the percentage of inconclusive unenhanced scans in people with cirrhosis could not be calculated from these data for a variety of reasons, particularly because the data contained estimates that encompassed both non-diagnostic and diagnostic images, and the use of contrast-enhanced ultrasound rather than unenhanced ultrasound in the studies. The committee concluded that the percentage of inconclusive unenhanced ultrasound scans was likely to be nearer 10–15%. At this level, contrast-enhanced MRI with gadolinium was more effective than contrast-enhanced ultrasound and had an ICER of £16,100 per QALY gained. Therefore, contrast-enhanced ultrasound was not a cost-effective option under this circumstance. Contrast-enhanced CT was dominated by contrast-enhanced ultrasound with a 10–15% rate of inconclusive scans. Given the uncertainty in the estimate of the prevalence of inconclusive unenhanced ultrasound scans, particularly in people with cirrhosis, and given that the optimal diagnostic strategy depends on this estimate, the committee recommended further research on this issue (see section 7).
The committee discussed the pressures on MRI departments in the NHS, many of which faced substantially greater demand for MRI than current capacity could supply. It was thought that, from anecdotal evidence, approximately 5.5% of people who would otherwise have been referred for an MRI scan did not have one, either because it was not available or not clinically appropriate (for example, those with a pacemaker) or because they would not tolerate a scan. The committee recommended the use of contrast-enhanced ultrasound with SonoVue for people who would not or could not receive a contrast-enhanced MRI scan.
The committee also considered whether patient preferences might impact on the selection of imaging modality. Given that contrast-enhanced ultrasound is less expensive than CT or MRI, the small improvements in health-related quality of life arising from CT and particularly MRI might be outweighed by a personal preference for ultrasound over the other modalities. No data on patient preferences were identified by the External Assessment Group's systematic review. The committee recommended research on patient preferences, and their impact on quality of life, for contrast-enhanced ultrasound and other imaging modalities and whether there are likely differences between contrast-enhanced ultrasound and the other imaging modalities (see section 7).
The committee discussed the level of training needed to perform a contrast-enhanced ultrasound. It was noted that an appropriate level of operator experience was needed to be able to successfully perform contrast-enhanced ultrasound and that currently there was a shortage in appropriately trained sonographers. The committee concluded that it would be desirable to develop a clinical support framework for sharing and discussing experiences of contrast-enhanced ultrasound. Moreover, NHS departments offering contrast-enhanced ultrasound for liver imaging should review whether they have appropriately trained staff and offer training if necessary by using, for example, the minimum training guidelines provided by the EFSUMB.
The committee noted that the economic analysis was based on the assumption that the contrast-enhanced ultrasound scan would be performed in the same appointment as the unenhanced ultrasound scan. Although alternative scenarios exploring the need to book an additional outpatient appointment (in 50% and 67% of cases) were assessed by the External Assessment Group, this did not affect the results of the economic analysis. The committee stated that there were significant benefits from having contrast-enhanced ultrasound performed in the same appointment as the unenhanced ultrasound scan, including patient convenience and the potential for reducing anxiety by ruling out a malignant lesion sooner. Also, savings from reducing the number of appointments are likely. In the committee's view the potential benefit of reducing anxiety by rapidly ruling out malignancy would be a significant advantage compared with the other imaging modalities and is a consequence of being able to perform contrast-enhanced ultrasound during the same appointment. In the committee's view performing contrast-enhanced ultrasound in the same appointment as unenhanced ultrasound was the optimal model of service delivery.
The committee considered possible equality impacts. It noted that although obesity may be a general barrier to the use of ultrasound in some people, its impact on image quality on an individual basis is unpredictable. The committee concluded that the recommendations would be unlikely to disadvantage those with obesity or protected groups.# Recommendations for further research
Research is recommended on the percentage of unenhanced ultrasound scans that are inconclusive, particularly in people with cirrhosis. Such studies should explicitly define and describe why scans are 'inconclusive'.
Research is recommended on patient preferences, and their impact on quality of life, for contrast-enhanced ultrasound and other imaging modalities. Ideally such research should compare all appropriate imaging modalities in the same patient group.# Review
NICE will update the literature search at least every 3 years to ensure that relevant new evidence is identified. NICE will contact product sponsors and other stakeholders about issues that may affect the value of the diagnostic technology. NICE may review and update the guidance at any time if significant new evidence becomes available.
Andrew DillonChief ExecutiveAugust 2012
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{'Recommendations': 'Contrast-enhanced ultrasound with SonoVue is recommended for characterising incidentally detected focal liver lesions in adults in whom an unenhanced ultrasound scan is inconclusive. An unenhanced ultrasound scan in which a focal liver lesion is detected, but not characterised, is defined as inconclusive.\n\nContrast-enhanced ultrasound with SonoVue is recommended for investigating potential liver metastases in adults:\n\nif contrast-enhanced computed tomography (CT) is not clinically appropriate, is not accessible or is not acceptable to the person, and\n\nin whom an unenhanced ultrasound scan is unsatisfactory and contrast is needed for further diagnosis.\n\nContrast-enhanced ultrasound with SonoVue is recommended for characterising focal liver lesions in adults whose cirrhosis is being monitored:\n\nif contrast-enhanced magnetic resonance imaging (MRI) is not clinically appropriate, is not accessible or is not acceptable to the person, and\n\nwhen unenhanced ultrasound scan is inconclusive.', 'The technology': 'SonoVue (Bracco UK), a pharmaceutical agent for diagnostic use only, is a contrast agent involving sulphur hexafluoride microbubbles. It is indicated for contrast-enhanced ultrasound imaging in adults when unenhanced imaging has been inconclusive. SonoVue has a European marketing authorisation for use in echocardiography, doppler imaging of macrovasculature (for example, cerebral arteries) and of microvasculature (for example, breast and liver lesions). Following input during the scoping phase of the evaluation, this evaluation focuses on the use of SonoVue for liver imaging. Additional details of the clinical condition and the technology are provided in sections 3 and 4 respectively.', 'Clinical need and practice': "# Current practice and the problem addressed\n\nUltrasound scanning, along with other imaging technologies such as CT and MRI, is important in diagnosing and planning treatment for many people with liver disease. Liver imaging sometimes identifies focal abnormalities that cannot be characterised initially and another test may be needed to further explore the abnormality. The main aim of subsequent liver imaging is to distinguish between cancer and benign abnormalities that are not likely to need further treatment. Liver lesions are commonly found at an initial unenhanced ultrasound scan. If the abnormality is not characterised by an unenhanced ultrasound scan, the person is usually referred for either MRI and/or CT. The definition of the term 'inconclusive' in this evaluation is an unenhanced ultrasound scan in which a focal liver lesion is detected but not characterised. The aim of this evaluation was to compare the clinical and cost effectiveness of contrast-enhanced ultrasound using the contrast agent SonoVue with contrast-enhanced CT and contrast-enhanced MRI for investigating and characterising focal liver lesions in adults, in whom previous liver imaging has been inconclusive. Three specific clinical indications were assessed:\n\ncharacterising focal liver lesions identified through monitoring of people with cirrhosis\n\ninvestigating potential liver metastases in people with colorectal cancer\n\ncharacterising incidentally detected focal liver lesions unrelated to the clinical indication for which the imaging was requested.\n\n## The condition\n\nIn the context of this evaluation, the term focal liver lesion refers to any focal area of perceived difference seen on imaging that occurs in 1 specific area of the liver. Focal liver lesions can be broadly classified as benign (for example, haemangioma, focal nodular hyperplasia, focal fatty infiltration or sparing, and adenoma) or malignant (for example, primary hepatocellular carcinoma, cholangiocarcinoma and liver metastases). Identifying or excluding malignancy is the primary aim of diagnostic imaging.\n\nThe distinction between benign and malignant lesions helps to determine the prognosis and subsequent treatment strategy. Benign asymptomatic liver lesions, which comprise as many as 70–75% of the focal liver lesions assessed in the UK, usually do not need treatment. Depending on the type of lesion, the person may be discharged or their condition may be monitored and the lesion rescanned in 6–12\xa0months. If a malignant lesion is identified it is important to distinguish between primary and secondary cancers because this is likely to affect how the condition is managed. Malignant lesions may be treated with a range of interventions, including chemotherapy, surgery and local ablative therapy.\n\nThere are 2 main types of liver cancer. A cancer that starts in the liver is known as a primary liver cancer and a cancer that spreads to the liver from another part of the body is known as metastatic cancer. Approximately 3200 people in the UK are diagnosed with primary liver cancer each year, whereas approximately 90,000 people are diagnosed with liver metastases.\n\nMost people with a diagnosis of primary liver cancer (approximately 85%) have a hepatocellular carcinoma. A major risk factor for developing hepatocellular carcinoma is underlying cirrhosis (scarring of liver tissue). Cirrhosis commonly results from alcoholism, hepatitis B and C, and fatty liver disease. Primary liver cancer is the second most rapidly increasing cancer in men and the third in women (increases of 38% and 28% respectively in the past decade).\n\nPrimary liver cancer in adults has a poor prognosis because it tends to be diagnosed in the advanced stages. Only a minority of cases of primary liver cancer are diagnosed in the early stages when surgery may help. The prognosis of primary liver cancer depends on the extent of disease and underlying liver function. About 20% of people with primary liver cancer live for at least 1\xa0year after diagnosis. Around 5% live for at least 5\xa0years.\n\nThe primary cancers most commonly leading to metastases in the liver originate in the breast, lung and bowel (colorectal). The origin of the primary cancer is important because the cells of the liver metastases are the same as those of the primary cancer, and liver metastases are likely to be treated according to the cell type of the primary cancer. The prognosis of liver metastases depends on the extent of the disease and comorbidities. For example, 40–60% of people with stage\xa04 colorectal cancer with resectable liver metastases will live for 5\xa0years after surgery.\n\n## The diagnostic and care pathways\n\nContrast-enhanced ultrasound could be included in the diagnostic pathway as a replacement for contrast-enhanced CT/contrast-enhanced MRI (figure 1), or as a triage step to reduce the use of contrast-enhanced CT/contrast-enhanced MRI. The available data only allowed contrast-enhanced ultrasound with SonoVue as a replacement for contrast-enhanced CT/contrast-enhanced MRI to be included in the economic analysis.\n\nFigure 1 Diagnostic pathway for liver imaging with contrast-enhanced ultrasound as a replacement for contrast-enhanced CT/contrast-enhanced MRI\n\nAbbreviations: CEUS, contrast-enhanced ultrasound; US, ultrasound.\n\nIn general, care pathways for people with liver cancer are guided by prognosis. Prognosis depends on both the extent of the tumour and on comorbidity. Improvements in survival as a result of treatment largely depend on the disease stage at diagnosis: the earlier the diagnosis is made, the greater the chance for successful treatment. Detailed care pathways for the 3 indications considered in this assessment can be found in section 3.4 of the diagnostics assessment report.\n\nThe European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) produced guidelines and good clinical practice recommendations for contrast-enhanced ultrasound in 2004. The latest version was published in 2008 and is currently being updated.\n\nThe 2008 EFSUMB guidelines recommend the use of contrast-enhanced ultrasound for the characterisation of focal liver lesions in a range of indications. The guidelines also provide information on the typical enhancement patterns associated with various types of benign and malignant liver lesions.\n\nThe treatment of primary hepatocellular carcinoma has been addressed in published technology appraisals guidance, and NICE has issued interventional procedure guidance on a number of individual interventions for primary hepatocellular carcinoma and liver metastases (see the NICE website for details). NICE clinical guideline on colorectal cancer recommends the use of CT in staging of colorectal cancer, which includes the identification of liver metastases. Expert opinion suggests that there may be significant regional variation within the NHS in the characterisation of focal liver lesions.", 'The diagnostic tests': '# SonoVue\n\nSonoVue is a second-generation contrast agent that uses sulphur hexafluoride microbubbles for contrast-enhanced ultrasound imaging in adults. SonoVue is a low solubility gas contrast agent that allows imaging at low mechanical index, which leads to effective suppression of the tissue signal. It is used to enhance the echogenicity of the blood and can thus improve the signal to noise ratio in ultrasound. SonoVue has a UK marketing authorisation for diagnostic use only. The summary of product characteristics states that SonoVue improves display of the blood vessels in liver lesions during doppler sonography, allowing more specific characterisation of lesions. The summary of product characteristics also states that SonoVue should only be used in people in whom unenhanced ultrasound is inconclusive.\n\nSonoVue consists of a kit containing a vial of sulphur hexafluoride gas and phospholipid powder, a prefilled syringe of solvent (sodium chloride solution) and a transfer and ventilation system (mini spike). The saline is introduced into the vial by the mini spike delivery system and once reconstituted, microbubbles are formed. These microbubbles are the contrast agent which is injected into a peripheral vein at the antecubital fossa. When the ultrasound probe is placed on the abdomen, ultrasound waves cause the microbubbles to resonate so that a signal is picked up by a transducer and an image is formed on a screen.\n\nSonoVue remains within the blood vessels and, depending on the type of lesion, it shows a pattern of uptake similar to that of contrast agents used for imaging blood vessels in CT or MRI. The contrast agent is broken down by the body after a few minutes. The sulphur hexafluoride gas is exhaled through the lungs and the phospholipid component of the microbubble shell is metabolised (re-entering the endogenous phospholipid metabolic pathway).\n\n# Comparator\n\nPeople with inconclusive unenhanced ultrasound are currently referred for contrast-enhanced CT and/or contrast-enhanced MRI. These are the comparators for this assessment. Contrast-enhanced MRI generally uses gadolinium-based vascular contrast agents. These can differentiate between benign and malignant focal liver lesions by vascular enhancement patterns in a similar way to contrast agents used for contrast-enhanced CT and contrast-enhanced ultrasound. However, contrast-enhanced MRI of the liver can also use hepatocyte-specific contrast agents. These include superparamagnetic iron oxide (SPIO) and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA).\n\nExpert opinion indicated that biopsy would not be performed as the next test when unenhanced ultrasound was inconclusive. Therefore, biopsy was not considered a relevant comparator in this assessment.\n\nThe comparators used in the model were:\n\ncontrast-enhanced CT\n\ncontrast-enhanced MRI using gadolinium as the contrast agent\n\ncontrast-enhanced MRI using SPIO as the contrast agent.', 'Outcomes': "The Diagnostics Advisory Committee (section 10) considered evidence from a number of sources.\n\n# How outcomes were assessed\n\nA systematic review of the effectiveness of contrast-enhanced ultrasound using SonoVue compared with contrast-enhanced CT and contrast-enhanced MRI was undertaken by the External Assessment Group. The outcome measures included:\n\nthe effect of testing on the treatment plan (for example, surgical or medical management, or palliative care)\n\nthe effect of pre-treatment testing on clinical outcome (for example, overall survival, progression-free survival)\n\nprognosis – the ability of the test result to predict clinical outcome (for example, overall survival, progression-free survival, response to treatment)\n\ntest accuracy and number of people or lesions for which no conclusive diagnostic information could be obtained with contrast-enhanced ultrasound using SonoVue.\n\nRadiation exposure was not considered a relevant outcome because the population is mostly older adults in whom additional incident cancers as a result of imaging are likely to be minimal.\n\nA systematic review of the evidence on cost effectiveness for SonoVue was undertaken by the External Assessment Group. The External Assessment Group constructed multiple de novo models. The outcomes of interest for the modelling were costs and the morbidity and mortality associated with the investigation and characterisation of focal liver lesions and their treatment. These included survival and health-related quality of life, including the impact of adverse events associated with treatment (such as chemotherapy).\n\nDiagnostic technologies themselves do not usually have direct evidence for health-related quality of life, and the de novo models therefore followed a linked evidence approach in which intermediate outcomes (results of the test/s) were linked to the care pathway to estimate clinical outcomes and hence quality-adjusted life year (QALY) gains. Costs and QALYs were assigned to SonoVue and the comparators.\n\n# Clinical effectiveness\n\nA total of 17 studies in 18 publications were included in the assessment. All of the included studies were test accuracy studies:\n\nconcerned the use of contrast-enhanced ultrasound with SonoVue for characterising focal liver lesions identified during routine monitoring of people with cirrhosis\n\nassessed the performance of contrast-enhanced ultrasound with SonoVue for investigating potential liver metastases in people with known primary cancers (mostly colorectal cancer)\n\nconcerned the use of contrast-enhanced ultrasound with SonoVue for characterising incidentally detected focal liver lesions.\n\nOnly 1 of the studies of test accuracy included in this assessment reported information on adverse events related to testing. In this study there were no adverse events associated with contrast-enhanced ultrasound with SonoVue. There was no information about the comparator (contrast-enhanced MRI with gadolinium). A large, retrospective safety study of contrast-enhanced ultrasound with SonoVue in abdominal imaging did not meet the inclusion criteria for this assessment but reported data from 23,188 investigations in 29 centres in Italy. This study found 29 incidents of adverse events, of which 2 were graded as serious, 1 as severe, 3 as moderate and 23 as mild. There were no fatal adverse events. Most non-serious adverse events resolved without intervention.\n\nAll included studies were published in 2006 or later. Most were conducted in Europe (most in Italy or Spain). Two studies reported funding from the manufacturer of SonoVue.\n\n## Results by clinical indication\n\nTest accuracy data in relation to each clinical indication assessed are summarised below.\n\nStudies conducted in people with cirrhosis during routine monitoring all concerned the differentiation of hepatocellular carcinoma from other lesion types in small to medium (<30\xa0mm) focal liver lesions. The definition of a positive test for hepatocellular carcinoma varied across studies. Studies assessing contrast-enhanced MRI used 3 contrast agents: gadolinium (a vascular contrast agent), SPIO (a hepatocyte-specific contrast agent) and Gd-EOB-DTPA (a 'combined' vascular and hepatocyte-specific contrast agent). There was no consistent evidence for any significant difference in test performance between the 3 imaging modalities (contrast-enhanced ultrasound, contrast-enhanced CT and contrast-enhanced MRI) and the 3 MRI contrast media assessed. When the definition of hepatocellular carcinoma given in the EFSUMB guidelines (arterial phase enhancement followed by portal-venous washout) was used, estimates of the sensitivity and specificity of each of the imaging modalities varied across studies. There was some evidence, from 1 study comparing contrast-enhanced ultrasound and contrast-enhanced MRI using gadolinium, that these imaging techniques may be better at ruling out hepatocellular carcinoma in focal liver lesions between 11 and 30\xa0mm (sensitivities were 92% and 95% respectively) than in small focal liver lesions\xa010\xa0mm or less (sensitivities 27% and 73% respectively). However, this study did not use the EFSUMB definition of hepatocellular carcinoma. It is therefore possible that some of the variation in sensitivity estimates in studies of focal liver lesions smaller than\xa030\xa0mm may be a result of differences in the size distribution of focal liver lesions included. The evidence suggested that contrast-enhanced ultrasound alone may be adequate to rule out hepatocellular carcinoma for focal liver lesions between 11 and 30\xa0mm.\n\nStudies of the diagnosis of liver metastases using imaging with vascular contrast media (contrast-enhanced ultrasound, contrast-enhanced CT and contrast-enhanced MRI with gadolinium), in which definitions of a positive imaging test were reported, gave various descriptions of peripheral rim enhancement as the criteria for liver metastases. Two studies also reported data for contrast-enhanced MRI with SPIO. There was no evidence of any consistent difference in test performance between the 3 imaging modalities and the different contrast media assessed. Per patient sensitivity estimates, from 2 studies, were generally high: 83% for all imaging modalities and both MRI contrast agents in 1 study of people with colorectal cancer and more than\xa095% for both contrast-enhanced ultrasound and contrast-enhanced CT in a second study of people with various primary cancers (mostly colorectal cancer). The only previous systematic review of contrast-enhanced ultrasound with SonoVue for the diagnosis of liver metastases did not include any comparator tests and reported sensitivities ranging from 79% to 100%. The limited data available indicate that contrast-enhanced ultrasound alone may be adequate to rule out liver metastases in people with known primary malignancies.\n\nThe primary outcome measure reported by studies conducted in people with incidentally detected focal liver lesions was test accuracy for the differentiation of malignant from benign liver lesions. Studies consistently used definitions of the imaging criteria for hepatocellular carcinoma and liver metastases which were similar to those reported in the EFSUMB guidelines on the use of contrast-enhanced ultrasound. All studies reported no significant difference in the accuracy of contrast-enhanced ultrasound, contrast-enhanced CT and contrast-enhanced MRI for characterising focal liver lesions. The pooled estimates of sensitivity for the detection of 'any liver malignancy' were approximately 95% for both contrast-enhanced ultrasound and contrast-enhanced CT. The pooled estimates of specificity were 94% and 93% respectively, based on data from 4 studies. The single study comparing contrast-enhanced ultrasound with contrast-enhanced MRI used gadolinium for MRI in all people, with the addition of SPIO in an unspecified number. This study reported sensitivity estimates of 91% and 82% respectively, and corresponding specificity estimates of 67% and 63%. Data from 1\xa0study indicated that combined imaging using both contrast-enhanced ultrasound and contrast-enhanced CT did not increase sensitivity when a positive result on either modality was treated as 'test positive'. This, combined with the high estimates of sensitivity, indicates that contrast-enhanced ultrasound alone may be adequate to rule out liver malignancy in people with incidentally detected focal liver lesions.\n\n# Economic analysis\n\nFour studies were identified that met the inclusion criteria for an economic analysis of the use of SonoVue in contrast-enhanced ultrasound.\n\nAlthough all the studies were of reasonably good quality, they did not fully address the cost effectiveness of SonoVue as defined in this assessment. Limitations included restricted information about disease management and progression, choice of equipment and administrative procedures in different settings, inclusion of costing elements in the calculation, and health outcomes. Zaim et al. (2011) was the only study that modelled disease management and reported health outcomes relevant to this assessment, but the follow-up was only 24\xa0months.\n\nThe External Assessment Group performed a de novo analysis to address specifically the decision problem for this evaluation and to estimate the cost effectiveness of SonoVue in England.\n\nThe External Assessment Group conducted an analysis of contrast-enhanced ultrasound using SonoVue for assessing focal liver lesions in adults, in whom unenhanced ultrasound or other liver imaging has been inconclusive. Three separate models were used for 3 clinical applications for which the most data on test performance were available and experts suggested there was most likely to be clinical benefit:\n\ncirrhosis surveillance (for characterising focal liver lesions identified through monitoring of people with cirrhosis)\n\ninvestigating potential liver metastases in colorectal cancer\n\ncharacterising incidentally detected focal liver lesions.\n\nIn each model, contrast-enhanced ultrasound with SonoVue was compared with contrast-enhanced CT, contrast-enhanced MRI using gadolinium and/or contrast-enhanced MRI using SPIO. Average costs, expected life years and expected QALYs per person were calculated for the above technologies.\n\n## Costs\n\nCosts of contrast-enhanced and unenhanced ultrasound were informed by expert clinical opinion and cost information provided the manufacturer of SonoVue. The costs of using the contrast agent, including cannulation, were assumed to be £48.70 (estimate supplied by the manufacturer and agreed by clinicians). In addition, contrast-enhanced ultrasound was expected to take longer than unenhanced ultrasound. Therefore, the External Assessment Group used the difference between the reference costs of an ultrasound taking less than 20\xa0minutes (£55) and an ultrasound taking more than 20\xa0minutes (£71) as the additional time costs of contrast-enhanced ultrasound. The total additional cost was therefore estimated to be £65. This assumed that contrast-enhanced ultrasound is performed in the same appointment as the unenhanced scan. Costs of the other diagnostic tests were based on 2011 NHS reference costs.\n\n## Cost effectiveness\n\nA model description, test accuracy data and results of the base-case and additional analyses are provided below for each of the 3 models.\n\nModel description\n\nThe model was a modified version of a model produced by the Peninsula Technology Assessment Group (the PenTAG cirrhosis surveillance model). The population consisted of people with a diagnosis of compensated cirrhosis entering a surveillance programme (aged 70\xa0years or younger with no pre-existing medical conditions that would preclude treatment with liver transplant or hepatic resection [including current alcohol or intravenous drug misuse]). The time horizon was a lifetime and the cycle duration was 1\xa0month. Patients in the model can develop hepatocellular carcinoma. In the base-case analysis monitoring takes place every 6\xa0months, and stops when people reach 70\xa0years.\n\nTest accuracy data used in the model\n\nIt was assumed that the first test used for monitoring was unenhanced ultrasound. The test performance of unenhanced ultrasound used in the model is shown in table\xa01 and was based on the study by Bennett et al. (2002) as used in the health technology assessment report by Thompson Coon et al. (2007). This study was preferred over other studies because it distinguished between small, medium and large tumours, and had a reasonable sample size (n=200).\n\nTumour size\n\nSensitivity\n\nSmall\n\n\n\nMedium\n\n\n\nLarge\n\n\n\n*The false-positive rate was 0.04.\n\nAdditional imaging takes place when unenhanced ultrasound is inconclusive. About 43% of unenhanced ultrasounds were estimated to be inconclusive, based on information provided by the manufacturer of SonoVue. In the base-case analysis, the probability of identifying hepatocellular carcinoma and the proportion of people with a false-positive test result were taken from Leoni et al. (2010). Data from this study were used because diagnostic criteria matched the EFSUMB guidance on the use of contrast-enhanced ultrasound and the performance of contrast-enhanced ultrasound, contrast-enhanced CT and contrast-enhanced MRI with gadolinium was reported in the same population. The study included people with liver lesions between 1 and 3\xa0cm. In the base-case analysis the External Assessment Group used these results to model the diagnostic accuracy for both small (<2\xa0cm) and medium (2–5\xa0cm) tumours (table 2). The sensitivity for identifying large hepatocellular carcinomas was assumed to be 100% for all confirmatory imaging tests, and this assumption was agreed by the clinical experts.\n\nTest\n\nSensitivity for identifying small and medium tumours\n\nContrast-enhanced ultrasound\n\n\n\nContrast-enhanced CT\n\n\n\nContrast-enhanced MRI with gadolinium\n\n\n\n*False-positive rates were 0.03, 0.03 and 0.01 for contrast-enhanced ultrasound, contrast-enhanced CT and contrast-enhanced MRI with gadolinium respectively.\n\nBase-case cost effectiveness results\n\nContrast-enhanced ultrasound had the lowest discounted lifetime costs per person (£35,744), followed by contrast-enhanced CT (£36,124) and contrast-enhanced MRI with gadolinium (£36,807). Compared with contrast-enhanced ultrasound, contrast-enhanced CT was as effective but more costly, and was thus considered to be dominated by contrast-enhanced ultrasound. Contrast-enhanced MRI with gadolinium cost £1063 more per person than contrast-enhanced ultrasound, but also yielded 0.022 more QALYs, giving an incremental cost-effectiveness ratio (ICER) of £48,454 per QALY gained. Contrast-enhanced ultrasound is more cost-effective than contrast-enhanced MRI at £20,000 per QALY gained because although less effective it costs less and the ICER for contrast-enhanced MRI compared with contrast-enhanced ultrasound is above this value.\n\nAdditional analyses\n\nA range of additional analyses were performed by the External Assessment Group. Compared with contrast-enhanced MRI with gadolinium (and contrast-enhanced CT), contrast-enhanced ultrasound was the most cost effective option in many of the additional analyses, except when it was assumed that all positive (true and false) unenhanced ultrasound examinations were subject to confirmatory testing instead of only the inconclusive results, and when the proportion of people estimated to have an inconclusive unenhanced ultrasound was considerably lower (20% instead of 43%). These 2 analyses resulted in ICERs for contrast-enhanced MRI with gadolinium compared with contrast-enhanced ultrasound of £12,806 and £16,121 per QALY gained respectively (contrast-enhanced CT was dominated by contrast-enhanced ultrasound in both cases).\n\nIn probabilistic sensitivity analysis with over 5000 replications, at £20,000 per QALY gained the probability that contrast-enhanced ultrasound, contrast-enhanced CT or contrast-enhanced MRI with gadolinium was most cost effective was 99%, 0% and 1% respectively.\n\nModel description\n\nThe model was a modified version of the model developed by Brush et al. (2011). The population consisted of people who had previously had surgery for primary colorectal cancer and who, during routine follow-up, were identified as potentially having a metastatic recurrence. The time horizon was a lifetime and the cycle duration was 1\xa0year.\n\nTest accuracy data used in the model\n\nThe test performance used in the base case was from Mainenti et al. (2010) because this study compared all 3 alternative tests (contrast-enhanced CT, contrast-enhanced MRI with gadolinium, contrast-enhanced MRI with SPIO) with contrast-enhanced ultrasound (table\xa03).\n\nTest\n\nSensitivity\n\nSpecificity\n\nContrast-enhanced ultrasound\n\n\n\n\n\nContrast-enhanced CT\n\n\n\n\n\nContrast-enhanced MRI with gadolinium\n\n\n\n\n\nContrast-enhanced MRI with SPIO\n\n\n\n\n\nBase-case cost effectiveness results\n\nIn the base-case analysis, using the different imaging techniques to investigate potential liver metastases from colorectal cancer resulted in equal expected lifetime QALYs (8.364). Contrast-enhanced ultrasound and contrast-enhanced CT were the least costly tests, with expected lifetime costs of approximately £7510 per person. Contrast-enhanced MRI with gadolinium (£7688) and contrast-enhanced MRI with SPIO (£7722) were both more costly than, and thus dominated by, contrast-enhanced CT and contrast-enhanced ultrasound. Contrast-enhanced ultrasound and contrast-enhanced CT were cost-effective technologies, with equal expected costs and effectiveness.\n\nAdditional analyses\n\nA range of additional analyses were performed by the External Assessment Group. Analyses that had an impact on the results of the base-case analysis are summarised here. In the base-case analysis it was assumed that people who were incorrectly diagnosed with liver metastases would have a biopsy and the incorrect diagnosis would be discovered before treatment. If this is not assumed, and people could receive unnecessary treatment, the lower specificity of contrast-enhanced ultrasound had larger consequences. This led to contrast-enhanced ultrasound being both the most costly and the least effective option, and contrast-enhanced MRI with gadolinium dominating all other tests. When alternative sources of test performance were used, from Jones et al. (2011) and Clevert et al. (2009), contrast-enhanced ultrasound was the cost-effective option in both scenarios.\n\nIn probabilistic sensitivity analysis with 5000 replications, at £20,000 per QALY gained contrast-enhanced CT had the highest probability of being cost effective (48%), followed by contrast-enhanced ultrasound (47%), contrast-enhanced MRI with gadolinium (3%) and contrast-enhanced MRI with SPIO (2%).\n\nModel description\n\nPeople with incidentally detected focal liver lesions can have a variety of conditions, ranging from malignant lesions such as hepatocellular carcinoma and metastases to different types of benign lesions. The prognosis and costs for people diagnosed with hepatocellular carcinoma were modelled using the cirrhosis surveillance model, whereas the prognosis and costs for people with liver metastases were modelled using the liver metastases model. The model took a lifetime time horizon. The costs, life years and QALYs for people with a malignancy other than hepatocellular carcinoma or metastases were assumed to be equal to those in people with hepatocellular carcinoma. However, it was known in advance of the modelling that the costs and QALYs for these people would have a limited effect on the cost effectiveness of contrast-enhanced ultrasound, because its sensitivity was very similar to that of the comparators and the prior probability of other malignancies was small.\n\nTest accuracy data used in the model\n\nThe approach used in the base case was to take the results from the meta-analysis of 4 studies that compared contrast-enhanced ultrasound with contrast-enhanced CT for the differentiation of malignant and benign lesions. Table\xa04 illustrates the similar performance of the 2 tests.\n\n-\n\nEstimate\n\n% confidence interval (exact method)\n\nSensitivity of contrast-enhanced ultrasound\n\n%\n\n% to 96.6%\n\nSensitivity of contrast-enhanced CT\n\n%\n\n% to 96.1%\n\nSpecificity of contrast-enhanced ultrasound\n\n%\n\n% to 96.3%\n\nSpecificity of contrast-enhanced CT\n\n%\n\n% to 95.8%\n\nOnly 1 study, Seitz (2010), compared the test accuracy of contrast-enhanced ultrasound with MRI (a sensitivity of 77.3% and 63.6% and a specificity of 75.0 and 76.7, respectively, were used in the base case). This study reported that all people in a subgroup had contrast-enhanced MRI with gadolinium, and that a subset of these people also had MRI with a SPIO contrast agent. It was difficult to determine the different accuracies of MRI with the 2 different contrast agents from the study, and therefore sections relating to the use of MRI in the characterisation of incidentally detected focal liver lesions refer to contrast-enhanced MRI overall.\n\nBase-case cost-effectiveness results\n\nThe lower costs of contrast-enhanced ultrasound combined with slightly better test performance meant that contrast-enhanced ultrasound dominated both contrast-enhanced CT (contrast-enhanced ultrasound cost £52 less and yielded 0.0002 additional QALYs) and contrast-enhanced MRI (contrast-enhanced ultrasound cost £131 less and yielded 0.0026 additional QALYs).\n\nAdditional analyses\n\nA range of additional analyses were performed by the External Assessment Group. Although these analyses changed the absolute costs and effectiveness of the different strategies, they did not lead to any significant changes in the incremental costs and effectiveness of contrast-enhanced ultrasound compared with contrast-enhanced CT or contrast-enhanced MRI. The cost of the tests was the most critical factor in the analyses. The impact of other factors (for example, prior probabilities of a particular diagnosis and costs of treatment) was minimal because the accuracy of the tests was so similar.\n\nProbabilistic sensitivity analyses showed that the probability of contrast-enhanced ultrasound being cost effective compared with contrast-enhanced CT and contrast-enhanced MRI was greater than 95% at £20,000 per QALY gained.", 'Considerations': "The Diagnostics Advisory Committee reviewed the evidence on the clinical and cost effectiveness of contrast-enhanced ultrasound with SonoVue and noted that the technology was assessed in 3 clinical indications, in adults, when unenhanced ultrasound is inconclusive:\n\ncharacterising incidentally detected focal liver unrelated to the clinical indication for which the imaging was requested\n\ninvestigating potential liver metastases in people with colorectal cancer\n\ncharacterising focal liver lesions identified through monitoring of people with cirrhosis.\n\nIn general, the committee noted that most of the studies identified in the systematic review of clinical effectiveness were of diagnostic test accuracy and that the quality assessment of these studies, using QUADAS 2, highlighted significant limitations in the data. In particular, there was a 'high' risk of bias rating for the 'patient selection' domain from the use of a retrospective study design or from inappropriate exclusions of particular patient groups (for example, exclusion of people with a low probability of malignancy).\n\nThe committee thought that the large retrospective safety study of contrast-enhanced ultrasound with SonoVue in abdominal imaging showed that the safety profile of SonoVue was comparable to, if not better than, contrast-enhanced CT and contrast enhanced MRI.\n\nThe committee also considered the impact of the use of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), as a newer 'combined' vascular and hepatocyte-specific contrast agent for MRI. The External Assessment Group noted that, although most of the evidence for MRI was based on older contrast agents (such as SPIO), a study of people with cirrhosis by Blondin et al. (2011) did not suggest that the accuracy of Gd-EOB-DTPA was significantly different to that of contrast-enhanced ultrasound. Blondin et al. showed that sensitivity estimates were similar and high (>90%) for both contrast-enhanced ultrasound and Gd-EOB-DTPA contrast-enhanced MRI. Specificity appeared lower for contrast-enhanced ultrasound than for Gd-EOB-DTPA contrast-enhanced MRI, but the small number of people with benign lesions in this study resulted in high imprecision in specificity estimates: 50% (95% confidence interval [CI] 42 to 88%) for contrast-enhanced ultrasound and 83% (95% CI 36 to 100%) for Gd-EOB-DTPA contrast-enhanced MRI.\n\nThe committee considered contrast-enhanced ultrasound with SonoVue for characterising incidentally detected focal liver lesions and noted that, in liver imaging, this clinical indication would likely be the most common application of the technology. The committee noted that the base-case analysis showed clinically insignificant increases in effectiveness for contrast-enhanced ultrasound compared with contrast-enhanced CT and MRI (incremental QALYs for contrast-enhanced ultrasound compared with contrast-enhanced CT were 0.00016, and for contrast-enhanced ultrasound compared with contrast-enhanced MRI, 0.0026). Moreover, there were cost decreases with contrast-enhanced ultrasound (£52 compared with contrast-enhanced CT, and £131 compared with contrast-enhanced MRI). Thus contrast-enhanced ultrasound with SonoVue dominated the comparators. Probabilistic sensitivity analysis revealed that there was little uncertainty about the cost effectiveness of contrast-enhanced ultrasound compared with the other 2 imaging techniques. Additional analyses did not lead to significant changes in the incremental costs and effectiveness of contrast-enhanced ultrasound compared with contrast-enhanced CT or contrast-enhanced MRI. Therefore, the committee concluded that it could recommend contrast-enhanced ultrasound with SonoVue for characterising incidentally detected focal liver lesions.\n\nThe committee considered contrast-enhanced ultrasound with SonoVue for investigating potential liver metastases in people with colorectal cancer and noted that the NICE clinical guideline on colorectal cancer recommends the use of CT in staging of colorectal cancer, which includes the identification of liver metastases. Therefore, the use of contrast-enhanced ultrasound with SonoVue would only be applicable in a small number of cases (for example, if contrast-enhanced CT is not clinically appropriate, is not accessible, is not acceptable to the person, or is inconclusive). The committee considered the economic analysis performed by the External Assessment Group and noted that the base-case analysis showed that contrast-enhanced CT was cost effective; however, contrast-enhanced ultrasound with SonoVue generated equal benefits and was only £1 more costly. The committee considered a range of additional analyses performed by the External Assessment Group. In the base-case analysis it was assumed that people who were incorrectly diagnosed with liver metastases (false-positives) would receive biopsy and the incorrect diagnosis would be discovered before treatment. If this is not assumed, then people could receive unnecessary treatment and the lower specificity of contrast-enhanced ultrasound resulted in increased costs and reduced effectiveness. Contrast-enhanced MRI with gadolinium dominates all other tests under this assumption. The committee discussed that although the diagnostic pathway varies depending on the clinical scenario, most people would be unlikely to receive unnecessary treatment. This is because the multidisciplinary team would probably seek assurance (from further imaging or a watch and wait strategy) before starting treatment. Direct biopsies of liver metastases may make the metastases inoperable, so they are unlikely to be performed. Therefore, the committee recommended the use of contrast-enhanced ultrasound with SonoVue for investigating potential liver metastases from colorectal cancer, when contrast-enhanced CT is not clinically appropriate, is not accessible or is not acceptable to the person.\n\nThe committee considered the applicability of the colorectal cancer analysis to metastases from other primary cancers. It concluded that the data for diagnostic accuracy are equally applicable to liver metastases from other primary cancers (because the liver is being imaged in all cases). Although the treatment of metastases may vary by type of primary cancer, the committee did not consider that this would affect the cost effectiveness of SonoVue sufficiently for it to modify its decision not to limit its recommendations to potential liver metastases from colorectal cancer.\n\nThe committee considered contrast-enhanced ultrasound with SonoVue for characterising focal liver lesions identified through monitoring people with cirrhosis. The committee considered the economic analysis performed by the External Assessment Group and noted that the base-case analysis showed that contrast-enhanced ultrasound with SonoVue was cost effective. The committee felt that the clinical evidence base was weaker for this indication, as noted in the diagnostics assessment report.\n\nThe committee considered several circumstances that would result in contrast-enhanced ultrasound being less cost effective. First, the modelling assumed that all people with diagnoses of hepatocellular carcinoma on characterisation scans, regardless of modality, would have subsequent scans with CT or MRI for treatment planning. The committee heard from experts that although lesions characterised with contrast-enhanced ultrasound would need subsequent CT or MRI scans, focal liver lesions characterised with CT or MRI would not usually need a second scan. The External Assessment Group determined that the extra scans did not add significantly to the overall cost and would not affect the overall cost effectiveness.\n\nThe committee also noted that in the base case, a high proportion of people who had an initial unenhanced ultrasound were assumed to have inconclusive scans (43%, from data supplied by the manufacturer of SonoVue). The committee noted that it was difficult for the External Assessment Group to ascertain accurate estimates for this parameter in people with cirrhosis because of variation in the definition of 'inconclusive' in the studies and clinical practice. The committee heard from clinical experts that this estimate did not reflect clinical practice and that inconclusive scans normally occur in a much lower proportion of people (10–15%) who then need further imaging to characterise their lesion(s). The External Assessment Group reviewed data submitted by the manufacturer and concluded that the percentage of inconclusive unenhanced scans in people with cirrhosis could not be calculated from these data for a variety of reasons, particularly because the data contained estimates that encompassed both non-diagnostic and diagnostic images, and the use of contrast-enhanced ultrasound rather than unenhanced ultrasound in the studies. The committee concluded that the percentage of inconclusive unenhanced ultrasound scans was likely to be nearer 10–15%. At this level, contrast-enhanced MRI with gadolinium was more effective than contrast-enhanced ultrasound and had an ICER of £16,100 per QALY gained. Therefore, contrast-enhanced ultrasound was not a cost-effective option under this circumstance. Contrast-enhanced CT was dominated by contrast-enhanced ultrasound with a 10–15% rate of inconclusive scans. Given the uncertainty in the estimate of the prevalence of inconclusive unenhanced ultrasound scans, particularly in people with cirrhosis, and given that the optimal diagnostic strategy depends on this estimate, the committee recommended further research on this issue (see section\xa07).\n\nThe committee discussed the pressures on MRI departments in the NHS, many of which faced substantially greater demand for MRI than current capacity could supply. It was thought that, from anecdotal evidence, approximately 5.5% of people who would otherwise have been referred for an MRI scan did not have one, either because it was not available or not clinically appropriate (for example, those with a pacemaker) or because they would not tolerate a scan. The committee recommended the use of contrast-enhanced ultrasound with SonoVue for people who would not or could not receive a contrast-enhanced MRI scan.\n\nThe committee also considered whether patient preferences might impact on the selection of imaging modality. Given that contrast-enhanced ultrasound is less expensive than CT or MRI, the small improvements in health-related quality of life arising from CT and particularly MRI might be outweighed by a personal preference for ultrasound over the other modalities. No data on patient preferences were identified by the External Assessment Group's systematic review. The committee recommended research on patient preferences, and their impact on quality of life, for contrast-enhanced ultrasound and other imaging modalities and whether there are likely differences between contrast-enhanced ultrasound and the other imaging modalities (see section 7).\n\nThe committee discussed the level of training needed to perform a contrast-enhanced ultrasound. It was noted that an appropriate level of operator experience was needed to be able to successfully perform contrast-enhanced ultrasound and that currently there was a shortage in appropriately trained sonographers. The committee concluded that it would be desirable to develop a clinical support framework for sharing and discussing experiences of contrast-enhanced ultrasound. Moreover, NHS departments offering contrast-enhanced ultrasound for liver imaging should review whether they have appropriately trained staff and offer training if necessary by using, for example, the minimum training guidelines provided by the EFSUMB.\n\nThe committee noted that the economic analysis was based on the assumption that the contrast-enhanced ultrasound scan would be performed in the same appointment as the unenhanced ultrasound scan. Although alternative scenarios exploring the need to book an additional outpatient appointment (in 50% and 67% of cases) were assessed by the External Assessment Group, this did not affect the results of the economic analysis. The committee stated that there were significant benefits from having contrast-enhanced ultrasound performed in the same appointment as the unenhanced ultrasound scan, including patient convenience and the potential for reducing anxiety by ruling out a malignant lesion sooner. Also, savings from reducing the number of appointments are likely. In the committee's view the potential benefit of reducing anxiety by rapidly ruling out malignancy would be a significant advantage compared with the other imaging modalities and is a consequence of being able to perform contrast-enhanced ultrasound during the same appointment. In the committee's view performing contrast-enhanced ultrasound in the same appointment as unenhanced ultrasound was the optimal model of service delivery.\n\nThe committee considered possible equality impacts. It noted that although obesity may be a general barrier to the use of ultrasound in some people, its impact on image quality on an individual basis is unpredictable. The committee concluded that the recommendations would be unlikely to disadvantage those with obesity or protected groups.", 'Recommendations for further research': "Research is recommended on the percentage of unenhanced ultrasound scans that are inconclusive, particularly in people with cirrhosis. Such studies should explicitly define and describe why scans are 'inconclusive'.\n\nResearch is recommended on patient preferences, and their impact on quality of life, for contrast-enhanced ultrasound and other imaging modalities. Ideally such research should compare all appropriate imaging modalities in the same patient group.", 'Review': 'NICE will update the literature search at least every 3\xa0years to ensure that relevant new evidence is identified. NICE will contact product sponsors and other stakeholders about issues that may affect the value of the diagnostic technology. NICE may review and update the guidance at any time if significant new evidence becomes available.\n\nAndrew DillonChief ExecutiveAugust 2012'}
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https://www.nice.org.uk/guidance/dg5
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Evidence-based recommendations on SonoVue (sulphur hexafluoride microbubbles) for contrast-enhanced ultrasound imaging of the liver.
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2bfad162b2df13a3c3a1470519948b89ea4bea98
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nice
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Bevacizumab in combination with capecitabine for the first-line treatment of metastatic breast cancer
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Bevacizumab in combination with capecitabine for the first-line treatment of metastatic breast cancer
Evidence-based recommendations on bevacizumab (Avastin), with capecitabine, for treating metastatic breast cancer in adults.
# Guidance
Bevacizumab in combination with capecitabine is not recommended within its marketing authorisation for the first-line treatment of metastatic breast cancer, that is, when treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate, or when taxanes or anthracyclines have been used as part of adjuvant treatment within the past 12 months.
People currently receiving bevacizumab in combination with capecitabine that is not recommended according to 1.1 should have the option to continue treatment until they and their clinician consider it appropriate to stop.# The technology
Bevacizumab (Avastin, Roche) is a humanised anti-vascular endothelial growth factor (VEGF) monoclonal antibody that inhibits VEGF-induced signalling and inhibits VEGF-driven angiogenesis. This reduces vascularisation of tumours, thereby inhibiting tumour growth. Bevacizumab is administered by intravenous infusion. Bevacizumab in combination with capecitabine has a marketing authorisation for 'first-line treatment of patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with bevacizumab in combination with capecitabine'.
The summary of product characteristics lists the following adverse reactions that may be associated with bevacizumab treatment: gastrointestinal perforations, fistulae, wound healing complications, hypertension, proteinuria, arterial and venous thromboembolism, haemorrhage, pulmonary haemorrhage/haemoptysis, congestive heart failure, reversible posterior leucoencephalopathy syndrome, hypersensitivity/infusion reactions, osteonecrosis of the jaw, ovarian failure and neutropenia. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Bevacizumab is available in 100 mg and 400 mg vials at net prices of £242.66 and £924.40, respectively (excluding VAT; 'British national formulary' edition 63). The recommended dose is 10 mg/kg body weight given once every 2 weeks or 15 mg/kg body weight given once every 3 weeks. The manufacturer estimated the price of bevacizumab (excluding VAT and assuming wastage) to be £2577 for a patient weighing 72.1 kg at a dosage of 15 mg/kg every 3 weeks, amounting to an average monthly cost of £3689. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of bevacizumab and a review of this submission by the Evidence Review Group (ERG; appendix B).
# Clinical effectiveness
The manufacturer conducted a literature search and identified 2 randomised controlled trials (TURANDOT and RIBBON-1) that investigate the effect of first-line bevacizumab plus capecitabine in adults with metastatic breast cancer. The TURANDOT trial was excluded because it is ongoing and no efficacy data are available. The RIBBON-1 trial was an international, multicentre, double-blind, phase III, randomised, placebo-controlled trial comparing bevacizumab plus chemotherapy with chemotherapy alone for the first-line treatment of HER2-negative, locally recurrent or metastatic breast cancer.
The RIBBON-1 trial enrolled 1237 patients to receive bevacizumab plus chemotherapy or chemotherapy plus placebo. Investigators were able to select their choice of chemotherapy before randomisation. Patients were enrolled into 2 different cohorts; in 1 cohort patients received either an anthracycline or a taxane, and in the other cohort patients received capecitabine, reflecting the choice of first-line therapy for these patients in routine clinical practice. Patients were then randomised to bevacizumab plus the chosen chemotherapy or to the chosen chemotherapy plus placebo. The manufacturer stated that only the results from the capecitabine cohort provided evidence on the use of bevacizumab in its licensed indication, in combination with capecitabine for the first-line treatment of metastatic breast cancer. The manufacturer highlighted that anthracyclines and taxanes were not considered appropriate as first-line treatment for all patients in the capecitabine cohort; about 40% of the patients had previously received taxanes and around 63% had received anthracycline therapy for early breast cancer.
In the capecitabine cohort of the RIBBON-1 trial 615 patients were randomised in a 2:1 ratio to the bevacizumab plus capecitabine arm (n=409) and the capecitabine plus placebo arm (n=206). Randomisation was stratified by the following criteria: disease-free interval (12 months or less, more than 12 months since completion of adjuvant chemotherapy or surgery if no adjuvant chemotherapy); previous adjuvant chemotherapy; and number of metastatic sites (fewer than 3, 3 or more). The dosage of bevacizumab was 15 mg/kg by intravenous infusion every 3 weeks, and the dosage of capecitabine was 1000 mg/m2 orally twice daily for 2 weeks of a 3-week cycle. Treatment was continued until disease progression, unacceptable toxicity, investigator or patient decision to stop treatment, or death. Patients continued to receive capecitabine if bevacizumab was discontinued before disease progression. After disease progression, patients in either arm could move to an open-label phase consisting of treatment including bevacizumab and chemotherapy at the investigator's discretion. Patients who chose not to enter the post-progression phase and patients who discontinued treatment during the post-progression phase were followed up in a survival follow-up phase.
The primary endpoint in the trial was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. It was defined as the time from randomisation to first disease progression or death from any cause. Progression-free survival based on an Independent Review Committee (IRC) review of the data was considered a secondary endpoint and presented as a sensitivity analysis to support the investigator-assessed primary endpoint. Other secondary endpoints included objective response rates, defined as the percentage of patients with a complete or partial response determined on 2 consecutive assessments more than 4 weeks apart; duration of objective response, defined as the time from the first tumour assessment that supported an objective response to the time of disease progression, or death from any cause; overall survival, defined as the time from randomisation until death from any cause; and the 1-year survival rate, defined as the percentage of patients still alive 1 year after randomisation. In addition, progression-free survival and overall survival were calculated for a number of pre-specified subgroups, post hoc exploratory subgroups, and subgroups specified after the trial had begun but before the analysis was completed (for example, the subgroup of patients previously treated with a taxane, which was included in the manufacturer's economic model).
There was a statistically significant increase in the investigator assessed median progression-free survival of 2.9 months, from 5.7 months in the capecitabine plus placebo arm to 8.6 months in the bevacizumab plus capecitabine arm. The stratified hazard ratio for progression was 0.69 (95% confidence interval 0.564 to 0.840, p=0.0002). Median overall survival improved by 2.9 months, from 22.8 months with capecitabine plus placebo to 25.7 months with bevacizumab plus capecitabine. The stratified hazard ratio for death was 0.88 (95% CI 0.69 to 1.13, p=0.33), indicating a 12% improvement in overall survival with bevacizumab plus capecitabine compared with capecitabine plus placebo. However this improvement was not statistically significant. The manufacturer acknowledged that the results from the patients who crossed over to bevacizumab in the open-label post-progression phase of the trial (44.7% in the bevacizumab/capecitabine arm and 52.4% in the capecitabine/placebo arm) may have confounded overall survival results. This was because the trial was not designed to evaluate the effect of subsequent therapies.
A number of subgroup analyses for progression-free survival (16 in total) and for overall survival (24 in total) with no correction for multiple testing were presented in the manufacturer's submission. The manufacturer highlighted that bevacizumab plus capecitabine gave a progression-free survival benefit over capecitabine plus placebo in all of the pre-specified subgroups defined by stratification variables, although not all were statistically significant. The manufacturer investigated a number of additional planned and post hoc subgroups and showed that some subgroups (for example, the group previously treated with a taxane) had a greater overall survival benefit than the intention-to-treat (ITT) population of the capecitabine cohort.
The manufacturer focused on the subgroup of patients who had a previous adjuvant or neo-adjuvant taxane. This subgroup of 245 patients had an increase in median progression-free survival of 4.5 months, from 4.2 months in the capecitabine plus placebo arm to 8.7 months in the bevacizumab plus capecitabine arm. The hazard ratio for progression was 0.62 (95% CI 0.45 to 0.84). This benefit also translated into an overall survival benefit, with an increase in median overall survival of 7.9 months, from 20.5 months in the capecitabine plus placebo arm to 28.4 months in the bevacizumab plus capecitabine arm. The hazard ratio for death was 0.67 (95% CI 0.46 to 0.98). These overall survival results were based on 70 deaths in the bevacizumab plus capecitabine arm and 44 deaths in the capecitabine plus placebo arm. The manufacturer stated that patients previously treated with a taxane had worse outcomes than the patients in the ITT population, and the addition of bevacizumab increased their progression-free survival and overall survival to levels similar to or above those of the ITT population. The manufacturer presented the results of two similar metastatic breast cancer trials (the AVADO and E2100 trials) which demonstrated the same pattern of progression-free and overall survival gains from bevacizumab in patients who have previously received a taxane. The AVADO trial compared bevacizumab plus docetaxel with docetaxel plus placebo, and the E2100 trial compared bevacizumab plus paclitaxel with paclitaxel alone.
The primary safety analyses were based on all patients who received any trial treatment, defined as at least 1 full or partial dose of either trial treatment during the blinded phase of the trial. This population was referred to by the manufacturer as the safety population. The manufacturer stated that adding bevacizumab to capecitabine resulted in adverse events that were predictable based on previous use of bevacizumab, and generally manageable. Grade 3–5 adverse events were higher with bevacizumab plus capecitabine (36.6%) compared with capecitabine plus placebo (22.9%). In addition, the following adverse events were higher with bevacizumab plus capecitabine compared with capecitabine plus placebo: hypertension (10.6% compared with 1%), proteinuria (2.2% compared with 0%), sensory neuropathy (3% compared with 0.5%) and venous thromboembolic events (5% compared with 3.5%).
Health-related quality of life data were not collected in theRIBBON-1 trial. The manufacturer stated that the most important factor causing distress among cancer patients was the fear of disease progression. Therefore a major objective of each successive line of therapy, in addition to extending overall survival, was to maintain progression-free survival for as long as possible.
The ERG stated that the literature search conducted by the manufacturer was appropriate, that all relevant studies had been identified, and that the RIBBON-1 trial on which the manufacturer's submission was based was relevant to the decision problem in its analysis. The ERG stated that the patient population in the trial was in line with the marketing authorisation for bevacizumab in combination with capecitabine. The ERG commented that the trial was well conducted, the baseline characteristics appeared to be balanced across the treatment groups, and the stratification factors were appropriate. The ERG noted that the dose for capecitabine in the trial was 1000 mg/m2 rather than the licensed dose of 1250 mg/m2. However, this was considered appropriate and in line with clinical practice. The ERG stated that the results from the trial could be generalised to patients in the UK.
The ERG noted that the hazard ratios for investigator- and IRC-assessed progression-free survival were almost identical, indicating that the evidence of progression-free survival benefit with bevacizumab plus capecitabine was robust. The ERG was aware that the progression-free survival benefit did not translate into a statistically significant overall survival benefit, but stated that interpreting differences in overall survival was difficult because patients from both the capecitabine plus placebo arm and the bevacizumab plus capecitabine arm were able to cross over to receive bevacizumab in the open-label phase of the trial. Other anticancer therapies were also available on progression, and in a minority of instances before progression, so bias may have been introduced.
The ERG noted the subgroup analyses conducted by the manufacturer, and commented that most increases in progression-free survival with bevacizumab plus capecitabine compared with capecitabine plus placebo were statistically significant in these subgroups. However, the only overall survival results that were statistically significant were for subgroups of patients younger than 50 years and subgroups of patients previously treated with a taxane or anthracycline as neoadjuvant or adjuvant chemotherapy. The ERG stated that the results of the subgroup analyses should be considered with caution because no statistical adjustments were performed to control for multiple testing in any of the 40 subgroups and of all outcomes, thus increasing the likelihood of significant results emerging by chance when using the usual level of significance of 5%.
The ERG agreed that there was a greater proportion of adverse events in the bevacizumab plus capecitabine arm, but that no new safety concerns were identified. The ERG also agreed that bevacizumab plus capecitabine did not lead to a clinically relevant increase in adverse events typically associated with chemotherapy, such as febrile neutropenia, neutropenia, and sensory neuropathy. The ERG stated that the difference in adverse events between the 2 arms could largely be attributed to differences in grade 3 adverse events (27% in the bevacizumab plus capecitabine arm compared with 14% in the capecitabine plus placebo arm).
Regarding the safety of bevacizumab plus capecitabine compared with capecitabine plus placebo in the subgroup of people who had previously received a taxane, the ERG stated that it was not possible to compare the proportions of patients who experienced any adverse events, any grade 3–5 adverse events, any serious adverse events or any adverse events leading to discontinuation of bevacizumab or placebo because the manufacturer did not present these data. The ERG extracted some data from the economic model, and stated that adverse events of special interest mostly appeared to be similar in frequency in the subgroup and in the overall trial population. A slightly greater proportion of patients in the subgroup reported grade 3 or higher cardiac disorders (4.4%) than in the overall safety population (2.1%). However, the ERG stated that these findings must be viewed with caution because of the small numbers of patients in this subgroup.
# Cost effectiveness
In a systematic review of the literature the manufacturer found no cost-effectiveness studies comparing bevacizumab plus capecitabine with capecitabine plus placebo as first-line treatments for metastatic breast cancer. No relevant cost-effectiveness analyses were identified. The economic evaluation was based on the subgroup of patients from the RIBBON-1 trial who had previously received a taxane, and all efficacy and treatment duration parameters were derived from this subgroup. The manufacturer assumed that patients in this subgroup would probably have received an anthracycline as well. The manufacturer stated that this subgroup reflected the marketing authorisation for capecitabine. Capecitabine monotherapy has a marketing authorisation for 'the treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated'. The manufacturer acknowledged that this post hoc subgroup analysis of patients previously treated with a taxane was the main weakness of the economic evaluation.
The manufacturer developed a 3-state model. All patients enter the model in the progression-free survival health state and in each month can either progress to a 'worse' health state (that is, from progression-free survival to progressed disease or from either state to death) or remain in the same health state. The manufacturer stated that these health states were consistent with previous modelling of metastatic cancer. The progression-free survival health state is designed to capture a patient's relatively high quality of life before disease progression and the progressed disease state is designed to capture the relatively poor quality of life after disease progression. Survival data from the capecitabine plus placebo arm of the subgroup previously treated with a taxane from the RIBBON-1 trial were used to inform disease progression in the comparator arm. The treatment duration in the trial was used to determine the expected cost of treatment with each regimen in the base case. The model has a 1-month cycle length, includes a half-cycle correction and both costs and benefits are discounted at 3.5%. The time horizon was 15 years.
The proportions of patients who are progression-free in each month were taken directly from Kaplan-Meier survival curves for each treatment arm in the RIBBON-1 trial until the 12th month of treatment, after which an exponential distribution of survival time was assumed. The number of patients in each treatment arm dying from any cause while in the progression-free survival state was used to derive a constant rate and probability of mortality. The mortality rate in the progression-free survival state was assumed to be at least as great as the underlying sex- and age-related mortality in the general population.
A number of tunnel states, health states which can only be passed through in a certain order, were generated for patients with progressed disease according to the time spent in this state. The tunnel states were arranged so that each state had a progression only to death or the next temporary state. Patients who entered the progressed disease state had a probability of dying that increased each month based on an extrapolation of the survival data for patients with progressed disease. Mean overall survival was the sum of mean duration of progression-free survival and mean duration of progressed disease.
During the progressed disease phase, patients in the capecitabine cohort of the RIBBON-1 trial received a variety of different therapies. The manufacturer modelled survival in progressed disease based on adjusted analyses that aimed to 'uncross' the survival curves by excluding survival gains from patients who crossed over to bevacizumab in the open-label phase of the trial. An exponential survival distribution was assumed thereafter. The data were 'uncrossed' using a rank preserving structural failure time model to take account of the bias that may have been introduced by allowing patients from both treatment arms to receive bevacizumab after progression, potentially distorting overall survival rates in the control arm.
The manufacturer carried out a literature review to identify relevant health-related quality of life data to use in the economic evaluation. Three studies that measured utility values directly were identified and, of these, the manufacturer calculated utility values for progression-free survival and progressed disease from the results of the mixed model analysis presented by Lloyd et al. (2006). The manufacturer stated that it was most appropriate to use a base-case progression-free survival utility value that was derived from a large population, and then to adjust that base-case utility by response rate. In addition, the utility values from Lloyd et al. have been used in previous health technology appraisals for metastatic breast cancer. For patients in the progressed disease state, a health state utility value of 0.496 was incorporated in both treatment arms. For patients in the progression-free survival state a treatment-specific weighted average of the values for stable disease and treatment response, based on the reported overall response rate, was calculated: 0.784 in the bevacizumab plus capecitabine arm and 0.774 in the capecitabine plus placebo arm. The manufacturer acknowledged that the utility values reported by Lloyd et al. were not derived from patient experience, and presented a sensitivity analysis using data from Peasgood et al. (2010) to derive estimated utilities from patients valuing their own health.
The drug costs incorporated in the model for bevacizumab plus capecitabine and capecitabine were from BNF 62 (£4001.53 per month and £312.41 per month respectively). No vial sharing was assumed for bevacizumab. The manufacturer's submission assumed administration and pharmacy costs of £348.82 in the first month and £205.97 per month for subsequent months of treatment with bevacizumab and capecitabine. Administration and pharmacy costs for capecitabine alone were assumed to be £255.32 per month. The manufacturer stated that in clinical practice some patients stop treatment before disease progression, and therefore it is essential to consider the distinction between disease progression and treatment discontinuation when evaluating the real incremental cost. In order to account for this difference, patient data on treatment duration were used to produce 'time to off treatment' Kaplan-Meier curves that could be used to determine the proportion of patients still receiving bevacizumab and/or capecitabine each month.
Progression-free survival health state costs were based on Advanced breast cancer: diagnosis and treatment (NICE clinical guideline 81) 'package 1' with the addition of an outpatient consultation with an oncologist and a computed tomography (CT) scan assumed to occur every 3 months, and were estimated to be £263.55 per month. Progressed disease health state costs were based on NICE clinical guideline 81 'package 2' and estimated to be £804.00 per month. The same costs and utilities were assumed regardless of first-line treatment. Adverse events of grade 3 or 4 severity occurring in greater than 2% of patients were incorporated into the analysis. When clinical advice indicated that the usual response to the adverse event was discontinuation of treatment (for peripheral sensory neuropathy, hand-foot syndrome and proteinuria), it was assumed this had been accounted for elsewhere in the model and no additional costs were accrued. In addition, treatment of diarrhoea was considered to have negligible contribution to costs. Therefore only costs associated with deep vein thrombosis and hypertension were included in the model. All adverse events were assumed to occur in month 1 for both treatment arms and were therefore not discounted.
The manufacturer did not include terminal care costs in the model, stating that these would refer to costs in the last 2 weeks of life and would therefore have a minimal impact on the ICER irrespective of the regimen received. In addition, no second-line treatment costs were included in the model because it was assumed that the duration of second-line treatment would be the same for a patient receiving first-line bevacizumab plus capecitabine as for a patient receiving first-line capecitabine alone, and the second-line costs in each arm would cancel each other out.
The base-case results indicated incremental costs of £38,924 and incremental QALYs of 0.5034 for bevacizumab plus capecitabine compared with capecitabine alone. The cost per QALY gained was £77,318 for bevacizumab plus capecitabine compared with capecitabine alone. The manufacturer conducted deterministic sensitivity analyses for a range of parameters. The manufacturer stated that the cost-effectiveness results were most sensitive to the costs and utilities associated with progressed disease.
The manufacturer conducted a scenario analysis using utility values from Peasgood et al. but this had little impact on the ICER and did not result in it increasing above £79,991 per QALY gained. A second scenario analysis was conducted including different formulations of vinorelbine as the comparator. It was assumed that vinorelbine had an equivalent efficacy and safety profile to capecitabine, with different list prices and costs of administration. The ICER was £58,972 per QALY gained for bevacizumab plus capecitabine compared with oral vinorelbine, £76,198 per QALY gained compared with branded intravenous vinorelbine, and £80,260 per QALY gained compared with generic intravenous vinorelbine.
The manufacturer conducted a probabilistic sensitivity analysis and concluded that bevacizumab plus capecitabine compared with capecitabine alone had a 0% probability of being cost effective if the maximum acceptable ICER was £30,000 to £50,000 per QALY gained. In response to consultation, the manufacturer provided the ICER based on the probabilistic sensitivity analysis, which was £80,073 per QALY gained for bevacizumab plus capecitabine compared with capecitabine alone (mean incremental costs were £40,161 , mean incremental QALYs were 0.502 ).
The manufacturer acknowledged that its economic evaluation was only relevant to patients with similar characteristics to those randomised to the capecitabine cohort of the RIBBON-1 trial who had previously been treated with a taxane. The ERG requested additional cost-effectiveness data for the ITT population of the capecitabine cohort for clarification. However, the manufacturer stated that because the submitted analysis calculated an ICER of £77,318 per QALY gained for the subgroup previously treated with a taxane, analysis of the ITT population would result in a larger ICER and therefore would not be considered a cost-effective use of NHS resources.
The ERG had concerns about the population used in the manufacturer's economic model. The ERG highlighted that the manufacturer had based its economic modelling on the subgroup of patients who had previously been treated with a taxane, because the manufacturer considered this population to represent the population for whom capecitabine is licensed: patients with metastatic breast cancer after failure of taxanes and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated. The ERG agreed that most patients in this subgroup would probably have previously received an anthracycline in addition to a taxane. However, the ERG questioned whether their treatment would be considered to have failed because the RIBBON-1 trial excluded patients who had received an adjuvant taxane or anthracycline in the last 12 months. The ERG did not consider the subgroup of patients who had previously received a taxane to be the appropriate group of patients. The ERG considered the ITT population in the capecitabine cohort to be the appropriate population because it represents the population in the final scope issued by NICE and the population specified in the marketing authorisation for bevacizumab. In addition, the ERG identified that there appeared to be baseline differences between the subgroup of patients who had previously received a taxane and the ITT population. In particular, the ERG noted from differences in the mean and median age and Eastern Cooperative Oncology Group (ECOG) performance status that the population of patients who had previously received a taxane appeared to be younger and healthier. The ERG also noted that the differences in progression-free and overall survival between the bevacizumab plus capecitabine and capecitabine plus placebo arms appeared to be greater in the subgroup of patients previously treated with a taxane than in the ITT population, as well as being statistically significant. However, the ERG reiterated that because no statistical adjustments were made to control for multiple testing in all subgroups and of all outcomes, these findings may have occurred by chance, and must be interpreted with caution.
The ERG raised some concerns about the structure and design of the manufacturer's economic model. The ERG noted that the manufacturer adapted a model structure previously used in NICE appraisals of cancer drugs. However, the ERG raised concerns that although the model covered a period of 15 years, no further chemotherapy was considered within the model following disease progression after treatment with bevacizumab plus capecitabine or capecitabine alone. This could have led to substantial bias, because if progression-free survival differed between the arms, the discounted costs and benefits of subsequent treatments would also have differed. Further, if the proportion of patients able to receive subsequent lines of therapy differed between the arms then the costs and outcomes would also have been different.
The ERG was satisfied that the modelling approach used by the manufacturer to estimate progression-free survival from the RIBBON-1 trial using Kaplan-Meier methods for the first 12 months and assuming an exponential distribution thereafter was credible. The ERG noted that the approach was similar for progressed disease, however the manufacturer had 'uncrossed' the data using the rank preserving structural failure time model to minimise bias. The ERG stated that this approach was unsuitable when a large proportion of patients from both arms cross over. The ERG noted that 44.7% of patients in the bevacizumab plus capecitabine arm and 52.4% of patients in the capecitabine plus placebo arm received bevacizumab after disease progression. Further, patients in the modelled subgroup who previously received a taxane also received other therapies after progression. The ERG stated that given the limitations of the rank preserving structural failure time model and without any other estimate to adjust for crossover, they were unable to confirm the likely effect of the crossover and post-progression therapies on overall survival in this subgroup and caution should be exercised when interpreting the manufacturer's overall survival results.
The ERG undertook an analysis of the original progressed disease trial data (rather than the 'uncrossed' data) to explore survival during this phase. This analysis separated the bevacizumab plus capecitabine and capecitabine plus placebo arms according to whether patients had crossed over to a different treatment or not. A comparison of survival times during the progressed disease phase indicated that survival is similar in each group and overall, the 4 groups in the RIBBON-1 trial did not show strong evidence of heterogeneity. However, the capecitabine plus placebo group with no crossover appeared to differ when tested pairwise against the other 3 groups. Therefore, the ERG explored 2 different scenarios. The first scenario grouped all patients together and modelled a scenario in which survival after progression was equivalent irrespective of first-line therapy or crossover (common projection scenario). This method resulted in an ICER of £171,411 per QALY gained for bevacizumab plus capecitabine compared with capecitabine alone. The second scenario grouped together all the bevacizumab plus capecitabine patients and the capecitabine plus placebo patients who crossed over, and considered the capecitabine plus placebo patients who did not cross over separately (different projections scenario). This method resulted in an ICER of £92,060 per QALY gained for bevacizumab plus capecitabine compared with capecitabine alone. The ERG stated that the second scenario allowed a clear comparison between patients who did and did not receive bevacizumab during the trial and gives a representation of the effect of crossover. The ERG highlighted that each analysis portrayed an extreme, allowing consideration of a best and worst case scenario for the effect of crossover on post-progression survival.
The ERG conducted a sensitivity analysis to study the impact of including the licensed dose of capecitabine (1250 mg/m2) rather than the dose widely used in clinical practice (1000 mg/m2). It found that changing the dose of capecitabine to 1250 mg/m2 results in an overall incremental increase in drug costs of £3782 and an accompanying increase of £7512 per QALY gained in the ICER estimate. The ERG re-estimated the costs of therapy based on the distribution of patient body weight and body surface area in a UK-specific cohort of patients rather than using a simple average based on trial data. The ERG found that this resulted in an increase in drug costs of £2966 per patient in the bevacizumab plus capecitabine arm and an increase of £50 per patient in the capecitabine alone arm. The adjustment resulted in a revised ICER that was £5793 higher per QALY gained than the manufacturer's base-case ICER. The ERG also added in the costs of terminal care during the last 2 weeks of life, as specified in the guideline on Advanced breast cancer: diagnosis and treatment (NICE clinical guideline 81), and these adjustments resulted in a revised ICER that was £105 lower per QALY gained than the manufacturer's base-case ICER.
The ERG noted that the utility values used in the manufacturer's model were estimated using the statistical model detailed in a study by Lloyd et al. The ERG noted that there is a lack of consensus among economists in relation to the most appropriate value for age in the Lloyd et al. model, that is, whether it should be the age of the population surveyed in the study or the age of the population taking part in the original health state valuation exercise carried out by Kind et al. (1999). The ERG noted that the manufacturer used 47 years, the mean age of the population taking part in the original Kind et al. study, with the advantage that it was consistent with standard UK EQ-5D tariff scores. However, the ERG stated that the lack of consensus relating to the most appropriate age to use introduces a degree of uncertainty to the utility values used in the model. The ERG also corrected for a typing mistake in the formula used in the manufacturer's model in the capecitabine alone arm and this resulted in a revised ICER that was £786 lower per QALY gained than the manufacturer's base-case ICER.
The combined impact of the ERG's revisions to the drug costs, terminal care costs and utility estimates in the manufacturer's base case resulted in an ICER of £82,162 per QALY gained for bevacizumab plus capecitabine compared with capecitabine alone. In addition, combining these revisions with the revised progressed disease estimates resulted in an ICER of £181,648 per QALY gained when using the common projection scenario and £97,963 per QALY gained when using the different projections scenario. The ERG also agreed with the manufacturer that the base-case ICER cannot be considered to be generalisable to the whole population covered by the marketing authorisation and that it was likely to be higher than the ICER for the modelled subgroup.
Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from # Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab in combination with capecitabine, having considered evidence on the nature of metastatic breast cancer and the value placed on the benefits of bevacizumab in combination with capecitabine by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee considered the clinical need for treatment in patients with metastatic breast cancer for whom treatment with other chemotherapy options, including taxanes or anthracyclines, is not considered appropriate. The Committee heard from the clinical specialist that there was broad agreement among breast cancer specialists that the case for incorporating bevacizumab into first-line treatment was stronger for patients with triple negative breast cancer (breast cancer that is oestrogen-, progesterone- and HER2-receptor negative) with aggressive visceral disease, for whom there were limited treatment options. The Committee heard from the patient expert and clinical specialist that prolonging progression-free survival was very important for patients with advanced breast cancer, but this had to be coupled with maximising quality of life at the same time. The adverse events associated with treatment were therefore also of significance, as was the method of administration and convenience of therapy. The Committee concluded that bevacizumab plus capecitabine represented an option for patients with limited treatment options, and that an improvement in progression-free survival combined with a quality of life benefit, and the adverse event profile were key considerations.
# Clinical effectiveness
The Committee considered the generalisability of the RIBBON-1 trial to UK clinical practice. The Committee was aware of NICE clinical guideline 81 for advanced breast cancer in which capecitabine follows both anthracycline and taxane therapy in the care pathway. It noted the design of the RIBBON-1 trial, which had 2 cohorts of patients; those to be treated with anthracyclines or a taxane and those to be treated with capecitabine. The Committee noted that 63% of the capecitabine cohort had received prior anthracycline therapy and 40% had received prior taxane therapy. Because there was likely to have been considerable overlap between these 2 groups (and perhaps total overlap, as assumed by the manufacturer), a significant percentage of patients (up to 37%) could have received capecitabine for first-line treatment of their metastatic breast cancer as their first ever chemotherapy. The Committee considered that this meant that this group of patients was not representative of the typical UK metastatic breast cancer population. The Committee also noted that the 60% of patients in the capecitabine cohort of the RIBBON-1 trial who had not received prior taxane therapy had good performance status and yet taxane treatment was not considered appropriate for them. In addition, the Committee observed that 30% of the patients in the prior taxane subgroup for whom taxanes were not considered appropriate (as indicated by the entry criteria for the capecitabine arm of the RIBBON-1 trial) subsequently received taxanes after disease progression. However, the Committee was aware that the decision to treat with capecitabine or a taxane could also be based on other factors which may be important to patients, such as the lack of hair loss with capecitabine. The Committee concluded that there were still some issues about the generalisability of the RIBBON-1 trial to clinical practice in the UK. This was because a significant proportion of patients in the trial had not received previous chemotherapy, and taxanes had not been considered for a significant proportion despite their young age and good performance status.
The Committee also noted that the dose of capecitabine in the trial was 1000 mg/m2 rather than the licensed dose of 1250 mg/m2. The Committee was aware that the dose of capecitabine used in UK practice was often lower in older patients and those with poor performance status, but observed that all patients in the RIBBON-1 trial were of ECOG performance status 0 or 1 and the median age was 56 years. However, it noted the comments during consultation that some clinicians in the UK start at a dose lower than the licensed dose (often 1000 mg/m2) even in fitter patients. The Committee therefore concluded that the dose of capecitabine used in the trial may have some relevance to clinical practice in the UK.
The Committee considered the clinical-effectiveness data from the capecitabine cohort of the RIBBON-1 trial for the comparison of bevacizumab plus capecitabine with capecitabine plus placebo. The Committee noted that the results from the ITT population demonstrated a statistically significant median investigator-assessed progression-free survival benefit of 2.9 months for bevacizumab plus capecitabine compared with capecitabine plus placebo. However, the Committee noted this improvement in progression-free survival did not translate into a statistically significant improvement in overall survival. The Committee was aware that patients from both arms of the trial could receive treatment with bevacizumab after disease progression as well as other subsequent treatments and that all these subsequent therapies could have confounded the relative treatment effect in terms of overall survival. The Committee also noted that no quality of life data had been collected in the trial. The Committee considered quality of life to be an important outcome measure in advanced cancer and that this was an omission from the trial. Without quality of life data and a statistically significant improvement in overall survival, the Committee explored the value of an increase in progression-free survival. The Committee was aware of a statement from the clinical specialist that the most important outcome for patients with metastatic breast cancer is prolonging disease-free survival. However, the Committee heard from the patient expert that patients would value an increase in progression-free survival when it is accompanied by an improvement in quality of life that would allow them to carry out normal daily activities. The Committee concluded that bevacizumab plus capecitabine improved progression-free survival relative to capecitabine plus placebo, but that there was no robust evidence that it improved overall survival and that its effects on health-related quality of life had not been captured.
The Committee discussed the adverse event profile associated with bevacizumab plus capecitabine compared with capecitabine plus placebo. The Committee noted that grade 3–5 adverse events were higher with bevacizumab plus capecitabine (36.6%) compared with capecitabine plus placebo (22.9%). In addition, the number of patients with hypertension, proteinuria, sensory neuropathy and venous thromboembolic events was higher with bevacizumab plus capecitabine compared with capecitabine plus placebo. The Committee considered that the adverse event profile of bevacizumab plus capecitabine was particularly important because if people opt for capecitabine instead of taxane-based treatment it may be an indication that a better adverse event profile was important to them. The Committee concluded that bevacizumab plus capecitabine had a less favourable adverse event profile than capecitabine plus placebo.
The Committee noted that no clinical evidence of the effectiveness of bevacizumab plus capecitabine compared with vinorelbine was presented by the manufacturer as specified in the final scope issued by NICE. The Committee noted the manufacturer's statement that capecitabine is generally preferred to vinorelbine in in UK clinical practice and that vinorelbine had been included as a comparator as part of the scenario analysis in the economic modelling. The Committee concluded that, without studies that would allow for an indirect comparison of bevacizumab plus capecitabine with vinorelbine, and without evidence to suggest that vinorelbine was superior to capecitabine, it was appropriate for capecitabine to be presented as the main comparator.
The Committee examined the subgroup analysis conducted by the manufacturer comparing bevacizumab plus capecitabine with capecitabine plus placebo in patients who had previously received a taxane. The Committee was aware that the differences in progression-free and overall survival between the bevacizumab plus capecitabine and capecitabine plus placebo arms were statistically significantly greater in this subgroup of patients. However, the Committee noted that previous taxane therapy was not a stratification factor at randomisation and that this subgroup was specified after the trial had begun but before the analysis was completed. The Committee also noted that the overall survival results were based on small numbers of events: 70 deaths in the bevacizumab plus capecitabine arm and 44 deaths in the capecitabine plus placebo arm. In addition, the Committee was aware that no statistical adjustments were made to control for multiple testing, thus increasing the risk of chance findings. The Committee considered the manufacturer's original submission and their consultation comments about an increased benefit observed in the prior taxane subgroup compared with the ITT population in other metastatic breast cancer trials of bevacizumab as part of first-line chemotherapy (the AVADO and E2100 trials). The Committee noted that although the prior taxane subgroups showed significant benefits with bevacizumab in the AVADO and E2100 trials, the benefits were not replicated in the prior taxane subgroup in the anthracycline/taxane cohort of RIBBON-1. The Committee heard from the clinical specialist that the prior taxane subgroup was a clinically relevant subgroup given the current treatment pathway of metastatic breast cancer. The Committee also noted the comment from the consultees and clinical specialist that women with triple negative breast cancer for whom there are limited treatment options are the most clinically relevant subgroup, with a realistic chance of benefitting from bevacizumab plus capecitabine treatment. However, the Committee was aware that the RIBBON-1 trial results did not show an advantage for bevacizumab plus capecitabine in this triple negative subgroup. The Committee was concerned about the robustness of the data from the AVADO and E2100 trials because of the small patient numbers in the prior taxane subgroups in the AVADO and E2100 trials and the unblinding and non-stratification for prior taxane use in the E2100 trial. It noted that although the progression-free survival and overall survival benefits were higher in the prior taxane subgroups in the E2100, AVADO and the capecitabine cohort of the RIBBON-1 trials, there was no biologically plausible reason why bevacizumab plus capecitabine would be more effective in this subgroup than in the ITT population. The Committee therefore considered that a formal study would be needed to confirm these benefits, as had been recognised by the manufacturer. The Committee concluded that the results from the prior taxane subgroup of the RIBBON-1 trial were not sufficiently robust to use for the development of guidance.
# Cost effectiveness
The Committee considered the manufacturer's economic model and the ERG's critique of this model. The Committee was aware that the manufacturer had based the economic evaluation on the subgroup of patients who had previously received a taxane rather than the Committee's preferred choice of the whole capecitabine cohort (the ITT population). The Committee noted the manufacturer's and ERG's statements that an analysis of the ITT population would result in a larger ICER than the £77,000 per QALY gained for the subgroup included in the manufacturer's base-case analysis. The Committee agreed with this assessment. The Committee considered the ERG critique and explorations of the manufacturer's model to determine the most plausible ICER for the subgroup previously treated with a taxane. The aim was to establish a benchmark for the incremental cost per QALY gained for the ITT population.
The Committee noted the explorations made by the ERG to the economic model:
basing costs on the distribution of patient body weight and body surface area in a UK-specific cohort of patients rather than using a simple average based on trial data
including costs of terminal care during the last 2 weeks of life
correcting a typing mistake in the calculation of utilities.The Committee noted that these changes resulted in the ERG's estimated ICER of £82,000 per QALY gained for bevacizumab plus capecitabine compared with capecitabine alone. The Committee concluded that these explorations were appropriate.
The Committee noted the ERG's concerns around the rank preserving structural failure time method used by the manufacturer to account for the effect of crossover to open-label bevacizumab in the modelling of survival in the progressed disease state. The Committee discussed the ways in which the analyses were adjusted for crossover by the manufacturer and the ERG. The Committee was unclear as to whether these were appropriate (or whether any other method would be appropriate) or would introduce potential bias because about half the patients in both arms of the trial crossed over to have open-label bevacizumab after disease progression. The Committee also noted that the subsequent treatments received had not been modelled, which in combination with the impact of crossover, could have led to confounding of the overall survival results. The ERG confirmed that it had not been possible to estimate the effect of these factors on overall survival. The Committee noted that 60% of the manufacturer's base-case QALY gain was from the progressed disease phase and it was unsure of the impact of crossover on this finding. The Committee concluded that given these uncertainties, the manufacturer's modelled overall survival results could not be considered robust.
The Committee noted that in the manufacturer's model, the costs of administration and pharmacy time from the second cycle onwards was £255 in the capecitabine alone arm and £206 in the bevacizumab plus capecitabine arm. The Committee discussed that it was unexpected that the costs associated with bevacizumab plus capecitabine would be lower than the costs for capecitabine alone. The Committee accepted that although these costs were based on NHS reference costs, it would have been possible to generate more plausible values. The Committee concluded that despite the incorporation of NHS tariffs, the discrepancy in the costs of administration and pharmacy time contributed to the uncertainty associated with the results of the manufacturer's economic model.
The Committee noted that the ERG had carried out an exploratory analysis of the progressed disease trial data to explore survival during this phase, assuming equal survival in each arm of the model (common projection scenario) as well as assuming different survival in each arm of the model depending on what the first treatment was (different projections scenario). The Committee noted that this analysis, in combination with the rest of the ERG changes, resulted in an ICER of £182,000 per QALY gained for the common projection model and £98,000 per QALY gained for the different projections model for bevacizumab plus capecitabine compared with capecitabine alone. In addition, the Committee was also aware that a disutility for adverse events had not been applied in the manufacturer's model, despite utility estimates being available in the literature to account for adverse events, and it was likely that this could have resulted in underestimated ICERs. The Committee concluded that given all of the uncertainties, it was not possible to determine the most plausible ICER for bevacizumab plus capecitabine compared with capecitabine alone for the subgroup of patients who were previously treated with a taxane. However, it was convinced that the ICER would be higher than the most optimistic ICER of £82,000 per QALY gained resulting from the ERG explorations. The Committee considered that the ICER for bevacizumab plus capecitabine compared with capecitabine alone in the ITT population would be even higher (see section 4.9). The Committee noted the comments received during consultation, but considered that there was no evidence to alter its conclusion that the ICER for bevacizumab plus capecitabine compared with capecitabine alone would be higher than £82,000 per QALY gained. The Committee concluded that given the lack of robust evidence of survival benefit supplemented by the high ICER, bevacizumab plus capecitabine as a first-line treatment for metastatic breast cancer was not a cost-effective use of NHS resources.
The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of people with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case of the economic modelling are plausible, objective and robust.
The Committee discussed whether bevacizumab plus capecitabine for the first-line treatment of metastatic breast cancer fulfilled the criteria for a life-extending, end-of-life treatment. The Committee noted that bevacizumab is licensed for a relatively large population across a range of indications in the treatment of breast, colorectal, renal and non-small-cell lung cancers. Therefore, it does not meet the criterion of the supplementary advice that the treatment should be licensed for small populations. Having established that bevacizumab did not meet the population criterion, the Committee decided it was not necessary to make a decision about the life expectancy or extension to life criteria. The Committee concluded on this basis that bevacizumab plus capecitabine did not fulfil the criteria for being a life-extending, end-of-life treatment.
The Committee recognised the novel mode of action of bevacizumab, which may benefit breast cancer patients whose treatment options are limited. However, it considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations. The Committee therefore concluded that the innovative aspects of bevacizumab were already incorporated in the economic model and it did not alter its decision on the cost effectiveness of bevacizumab in combination with capecitabine.
# Summary of Appraisal Committee's key conclusions
TA263 (STA)
Appraisal title: Bevacizumab in combination with capecitabine for the first-line treatment of metastatic breast cancer
Section
Key conclusion
Bevacizumab in combination with capecitabine is not recommended within its marketing authorisation for the first-line treatment of metastatic breast cancer, that is, when treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate, or when taxanes or anthracyclines have been used as part of adjuvant treatment within the past 12 months.
The Committee considered that the results from the manufacturer's economic analysis, based on a subgroup of patients who were previously treated with a taxane, were not robust. The Committee was not able to determine the most plausible ICER for this subgroup but was convinced it would be higher than the ICER of £82,000 per QALY gained resulting from the ERG explorations. The Committee considered that the ICER for the ITT population would be even higher.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee heard from the patient expert and clinical specialist that prolonging progression-free survival was very important for patients with advanced breast cancer, but this had to be coupled with maximising quality of life at the same time. The Committee concluded that bevacizumab plus capecitabine represented an option for patients with limited treatment options, and that an improvement in quality of life benefit, and the adverse event profile were key considerations.
The technology
Proposed benefits of the technology
The Committee concluded that bevacizumab plus capecitabine improved progression-free survival relative to capecitabine plus placebo, but that there was no robust evidence that it improved overall survival and that its effects on health-related quality of life had not been captured.
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee concluded that the innovative aspects of bevacizumab were already incorporated in the economic model and that there were no additional gains in health-related quality of life over those already included in the QALY calculations.
What is the position of the treatment in the pathway of care for the condition?
Bevacizumab in combination with capecitabine has a marketing authorisation for 'first-line treatment of patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with bevacizumab in combination with capecitabine'.
Adverse reactions
The Committee noted that grade 3–5 adverse events were higher with bevacizumab plus capecitabine (36.6%) compared with capecitabine plus placebo (22.9%). In addition, the number of patients with hypertension, proteinuria, sensory neuropathy and venous thromboembolic events was higher with bevacizumab plus capecitabine compared with capecitabine plus placebo. The Committee concluded that bevacizumab plus capecitabine had a less favourable adverse event profile than capecitabine plus placebo.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
Data from the capecitabine cohort of the RIBBON-1 trial formed the clinical-effectiveness evidence in the manufacturer's submission.
The Committee noted that no quality of life data had been collected in the trial. The Committee considered quality of life to be an important outcome measure in advanced cancer and that this was an omission from the trial.
Relevance to general clinical practice in the NHS
The Committee noted that 60% of patients in the capecitabine cohort of the RIBBON-1 trial had not received prior taxane therapy, had good performance status and yet taxane treatment was not considered appropriate for them.
The Committee also noted that the dose of capecitabine in the trial was 1000 mg/m2 rather than the licensed dose of 1250 mg/m2. The Committee was aware that the dose of capecitabine used in UK practice was often lower in older patients and those with poor performance status, but observed that all patients in the RIBBON-1 trial were of ECOG performance status 0 or 1 and the median age was 56 years. However, the Committee considered the comments during consultation that some clinicians in the UK start at a dose lower than the licensed dose (often 1000 mg/m2) even in fitter patients. The Committee concluded that the dose of capecitabine used in the trial may have some relevance to clinical practice in the UK.
Uncertainties generated by the evidence
The Committee was aware that patients from both arms of the trial could receive treatment with bevacizumab after disease progression as well as other subsequent treatments and that all these subsequent therapies could have confounded the relative treatment effect in terms of overall survival. The Committee also noted that no quality of life data had been collected in the trial. The Committee concluded that bevacizumab plus capecitabine improved progression-free survival relative to capecitabine plus placebo, but that there was no robust evidence that it improved overall survival and that its effects on health-related quality of life had not been captured.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee examined the subgroup analysis conducted by the manufacturer comparing bevacizumab plus capecitabine with capecitabine plus placebo in patients who had previously received a taxane. However, the Committee noted that previous taxane therapy was not a stratification factor at randomisation and that this subgroup was specified after the trial had begun but before the analysis was completed. The Committee also heard that the overall survival results were based on small numbers of events and that no statistical adjustments were made to control for multiple testing, thus increasing the risk of chance findings. The Committee considered that there was no biologically plausible reason why bevacizumab plus capecitabine would be more effective in this subgroup than in the ITT population. The Committee concluded that the results from the prior taxane subgroup of the RIBBON-1 trial were not sufficiently robust to use for the development of guidance.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee noted that the results from the ITT population demonstrated a statistically significant median investigator-assessed progression-free survival benefit of 2.9 months for bevacizumab plus capecitabine compared with capecitabine plus placebo.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee considered the cost effectiveness of bevacizumab and capecitabine compared with capecitabine alone based on the manufacturer's model and critique by the ERG.
The Committee was aware that the manufacturer had based the economic evaluation on the subgroup of patients who had previously received a taxane rather than the Committee's preferred choice of the whole capecitabine cohort (the ITT population). The Committee noted the manufacturer's and ERG's statements that an analysis of the ITT population would result in a larger ICER than for the subgroup included in the base-case analysis. The Committee agreed with this assessment.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted the explorations made by the ERG to the costs of therapy and concluded that these adjustments were appropriate.
The Committee noted the ERG's concerns around the rank preserving structural failure time method used by the manufacturer to account for the effect of crossover to open-label bevacizumab in the modelling of survival in the progressed disease state. The Committee discussed the ways in which the analyses were adjusted for crossover but was unclear as to the most appropriate method without introducing bias. The Committee also noted that the subsequent treatments had not been modelled, which in combination with the impact of crossover, could have led to confounding of the overall survival results.
The Committee discussed that it was unexpected that the costs of administration and pharmacy time associated with bevacizumab plus capecitabine would be lower than the costs for capecitabine alone. The Committee concluded that despite the incorporation of NHS tariffs, this discrepancy contributed to the uncertainty associated with the results of the manufacturer's economic model.
The Committee was also aware that a disutility from adverse events had not been applied in the manufacturer's model, despite utility estimates being available in the literature to account for adverse events, and it was likely that this could have resulted in underestimated ICERs.
Incorporation of health-related quality of life benefits and utility values
The Committee noted that no quality of life data had been collected in the trial and that the economic analysis included utility values from a literature review. The Committee was also aware that a disutility for adverse events had not been applied in the manufacturer's model, despite utility estimates being available in the literature to account for adverse events, and it was likely that this could have resulted in underestimated ICERs.
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee recognised the novel mode of action of bevacizumab, which may benefit breast cancer patients whose treatment options are limited. However, it considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee concluded that the results from the prior taxane subgroup of the RIBBON-1 trial were not sufficiently robust to use for the development of guidance. The Committee only considered the economic analysis based on this subgroup to establish a benchmark for the incremental cost per QALY gained for the ITT population.
What are the key drivers of cost effectiveness?
The costs of therapy adopted in the manufacturer's model, the impact of crossover and lack of modelling of subsequent treatments were key drivers of uncertainty around cost effectiveness.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee concluded that given all of the uncertainties, it was not possible to determine the most plausible ICER for bevacizumab plus capecitabine compared with capecitabine alone for the subgroup of patients who were previously treated with a taxane. However, it was convinced that the ICER would be higher than the ICER of £82,000 per QALY gained resulting from the ERG explorations. The Committee considered that the ICER for bevacizumab plus capecitabine compared with capecitabine alone in the ITT population would be even higher.
Additional factors taken into account
Patient access schemes (PPRS)
None
End-of-life considerations
The Committee discussed whether bevacizumab plus capecitabine for the first-line treatment of metastatic breast cancer fulfilled the criteria for a life-extending, end-of-life treatment. The Committee noted that bevacizumab is licensed for a relatively large population across a range of indications in the treatment of breast, colorectal, renal and non-small-cell lung cancers. Therefore, it does not meet the criterion of the supplementary advice from NICE that the treatment should be licensed for small populations. Having established that bevacizumab did not meet the population criterion, the Committee decided it was not necessary to make a decision about the life expectancy or extension to life criteria. The Committee concluded on this basis that bevacizumab plus capecitabine did not fulfil the criteria for being a life-extending, end-of-life treatment.
Equalities considerations and social value judgements
No equality issues were identified during the scoping process or the appraisal.
--# Recommendations for further research
Studies exploring the effectiveness of bevacizumab in people previously treated with a taxane and its effects on health-related quality of life.# Related NICE guidance
Published
Bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer. NICE technology appraisal guidance 214 (2011).
Advanced breast cancer: diagnosis and management. NICE clinical guideline 81 (2009).
Gemcitabine for the treatment of metastatic breast cancer. NICE technology appraisal guidance 116 (2007).# Review of guidance
The guidance on this technology will be considered for review in June 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveAugust 2012# Changes after publication
February 2014:
minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Bevacizumab in combination with capecitabine is not recommended within its marketing authorisation for the first-line treatment of metastatic breast cancer, that is, when treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate, or when taxanes or anthracyclines have been used as part of adjuvant treatment within the past 12\xa0months.\n\nPeople currently receiving bevacizumab in combination with capecitabine that is not recommended according to 1.1 should have the option to continue treatment until they and their clinician consider it appropriate to stop.', 'The technology ': "Bevacizumab (Avastin, Roche) is a humanised anti-vascular endothelial growth factor (VEGF) monoclonal antibody that inhibits VEGF-induced signalling and inhibits VEGF-driven angiogenesis. This reduces vascularisation of tumours, thereby inhibiting tumour growth. Bevacizumab is administered by intravenous infusion. Bevacizumab in combination with capecitabine has a marketing authorisation for 'first-line treatment of patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12\xa0months should be excluded from treatment with bevacizumab in combination with capecitabine'.\n\nThe summary of product characteristics lists the following adverse reactions that may be associated with bevacizumab treatment: gastrointestinal perforations, fistulae, wound healing complications, hypertension, proteinuria, arterial and venous thromboembolism, haemorrhage, pulmonary haemorrhage/haemoptysis, congestive heart failure, reversible posterior leucoencephalopathy syndrome, hypersensitivity/infusion reactions, osteonecrosis of the jaw, ovarian failure and neutropenia. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nBevacizumab is available in 100\xa0mg and 400\xa0mg vials at net prices of £242.66 and £924.40, respectively (excluding VAT; 'British national formulary' [BNF] edition 63). The recommended dose is 10\xa0mg/kg body weight given once every 2\xa0weeks or 15\xa0mg/kg body weight given once every 3\xa0weeks. The manufacturer estimated the price of bevacizumab (excluding VAT and assuming wastage) to be £2577 for a patient weighing 72.1\xa0kg at a dosage of 15\xa0mg/kg every 3\xa0weeks, amounting to an average monthly cost of £3689. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of bevacizumab and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\n# Clinical effectiveness\n\nThe manufacturer conducted a literature search and identified 2\xa0randomised controlled trials (TURANDOT and RIBBON-1) that investigate the effect of first-line bevacizumab plus capecitabine in adults with metastatic breast cancer. The TURANDOT trial was excluded because it is ongoing and no efficacy data are available. The RIBBON-1 trial was an international, multicentre, double-blind, phase III, randomised, placebo-controlled trial comparing bevacizumab plus chemotherapy with chemotherapy alone for the first-line treatment of HER2-negative, locally recurrent or metastatic breast cancer.\n\nThe RIBBON-1 trial enrolled 1237\xa0patients to receive bevacizumab plus chemotherapy or chemotherapy plus placebo. Investigators were able to select their choice of chemotherapy before randomisation. Patients were enrolled into 2\xa0different cohorts; in 1\xa0cohort patients received either an anthracycline or a taxane, and in the other cohort patients received capecitabine, reflecting the choice of first-line therapy for these patients in routine clinical practice. Patients were then randomised to bevacizumab plus the chosen chemotherapy or to the chosen chemotherapy plus placebo. The manufacturer stated that only the results from the capecitabine cohort provided evidence on the use of bevacizumab in its licensed indication, in combination with capecitabine for the first-line treatment of metastatic breast cancer. The manufacturer highlighted that anthracyclines and taxanes were not considered appropriate as first-line treatment for all patients in the capecitabine cohort; about 40% of the patients had previously received taxanes and around 63% had received anthracycline therapy for early breast cancer.\n\nIn the capecitabine cohort of the RIBBON-1 trial 615\xa0patients were randomised in a 2:1 ratio to the bevacizumab plus capecitabine arm (n=409) and the capecitabine plus placebo arm (n=206). Randomisation was stratified by the following criteria: disease-free interval (12\xa0months or less, more than 12\xa0months since completion of adjuvant chemotherapy or surgery if no adjuvant chemotherapy); previous adjuvant chemotherapy; and number of metastatic sites (fewer than 3, 3 or more). The dosage of bevacizumab was 15\xa0mg/kg by intravenous infusion every 3\xa0weeks, and the dosage of capecitabine was 1000\xa0mg/m2 orally twice daily for 2\xa0weeks of a 3-week cycle. Treatment was continued until disease progression, unacceptable toxicity, investigator or patient decision to stop treatment, or death. Patients continued to receive capecitabine if bevacizumab was discontinued before disease progression. After disease progression, patients in either arm could move to an open-label phase consisting of treatment including bevacizumab and chemotherapy at the investigator's discretion. Patients who chose not to enter the post-progression phase and patients who discontinued treatment during the post-progression phase were followed up in a survival follow-up phase.\n\nThe primary endpoint in the trial was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. It was defined as the time from randomisation to first disease progression or death from any cause. Progression-free survival based on an Independent Review Committee (IRC) review of the data was considered a secondary endpoint and presented as a sensitivity analysis to support the investigator-assessed primary endpoint. Other secondary endpoints included objective response rates, defined as the percentage of patients with a complete or partial response determined on 2\xa0consecutive assessments more than 4\xa0weeks apart; duration of objective response, defined as the time from the first tumour assessment that supported an objective response to the time of disease progression, or death from any cause; overall survival, defined as the time from randomisation until death from any cause; and the 1-year survival rate, defined as the percentage of patients still alive 1\xa0year after randomisation. In addition, progression-free survival and overall survival were calculated for a number of pre-specified subgroups, post hoc exploratory subgroups, and subgroups specified after the trial had begun but before the analysis was completed (for example, the subgroup of patients previously treated with a taxane, which was included in the manufacturer's economic model).\n\nThere was a statistically significant increase in the investigator assessed median progression-free survival of 2.9\xa0months, from 5.7\xa0months in the capecitabine plus placebo arm to 8.6\xa0months in the bevacizumab plus capecitabine arm. The stratified hazard ratio for progression was 0.69 (95% confidence interval [CI] 0.564 to 0.840, p=0.0002). Median overall survival improved by 2.9\xa0months, from 22.8\xa0months with capecitabine plus placebo to 25.7\xa0months with bevacizumab plus capecitabine. The stratified hazard ratio for death was 0.88 (95% CI 0.69 to 1.13, p=0.33), indicating a 12% improvement in overall survival with bevacizumab plus capecitabine compared with capecitabine plus placebo. However this improvement was not statistically significant. The manufacturer acknowledged that the results from the patients who crossed over to bevacizumab in the open-label post-progression phase of the trial (44.7% in the bevacizumab/capecitabine arm and 52.4% in the capecitabine/placebo arm) may have confounded overall survival results. This was because the trial was not designed to evaluate the effect of subsequent therapies.\n\nA number of subgroup analyses for progression-free survival (16 in total) and for overall survival (24 in total) with no correction for multiple testing were presented in the manufacturer's submission. The manufacturer highlighted that bevacizumab plus capecitabine gave a progression-free survival benefit over capecitabine plus placebo in all of the pre-specified subgroups defined by stratification variables, although not all were statistically significant. The manufacturer investigated a number of additional planned and post hoc subgroups and showed that some subgroups (for example, the group previously treated with a taxane) had a greater overall survival benefit than the intention-to-treat (ITT) population of the capecitabine cohort.\n\nThe manufacturer focused on the subgroup of patients who had a previous adjuvant or neo-adjuvant taxane. This subgroup of 245\xa0patients had an increase in median progression-free survival of 4.5\xa0months, from 4.2\xa0months in the capecitabine plus placebo arm to 8.7\xa0months in the bevacizumab plus capecitabine arm. The hazard ratio for progression was 0.62 (95% CI 0.45 to 0.84). This benefit also translated into an overall survival benefit, with an increase in median overall survival of 7.9\xa0months, from 20.5\xa0months in the capecitabine plus placebo arm to 28.4\xa0months in the bevacizumab plus capecitabine arm. The hazard ratio for death was 0.67 (95% CI 0.46 to 0.98). These overall survival results were based on 70\xa0deaths in the bevacizumab plus capecitabine arm and 44\xa0deaths in the capecitabine plus placebo arm. The manufacturer stated that patients previously treated with a taxane had worse outcomes than the patients in the ITT population, and the addition of bevacizumab increased their progression-free survival and overall survival to levels similar to or above those of the ITT population. The manufacturer presented the results of two similar metastatic breast cancer trials (the AVADO and E2100 trials) which demonstrated the same pattern of progression-free and overall survival gains from bevacizumab in patients who have previously received a taxane. The AVADO trial compared bevacizumab plus docetaxel with docetaxel plus placebo, and the E2100 trial compared bevacizumab plus paclitaxel with paclitaxel alone.\n\nThe primary safety analyses were based on all patients who received any trial treatment, defined as at least 1 full or partial dose of either trial treatment during the blinded phase of the trial. This population was referred to by the manufacturer as the safety population. The manufacturer stated that adding bevacizumab to capecitabine resulted in adverse events that were predictable based on previous use of bevacizumab, and generally manageable. Grade 3–5 adverse events were higher with bevacizumab plus capecitabine (36.6%) compared with capecitabine plus placebo (22.9%). In addition, the following adverse events were higher with bevacizumab plus capecitabine compared with capecitabine plus placebo: hypertension (10.6% compared with 1%), proteinuria (2.2% compared with 0%), sensory neuropathy (3% compared with 0.5%) and venous thromboembolic events (5% compared with 3.5%).\n\nHealth-related quality of life data were not collected in theRIBBON-1 trial. The manufacturer stated that the most important factor causing distress among cancer patients was the fear of disease progression. Therefore a major objective of each successive line of therapy, in addition to extending overall survival, was to maintain progression-free survival for as long as possible.\n\nThe ERG stated that the literature search conducted by the manufacturer was appropriate, that all relevant studies had been identified, and that the RIBBON-1 trial on which the manufacturer's submission was based was relevant to the decision problem in its analysis. The ERG stated that the patient population in the trial was in line with the marketing authorisation for bevacizumab in combination with capecitabine. The ERG commented that the trial was well conducted, the baseline characteristics appeared to be balanced across the treatment groups, and the stratification factors were appropriate. The ERG noted that the dose for capecitabine in the trial was 1000\xa0mg/m2 rather than the licensed dose of 1250\xa0mg/m2. However, this was considered appropriate and in line with clinical practice. The ERG stated that the results from the trial could be generalised to patients in the UK.\n\nThe ERG noted that the hazard ratios for investigator- and IRC-assessed progression-free survival were almost identical, indicating that the evidence of progression-free survival benefit with bevacizumab plus capecitabine was robust. The ERG was aware that the progression-free survival benefit did not translate into a statistically significant overall survival benefit, but stated that interpreting differences in overall survival was difficult because patients from both the capecitabine plus placebo arm and the bevacizumab plus capecitabine arm were able to cross over to receive bevacizumab in the open-label phase of the trial. Other anticancer therapies were also available on progression, and in a minority of instances before progression, so bias may have been introduced.\n\nThe ERG noted the subgroup analyses conducted by the manufacturer, and commented that most increases in progression-free survival with bevacizumab plus capecitabine compared with capecitabine plus placebo were statistically significant in these subgroups. However, the only overall survival results that were statistically significant were for subgroups of patients younger than 50\xa0years and subgroups of patients previously treated with a taxane or anthracycline as neoadjuvant or adjuvant chemotherapy. The ERG stated that the results of the subgroup analyses should be considered with caution because no statistical adjustments were performed to control for multiple testing in any of the 40\xa0subgroups and of all outcomes, thus increasing the likelihood of significant results emerging by chance when using the usual level of significance of 5%.\n\nThe ERG agreed that there was a greater proportion of adverse events in the bevacizumab plus capecitabine arm, but that no new safety concerns were identified. The ERG also agreed that bevacizumab plus capecitabine did not lead to a clinically relevant increase in adverse events typically associated with chemotherapy, such as febrile neutropenia, neutropenia, and sensory neuropathy. The ERG stated that the difference in adverse events between the 2\xa0arms could largely be attributed to differences in grade 3 adverse events (27% in the bevacizumab plus capecitabine arm compared with 14% in the capecitabine plus placebo arm).\n\nRegarding the safety of bevacizumab plus capecitabine compared with capecitabine plus placebo in the subgroup of people who had previously received a taxane, the ERG stated that it was not possible to compare the proportions of patients who experienced any adverse events, any grade 3–5 adverse events, any serious adverse events or any adverse events leading to discontinuation of bevacizumab or placebo because the manufacturer did not present these data. The ERG extracted some data from the economic model, and stated that adverse events of special interest mostly appeared to be similar in frequency in the subgroup and in the overall trial population. A slightly greater proportion of patients in the subgroup reported grade 3 or higher cardiac disorders (4.4%) than in the overall safety population (2.1%). However, the ERG stated that these findings must be viewed with caution because of the small numbers of patients in this subgroup.\n\n# Cost effectiveness\n\nIn a systematic review of the literature the manufacturer found no cost-effectiveness studies comparing bevacizumab plus capecitabine with capecitabine plus placebo as first-line treatments for metastatic breast cancer. No relevant cost-effectiveness analyses were identified. The economic evaluation was based on the subgroup of patients from the RIBBON-1 trial who had previously received a taxane, and all efficacy and treatment duration parameters were derived from this subgroup. The manufacturer assumed that patients in this subgroup would probably have received an anthracycline as well. The manufacturer stated that this subgroup reflected the marketing authorisation for capecitabine. Capecitabine monotherapy has a marketing authorisation for 'the treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated'. The manufacturer acknowledged that this post hoc subgroup analysis of patients previously treated with a taxane was the main weakness of the economic evaluation.\n\nThe manufacturer developed a 3-state model. All patients enter the model in the progression-free survival health state and in each month can either progress to a 'worse' health state (that is, from progression-free survival to progressed disease or from either state to death) or remain in the same health state. The manufacturer stated that these health states were consistent with previous modelling of metastatic cancer. The progression-free survival health state is designed to capture a patient's relatively high quality of life before disease progression and the progressed disease state is designed to capture the relatively poor quality of life after disease progression. Survival data from the capecitabine plus placebo arm of the subgroup previously treated with a taxane from the RIBBON-1 trial were used to inform disease progression in the comparator arm. The treatment duration in the trial was used to determine the expected cost of treatment with each regimen in the base case. The model has a 1-month cycle length, includes a half-cycle correction and both costs and benefits are discounted at 3.5%. The time horizon was 15\xa0years.\n\nThe proportions of patients who are progression-free in each month were taken directly from Kaplan-Meier survival curves for each treatment arm in the RIBBON-1 trial until the 12th month of treatment, after which an exponential distribution of survival time was assumed. The number of patients in each treatment arm dying from any cause while in the progression-free survival state was used to derive a constant rate and probability of mortality. The mortality rate in the progression-free survival state was assumed to be at least as great as the underlying sex- and age-related mortality in the general population.\n\nA number of tunnel states, health states which can only be passed through in a certain order, were generated for patients with progressed disease according to the time spent in this state. The tunnel states were arranged so that each state had a progression only to death or the next temporary state. Patients who entered the progressed disease state had a probability of dying that increased each month based on an extrapolation of the survival data for patients with progressed disease. Mean overall survival was the sum of mean duration of progression-free survival and mean duration of progressed disease.\n\nDuring the progressed disease phase, patients in the capecitabine cohort of the RIBBON-1 trial received a variety of different therapies. The manufacturer modelled survival in progressed disease based on adjusted analyses that aimed to 'uncross' the survival curves by excluding survival gains from patients who crossed over to bevacizumab in the open-label phase of the trial. An exponential survival distribution was assumed thereafter. The data were 'uncrossed' using a rank preserving structural failure time model to take account of the bias that may have been introduced by allowing patients from both treatment arms to receive bevacizumab after progression, potentially distorting overall survival rates in the control arm.\n\nThe manufacturer carried out a literature review to identify relevant health-related quality of life data to use in the economic evaluation. Three studies that measured utility values directly were identified and, of these, the manufacturer calculated utility values for progression-free survival and progressed disease from the results of the mixed model analysis presented by Lloyd et al. (2006). The manufacturer stated that it was most appropriate to use a base-case progression-free survival utility value that was derived from a large population, and then to adjust that base-case utility by response rate. In addition, the utility values from Lloyd et al. have been used in previous health technology appraisals for metastatic breast cancer. For patients in the progressed disease state, a health state utility value of 0.496 was incorporated in both treatment arms. For patients in the progression-free survival state a treatment-specific weighted average of the values for stable disease and treatment response, based on the reported overall response rate, was calculated: 0.784 in the bevacizumab plus capecitabine arm and 0.774 in the capecitabine plus placebo arm. The manufacturer acknowledged that the utility values reported by Lloyd et al. were not derived from patient experience, and presented a sensitivity analysis using data from Peasgood et al. (2010) to derive estimated utilities from patients valuing their own health.\n\nThe drug costs incorporated in the model for bevacizumab plus capecitabine and capecitabine were from BNF 62 (£4001.53 per month and £312.41 per month respectively). No vial sharing was assumed for bevacizumab. The manufacturer's submission assumed administration and pharmacy costs of £348.82 in the first month and £205.97 per month for subsequent months of treatment with bevacizumab and capecitabine. Administration and pharmacy costs for capecitabine alone were assumed to be £255.32 per month. The manufacturer stated that in clinical practice some patients stop treatment before disease progression, and therefore it is essential to consider the distinction between disease progression and treatment discontinuation when evaluating the real incremental cost. In order to account for this difference, patient data on treatment duration were used to produce 'time to off treatment' Kaplan-Meier curves that could be used to determine the proportion of patients still receiving bevacizumab and/or capecitabine each month.\n\nProgression-free survival health state costs were based on Advanced breast cancer: diagnosis and treatment (NICE clinical guideline 81) 'package 1' with the addition of an outpatient consultation with an oncologist and a computed tomography (CT) scan assumed to occur every 3\xa0months, and were estimated to be £263.55 per month. Progressed disease health state costs were based on NICE clinical guideline 81 'package 2' and estimated to be £804.00 per month. The same costs and utilities were assumed regardless of first-line treatment. Adverse events of grade 3 or 4 severity occurring in greater than 2% of patients were incorporated into the analysis. When clinical advice indicated that the usual response to the adverse event was discontinuation of treatment (for peripheral sensory neuropathy, hand-foot syndrome and proteinuria), it was assumed this had been accounted for elsewhere in the model and no additional costs were accrued. In addition, treatment of diarrhoea was considered to have negligible contribution to costs. Therefore only costs associated with deep vein thrombosis and hypertension were included in the model. All adverse events were assumed to occur in month 1 for both treatment arms and were therefore not discounted.\n\nThe manufacturer did not include terminal care costs in the model, stating that these would refer to costs in the last 2\xa0weeks of life and would therefore have a minimal impact on the ICER irrespective of the regimen received. In addition, no second-line treatment costs were included in the model because it was assumed that the duration of second-line treatment would be the same for a patient receiving first-line bevacizumab plus capecitabine as for a patient receiving first-line capecitabine alone, and the second-line costs in each arm would cancel each other out.\n\nThe base-case results indicated incremental costs of £38,924 and incremental QALYs of 0.5034 for bevacizumab plus capecitabine compared with capecitabine alone. The cost per QALY gained was £77,318 for bevacizumab plus capecitabine compared with capecitabine alone. The manufacturer conducted deterministic sensitivity analyses for a range of parameters. The manufacturer stated that the cost-effectiveness results were most sensitive to the costs and utilities associated with progressed disease.\n\nThe manufacturer conducted a scenario analysis using utility values from Peasgood et al. but this had little impact on the ICER and did not result in it increasing above £79,991 per QALY gained. A second scenario analysis was conducted including different formulations of vinorelbine as the comparator. It was assumed that vinorelbine had an equivalent efficacy and safety profile to capecitabine, with different list prices and costs of administration. The ICER was £58,972 per QALY gained for bevacizumab plus capecitabine compared with oral vinorelbine, £76,198 per QALY gained compared with branded intravenous vinorelbine, and £80,260 per QALY gained compared with generic intravenous vinorelbine.\n\nThe manufacturer conducted a probabilistic sensitivity analysis and concluded that bevacizumab plus capecitabine compared with capecitabine alone had a 0% probability of being cost effective if the maximum acceptable ICER was £30,000 to £50,000 per QALY gained. In response to consultation, the manufacturer provided the ICER based on the probabilistic sensitivity analysis, which was £80,073 per QALY gained for bevacizumab plus capecitabine compared with capecitabine alone (mean incremental costs were £40,161 [95% CI 36,703 to 45,079], mean incremental QALYs were 0.502 [95% CI 0.33 to 0.66]).\n\nThe manufacturer acknowledged that its economic evaluation was only relevant to patients with similar characteristics to those randomised to the capecitabine cohort of the RIBBON-1 trial who had previously been treated with a taxane. The ERG requested additional cost-effectiveness data for the ITT population of the capecitabine cohort for clarification. However, the manufacturer stated that because the submitted analysis calculated an ICER of £77,318 per QALY gained for the subgroup previously treated with a taxane, analysis of the ITT population would result in a larger ICER and therefore would not be considered a cost-effective use of NHS resources.\n\nThe ERG had concerns about the population used in the manufacturer's economic model. The ERG highlighted that the manufacturer had based its economic modelling on the subgroup of patients who had previously been treated with a taxane, because the manufacturer considered this population to represent the population for whom capecitabine is licensed: patients with metastatic breast cancer after failure of taxanes and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated. The ERG agreed that most patients in this subgroup would probably have previously received an anthracycline in addition to a taxane. However, the ERG questioned whether their treatment would be considered to have failed because the RIBBON-1 trial excluded patients who had received an adjuvant taxane or anthracycline in the last 12\xa0months. The ERG did not consider the subgroup of patients who had previously received a taxane to be the appropriate group of patients. The ERG considered the ITT population in the capecitabine cohort to be the appropriate population because it represents the population in the final scope issued by NICE and the population specified in the marketing authorisation for bevacizumab. In addition, the ERG identified that there appeared to be baseline differences between the subgroup of patients who had previously received a taxane and the ITT population. In particular, the ERG noted from differences in the mean and median age and Eastern Cooperative Oncology Group (ECOG) performance status that the population of patients who had previously received a taxane appeared to be younger and healthier. The ERG also noted that the differences in progression-free and overall survival between the bevacizumab plus capecitabine and capecitabine plus placebo arms appeared to be greater in the subgroup of patients previously treated with a taxane than in the ITT population, as well as being statistically significant. However, the ERG reiterated that because no statistical adjustments were made to control for multiple testing in all subgroups and of all outcomes, these findings may have occurred by chance, and must be interpreted with caution.\n\nThe ERG raised some concerns about the structure and design of the manufacturer's economic model. The ERG noted that the manufacturer adapted a model structure previously used in NICE appraisals of cancer drugs. However, the ERG raised concerns that although the model covered a period of 15\xa0years, no further chemotherapy was considered within the model following disease progression after treatment with bevacizumab plus capecitabine or capecitabine alone. This could have led to substantial bias, because if progression-free survival differed between the arms, the discounted costs and benefits of subsequent treatments would also have differed. Further, if the proportion of patients able to receive subsequent lines of therapy differed between the arms then the costs and outcomes would also have been different.\n\nThe ERG was satisfied that the modelling approach used by the manufacturer to estimate progression-free survival from the RIBBON-1 trial using Kaplan-Meier methods for the first 12\xa0months and assuming an exponential distribution thereafter was credible. The ERG noted that the approach was similar for progressed disease, however the manufacturer had 'uncrossed' the data using the rank preserving structural failure time model to minimise bias. The ERG stated that this approach was unsuitable when a large proportion of patients from both arms cross over. The ERG noted that 44.7% of patients in the bevacizumab plus capecitabine arm and 52.4% of patients in the capecitabine plus placebo arm received bevacizumab after disease progression. Further, patients in the modelled subgroup who previously received a taxane also received other therapies after progression. The ERG stated that given the limitations of the rank preserving structural failure time model and without any other estimate to adjust for crossover, they were unable to confirm the likely effect of the crossover and post-progression therapies on overall survival in this subgroup and caution should be exercised when interpreting the manufacturer's overall survival results.\n\nThe ERG undertook an analysis of the original progressed disease trial data (rather than the 'uncrossed' data) to explore survival during this phase. This analysis separated the bevacizumab plus capecitabine and capecitabine plus placebo arms according to whether patients had crossed over to a different treatment or not. A comparison of survival times during the progressed disease phase indicated that survival is similar in each group and overall, the 4\xa0groups in the RIBBON-1 trial did not show strong evidence of heterogeneity. However, the capecitabine plus placebo group with no crossover appeared to differ when tested pairwise against the other 3\xa0groups. Therefore, the ERG explored 2 different scenarios. The first scenario grouped all patients together and modelled a scenario in which survival after progression was equivalent irrespective of first-line therapy or crossover (common projection scenario). This method resulted in an ICER of £171,411 per QALY gained for bevacizumab plus capecitabine compared with capecitabine alone. The second scenario grouped together all the bevacizumab plus capecitabine patients and the capecitabine plus placebo patients who crossed over, and considered the capecitabine plus placebo patients who did not cross over separately (different projections scenario). This method resulted in an ICER of £92,060 per QALY gained for bevacizumab plus capecitabine compared with capecitabine alone. The ERG stated that the second scenario allowed a clear comparison between patients who did and did not receive bevacizumab during the trial and gives a representation of the effect of crossover. The ERG highlighted that each analysis portrayed an extreme, allowing consideration of a best and worst case scenario for the effect of crossover on post-progression survival.\n\nThe ERG conducted a sensitivity analysis to study the impact of including the licensed dose of capecitabine (1250\xa0mg/m2) rather than the dose widely used in clinical practice (1000\xa0mg/m2). It found that changing the dose of capecitabine to 1250\xa0mg/m2 results in an overall incremental increase in drug costs of £3782 and an accompanying increase of £7512 per QALY gained in the ICER estimate. The ERG re-estimated the costs of therapy based on the distribution of patient body weight and body surface area in a UK-specific cohort of patients rather than using a simple average based on trial data. The ERG found that this resulted in an increase in drug costs of £2966 per patient in the bevacizumab plus capecitabine arm and an increase of £50 per patient in the capecitabine alone arm. The adjustment resulted in a revised ICER that was £5793 higher per QALY gained than the manufacturer's base-case ICER. The ERG also added in the costs of terminal care during the last 2\xa0weeks of life, as specified in the guideline on Advanced breast cancer: diagnosis and treatment (NICE clinical guideline 81), and these adjustments resulted in a revised ICER that was £105 lower per QALY gained than the manufacturer's base-case ICER.\n\nThe ERG noted that the utility values used in the manufacturer's model were estimated using the statistical model detailed in a study by Lloyd et al. The ERG noted that there is a lack of consensus among economists in relation to the most appropriate value for age in the Lloyd et al. model, that is, whether it should be the age of the population surveyed in the study or the age of the population taking part in the original health state valuation exercise carried out by Kind et al. (1999). The ERG noted that the manufacturer used 47\xa0years, the mean age of the population taking part in the original Kind et al. study, with the advantage that it was consistent with standard UK EQ-5D tariff scores. However, the ERG stated that the lack of consensus relating to the most appropriate age to use introduces a degree of uncertainty to the utility values used in the model. The ERG also corrected for a typing mistake in the formula used in the manufacturer's model in the capecitabine alone arm and this resulted in a revised ICER that was £786 lower per QALY gained than the manufacturer's base-case ICER.\n\nThe combined impact of the ERG's revisions to the drug costs, terminal care costs and utility estimates in the manufacturer's base case resulted in an ICER of £82,162 per QALY gained for bevacizumab plus capecitabine compared with capecitabine alone. In addition, combining these revisions with the revised progressed disease estimates resulted in an ICER of £181,648 per QALY gained when using the common projection scenario and £97,963 per QALY gained when using the different projections scenario. The ERG also agreed with the manufacturer that the base-case ICER cannot be considered to be generalisable to the whole population covered by the marketing authorisation and that it was likely to be higher than the ICER for the modelled subgroup.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report, which are available from http://guidance.nice.org.uk/TA263", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab in combination with capecitabine, having considered evidence on the nature of metastatic breast cancer and the value placed on the benefits of bevacizumab in combination with capecitabine by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee considered the clinical need for treatment in patients with metastatic breast cancer for whom treatment with other chemotherapy options, including taxanes or anthracyclines, is not considered appropriate. The Committee heard from the clinical specialist that there was broad agreement among breast cancer specialists that the case for incorporating bevacizumab into first-line treatment was stronger for patients with triple negative breast cancer (breast cancer that is oestrogen-, progesterone- and HER2-receptor negative) with aggressive visceral disease, for whom there were limited treatment options. The Committee heard from the patient expert and clinical specialist that prolonging progression-free survival was very important for patients with advanced breast cancer, but this had to be coupled with maximising quality of life at the same time. The adverse events associated with treatment were therefore also of significance, as was the method of administration and convenience of therapy. The Committee concluded that bevacizumab plus capecitabine represented an option for patients with limited treatment options, and that an improvement in progression-free survival combined with a quality of life benefit, and the adverse event profile were key considerations.\n\n# Clinical effectiveness\n\nThe Committee considered the generalisability of the RIBBON-1 trial to UK clinical practice. The Committee was aware of NICE clinical guideline 81 for advanced breast cancer in which capecitabine follows both anthracycline and taxane therapy in the care pathway. It noted the design of the RIBBON-1 trial, which had 2\xa0cohorts of patients; those to be treated with anthracyclines or a taxane and those to be treated with capecitabine. The Committee noted that 63% of the capecitabine cohort had received prior anthracycline therapy and 40% had received prior taxane therapy. Because there was likely to have been considerable overlap between these 2\xa0groups (and perhaps total overlap, as assumed by the manufacturer), a significant percentage of patients (up to 37%) could have received capecitabine for first-line treatment of their metastatic breast cancer as their first ever chemotherapy. The Committee considered that this meant that this group of patients was not representative of the typical UK metastatic breast cancer population. The Committee also noted that the 60% of patients in the capecitabine cohort of the RIBBON-1 trial who had not received prior taxane therapy had good performance status and yet taxane treatment was not considered appropriate for them. In addition, the Committee observed that 30% of the patients in the prior taxane subgroup for whom taxanes were not considered appropriate (as indicated by the entry criteria for the capecitabine arm of the RIBBON-1 trial) subsequently received taxanes after disease progression. However, the Committee was aware that the decision to treat with capecitabine or a taxane could also be based on other factors which may be important to patients, such as the lack of hair loss with capecitabine. The Committee concluded that there were still some issues about the generalisability of the RIBBON-1 trial to clinical practice in the UK. This was because a significant proportion of patients in the trial had not received previous chemotherapy, and taxanes had not been considered for a significant proportion despite their young age and good performance status.\n\nThe Committee also noted that the dose of capecitabine in the trial was 1000\xa0mg/m2 rather than the licensed dose of 1250\xa0mg/m2. The Committee was aware that the dose of capecitabine used in UK practice was often lower in older patients and those with poor performance status, but observed that all patients in the RIBBON-1 trial were of ECOG performance status 0 or 1 and the median age was 56\xa0years. However, it noted the comments during consultation that some clinicians in the UK start at a dose lower than the licensed dose (often 1000\xa0mg/m2) even in fitter patients. The Committee therefore concluded that the dose of capecitabine used in the trial may have some relevance to clinical practice in the UK.\n\nThe Committee considered the clinical-effectiveness data from the capecitabine cohort of the RIBBON-1 trial for the comparison of bevacizumab plus capecitabine with capecitabine plus placebo. The Committee noted that the results from the ITT population demonstrated a statistically significant median investigator-assessed progression-free survival benefit of 2.9\xa0months for bevacizumab plus capecitabine compared with capecitabine plus placebo. However, the Committee noted this improvement in progression-free survival did not translate into a statistically significant improvement in overall survival. The Committee was aware that patients from both arms of the trial could receive treatment with bevacizumab after disease progression as well as other subsequent treatments and that all these subsequent therapies could have confounded the relative treatment effect in terms of overall survival. The Committee also noted that no quality of life data had been collected in the trial. The Committee considered quality of life to be an important outcome measure in advanced cancer and that this was an omission from the trial. Without quality of life data and a statistically significant improvement in overall survival, the Committee explored the value of an increase in progression-free survival. The Committee was aware of a statement from the clinical specialist that the most important outcome for patients with metastatic breast cancer is prolonging disease-free survival. However, the Committee heard from the patient expert that patients would value an increase in progression-free survival when it is accompanied by an improvement in quality of life that would allow them to carry out normal daily activities. The Committee concluded that bevacizumab plus capecitabine improved progression-free survival relative to capecitabine plus placebo, but that there was no robust evidence that it improved overall survival and that its effects on health-related quality of life had not been captured.\n\nThe Committee discussed the adverse event profile associated with bevacizumab plus capecitabine compared with capecitabine plus placebo. The Committee noted that grade 3–5 adverse events were higher with bevacizumab plus capecitabine (36.6%) compared with capecitabine plus placebo (22.9%). In addition, the number of patients with hypertension, proteinuria, sensory neuropathy and venous thromboembolic events was higher with bevacizumab plus capecitabine compared with capecitabine plus placebo. The Committee considered that the adverse event profile of bevacizumab plus capecitabine was particularly important because if people opt for capecitabine instead of taxane-based treatment it may be an indication that a better adverse event profile was important to them. The Committee concluded that bevacizumab plus capecitabine had a less favourable adverse event profile than capecitabine plus placebo.\n\nThe Committee noted that no clinical evidence of the effectiveness of bevacizumab plus capecitabine compared with vinorelbine was presented by the manufacturer as specified in the final scope issued by NICE. The Committee noted the manufacturer's statement that capecitabine is generally preferred to vinorelbine in in UK clinical practice and that vinorelbine had been included as a comparator as part of the scenario analysis in the economic modelling. The Committee concluded that, without studies that would allow for an indirect comparison of bevacizumab plus capecitabine with vinorelbine, and without evidence to suggest that vinorelbine was superior to capecitabine, it was appropriate for capecitabine to be presented as the main comparator.\n\nThe Committee examined the subgroup analysis conducted by the manufacturer comparing bevacizumab plus capecitabine with capecitabine plus placebo in patients who had previously received a taxane. The Committee was aware that the differences in progression-free and overall survival between the bevacizumab plus capecitabine and capecitabine plus placebo arms were statistically significantly greater in this subgroup of patients. However, the Committee noted that previous taxane therapy was not a stratification factor at randomisation and that this subgroup was specified after the trial had begun but before the analysis was completed. The Committee also noted that the overall survival results were based on small numbers of events: 70\xa0deaths in the bevacizumab plus capecitabine arm and 44\xa0deaths in the capecitabine plus placebo arm. In addition, the Committee was aware that no statistical adjustments were made to control for multiple testing, thus increasing the risk of chance findings. The Committee considered the manufacturer's original submission and their consultation comments about an increased benefit observed in the prior taxane subgroup compared with the ITT population in other metastatic breast cancer trials of bevacizumab as part of first-line chemotherapy (the AVADO and E2100 trials). The Committee noted that although the prior taxane subgroups showed significant benefits with bevacizumab in the AVADO and E2100 trials, the benefits were not replicated in the prior taxane subgroup in the anthracycline/taxane cohort of RIBBON-1. The Committee heard from the clinical specialist that the prior taxane subgroup was a clinically relevant subgroup given the current treatment pathway of metastatic breast cancer. The Committee also noted the comment from the consultees and clinical specialist that women with triple negative breast cancer for whom there are limited treatment options are the most clinically relevant subgroup, with a realistic chance of benefitting from bevacizumab plus capecitabine treatment. However, the Committee was aware that the RIBBON-1 trial results did not show an advantage for bevacizumab plus capecitabine in this triple negative subgroup. The Committee was concerned about the robustness of the data from the AVADO and E2100 trials because of the small patient numbers in the prior taxane subgroups in the AVADO and E2100 trials and the unblinding and non-stratification for prior taxane use in the E2100 trial. It noted that although the progression-free survival and overall survival benefits were higher in the prior taxane subgroups in the E2100, AVADO and the capecitabine cohort of the RIBBON-1 trials, there was no biologically plausible reason why bevacizumab plus capecitabine would be more effective in this subgroup than in the ITT population. The Committee therefore considered that a formal study would be needed to confirm these benefits, as had been recognised by the manufacturer. The Committee concluded that the results from the prior taxane subgroup of the RIBBON-1 trial were not sufficiently robust to use for the development of guidance.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's economic model and the ERG's critique of this model. The Committee was aware that the manufacturer had based the economic evaluation on the subgroup of patients who had previously received a taxane rather than the Committee's preferred choice of the whole capecitabine cohort (the ITT population). The Committee noted the manufacturer's and ERG's statements that an analysis of the ITT population would result in a larger ICER than the £77,000 per QALY gained for the subgroup included in the manufacturer's base-case analysis. The Committee agreed with this assessment. The Committee considered the ERG critique and explorations of the manufacturer's model to determine the most plausible ICER for the subgroup previously treated with a taxane. The aim was to establish a benchmark for the incremental cost per QALY gained for the ITT population.\n\nThe Committee noted the explorations made by the ERG to the economic model:\n\nbasing costs on the distribution of patient body weight and body surface area in a UK-specific cohort of patients rather than using a simple average based on trial data\n\nincluding costs of terminal care during the last 2\xa0weeks of life\n\ncorrecting a typing mistake in the calculation of utilities.The Committee noted that these changes resulted in the ERG's estimated ICER of £82,000 per QALY gained for bevacizumab plus capecitabine compared with capecitabine alone. The Committee concluded that these explorations were appropriate.\n\nThe Committee noted the ERG's concerns around the rank preserving structural failure time method used by the manufacturer to account for the effect of crossover to open-label bevacizumab in the modelling of survival in the progressed disease state. The Committee discussed the ways in which the analyses were adjusted for crossover by the manufacturer and the ERG. The Committee was unclear as to whether these were appropriate (or whether any other method would be appropriate) or would introduce potential bias because about half the patients in both arms of the trial crossed over to have open-label bevacizumab after disease progression. The Committee also noted that the subsequent treatments received had not been modelled, which in combination with the impact of crossover, could have led to confounding of the overall survival results. The ERG confirmed that it had not been possible to estimate the effect of these factors on overall survival. The Committee noted that 60% of the manufacturer's base-case QALY gain was from the progressed disease phase and it was unsure of the impact of crossover on this finding. The Committee concluded that given these uncertainties, the manufacturer's modelled overall survival results could not be considered robust.\n\nThe Committee noted that in the manufacturer's model, the costs of administration and pharmacy time from the second cycle onwards was £255 in the capecitabine alone arm and £206 in the bevacizumab plus capecitabine arm. The Committee discussed that it was unexpected that the costs associated with bevacizumab plus capecitabine would be lower than the costs for capecitabine alone. The Committee accepted that although these costs were based on NHS reference costs, it would have been possible to generate more plausible values. The Committee concluded that despite the incorporation of NHS tariffs, the discrepancy in the costs of administration and pharmacy time contributed to the uncertainty associated with the results of the manufacturer's economic model.\n\nThe Committee noted that the ERG had carried out an exploratory analysis of the progressed disease trial data to explore survival during this phase, assuming equal survival in each arm of the model (common projection scenario) as well as assuming different survival in each arm of the model depending on what the first treatment was (different projections scenario). The Committee noted that this analysis, in combination with the rest of the ERG changes, resulted in an ICER of £182,000 per QALY gained for the common projection model and £98,000 per QALY gained for the different projections model for bevacizumab plus capecitabine compared with capecitabine alone. In addition, the Committee was also aware that a disutility for adverse events had not been applied in the manufacturer's model, despite utility estimates being available in the literature to account for adverse events, and it was likely that this could have resulted in underestimated ICERs. The Committee concluded that given all of the uncertainties, it was not possible to determine the most plausible ICER for bevacizumab plus capecitabine compared with capecitabine alone for the subgroup of patients who were previously treated with a taxane. However, it was convinced that the ICER would be higher than the most optimistic ICER of £82,000 per QALY gained resulting from the ERG explorations. The Committee considered that the ICER for bevacizumab plus capecitabine compared with capecitabine alone in the ITT population would be even higher (see section 4.9). The Committee noted the comments received during consultation, but considered that there was no evidence to alter its conclusion that the ICER for bevacizumab plus capecitabine compared with capecitabine alone would be higher than £82,000 per QALY gained. The Committee concluded that given the lack of robust evidence of survival benefit supplemented by the high ICER, bevacizumab plus capecitabine as a first-line treatment for metastatic breast cancer was not a cost-effective use of NHS resources.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of people with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe Committee discussed whether bevacizumab plus capecitabine for the first-line treatment of metastatic breast cancer fulfilled the criteria for a life-extending, end-of-life treatment. The Committee noted that bevacizumab is licensed for a relatively large population across a range of indications in the treatment of breast, colorectal, renal and non-small-cell lung cancers. Therefore, it does not meet the criterion of the supplementary advice that the treatment should be licensed for small populations. Having established that bevacizumab did not meet the population criterion, the Committee decided it was not necessary to make a decision about the life expectancy or extension to life criteria. The Committee concluded on this basis that bevacizumab plus capecitabine did not fulfil the criteria for being a life-extending, end-of-life treatment.\n\nThe Committee recognised the novel mode of action of bevacizumab, which may benefit breast cancer patients whose treatment options are limited. However, it considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations. The Committee therefore concluded that the innovative aspects of bevacizumab were already incorporated in the economic model and it did not alter its decision on the cost effectiveness of bevacizumab in combination with capecitabine.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA263 (STA)\n\n\n\nAppraisal title: Bevacizumab in combination with capecitabine for the first-line treatment of metastatic breast cancer\n\nSection\n\nKey conclusion\n\nBevacizumab in combination with capecitabine is not recommended within its marketing authorisation for the first-line treatment of metastatic breast cancer, that is, when treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate, or when taxanes or anthracyclines have been used as part of adjuvant treatment within the past 12\xa0months.\n\n\n\n\n\nThe Committee considered that the results from the manufacturer's economic analysis, based on a subgroup of patients who were previously treated with a taxane, were not robust. The Committee was not able to determine the most plausible ICER for this subgroup but was convinced it would be higher than the ICER of £82,000 per QALY gained resulting from the ERG explorations. The Committee considered that the ICER for the ITT population would be even higher.\n\n\n\n, 4.13\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\n\n\nThe Committee heard from the patient expert and clinical specialist that prolonging progression-free survival was very important for patients with advanced breast cancer, but this had to be coupled with maximising quality of life at the same time. The Committee concluded that bevacizumab plus capecitabine represented an option for patients with limited treatment options, and that an improvement in quality of life benefit, and the adverse event profile were key considerations.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\nThe Committee concluded that bevacizumab plus capecitabine improved progression-free survival relative to capecitabine plus placebo, but that there was no robust evidence that it improved overall survival and that its effects on health-related quality of life had not been captured.\n\n\n\n\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee concluded that the innovative aspects of bevacizumab were already incorporated in the economic model and that there were no additional gains in health-related quality of life over those already included in the QALY calculations.\n\n\n\n\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nBevacizumab in combination with capecitabine has a marketing authorisation for 'first-line treatment of patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12\xa0months should be excluded from treatment with bevacizumab in combination with capecitabine'.\n\n\n\n\n\nAdverse reactions\n\n\n\nThe Committee noted that grade 3–5 adverse events were higher with bevacizumab plus capecitabine (36.6%) compared with capecitabine plus placebo (22.9%). In addition, the number of patients with hypertension, proteinuria, sensory neuropathy and venous thromboembolic events was higher with bevacizumab plus capecitabine compared with capecitabine plus placebo. The Committee concluded that bevacizumab plus capecitabine had a less favourable adverse event profile than capecitabine plus placebo.\n\n\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nData from the capecitabine cohort of the RIBBON-1 trial formed the clinical-effectiveness evidence in the manufacturer's submission.\n\n\n\nThe Committee noted that no quality of life data had been collected in the trial. The Committee considered quality of life to be an important outcome measure in advanced cancer and that this was an omission from the trial.\n\n\n\nRelevance to general clinical practice in the NHS\n\n\n\nThe Committee noted that 60% of patients in the capecitabine cohort of the RIBBON-1 trial had not received prior taxane therapy, had good performance status and yet taxane treatment was not considered appropriate for them.\n\n\n\nThe Committee also noted that the dose of capecitabine in the trial was 1000\xa0mg/m2 rather than the licensed dose of 1250\xa0mg/m2. The Committee was aware that the dose of capecitabine used in UK practice was often lower in older patients and those with poor performance status, but observed that all patients in the RIBBON-1 trial were of ECOG performance status 0 or 1 and the median age was 56\xa0years. However, the Committee considered the comments during consultation that some clinicians in the UK start at a dose lower than the licensed dose (often 1000\xa0mg/m2) even in fitter patients. The Committee concluded that the dose of capecitabine used in the trial may have some relevance to clinical practice in the UK.\n\n\n\n, 4.4\n\nUncertainties generated by the evidence\n\n\n\nThe Committee was aware that patients from both arms of the trial could receive treatment with bevacizumab after disease progression as well as other subsequent treatments and that all these subsequent therapies could have confounded the relative treatment effect in terms of overall survival. The Committee also noted that no quality of life data had been collected in the trial. The Committee concluded that bevacizumab plus capecitabine improved progression-free survival relative to capecitabine plus placebo, but that there was no robust evidence that it improved overall survival and that its effects on health-related quality of life had not been captured.\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee examined the subgroup analysis conducted by the manufacturer comparing bevacizumab plus capecitabine with capecitabine plus placebo in patients who had previously received a taxane. However, the Committee noted that previous taxane therapy was not a stratification factor at randomisation and that this subgroup was specified after the trial had begun but before the analysis was completed. The Committee also heard that the overall survival results were based on small numbers of events and that no statistical adjustments were made to control for multiple testing, thus increasing the risk of chance findings. The Committee considered that there was no biologically plausible reason why bevacizumab plus capecitabine would be more effective in this subgroup than in the ITT population. The Committee concluded that the results from the prior taxane subgroup of the RIBBON-1 trial were not sufficiently robust to use for the development of guidance.\n\n\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee noted that the results from the ITT population demonstrated a statistically significant median investigator-assessed progression-free survival benefit of 2.9\xa0months for bevacizumab plus capecitabine compared with capecitabine plus placebo.\n\n\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nThe Committee considered the cost effectiveness of bevacizumab and capecitabine compared with capecitabine alone based on the manufacturer's model and critique by the ERG.\n\nThe Committee was aware that the manufacturer had based the economic evaluation on the subgroup of patients who had previously received a taxane rather than the Committee's preferred choice of the whole capecitabine cohort (the ITT population). The Committee noted the manufacturer's and ERG's statements that an analysis of the ITT population would result in a larger ICER than for the subgroup included in the base-case analysis. The Committee agreed with this assessment.\n\n\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted the explorations made by the ERG to the costs of therapy and concluded that these adjustments were appropriate.\n\n\n\n\n\n\n\nThe Committee noted the ERG's concerns around the rank preserving structural failure time method used by the manufacturer to account for the effect of crossover to open-label bevacizumab in the modelling of survival in the progressed disease state. The Committee discussed the ways in which the analyses were adjusted for crossover but was unclear as to the most appropriate method without introducing bias. The Committee also noted that the subsequent treatments had not been modelled, which in combination with the impact of crossover, could have led to confounding of the overall survival results.\n\n\n\nThe Committee discussed that it was unexpected that the costs of administration and pharmacy time associated with bevacizumab plus capecitabine would be lower than the costs for capecitabine alone. The Committee concluded that despite the incorporation of NHS tariffs, this discrepancy contributed to the uncertainty associated with the results of the manufacturer's economic model.\n\n\n\n\n\nThe Committee was also aware that a disutility from adverse events had not been applied in the manufacturer's model, despite utility estimates being available in the literature to account for adverse events, and it was likely that this could have resulted in underestimated ICERs.\n\n\n\nIncorporation of health-related quality of life benefits and utility values\n\n\n\nThe Committee noted that no quality of life data had been collected in the trial and that the economic analysis included utility values from a literature review. The Committee was also aware that a disutility for adverse events had not been applied in the manufacturer's model, despite utility estimates being available in the literature to account for adverse events, and it was likely that this could have resulted in underestimated ICERs.\n\n\n\n, 4.13\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee recognised the novel mode of action of bevacizumab, which may benefit breast cancer patients whose treatment options are limited. However, it considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee concluded that the results from the prior taxane subgroup of the RIBBON-1 trial were not sufficiently robust to use for the development of guidance. The Committee only considered the economic analysis based on this subgroup to establish a benchmark for the incremental cost per QALY gained for the ITT population.\n\n, 4.9\n\nWhat are the key drivers of cost effectiveness?\n\nThe costs of therapy adopted in the manufacturer's model, the impact of crossover and lack of modelling of subsequent treatments were key drivers of uncertainty around cost effectiveness.\n\n, 4.11, 4.13\n\n\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nThe Committee concluded that given all of the uncertainties, it was not possible to determine the most plausible ICER for bevacizumab plus capecitabine compared with capecitabine alone for the subgroup of patients who were previously treated with a taxane. However, it was convinced that the ICER would be higher than the ICER of £82,000 per QALY gained resulting from the ERG explorations. The Committee considered that the ICER for bevacizumab plus capecitabine compared with capecitabine alone in the ITT population would be even higher.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\n\n\nNone\n\n--\n\nEnd-of-life considerations\n\n\n\nThe Committee discussed whether bevacizumab plus capecitabine for the first-line treatment of metastatic breast cancer fulfilled the criteria for a life-extending, end-of-life treatment. The Committee noted that bevacizumab is licensed for a relatively large population across a range of indications in the treatment of breast, colorectal, renal and non-small-cell lung cancers. Therefore, it does not meet the criterion of the supplementary advice from NICE that the treatment should be licensed for small populations. Having established that bevacizumab did not meet the population criterion, the Committee decided it was not necessary to make a decision about the life expectancy or extension to life criteria. The Committee concluded on this basis that bevacizumab plus capecitabine did not fulfil the criteria for being a life-extending, end-of-life treatment.\n\n\n\nEqualities considerations and social value judgements\n\nNo equality issues were identified during the scoping process or the appraisal.\n\n--", 'Recommendations for further research ': 'Studies exploring the effectiveness of bevacizumab in people previously treated with a taxane and its effects on health-related quality of life.', 'Related NICE guidance': 'Published\n\nBevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer. NICE technology appraisal guidance 214 (2011).\n\nAdvanced breast cancer: diagnosis and management. NICE clinical guideline 81 (2009).\n\nGemcitabine for the treatment of metastatic breast cancer. NICE technology appraisal guidance 116 (2007).', 'Review of guidance': 'The guidance on this technology will be considered for review in June 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveAugust 2012', 'Changes after publication': 'February 2014:\n minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta263
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Evidence-based recommendations on bevacizumab (Avastin), with capecitabine, for treating metastatic breast cancer in adults.
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ceef0c3f8e89d9178c58bd70f14dac0eb9bc3bb8
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Mega Soft Patient Return Electrode for use during monopolar electrosurgery
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Mega Soft Patient Return Electrode for use during monopolar electrosurgery
Evidence-based recommendations on Mega Soft Patient Return Electrode for use during monopolar electrosurgery.
# Recommendations
NICE medical technologies guidance addresses specific technologies notified to NICE by sponsors. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice.
The use of the Mega Soft Patient Return Electrode during monopolar electrosurgery may offer advantages for selected patients: for example, those who would need shaving before the application of adhesive electrode pads and those with fragile or damaged skin.
It is plausible that the Mega Soft Patient Return Electrode reduces the risk of burns related to the diathermy patient return electrode where surgery is carried out in the context of good operating theatre practice. The published clinical evidence comparing the Mega Soft Patient Return Electrode against disposable single-use patient return electrodes for use during monopolar electrosurgery is limited, but there have been no reports of burns as a result of its use in the UK.
There may be system benefits for operating theatre staff using the Mega Soft Patient Return Electrode in terms of increased convenience and reduced setting up time. These benefits are more likely to be realised for inpatient operating lists than for day case surgery, and do not appear to lead to a significant reduction in resource utilisation. The economic evidence and cost modelling demonstrate near equivalent resource use to current practice.
Clinicians and managers considering the adoption of the Mega Soft Patient Return Electrode should therefore, in judging the likely benefits, take into account current practice in their operating theatres with regard to prevention of alternative site burns and the proportion of inpatient operations for which it would be used.# The technology
# Description of the technology
The Mega Soft Patient Return Electrode (Megadyne, Johnson & Johnson Medical Ltd) is a reusable dispersive capacitive electrode designed for use during monopolar electrosurgery. The electrode, which is incorporated into a pad, is intended to reduce the risk of burns and to provide pressure relief.
Electrosurgery uses high frequency current to achieve surgical effects such as cutting and coagulation. It is commonly referred to as diathermy. Monopolar electrosurgery (monopolar diathermy) specifically relies on the patient forming part of the electrical circuit. In addition to the patient's tissue, the electrical circuit also includes the electrosurgical unit, which generates the electrical current, an active electrode and a patient return electrode. High frequency electrical current is conducted from the target tissue to an electrosurgical unit, or generator. When the surgeon touches a selected area of the patient's tissue with the electrosurgery tool (the active electrode), current passes from the tool, is distributed widely throughout the patient's body and then returns to the electrosurgical unit via a patient return (dispersive) electrode. In current NHS clinical practice, the electrical circuit is completed by using an adhesive disposable single-use pad with an integral return electrode, which is attached directly to the patient's skin (patient return electrode). These electrodes consist of a conductive foil covered by a polymer. The Mega Soft Patient Return Electrode is incorporated into a large pressure-relieving pad (approximately 117 cm x 51 cm x 1.25 cm) that is placed on the operating table on which the patient lies. When the patient lies on the pad containing the Mega Soft Patient Return Electrode the electrical circuit is completed.
A standard disposable single-use patient return electrode measures approximately 12 cm x 13 cm. The area covered by the pad needs to be large enough to maximise conduction of electrical energy away from the patient (disperse the electrical current) and so minimise the rise in skin temperature. A standard patient return electrode is therefore also known as a dispersive electrode. It may also be called a neutral electrode, and this is the name used in the relevant technical standard specification, for example the IEC 60601-2-2-2009. In clinical practice, the standard patient return electrode is commonly referred to as a diathermy pad.
A standard disposable single-use patient return electrode forms a resistive circuit and the direct electrical connection relies on good contact with the patient. The Mega Soft Patient Return Electrode does not rely on direct contact with the patient and forms a capacitive circuit. The Mega Soft Patient Return Electrode is much larger than a standard disposable single-use patient return electrode and the sponsor states that this leads to a reduction in current density when compared with the disposable single-use patient return electrode. It should be noted that this will depend on the position of the patient and is likely to be true when the patient is lying supine and is in contact with a large area of the mat.
Most adverse events related to electrosurgery are patient burns. During electrosurgery, patients are at risk of 2 types of burn: return electrode site burns and alternative site burns. Return electrode site burns can occur when the contact area is reduced (for example, when a disposable pad partially peels off during surgery) and the current density increases. Some split disposable single-use patient return electrodes are designed to set off an alarm and cause the electrosurgical unit to cease to function when they start to peel off. Alternative site burns occur when some of the current does not follow the main circuit route, but finds an alternative path to earth rather than returning to the generator. If the alternative path is unintentionally directed towards the patient then a burn can occur. Most electrosurgical generators are isolated, which means the high frequency circuit is not referenced to earth directly. However, whenever high frequency currents are used, there is some leakage to earth, even in an isolated circuit. If the main circuit becomes harder to complete (for example, because of reduced patient contact with the return electrode), there is, in theory, an increased possibility of alternative current pathways that can result in alternative site burns.
During 2009/10 approximately 9.7 million inpatient surgical procedures were performed in the UK. It has been estimated that 2.81 million of these (29% of the total) involved general anaesthesia and lasted for more than 30 minutes. It is thought likely that monopolar electrosurgery is used in at least half of all surgical procedures; therefore patient return electrodes are used in around 1.4 million procedures per year.
The cost of the Mega Soft Patient Return Electrode given in the sponsor's submission is £1900 without VAT. The Mega Soft Patient Return Electrode can be used with all electrosurgical generators, with the exception of the ERBE generator when that is used on the High Cut and Endo Cut mode (as stated in the Mega Soft Patient Return Electrode instructions for use). It is recommended that each Mega Soft Patient Return Electrode is used for a maximum of 24 months.
The claimed benefits of the Mega Soft Patient Return Electrode presented by the sponsor are:
reduction in the incidence of burns in patients having monopolar electrosurgery, with a consequent drop in treatment and litigation costs
avoidance of skin shaving
reduction in skin irritation because the Mega Soft Patient Return Electrode is not attached directly to the patient's skin; this may be particularly applicable to patients with burns or other skin conditions as well as to paediatric patients and older patients with fragile skin
reduction in the risk of pressure-related injury resulting from immobility during surgery
reduction in staff time because the Mega Soft Patient Return Electrode is reusable, is not attached directly to the patient and therefore staff do not need to consider avoiding bony prominences, scar tissue and tattoos as they would when placing a disposable patient return electrode
cost saving and improved sustainability compared with current practice because the electrode is reusable and a separate pressure-relieving device may not be needed.
# Current management
Current practice is to apply a disposable single-use patient return electrode to the skin before monopolar electrosurgery. If electrical conduction is impaired at the skin-to-pad surface interface, the current density increases and this can lead to an increase in skin temperature, which exposes the patient to a risk of return electrode site burns. Electrical conduction can be impaired when the contact area of the standard disposable single-use patient return electrode is reduced by body hair, adipose tissue, bony prominences, fluid invasion, peeling or failure of the electrode to adhere to the patient, or scar tissue. To optimise electrode contact, care must be taken to place the electrode on hair-free areas without bony prominences. This may mean that the skin needs to be shaved before the electrode is applied.
Patient return electrodes used in current practice are single-use and disposable: they vary in 2 main respects. First, they may have split (dual) and non-split (single) electrodes. Second, they may have integral lead wires to attach them to the generator or they may be supplied without lead wires. If a patient return electrode has integral lead wires then these are discarded with the disposable electrode after use. Patient return electrodes without attached lead wires are connected to the generator by reusable lead wires. All types of patient return electrode are available in a range of sizes for adults and children. NHS procurement data indicate that the most commonly used type of patient return electrode in the NHS in England is the split adult disposable single-use patient return electrode without a lead wire.# Clinical evidence
# Summary of clinical evidence
Full details of all clinical outcomes considered by the Committee are available in the assessment report overview.
The key clinical outcomes for the Mega Soft Patient Return Electrode presented in the decision problem were:
incidence of patient return electrode site burns
incidence of alternative site burns
incidence of post-operative pressure ulcers
use of the device in certain patient subgroups.
The clinical evidence for the Mega Soft Patient Return Electrode was based on 2 published studies and 4 unpublished documents. The published studies were 1 technical evaluation (ECRI 2000) and 1 observational study (Sheridan 2003). Both studies evaluated the earlier version of the Mega Soft Patient Return Electrode, the Mega 2000. The unpublished evidence was 1 technical evaluation from the sponsor, testimonials from 2 USA hospitals about the Mega 2000 and the Mega Soft Patient Return Electrode, and 1 questionnaire from 3 London hospitals on the Mega Soft Patient Return Electrode.
ECRI (2000) was a laboratory study that examined the safety, efficacy and cost consequences of the Mega 2000 compared with standard disposable single-use patient return electrodes, in relation to relevant American and international technical standards. The tests were performed on 1 adult volunteer and on a piece of meat (tests that assessed the occurrence of burns). No statistical tests were reported. Mega 2000 was rated 'acceptable (with conditions)'. All the test results were rated as good except the results for the test of alternative current pathways, which were rated as fair. The Mega 2000 is the immediate predecessor product to the Mega Soft Patient Return Electrode and differs in not having a gel layer. Although the results cannot therefore be extrapolated between products, the External Assessment Centre considered that any observed differences between Mega 2000 and standard electrodes would be relevant to the Mega Soft Patient Return Electrode.
Sheridan (2003) reported an observational study of 17 children with extensive burns in a tertiary hospital in the USA. The children had only a few areas of the body suitable for placing the electrode and grounding the current. No statistical tests were reported. The results showed that Mega 2000 did not cause any burns, was convenient to use, and enabled effective patient grounding despite the presence of extensive burns.
A laboratory-based comparative technical study comparing the Mega Soft Patient Return Electrode with a disposable single-use split patient return electrode was submitted by the sponsor. The study has not been peer-reviewed. The tests were carried out on anaesthetised pigs. The main outcome was whether or not electrode site burns were observed (recorded as, yes or no). No statistical tests were reported. There was a rise in temperature of 9.7°C with the disposable split electrode compared with 1.2°C with the Mega Soft Patient Return Electrode. The IEC 60601-2-2-2006 standards for electrosurgery allow a maximum temperature increase of 6°C to minimise the risk of electrode site burns.
The sponsor provided 2 testimonial reports from Christus St Joseph's Hospital, USA in 2011. These were not clinical studies and no statistical tests were reported. There were no pre-defined outcomes. These hospitals initially used Mega 2000 and then switched to using Mega 2000 Soft (the US equivalent of the Mega Soft Patient Return Electrode) when it came onto the market. In both reports, Mega 2000/Mega 2000 Soft was compared indirectly with standard disposable single-use patient return electrodes for patient comfort and cost savings. Both hospitals issued statements saying that the Mega Soft Patient Return Electrode improved patient comfort and provided cost savings.
An evaluation report was based on the use of the Mega Soft Patient Return Electrode at 3 London hospitals. Over a period of 2 weeks, theatre nurses completed a questionnaire after surgery to rate the use of the Mega Soft Patient Return Electrode. No information was provided about the selection criteria of patients, the total sample size or the number of non-responders. Data were obtained after procedures were completed on 18 paediatric patients at 1 hospital and on 12 and 24 adult patients respectively at the other 2. Mean scores were provided, together with raw data submitted for each question. Scores were from 0 to 5, with a higher score indicating a better outcome, and were averaged. Overall, a rating of 4.7 was recorded for the Mega Soft Patient Return Electrode. The highest scores were for skin irritation and power settings (4.9) and the lowest score was for positioning (4.2).
## Committee considerations
The Committee noted that patient return electrode site burns are rare. It was advised that, on average, 117 electrosurgery burns are reported to the MHRA each year. Of these, approximately one-third are patient return electrode site burns and about two-thirds are alternative site burns. Expert advisers stated that, in their experience, patient return electrode site burns are very uncommon indeed, are not severe and can be treated with topical cream only. The Committee was advised that all types of burn can usually be avoided by good operating theatre practice.
The Committee noted that the published clinical evidence comparing the Mega Soft Patient Return Electrode against disposable single-use patient return electrodes for use during monopolar electrosurgery is limited and did not provide evidence of whether or not the device reduced the incidence of patient return electrode site burns in practice. The Committee accepted that there have been no reports of burns as a result of its use in the UK, and it acknowledged, therefore, that it is plausible that using the Mega Soft Patient Return Electrode reduces the risk of patient return electrode site burns, based on theoretical considerations. The Committee concluded that technical testing had shown that the Mega Soft Patient Return Electrode was safe in the normal circumstances of UK practice. It noted that no adverse incidents (and specifically no burns of any kind) had been reported from use of the Mega Soft Patient Return Electrode in the UK.
The Committee noted that the type of electrical circuit formed by the Mega Soft Patient Return Electrode can be associated, if good operating theatre practice is not adhered to, with an increased risk of alternative site burns compared with standard disposable single-use patient return electrodes. In the absence of evidence of this, and balancing the plausible reduction in patient return electrode site burns against the possible increase in alternative site burns if good operating theatre practice is not adhered to, the Committee judged that there was likely to be a similar overall risk of burns with the Mega Soft Patient Return Electrode compared with current practice. Any reduction in the overall risk of burns using the Mega Soft Patient Return Electrode would depend on good standards of operating theatre practice to minimise the incidence of alternative site burns. Therefore, clinicians and managers considering the adoption of the Mega Soft Patient Return Electrode should take into account current practice in their operating theatres with regard to prevention of alternative site burns.
The Committee accepted it was likely that the Mega Soft Patient Return Electrode may have practical advantages in selected patient groups, but despite a limited number of positive user feedback reports, there was a lack of clinical studies to support these claims. Examples are patients with fragile or damaged skin, and patients who would need shaving before application of standard disposable single-use patient return electrodes. The Committee noted estimates from clinical experts that between 20% and 30% of patients need to be shaved before the use of standard disposable single-use patient return electrodes. The Committee noted that adipose tissue, bony prominences, tattoos and scar tissue need to be considered, as well as body hair, when placing single-use patient return electrodes but not when using the Mega Soft Patient Return Electrode.# NHS considerations
# System impact
The sponsor claimed that using the Mega Soft Patient Return Electrode can reduce staff time. A patient can be placed on the Mega Soft Patient Return Electrode (which is already on the operating table) and does not need to have a suitable site selected for attaching a standard disposable single-use patient return electrode. The site of the Mega Soft Patient Return Electrode does not need to be checked at the end of the operation. In addition, some patients may need shaving before the use of a standard disposable single-use patient return electrode and this involves staff time and the use of a disposable razor.
The sponsor claimed that the Mega Soft Patient Return Electrode would be cost saving by offering improved sustainability compared with current practice because it is reusable and a separate pressure-relieving device may not be needed. During consultation, the sponsor submitted 6 sources of information, 1 of which was not relevant to this device. One was a pressure map evaluation of Mega 2000 Soft (the US equivalent of the Mega Soft Patient Return Electrode) from 2007. This showed that the best average pressure of 24.8 mmHg was measured using Mega 2000 Soft. If no pressure-relieving pad was used, the average pressure was 40.3 mmHg. Four studies evaluated pads made of the same visco-elastic polymer that is used in the Mega Soft Patient Return Electrode (including a randomised controlled trial of 446 patients). Overall, pads made of this material were found to reduce pressure and provide support.
During consultation, the sponsor submitted a simple waste calculator (a Microsoft Excel spreadsheet) to support the claim of improved sustainability. The calculator showed that waste is likely to be reduced if the Mega Soft Patient Return Electrode is used instead of disposable single-use patient return electrodes. The estimate from this waste calculator for 1 operating room, based on 3 operations a day, 4 days a week for 50 weeks of the year, was 9 lb of waste disposed for the Mega Soft Patient Return Electrode compared with 74.06 lb for single-use patient return electrodes. The waste calculator is based on US practice and has not been validated. It was not specified whether the waste figures were based on disposable single-use patient return electrodes with integral lead-wires or without integral lead wires.
## Committee considerations
The expert advisers stated that any necessary shaving of patients and placement of standard disposable single-use patient return electrodes are normally done at the same time as other tasks and therefore using the Mega Soft Patient Return Electrode would not save as much time as claimed. The Committee accepted these views and concluded that using the Mega Soft Patient Return Electrode would not normally result in a substantial reduction in theatre time and the time taken to prepare patients in the operating suite.
The Committee noted comments that, even if operating theatre time was unlikely to be reduced, the use of the Mega Soft Patient Return Electrode might be more convenient and reduce the burden on theatre staff. This could include removing the need to: shave some patients; select appropriate sites and fix adhesive standard disposable single-use patient return electrodes; adjust or change electrodes during surgery; or check electrode sites at the end of operations.
The Committee was advised that the possible advantages of using the Mega Soft Patient Return Electrode would be significantly influenced by whether it was used for inpatient or for day-case surgery. It heard that at least half of operations performed in the NHS are carried out as day cases and for these a fixed operating table is not generally used. For inpatient operations, the Mega Soft Patient Return Electrode can be placed on the operating table at the start of a day and left in place throughout any operating list. Patients can then be placed on the Mega Soft Patient Return Electrode when they are moved from the trolley on which they are anaesthetised to the operating table. The Mega Soft Patient Return Electrode is left on the operating table and cleaned between patients. By contrast, most day-case surgery is performed with the patient on a trolley. Patients are anaesthetised while on the trolley, which is then moved into the operating theatre and then to the recovery area: the patient remains on the same trolley throughout. This means that at least 2 Mega Soft Patient Return Electrodes would be needed for each day-case operating suite. Otherwise, placing each patient on the Mega Soft Patient Return Electrode would involve more time and inconvenience than applying and removing a standard disposable single-use patient return electrode. The Committee concluded that the patient, health system and any cost advantages of the Mega Soft Patient Return Electrode were likely to be realised only when it was used for inpatient surgery and not for day-case surgery.
The Committee considered the results from the waste calculator and whether these supported the claim for improved sustainability and the cost impact associated with the reusable nature of the Mega Soft Patient Return Electrode. It accepted that waste was likely to be reduced but was unable to reach any specific conclusions on this because of the lack of validated data.
The Committee noted that the Mega Soft Patient Return Electrode is compatible with all electrosurgical generators apart from certain settings on 1 specific generator (see section 2.7). It regarded compatibility with existing electrosurgical generators as fundamental to any consideration to adopt the Mega Soft Patient Return Electrode.
The Committee accepted the submitted evidence to support the claim that the Mega Soft Patient Return Electrode has acceptable pressure-relieving properties making it unnecessary (in most operations) for an additional pressure-relieving device to be used.# Cost considerations
# Cost evidence
No published economic evidence on the Mega Soft Patient Return Electrode was identified by the sponsor. The External Assessment Centre found 1 study (ECRI 2000) that undertook a cost consequences analysis of the Mega 2000 in the USA. The External Assessment Centre noted that ECRI reported that the frequency of use and cost differential meant that with greater use Mega 2000 became more cost saving; however, the values used in the study were not considered relevant to the decision problem.
The External Assessment Centre stated that no clinical evidence was presented on which to base the incidence of skin burns from standard disposable single-use patient return electrodes and their associated costs in the sponsor's model. Evidence was not included on the cost of procuring, storing and disposing of standard disposable single-use patient return electrodes. No independent evidence was supplied on the time saved in theatre by using the Mega Soft Patient Return Electrodes rather than standard disposable single-use patient return electrodes.
The sponsor submitted a de novo economic model that estimated the cost per operation for the Mega Soft Patient Return Electrode compared with a split standard disposable single-use patient return electrode and a non-split standard disposable single-use patient return electrode in adult and paediatric patients undergoing monopolar electrosurgery. The analysis was from the NHS and personal social services perspective. Full details of all cost evidence and modelling considered by the Committee are available in the assessment report overview.
The model used linear formulae that described the relationships between the resource and cost variables. The model did not use any health states. The External Assessment Centre noted that this structure was appropriate to quantify the main cost differences between the technologies given the level of clinical evidence available.
The sponsor stated that several parameters were not included in the model because a lack of data meant that cost savings were not quantifiable. These included:
disposal of standard disposable single-use patient return electrodes
further surgery to treat skin burns from standard disposable single-use patient return electrodes
litigation because of skin burns from standard disposable single-use patient return electrodes
treatment of skin irritation from standard disposable single-use patient return electrodes
-rdering and storing boxes of standard disposable single-use patient return electrodes.
The sponsor's base-case analysis included several key assumptions:
The cost of the adult or paediatric Mega Soft Patient Return Electrode (without VAT) is £1900.
The Mega Soft Patient Return Electrode is used 3 times a day, 5 days a week, and 52 weeks a year (based on expert adviser estimates).
Four types of standard disposable single-use patient return electrode are used in the NHS. The prices given are based on prices from the manufacturers of the different electrodes. (The sponsor did not supply any prices for electrodes without lead wires.)
Split adult standard disposable single-use patient return electrodes with lead wire: £2.44 per electrode
Non-split adult standard disposable single-use patient return electrodes with lead wire: £2.60 per electrode
Split paediatric standard disposable single-use patient return electrodes with lead wire: £1.92 per electrode
Non-split paediatric standard disposable single-use patient return electrodes with lead wire: £1.74 per electrode
The price of an operating table pressure-relieving mattress was taken from 1 manufacturer and is £334.
The pressure-relieving mattress is used 3 times a day, 5 days a week for 52 weeks a year based on assumptions and estimates.
Costs of razors to shave patients were from razor manufacturers and are £1.13 for a disposable razor and £2.09 for a clipper head.
All patients need shaving before using a standard disposable single-use patient return electrode.
The discount rate of the Mega Soft Patient Return Electrode is 3.5% applied in year 0.
The lifespan of the Mega Soft Patient Return Electrode is 24 months.
The resource costs from the Personal Social Services Research Unit (PSSRU) are based on 'per operation hour' and are £347 per hour each for a surgeon and an anaesthetist and £41 per nurse.
The estimated time needed for site preparation when using a standard disposable single-use patient return electrode is 5 minutes.
The sponsor tested several of the base-case assumptions in deterministic 2-way sensitivity analyses. In these analyses, the following parameters were increased and decreased by 50% (with no probabilities attached for the likelihood of these events occurring):
number of operations per week
cost of standard disposable single-use patient return electrodes
cost of an operating table pressure-relieving mattress
life of an operating table pressure-relieving mattress
cost of razors for shaving
staff time and hourly staff costs.
The sponsor's base-case analysis estimated the cost per operation using the Mega Soft Patient Return Electrode compared with a standard disposable single-use patient return electrode with a lead wire. The findings showed savings of £70.83 per operation for adults and £70.31 for children when using the adult or the paediatric Mega Soft Patient Return Electrode respectively when the Mega Soft Patient Return Electrode was compared with split pad standard disposable single-use patient return electrodes. These were greater savings than when the Mega Soft Patient Return Electrode was compared with non-split pad standard disposable single-use patient return electrodes because of the higher cost of the split pads. More than 95% of the savings were from improving efficiency by saving 5 minutes per operation. More than 80% of the savings were from surgeon and anaesthetist time saved. The largest contribution to the cost saving was from surgeon and anaesthetist time saved (£57.84 per operating hour). Nurse time saved resulted in a further saving of £10.25 per operating hour.
The External Assessment Centre noted that the sponsor had not justified why its assumptions were the most plausible range of values. Furthermore, the sensitivity analysis did not capture the lower prices for standard disposable single-use patient return electrodes in 1 NHS trust. The sensitivity analyses demonstrated that the results of the sponsor's model were sensitive to assumptions about staff time and the cost per hour for surgeons, anaesthetists and nurses.
The External Assessment Centre expressed particular concerns about a number of parameters in the sponsor's model and carried out additional analyses to examine the impact of changing the following parameters:
Inclusion of VAT in the price of the Mega Soft Patient Return Electrode (£2280).
The most common type of disposable single-use patient return electrode used in the NHS is the split adult disposable single-use patient return electrode with no lead wire (£0.87). This is based on NHS Supply Chain figures.
The Mega Soft Patient Return Electrode is used 3 times a day, 4 days a week for 50 weeks a year (based on clinician estimates). This equates to 600 operations per year.
A razor costs £2.09 (disposable razors are no longer used).
Shaving of 40% of patients (based on clinician estimates that were obtained by the External Assessment Centre as part of its assessment).
There is no overall delay for site preparation when using a standard disposable single-use patient return electrode based on clinician advice.
The overall cost per operation when using the parameters described in section 5.10 is £2.16 for the comparator and £1.97 for an adult Mega Soft Patient Return Electrode. Therefore, this analysis demonstrated a cost saving of £0.19 per operation when using an adult Mega Soft Patient Return Electrode compared with a standard disposable single-use patient return electrode.
The overall cost per operation when using the parameters described in section 5.10 for the paediatric comparator (split paediatric standard disposable single-use patient return electrode with no lead wire) is £2.30 and for the paediatric Mega Soft Patient Return Electrode it is £1.97. This demonstrated a cost saving of £0.33 per operation using a paediatric Mega Soft Patient Return Electrode compared with a standard disposable single-use patient return electrode.
## Committee considerations
The Committee discussed the different assumptions presented to decide which were the most appropriate to use. It judged that:
VAT should be included for the price of the Mega Soft Patient Return Electrode.
NHS Supply Chain figures provided the most appropriate comparator (a split disposable single-use patient return electrode with no lead wire).
The External Assessment Centre's assumption of use of operating table pressure-relieving mattresses 3 times a day, 4 days a week, 50 weeks a year was reasonable.
There was unlikely to be any substantial saving of operating theatre time as a result of using the Mega Soft Patient Return Electrode.
The Committee considered that there was unlikely to be any substantial saving of operating theatre time as a result of using the Mega Soft Patient Return Electrode. Therefore, it did not accept the sponsor's base-case cost saving of £70.83 and judged that no significant saving would be made.
The Committee noted that the sponsor's base-case analysis assumed that 100% of patients are shaved before monopolar electrosurgery with a disposable single-use patient return electrode, but that the External Assessment Centre advised that the percentage is nearer to 40%, based on advice from clinicians. However, the Committee was advised by experts and heard from some of its members that in clinical practice the percentage of patients who need shaving is more likely to be between 20% and 30%. The Committee concluded that 30% was a reasonable figure to use for the cost model. If 30% of patients are shaved and all the other parameters in section 5.10 remain the same then the External Assessment Centre advised that the overall cost per operation when using the comparator would be reduced from £2.16 to £1.94. The overall cost per operation when using the Mega Soft Patient Return Electrode remains at £1.97 because patients do not need shaving for this electrode.
For paediatric patients, the sponsor's base-case analysis was also based on 100% of patients having monopolar electrosurgery needing to be shaved. The Committee was advised that it is unlikely that any child would need shaving and this figure should be 0%. If no patients are shaved and all the other parameters in section 5.10 remain the same then the Committee noted that the overall cost per operation when using the paediatric comparator is reduced from £2.30 to £1.46. This means that it would cost 51p more per operation to use the Mega Soft Patient Return Electrode because the overall cost per operation when using Mega Soft Patient Return Electrode would remain at £1.97.
The Committee concluded that the economic evidence and cost modelling demonstrate near equivalent resource use for the Mega Soft Patient Return Electrode to current practice. Expert advice suggested that claims for the Mega Soft Patient Return Electrode's benefit are greatly influenced by the circumstances in which it is used.# Conclusions
The Mega Soft Patient Return Electrode may have particular advantages for patients with fragile or damaged skin; these include patients with burns, patients with skin conditions, paediatric patients and older patients. It also has the advantage that no patient needs shaving whereas about 30% of patients may need to be shaved when disposable single-use patient return electrodes are used.
The Committee accepted that it is plausible that the Mega Soft Patient Return Electrode reduces the risk of patient return electrode site burns, based on theoretical considerations and on the lack of any reported burns in the UK. It made this judgement despite a very limited amount of published clinical evidence comparing the Mega Soft Patient Return Electrode with disposable patient return electrodes in monopolar electrosurgery.
Use of the Mega Soft Patient Return Electrode might theoretically increase the risk of alternative site burns. Good operating theatre practice minimises this risk and use of the Mega Soft Patient Return Electrode in this context could reduce the overall risk of burns from electrosurgery.
The Mega Soft Patient Return Electrode may be more convenient for theatre staff to use than standard disposable single-use patient return electrodes, but it is not likely to provide substantial savings in operating theatre time. The economic evidence and cost modelling demonstrated near equivalent resource use to current practice. Any health system or cost advantages are likely to be influenced significantly by whether the Mega Soft Patient Return Electrode is being considered for use for inpatient operating lists or day-case surgery.# Related NICE guidance
# Published
Suction diathermy adenoidectomy. NICE interventional procedure guidance 328 (2009).
Electrosurgery (diathermy and coblation) for tonsillectomy. NICE interventional procedure guidance 150 (2005).
## Under development
There is no related guidance under development.
Andrew DillonChief ExecutiveAugust 2012# About this guidance
NICE medical technology guidance addresses specific technologies notified to NICE by sponsors. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This 'case' is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies, which may offer similar advantages.
This guidance was developed using the NICE medical technologies guidance process.
We have produced a summary of this guidance for patients and carers.
Your
responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
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{'Recommendations': "NICE medical technologies guidance addresses specific technologies notified to NICE by sponsors. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice.\n\nThe use of the Mega Soft Patient Return Electrode during monopolar electrosurgery may offer advantages for selected patients: for example, those who would need shaving before the application of adhesive electrode pads and those with fragile or damaged skin.\n\nIt is plausible that the Mega Soft Patient Return Electrode reduces the risk of burns related to the diathermy patient return electrode where surgery is carried out in the context of good operating theatre practice. The published clinical evidence comparing the Mega Soft Patient Return Electrode against disposable single-use patient return electrodes for use during monopolar electrosurgery is limited, but there have been no reports of burns as a result of its use in the UK.\n\nThere may be system benefits for operating theatre staff using the Mega Soft Patient Return Electrode in terms of increased convenience and reduced setting up time. These benefits are more likely to be realised for inpatient operating lists than for day case surgery, and do not appear to lead to a significant reduction in resource utilisation. The economic evidence and cost modelling demonstrate near equivalent resource use to current practice.\n\nClinicians and managers considering the adoption of the Mega Soft Patient Return Electrode should therefore, in judging the likely benefits, take into account current practice in their operating theatres with regard to prevention of alternative site burns and the proportion of inpatient operations for which it would be used.", 'The technology': "# Description of the technology\n\nThe Mega Soft Patient Return Electrode (Megadyne, Johnson & Johnson Medical Ltd) is a reusable dispersive capacitive electrode designed for use during monopolar electrosurgery. The electrode, which is incorporated into a pad, is intended to reduce the risk of burns and to provide pressure relief.\n\nElectrosurgery uses high frequency current to achieve surgical effects such as cutting and coagulation. It is commonly referred to as diathermy. Monopolar electrosurgery (monopolar diathermy) specifically relies on the patient forming part of the electrical circuit. In addition to the patient's tissue, the electrical circuit also includes the electrosurgical unit, which generates the electrical current, an active electrode and a patient return electrode. High frequency electrical current is conducted from the target tissue to an electrosurgical unit, or generator. When the surgeon touches a selected area of the patient's tissue with the electrosurgery tool (the active electrode), current passes from the tool, is distributed widely throughout the patient's body and then returns to the electrosurgical unit via a patient return (dispersive) electrode. In current NHS clinical practice, the electrical circuit is completed by using an adhesive disposable single-use pad with an integral return electrode, which is attached directly to the patient's skin (patient return electrode). These electrodes consist of a conductive foil covered by a polymer. The Mega Soft Patient Return Electrode is incorporated into a large pressure-relieving pad (approximately 117\xa0cm\xa0x\xa051\xa0cm\xa0x\xa01.25\xa0cm) that is placed on the operating table on which the patient lies. When the patient lies on the pad containing the Mega Soft Patient Return Electrode the electrical circuit is completed.\n\nA standard disposable single-use patient return electrode measures approximately 12\xa0cm\xa0x\xa013\xa0cm. The area covered by the pad needs to be large enough to maximise conduction of electrical energy away from the patient (disperse the electrical current) and so minimise the rise in skin temperature. A standard patient return electrode is therefore also known as a dispersive electrode. It may also be called a neutral electrode, and this is the name used in the relevant technical standard specification, for example the IEC 60601-2-2-2009. In clinical practice, the standard patient return electrode is commonly referred to as a diathermy pad.\n\nA standard disposable single-use patient return electrode forms a resistive circuit and the direct electrical connection relies on good contact with the patient. The Mega Soft Patient Return Electrode does not rely on direct contact with the patient and forms a capacitive circuit. The Mega Soft Patient Return Electrode is much larger than a standard disposable single-use patient return electrode and the sponsor states that this leads to a reduction in current density when compared with the disposable single-use patient return electrode. It should be noted that this will depend on the position of the patient and is likely to be true when the patient is lying supine and is in contact with a large area of the mat.\n\nMost adverse events related to electrosurgery are patient burns. During electrosurgery, patients are at risk of 2 types of burn: return electrode site burns and alternative site burns. Return electrode site burns can occur when the contact area is reduced (for example, when a disposable pad partially peels off during surgery) and the current density increases. Some split disposable single-use patient return electrodes are designed to set off an alarm and cause the electrosurgical unit to cease to function when they start to peel off. Alternative site burns occur when some of the current does not follow the main circuit route, but finds an alternative path to earth rather than returning to the generator. If the alternative path is unintentionally directed towards the patient then a burn can occur. Most electrosurgical generators are isolated, which means the high frequency circuit is not referenced to earth directly. However, whenever high frequency currents are used, there is some leakage to earth, even in an isolated circuit. If the main circuit becomes harder to complete (for example, because of reduced patient contact with the return electrode), there is, in theory, an increased possibility of alternative current pathways that can result in alternative site burns.\n\nDuring 2009/10 approximately 9.7\xa0million inpatient surgical procedures were performed in the UK. It has been estimated that 2.81\xa0million of these (29% of the total) involved general anaesthesia and lasted for more than 30\xa0minutes. It is thought likely that monopolar electrosurgery is used in at least half of all surgical procedures; therefore patient return electrodes are used in around 1.4\xa0million procedures per year.\n\nThe cost of the Mega Soft Patient Return Electrode given in the sponsor's submission is £1900 without VAT. The Mega Soft Patient Return Electrode can be used with all electrosurgical generators, with the exception of the ERBE generator when that is used on the High Cut and Endo Cut mode (as stated in the Mega Soft Patient Return Electrode instructions for use). It is recommended that each Mega Soft Patient Return Electrode is used for a maximum of 24\xa0months.\n\nThe claimed benefits of the Mega Soft Patient Return Electrode presented by the sponsor are:\n\nreduction in the incidence of burns in patients having monopolar electrosurgery, with a consequent drop in treatment and litigation costs\n\navoidance of skin shaving\n\nreduction in skin irritation because the Mega Soft Patient Return Electrode is not attached directly to the patient's skin; this may be particularly applicable to patients with burns or other skin conditions as well as to paediatric patients and older patients with fragile skin\n\nreduction in the risk of pressure-related injury resulting from immobility during surgery\n\nreduction in staff time because the Mega Soft Patient Return Electrode is reusable, is not attached directly to the patient and therefore staff do not need to consider avoiding bony prominences, scar tissue and tattoos as they would when placing a disposable patient return electrode\n\ncost saving and improved sustainability compared with current practice because the electrode is reusable and a separate pressure-relieving device may not be needed.\n\n# Current management\n\nCurrent practice is to apply a disposable single-use patient return electrode to the skin before monopolar electrosurgery. If electrical conduction is impaired at the skin-to-pad surface interface, the current density increases and this can lead to an increase in skin temperature, which exposes the patient to a risk of return electrode site burns. Electrical conduction can be impaired when the contact area of the standard disposable single-use patient return electrode is reduced by body hair, adipose tissue, bony prominences, fluid invasion, peeling or failure of the electrode to adhere to the patient, or scar tissue. To optimise electrode contact, care must be taken to place the electrode on hair-free areas without bony prominences. This may mean that the skin needs to be shaved before the electrode is applied.\n\nPatient return electrodes used in current practice are single-use and disposable: they vary in 2 main respects. First, they may have split (dual) and non-split (single) electrodes. Second, they may have integral lead wires to attach them to the generator or they may be supplied without lead wires. If a patient return electrode has integral lead wires then these are discarded with the disposable electrode after use. Patient return electrodes without attached lead wires are connected to the generator by reusable lead wires. All types of patient return electrode are available in a range of sizes for adults and children. NHS procurement data indicate that the most commonly used type of patient return electrode in the NHS in England is the split adult disposable single-use patient return electrode without a lead wire.", 'Clinical evidence': "# Summary of clinical evidence\n\nFull details of all clinical outcomes considered by the Committee are available in the assessment report overview.\n\nThe key clinical outcomes for the Mega Soft Patient Return Electrode presented in the decision problem were:\n\nincidence of patient return electrode site burns\n\nincidence of alternative site burns\n\nincidence of post-operative pressure ulcers\n\nuse of the device in certain patient subgroups.\n\nThe clinical evidence for the Mega Soft Patient Return Electrode was based on 2 published studies and 4 unpublished documents. The published studies were 1 technical evaluation (ECRI 2000) and 1 observational study (Sheridan 2003). Both studies evaluated the earlier version of the Mega Soft Patient Return Electrode, the Mega 2000. The unpublished evidence was 1 technical evaluation from the sponsor, testimonials from 2 USA hospitals about the Mega 2000 and the Mega Soft Patient Return Electrode, and 1 questionnaire from 3 London hospitals on the Mega Soft Patient Return Electrode.\n\nECRI (2000) was a laboratory study that examined the safety, efficacy and cost consequences of the Mega 2000 compared with standard disposable single-use patient return electrodes, in relation to relevant American and international technical standards. The tests were performed on 1 adult volunteer and on a piece of meat (tests that assessed the occurrence of burns). No statistical tests were reported. Mega 2000 was rated 'acceptable (with conditions)'. All the test results were rated as good except the results for the test of alternative current pathways, which were rated as fair. The Mega 2000 is the immediate predecessor product to the Mega Soft Patient Return Electrode and differs in not having a gel layer. Although the results cannot therefore be extrapolated between products, the External Assessment Centre considered that any observed differences between Mega 2000 and standard electrodes would be relevant to the Mega Soft Patient Return Electrode.\n\nSheridan (2003) reported an observational study of 17 children with extensive burns in a tertiary hospital in the USA. The children had only a few areas of the body suitable for placing the electrode and grounding the current. No statistical tests were reported. The results showed that Mega 2000 did not cause any burns, was convenient to use, and enabled effective patient grounding despite the presence of extensive burns.\n\nA laboratory-based comparative technical study comparing the Mega Soft Patient Return Electrode with a disposable single-use split patient return electrode was submitted by the sponsor. The study has not been peer-reviewed. The tests were carried out on anaesthetised pigs. The main outcome was whether or not electrode site burns were observed (recorded as, yes or no). No statistical tests were reported. There was a rise in temperature of 9.7°C with the disposable split electrode compared with 1.2°C with the Mega Soft Patient Return Electrode. The IEC\xa060601-2-2-2006 standards for electrosurgery allow a maximum temperature increase of 6°C to minimise the risk of electrode site burns.\n\nThe sponsor provided 2 testimonial reports from Christus St Joseph's Hospital, USA in 2011. These were not clinical studies and no statistical tests were reported. There were no pre-defined outcomes. These hospitals initially used Mega 2000 and then switched to using Mega 2000 Soft (the US equivalent of the Mega Soft Patient Return Electrode) when it came onto the market. In both reports, Mega 2000/Mega 2000 Soft was compared indirectly with standard disposable single-use patient return electrodes for patient comfort and cost savings. Both hospitals issued statements saying that the Mega Soft Patient Return Electrode improved patient comfort and provided cost savings.\n\nAn evaluation report was based on the use of the Mega Soft Patient Return Electrode at 3 London hospitals. Over a period of 2\xa0weeks, theatre nurses completed a questionnaire after surgery to rate the use of the Mega Soft Patient Return Electrode. No information was provided about the selection criteria of patients, the total sample size or the number of non-responders. Data were obtained after procedures were completed on 18 paediatric patients at 1 hospital and on 12 and 24 adult patients respectively at the other 2. Mean scores were provided, together with raw data submitted for each question. Scores were from 0\xa0to\xa05, with a higher score indicating a better outcome, and were averaged. Overall, a rating of 4.7 was recorded for the Mega Soft Patient Return Electrode. The highest scores were for skin irritation and power settings (4.9) and the lowest score was for positioning (4.2).\n\n## Committee considerations\n\nThe Committee noted that patient return electrode site burns are rare. It was advised that, on average, 117 electrosurgery burns are reported to the MHRA each year. Of these, approximately one-third are patient return electrode site burns and about two-thirds are alternative site burns. Expert advisers stated that, in their experience, patient return electrode site burns are very uncommon indeed, are not severe and can be treated with topical cream only. The Committee was advised that all types of burn can usually be avoided by good operating theatre practice.\n\nThe Committee noted that the published clinical evidence comparing the Mega Soft Patient Return Electrode against disposable single-use patient return electrodes for use during monopolar electrosurgery is limited and did not provide evidence of whether or not the device reduced the incidence of patient return electrode site burns in practice. The Committee accepted that there have been no reports of burns as a result of its use in the UK, and it acknowledged, therefore, that it is plausible that using the Mega Soft Patient Return Electrode reduces the risk of patient return electrode site burns, based on theoretical considerations. The Committee concluded that technical testing had shown that the Mega Soft Patient Return Electrode was safe in the normal circumstances of UK practice. It noted that no adverse incidents (and specifically no burns of any kind) had been reported from use of the Mega Soft Patient Return Electrode in the UK.\n\nThe Committee noted that the type of electrical circuit formed by the Mega Soft Patient Return Electrode can be associated, if good operating theatre practice is not adhered to, with an increased risk of alternative site burns compared with standard disposable single-use patient return electrodes. In the absence of evidence of this, and balancing the plausible reduction in patient return electrode site burns against the possible increase in alternative site burns if good operating theatre practice is not adhered to, the Committee judged that there was likely to be a similar overall risk of burns with the Mega Soft Patient Return Electrode compared with current practice. Any reduction in the overall risk of burns using the Mega Soft Patient Return Electrode would depend on good standards of operating theatre practice to minimise the incidence of alternative site burns. Therefore, clinicians and managers considering the adoption of the Mega Soft Patient Return Electrode should take into account current practice in their operating theatres with regard to prevention of alternative site burns.\n\nThe Committee accepted it was likely that the Mega Soft Patient Return Electrode may have practical advantages in selected patient groups, but despite a limited number of positive user feedback reports, there was a lack of clinical studies to support these claims. Examples are patients with fragile or damaged skin, and patients who would need shaving before application of standard disposable single-use patient return electrodes. The Committee noted estimates from clinical experts that between 20% and 30% of patients need to be shaved before the use of standard disposable single-use patient return electrodes. The Committee noted that adipose tissue, bony prominences, tattoos and scar tissue need to be considered, as well as body hair, when placing single-use patient return electrodes but not when using the Mega Soft Patient Return Electrode.", 'NHS considerations': '# System impact\n\nThe sponsor claimed that using the Mega Soft Patient Return Electrode can reduce staff time. A patient can be placed on the Mega Soft Patient Return Electrode (which is already on the operating table) and does not need to have a suitable site selected for attaching a standard disposable single-use patient return electrode. The site of the Mega Soft Patient Return Electrode does not need to be checked at the end of the operation. In addition, some patients may need shaving before the use of a standard disposable single-use patient return electrode and this involves staff time and the use of a disposable razor.\n\nThe sponsor claimed that the Mega Soft Patient Return Electrode would be cost saving by offering improved sustainability compared with current practice because it is reusable and a separate pressure-relieving device may not be needed. During consultation, the sponsor submitted 6 sources of information, 1 of which was not relevant to this device. One was a pressure map evaluation of Mega 2000 Soft (the US equivalent of the Mega Soft Patient Return Electrode) from 2007. This showed that the best average pressure of 24.8\xa0mmHg was measured using Mega 2000 Soft. If no pressure-relieving pad was used, the average pressure was 40.3\xa0mmHg. Four studies evaluated pads made of the same visco-elastic polymer that is used in the Mega Soft Patient Return Electrode (including a randomised controlled trial of 446 patients). Overall, pads made of this material were found to reduce pressure and provide support.\n\nDuring consultation, the sponsor submitted a simple waste calculator (a Microsoft Excel spreadsheet) to support the claim of improved sustainability. The calculator showed that waste is likely to be reduced if the Mega Soft Patient Return Electrode is used instead of disposable single-use patient return electrodes. The estimate from this waste calculator for 1 operating room, based on 3 operations a day, 4\xa0days a week for 50\xa0weeks of the year, was 9\xa0lb of waste disposed for the Mega Soft Patient Return Electrode compared with 74.06\xa0lb for single-use patient return electrodes. The waste calculator is based on US practice and has not been validated. It was not specified whether the waste figures were based on disposable single-use patient return electrodes with integral lead-wires or without integral lead wires.\n\n## Committee considerations\n\nThe expert advisers stated that any necessary shaving of patients and placement of standard disposable single-use patient return electrodes are normally done at the same time as other tasks and therefore using the Mega Soft Patient Return Electrode would not save as much time as claimed. The Committee accepted these views and concluded that using the Mega Soft Patient Return Electrode would not normally result in a substantial reduction in theatre time and the time taken to prepare patients in the operating suite.\n\nThe Committee noted comments that, even if operating theatre time was unlikely to be reduced, the use of the Mega Soft Patient Return Electrode might be more convenient and reduce the burden on theatre staff. This could include removing the need to: shave some patients; select appropriate sites and fix adhesive standard disposable single-use patient return electrodes; adjust or change electrodes during surgery; or check electrode sites at the end of operations.\n\nThe Committee was advised that the possible advantages of using the Mega Soft Patient Return Electrode would be significantly influenced by whether it was used for inpatient or for day-case surgery. It heard that at least half of operations performed in the NHS are carried out as day cases and for these a fixed operating table is not generally used. For inpatient operations, the Mega Soft Patient Return Electrode can be placed on the operating table at the start of a day and left in place throughout any operating list. Patients can then be placed on the Mega Soft Patient Return Electrode when they are moved from the trolley on which they are anaesthetised to the operating table. The Mega Soft Patient Return Electrode is left on the operating table and cleaned between patients. By contrast, most day-case surgery is performed with the patient on a trolley. Patients are anaesthetised while on the trolley, which is then moved into the operating theatre and then to the recovery area: the patient remains on the same trolley throughout. This means that at least 2 Mega Soft Patient Return Electrodes would be needed for each day-case operating suite. Otherwise, placing each patient on the Mega Soft Patient Return Electrode would involve more time and inconvenience than applying and removing a standard disposable single-use patient return electrode. The Committee concluded that the patient, health system and any cost advantages of the Mega Soft Patient Return Electrode were likely to be realised only when it was used for inpatient surgery and not for day-case surgery.\n\nThe Committee considered the results from the waste calculator and whether these supported the claim for improved sustainability and the cost impact associated with the reusable nature of the Mega Soft Patient Return Electrode. It accepted that waste was likely to be reduced but was unable to reach any specific conclusions on this because of the lack of validated data.\n\nThe Committee noted that the Mega Soft Patient Return Electrode is compatible with all electrosurgical generators apart from certain settings on 1 specific generator (see section 2.7). It regarded compatibility with existing electrosurgical generators as fundamental to any consideration to adopt the Mega Soft Patient Return Electrode.\n\nThe Committee accepted the submitted evidence to support the claim that the Mega Soft Patient Return Electrode has acceptable pressure-relieving properties making it unnecessary (in most operations) for an additional pressure-relieving device to be used.', 'Cost considerations': "# Cost evidence\n\nNo published economic evidence on the Mega Soft Patient Return Electrode was identified by the sponsor. The External Assessment Centre found 1 study (ECRI 2000) that undertook a cost consequences analysis of the Mega 2000 in the USA. The External Assessment Centre noted that ECRI reported that the frequency of use and cost differential meant that with greater use Mega 2000 became more cost saving; however, the values used in the study were not considered relevant to the decision problem.\n\nThe External Assessment Centre stated that no clinical evidence was presented on which to base the incidence of skin burns from standard disposable single-use patient return electrodes and their associated costs in the sponsor's model. Evidence was not included on the cost of procuring, storing and disposing of standard disposable single-use patient return electrodes. No independent evidence was supplied on the time saved in theatre by using the Mega Soft Patient Return Electrodes rather than standard disposable single-use patient return electrodes.\n\nThe sponsor submitted a de novo economic model that estimated the cost per operation for the Mega Soft Patient Return Electrode compared with a split standard disposable single-use patient return electrode and a non-split standard disposable single-use patient return electrode in adult and paediatric patients undergoing monopolar electrosurgery. The analysis was from the NHS and personal social services perspective. Full details of all cost evidence and modelling considered by the Committee are available in the assessment report overview.\n\nThe model used linear formulae that described the relationships between the resource and cost variables. The model did not use any health states. The External Assessment Centre noted that this structure was appropriate to quantify the main cost differences between the technologies given the level of clinical evidence available.\n\nThe sponsor stated that several parameters were not included in the model because a lack of data meant that cost savings were not quantifiable. These included:\n\ndisposal of standard disposable single-use patient return electrodes\n\nfurther surgery to treat skin burns from standard disposable single-use patient return electrodes\n\nlitigation because of skin burns from standard disposable single-use patient return electrodes\n\ntreatment of skin irritation from standard disposable single-use patient return electrodes\n\nordering and storing boxes of standard disposable single-use patient return electrodes.\n\nThe sponsor's base-case analysis included several key assumptions:\n\nThe cost of the adult or paediatric Mega Soft Patient Return Electrode (without VAT) is £1900.\n\nThe Mega Soft Patient Return Electrode is used 3 times a day, 5\xa0days a week, and 52\xa0weeks a year (based on expert adviser estimates).\n\nFour types of standard disposable single-use patient return electrode are used in the NHS. The prices given are based on prices from the manufacturers of the different electrodes. (The sponsor did not supply any prices for electrodes without lead wires.)\n\n\n\nSplit adult standard disposable single-use patient return electrodes with lead wire: £2.44 per electrode\n\nNon-split adult standard disposable single-use patient return electrodes with lead wire: £2.60 per electrode\n\nSplit paediatric standard disposable single-use patient return electrodes with lead wire: £1.92 per electrode\n\nNon-split paediatric standard disposable single-use patient return electrodes with lead wire: £1.74 per electrode\n\n\n\nThe price of an operating table pressure-relieving mattress was taken from 1 manufacturer and is £334.\n\nThe pressure-relieving mattress is used 3 times a day, 5\xa0days a week for 52\xa0weeks a year based on assumptions and estimates.\n\nCosts of razors to shave patients were from razor manufacturers and are £1.13 for a disposable razor and £2.09 for a clipper head.\n\nAll patients need shaving before using a standard disposable single-use patient return electrode.\n\nThe discount rate of the Mega Soft Patient Return Electrode is 3.5% applied in year 0.\n\nThe lifespan of the Mega Soft Patient Return Electrode is 24\xa0months.\n\nThe resource costs from the Personal Social Services Research Unit (PSSRU) are based on 'per operation hour' and are £347 per hour each for a surgeon and an anaesthetist and £41 per nurse.\n\nThe estimated time needed for site preparation when using a standard disposable single-use patient return electrode is 5\xa0minutes.\n\nThe sponsor tested several of the base-case assumptions in deterministic 2-way sensitivity analyses. In these analyses, the following parameters were increased and decreased by 50% (with no probabilities attached for the likelihood of these events occurring):\n\nnumber of operations per week\n\ncost of standard disposable single-use patient return electrodes\n\ncost of an operating table pressure-relieving mattress\n\nlife of an operating table pressure-relieving mattress\n\ncost of razors for shaving\n\nstaff time and hourly staff costs.\n\nThe sponsor's base-case analysis estimated the cost per operation using the Mega Soft Patient Return Electrode compared with a standard disposable single-use patient return electrode with a lead wire. The findings showed savings of £70.83 per operation for adults and £70.31 for children when using the adult or the paediatric Mega Soft Patient Return Electrode respectively when the Mega Soft Patient Return Electrode was compared with split pad standard disposable single-use patient return electrodes. These were greater savings than when the Mega Soft Patient Return Electrode was compared with non-split pad standard disposable single-use patient return electrodes because of the higher cost of the split pads. More than 95% of the savings were from improving efficiency by saving 5\xa0minutes per operation. More than 80% of the savings were from surgeon and anaesthetist time saved. The largest contribution to the cost saving was from surgeon and anaesthetist time saved (£57.84 per operating hour). Nurse time saved resulted in a further saving of £10.25 per operating hour.\n\nThe External Assessment Centre noted that the sponsor had not justified why its assumptions were the most plausible range of values. Furthermore, the sensitivity analysis did not capture the lower prices for standard disposable single-use patient return electrodes in 1 NHS trust. The sensitivity analyses demonstrated that the results of the sponsor's model were sensitive to assumptions about staff time and the cost per hour for surgeons, anaesthetists and nurses.\n\nThe External Assessment Centre expressed particular concerns about a number of parameters in the sponsor's model and carried out additional analyses to examine the impact of changing the following parameters:\n\nInclusion of VAT in the price of the Mega Soft Patient Return Electrode (£2280).\n\nThe most common type of disposable single-use patient return electrode used in the NHS is the split adult disposable single-use patient return electrode with no lead wire (£0.87). This is based on NHS Supply Chain figures.\n\nThe Mega Soft Patient Return Electrode is used 3 times a day, 4\xa0days a week for 50\xa0weeks a year (based on clinician estimates). This equates to 600 operations per year.\n\nA razor costs £2.09 (disposable razors are no longer used).\n\nShaving of 40% of patients (based on clinician estimates that were obtained by the External Assessment Centre as part of its assessment).\n\nThere is no overall delay for site preparation when using a standard disposable single-use patient return electrode based on clinician advice.\n\nThe overall cost per operation when using the parameters described in section 5.10 is £2.16 for the comparator and £1.97 for an adult Mega Soft Patient Return Electrode. Therefore, this analysis demonstrated a cost saving of £0.19 per operation when using an adult Mega Soft Patient Return Electrode compared with a standard disposable single-use patient return electrode.\n\nThe overall cost per operation when using the parameters described in section 5.10 for the paediatric comparator (split paediatric standard disposable single-use patient return electrode with no lead wire) is £2.30 and for the paediatric Mega Soft Patient Return Electrode it is £1.97. This demonstrated a cost saving of £0.33 per operation using a paediatric Mega Soft Patient Return Electrode compared with a standard disposable single-use patient return electrode.\n\n## Committee considerations\n\nThe Committee discussed the different assumptions presented to decide which were the most appropriate to use. It judged that:\n\nVAT should be included for the price of the Mega Soft Patient Return Electrode.\n\nNHS Supply Chain figures provided the most appropriate comparator (a split disposable single-use patient return electrode with no lead wire).\n\nThe External Assessment Centre's assumption of use of operating table pressure-relieving mattresses 3 times a day, 4\xa0days a week, 50\xa0weeks a year was reasonable.\n\nThere was unlikely to be any substantial saving of operating theatre time as a result of using the Mega Soft Patient Return Electrode.\n\nThe Committee considered that there was unlikely to be any substantial saving of operating theatre time as a result of using the Mega Soft Patient Return Electrode. Therefore, it did not accept the sponsor's base-case cost saving of £70.83 and judged that no significant saving would be made.\n\nThe Committee noted that the sponsor's base-case analysis assumed that 100% of patients are shaved before monopolar electrosurgery with a disposable single-use patient return electrode, but that the External Assessment Centre advised that the percentage is nearer to 40%, based on advice from clinicians. However, the Committee was advised by experts and heard from some of its members that in clinical practice the percentage of patients who need shaving is more likely to be between 20% and 30%. The Committee concluded that 30% was a reasonable figure to use for the cost model. If 30% of patients are shaved and all the other parameters in section 5.10 remain the same then the External Assessment Centre advised that the overall cost per operation when using the comparator would be reduced from £2.16 to £1.94. The overall cost per operation when using the Mega Soft Patient Return Electrode remains at £1.97 because patients do not need shaving for this electrode.\n\nFor paediatric patients, the sponsor's base-case analysis was also based on 100% of patients having monopolar electrosurgery needing to be shaved. The Committee was advised that it is unlikely that any child would need shaving and this figure should be 0%. If no patients are shaved and all the other parameters in section 5.10 remain the same then the Committee noted that the overall cost per operation when using the paediatric comparator is reduced from £2.30 to £1.46. This means that it would cost 51p more per operation to use the Mega Soft Patient Return Electrode because the overall cost per operation when using Mega Soft Patient Return Electrode would remain at £1.97.\n\nThe Committee concluded that the economic evidence and cost modelling demonstrate near equivalent resource use for the Mega Soft Patient Return Electrode to current practice. Expert advice suggested that claims for the Mega Soft Patient Return Electrode's benefit are greatly influenced by the circumstances in which it is used.", 'Conclusions': 'The Mega Soft Patient Return Electrode may have particular advantages for patients with fragile or damaged skin; these include patients with burns, patients with skin conditions, paediatric patients and older patients. It also has the advantage that no patient needs shaving whereas about 30% of patients may need to be shaved when disposable single-use patient return electrodes are used.\n\nThe Committee accepted that it is plausible that the Mega Soft Patient Return Electrode reduces the risk of patient return electrode site burns, based on theoretical considerations and on the lack of any reported burns in the UK. It made this judgement despite a very limited amount of published clinical evidence comparing the Mega Soft Patient Return Electrode with disposable patient return electrodes in monopolar electrosurgery.\n\nUse of the Mega Soft Patient Return Electrode might theoretically increase the risk of alternative site burns. Good operating theatre practice minimises this risk and use of the Mega Soft Patient Return Electrode in this context could reduce the overall risk of burns from electrosurgery.\n\nThe Mega Soft Patient Return Electrode may be more convenient for theatre staff to use than standard disposable single-use patient return electrodes, but it is not likely to provide substantial savings in operating theatre time. The economic evidence and cost modelling demonstrated near equivalent resource use to current practice. Any health system or cost advantages are likely to be influenced significantly by whether the Mega Soft Patient Return Electrode is being considered for use for inpatient operating lists or day-case surgery.', 'Related NICE guidance': '# Published\n\nSuction diathermy adenoidectomy. NICE interventional procedure guidance 328 (2009).\n\nElectrosurgery (diathermy and coblation) for tonsillectomy. NICE interventional procedure guidance 150 (2005).\n\n## Under development\n\nThere is no related guidance under development.\n\nAndrew DillonChief ExecutiveAugust 2012', 'About this guidance': "NICE medical technology guidance addresses specific technologies notified to NICE by sponsors. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This 'case' is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies, which may offer similar advantages.\n\nThis guidance was developed using the NICE medical technologies guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour\n responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence, 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical Excellence\n\nLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780"}
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https://www.nice.org.uk/guidance/mtg11
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Evidence-based recommendations on Mega Soft Patient Return Electrode for use during monopolar electrosurgery.
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1ceca8bdc10bc0afd3436b435192442759705dbe
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nice
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Urinary incontinence in neurological disease: assessment and management
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Urinary incontinence in neurological disease: assessment and management
This guideline covers assessing and managing urinary incontinence in children, young people and adults with neurological disease. It aims to improve care by recommending specific treatments based on what symptoms and neurological conditions people have.
# Introduction
The lower urinary tract consists of the urinary bladder and the urethra. Its function is to store and expel urine in a coordinated and controlled manner. The central and peripheral nervous systems regulate this activity. Urinary symptoms can arise due to neurological disease in the brain, the suprasacral spinal cord, the sacral spinal cord or the peripheral nervous system. Damage within each of these areas tends to produce characteristic patterns of bladder and sphincter dysfunction. The nature of the damage to the nervous system is also important. In children, the neurological damage is often the result of congenital defects such as spina bifida or sacral agenesis. Conditions may produce a relatively fixed or stable injury to the nervous system (for example, stroke, spinal cord injury and cauda equina compression) or progressive damage (for example, dementia, Parkinson's disease, multiple sclerosis and peripheral neuropathy). Table 1 groups neurological conditions based on the anatomical site of the resulting neurological lesion with the likelihood of disease progression.
Congenital and perinatal conditions
Acquired, stable conditions
Acquired, progressive or degenerative conditions
Brain conditions
Cerebral palsy
Stroke
Head injury
Multiple sclerosis
Parkinson's disease
Dementia
Multiple system atrophy
Suprasacral spinal cord conditions
Spinal dysraphism (such as myelomeningocele)
Spinal cord injury
Multiple sclerosis
Cervical spondylosis with myelopathy
Sacral spinal cord or peripheral nerve conditions
Spinal dysraphism
Sacral agenesis
Anorectal anomalies
Cauda equina syndrome
Spinal cord injury
Peripheral nerve injury from radical pelvic surgery
Peripheral neuropathy
The proximity of the neurological centres controlling bowel and sexual functions to those involved in lower urinary tract function means that many people with neurological disease will have a combination of urinary, bowel and sexual dysfunction. The clinical team should not treat lower urinary tract problems in isolation but should address associated problems in other systems using a holistic approach.
Symptoms of neurogenic lower urinary tract dysfunction may relate to impaired urine storage and/or bladder emptying difficulties. Symptoms of impaired storage include increased frequency of urination and urinary incontinence. Urinary tract symptoms have a significant impact on quality of life, for example, they can cause embarrassment, lead to social isolation and impair activities of daily living. Incontinence is particularly problematic and can arise as a result of an overactive bladder, dysfunction of the urethral sphincters or a combination of the 2.
Secondary effects can also arise as a result of neurogenic lower urinary tract dysfunction. For example, there is a marked increase in the risk of urinary tract infection in people with neurogenic lower urinary tract dysfunction and kidney function can be lost as a result of abnormally high pressures within the bladder, from the effects of urinary tract infection and as a result of kidney stones.
Medical interventions often do not restore normal urinary function, and quality of life may be affected by the medical management of neurogenic lower urinary tract dysfunction. Many patients will have to cope with the side effects of medication, the social and psychological consequences of using intermittent self-catheterisation, the impact of indwelling catheterisation and the continuing use of pads or appliances. These may also have an impact on quality of life for family members and carers, and there may be issues related to the physical demands of caring for a person with neurological disease and urinary problems, as well as psychological, relationship and social pressures.
The economic cost of managing neurogenic lower urinary tract dysfunction is considerable. There are major costs associated with the use of pads, appliances, catheters, drug treatments and surgical interventions. A further financial burden arises from the person's requirements for carer, nursing and medical support. A person's ability to work can be affected by their neurogenic lower urinary tract dysfunction. Further significant expenditure is associated with the follow-up of patients, some of whom are placed on long-term urinary tract surveillance.
An overview of the clinical approach that is used when dealing with neurogenic lower urinary tract dysfunction is provided in 3 algorithms that are included in the full guideline.
The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.
This guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's good practice in prescribing and managing medicines and devices for further information. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Assessment of lower urinary tract dysfunction in patients with neurological conditions
Assessment applies to new people, those with changing symptoms and those needing periodic reassessment of their urinary tract management. The interval between routine assessments will be guided by the person's particular circumstances (for example, their age, diagnosis and type of management) but should not exceed 3 years.
These recommendations on assessment apply to people who have a neurological condition. If the assessment shows the incontinence to be non-neurogenic, see the NICE guidelines on lower urinary tract symptoms in men and urinary incontinence and pelvic organ prolapse in women for guidance on management.
## Clinical assessment
When assessing lower urinary tract dysfunction in a person with neurological disease, take a clinical history, including information about:
urinary tract symptoms
neurological symptoms and diagnosis (if known)
clinical course of the neurological disease
bowel symptoms
sexual function
comorbidities
use of prescription and other medication and therapies.
Assess the impact of the underlying neurological disease on factors that will affect how lower urinary tract dysfunction can be managed, such as:
mobility
hand function
cognitive function
social support
lifestyle.
Undertake a general physical examination that includes:
measuring blood pressure
an abdominal examination
an external genitalia examination
a vaginal or rectal examination if clinically indicated (for example, to look for evidence of pelvic floor prolapse, faecal loading or alterations in anal tone).
Carry out a focused neurological examination, which may need to include assessment of:
cognitive function
ambulation and mobility
hand function
lumbar and sacral spinal segment function.
Undertake a urine dipstick test using an appropriately collected sample to test for the presence of blood, glucose, protein, leukocytes and nitrites. Appropriate urine samples include clean-catch midstream samples, samples taken from a freshly inserted intermittent sterile catheter and samples taken from a catheter port. Do not take samples from leg bags.
If the dipstick test result and person's symptoms suggest an infection, arrange a urine bacterial culture and antibiotic sensitivity test before starting antibiotic treatment. Treatment need not be delayed but may be adapted when results are available.
Be aware that bacterial colonisation will be present in people using a catheter and so urine dipstick testing and bacterial culture may be unreliable for diagnosing active infection.
Ask people and their family members and carers to complete a 'fluid input/urine output chart' to record fluid intake, frequency of urination and volume of urine passed for a minimum of 3 days.
Consider measuring the urinary flow rate in people who are able to void voluntarily.
Measure the post-void residual urine volume by ultrasound, preferably using a portable scanner, and consider taking further measurements on different occasions to establish how bladder emptying varies at different times and in different circumstances.
Consider making a referral for a renal ultrasound scan in people who are at high risk of renal complications such as those with spina bifida or spinal cord injury.
Refer people for urgent investigation if they have any of the following 'red flag' signs and symptoms:
haematuria
recurrent urinary tract infections (for example, 3 or more infections in the last 6 months)
loin pain
recurrent catheter blockages (for example, catheters blocking within 6 weeks of being changed)
hydronephrosis or kidney stones on imaging
biochemical evidence of renal deterioration.
Be aware that unexplained changes in neurological symptoms (for example, confusion or worsening spasticity) can be caused by urinary tract disease, and consider further urinary tract investigation and treatment if this is suspected.
Refer people with changes in urinary function that may be due to new or progressing neurological disease needing specialist investigation (for example, syringomyelia, hydrocephalus, multiple system atrophy or cauda equina syndrome).
Assess the impact of lower urinary tract symptoms on the person's family members and carers and consider ways of reducing any adverse impact. If it is suspected that severe stress is leading to abuse, follow local safeguarding procedures.
## Urodynamic investigations
Do not offer urodynamic investigations (such as filling cystometry and pressure-flow studies) routinely to people who are known to have a low risk of renal complications (for example, most people with multiple sclerosis).
Offer video-urodynamic investigations to people who are known to have a high risk of renal complications (for example, people with spina bifida, spinal cord injury or anorectal abnormalities).
Offer urodynamic investigations before performing surgical treatments for neurogenic lower urinary tract dysfunction.
# Information and support
Offer people with neurogenic urinary tract dysfunction, their family members and carers specific information and training. Ensure that people who are starting to use, or are using, a bladder management system that involves the use of catheters, appliances or pads:
receive training, support and review from healthcare professionals who are trained to provide support in the relevant bladder management systems and are knowledgeable about the range of products available
have access to a range of products that meet their needs
have their products reviewed, at a maximum of 2 yearly intervals.
Tailor information and training to the person's physical condition and cognitive function to promote their active participation in care and self-management.
Inform people how to access further support and information from a healthcare professional about their urinary tract management.
NICE has produced guidance on the components of good patient experience in adult NHS services. All healthcare professionals should follow the recommendations in the NICE guideline on patient experience in adult NHS services. Recommendations on shared decision making and information enabling people to actively participate in their care can be found in the NICE guidelines on shared decision making and patient experience in adult NHS services.
# Treatment to improve bladder storage
## Behavioural treatments
Consider a behavioural management programme (for example, timed voiding, bladder retraining or habit retraining) for people with neurogenic lower urinary tract dysfunction:
-nly after assessment by a healthcare professional trained in the assessment of people with neurogenic lower urinary tract dysfunction and
in conjunction with education about lower urinary tract function for the person and/or their family members and carers.
When choosing a behavioural management programme, take into account that prompted voiding and habit retraining are particularly suitable for people with cognitive impairment.
## Antimuscarinics
In August 2012, not all antimuscarinics had a UK marketing authorisation for the indications in recommendations 1.3.3 to 1.3.5 or for use in both adults and children. See NICE's information on prescribing medicines.
Offer antimuscarinic drugs to people with:
spinal cord disease (for example, spinal cord injury or multiple sclerosis) and
symptoms of an overactive bladder such as increased frequency, urgency and incontinence.
Consider antimuscarinic drug treatment in people with:
conditions affecting the brain (for example, cerebral palsy, head injury or stroke) and
symptoms of an overactive bladder.
Consider antimuscarinic drug treatment in people with urodynamic investigations showing impaired bladder storage.
Monitor residual urine volume in people who are not using intermittent or indwelling catheterisation after starting antimuscarinic treatment.
When prescribing antimuscarinics, take into account that:
antimuscarinics known to cross the blood-brain barrier (for example, oxybutynin) have the potential to cause central nervous system-related side effects (such as confusion)
antimuscarinic treatment can reduce bladder emptying, which may increase the risk of urinary tract infections
antimuscarinic treatment may precipitate or exacerbate constipation.
## Botulinum toxin type A
In August 2012, botulinum toxin type A did not have a UK marketing authorisation for the indications in recommendations 1.3.8 to 1.3.11. See NICE's information on prescribing medicines.
Offer bladder wall injection with botulinum toxin type A to adults:
with spinal cord disease (for example, spinal cord injury or multiple sclerosis) and
with symptoms of an overactive bladder and
in whom antimuscarinic drugs have proved to be ineffective or poorly tolerated.
Consider bladder wall injection with botulinum toxin type A for children and young people:
with spinal cord disease and
with symptoms of an overactive bladder and
in whom antimuscarinic drugs have proved to be ineffective or poorly tolerated.
Offer bladder wall injection with botulinum toxin type A to adults:
with spinal cord disease and
with urodynamic investigations showing impaired bladder storage and
in whom antimuscarinic drugs have proved to be ineffective or poorly tolerated.
Consider bladder wall injection with botulinum toxin type A for children and young people:
with spinal cord disease and
with urodynamic investigations showing impaired bladder storage and
in whom antimuscarinic drugs have proved to be ineffective or poorly tolerated.
Before offering bladder wall injection with botulinum toxin type A:
explain to the person and/or their family members and carers that a catheterisation regimen is needed in most people with neurogenic lower urinary tract dysfunction after treatment, and
ensure that they are able and willing to manage such a regimen should urinary retention develop after the treatment.
Monitor residual urine volume in people who are not using a catheterisation regimen during treatment with botulinum toxin type A.
Monitor the upper urinary tract in people who are judged to be at risk of renal complications (for example, those with high intravesical pressures on filling cystometry) during treatment with botulinum toxin type A.
Ensure that people who have been offered continuing treatment with repeated botulinum toxin type A injections have prompt access to repeat injections when symptoms return.
## Augmentation cystoplasty
Consider augmentation cystoplasty using an intestinal segment for people:
with non-progressive neurological disorders and
complications of impaired bladder storage (for example, hydronephrosis or incontinence) and
-nly after a thorough clinical and urodynamic assessment and discussion with the patient and/or their family members and carers about complications, risks and alternative treatments.
Offer patients life-long follow-up after augmentation cystoplasty because of the risk of long-term complications. Potential complications include metabolic effects, such as the development of vitamin B12 deficiency and the development of bladder cancer.
# Treatment for stress incontinence
## Pelvic floor muscle training
Consider pelvic floor muscle training for people with:
lower urinary tract dysfunction due to multiple sclerosis or stroke or
-ther neurological conditions where the potential to voluntarily contract the pelvic floor is preserved. Select patients for this training after specialist pelvic floor assessment and consider combining treatment with biofeedback and/or electrical stimulation of the pelvic floor.
## Urethral tape and sling surgery
Consider autologous fascial sling surgery for people with neurogenic stress incontinence.
Do not routinely use synthetic tapes and slings in people with neurogenic stress incontinence because of the risk of urethral erosion.
## Artificial urinary sphincter
Consider surgery to insert an artificial urinary sphincter for people with neurogenic stress incontinence only if an alternative procedure, such as insertion of an autologous fascial sling, is less likely to control incontinence.
When considering inserting an artificial urinary sphincter:
discuss with the person and/or their family members and carers the risks associated with the device, the possible need for repeat operations and alternative procedures
ensure that the bladder has adequate low-pressure storage capacity.
Monitor the upper urinary tract after artificial urinary sphincter surgery (for example, using annual ultrasound scans), as bladder storage function can deteriorate in some people after treatment of their neurogenic stress incontinence.
# Treatment to improve bladder emptying
## Alpha-blockers
Do not offer alpha-blockers to people as a treatment for bladder emptying problems caused by neurological disease.
# Management with catheter valves
In people for whom it is appropriate a catheter valve may be used as an alternative to a drainage bag.
To ensure that a catheter valve is appropriate, take into consideration the person's preference, family member and carer support, manual dexterity, cognitive ability, and lower urinary tract function when offering a catheter valve as an alternative to continuous drainage into a bag.
Consider the need for continuing upper urinary tract surveillance in people who have impaired bladder storage (for example, due to reduced bladder compliance).
# Management with ileal conduit diversion
For people with neurogenic lower urinary tract dysfunction who have intractable, major problems with urinary tract management, such as incontinence or renal deterioration:
consider ileal conduit diversion (urostomy) and
discuss with the person the option of simultaneous cystectomy as prophylaxis against pyocystis.
# Treatment to prevent urinary tract infection
Do not routinely use antibiotic prophylaxis for urinary tract infections in people with neurogenic lower urinary tract dysfunction.
Consider antibiotic prophylaxis for people who have a recent history of frequent or severe urinary tract infections.
Before prescribing antibiotic prophylaxis for urinary tract infection:
investigate the urinary tract for an underlying treatable cause (such as urinary tract stones or incomplete bladder emptying)
take into account and discuss with the person the risks and benefits of prophylaxis
refer to local protocols approved by a microbiologist or discuss suitable regimens with a microbiologist.
Ensure that the need for ongoing prophylaxis in all people who are receiving antibiotic prophylaxis is regularly reviewed.
When changing catheters in patients with a long-term indwelling urinary catheter:
do not offer antibiotic prophylaxis routinely
consider antibiotic prophylaxis for patients who:
have a history of symptomatic urinary tract infection after catheter change or
experience trauma during catheterisation (trauma defined as frank haematuria after catheterisation or 2 or more attempts of catheterisation).In August 2012, no antibiotics had a UK marketing authorisation for this indication. See NICE's information on prescribing medicines.
# Monitoring and surveillance protocols
Do not rely on serum creatinine and estimated glomerular filtration rate in isolation for monitoring renal function in people with neurogenic lower urinary tract dysfunction. For more information on the measurement of kidney function, see the NICE guideline on chronic kidney disease.
Consider using isotopic glomerular filtration rate when an accurate measurement of glomerular filtration rate is required (for example, if imaging of the kidneys suggests that renal function might be compromised). For more information on the measurement of kidney function, see the NICE guideline on chronic kidney disease.
Offer lifelong ultrasound surveillance of the kidneys to people who are judged to be at high risk of renal complications (for example, consider surveillance ultrasound scanning at annual or 2 yearly intervals). Those at high risk include people with spinal cord injury or spina bifida and those with adverse features on urodynamic investigations such as impaired bladder compliance, detrusor-sphincter dyssynergia or vesico-ureteric reflux.
Do not use plain abdominal radiography for routine surveillance in people with neurogenic lower urinary tract dysfunction.
Consider urodynamic investigations as part of a surveillance regimen for people at high risk of urinary tract complications (for example, people with spina bifida, spinal cord injury or anorectal abnormalities).
Do not use cystoscopy for routine surveillance in people with neurogenic lower urinary tract dysfunction.
Do not use renal scintigraphy for routine surveillance in people with neurogenic lower urinary tract dysfunction.
# Potential complications: providing information and initial management
## Renal impairment
Discuss with the person, and their family members and carers, the increased risk of renal complications (such as kidney stones, hydronephrosis and scarring) in people with neurogenic urinary tract dysfunction (in particular those with spina bifida or spinal cord injury). Tell them the symptoms to look out for (such as loin pain, urinary tract infection and haematuria) and when to see a healthcare professional.
When discussing treatment options, tell the person that indwelling urethral catheters may be associated with higher risks of renal complications (such as kidney stones and scarring) than other forms of bladder management (such as intermittent self-catheterisation).
Use renal imaging to investigate symptoms that suggest upper urinary tract disease.
## Bladder stones
Discuss with the person, and their family members and carers, the increased risk of bladder stones in people with neurogenic lower urinary tract dysfunction. Tell them the symptoms to look out for that mean they should see a healthcare professional (for example, recurrent infection, recurrent catheter blockages or haematuria).
Discuss with the person, and their family members and carers, that indwelling catheters (urethral and suprapubic) are associated with a higher incidence of bladder stones compared with other forms of bladder management. Tell them the symptoms to look out for that mean they should see a healthcare professional (for example, recurrent infection, recurrent catheter blockages or haematuria).
Refer people with symptoms that suggest the presence of bladder stones (for example, recurrent catheter blockages, recurrent urinary tract infection or haematuria) for cystoscopy.
## Bladder cancer
Discuss with the person, and their family members and carers, that there may be an increased risk of bladder cancer in people with neurogenic lower urinary tract dysfunction, in particular those with a long history of neurogenic lower urinary tract dysfunction and complicating factors, such as recurrent urinary tract infections. Tell them the symptoms to look out for (especially haematuria) that mean they should see a healthcare professional.
Arrange urgent (within 2 weeks) investigation with urinary tract imaging and cystoscopy for people with:
visible haematuria or
increased frequency of urinary tract infections or
-ther unexplained lower urinary tract symptoms.
# Access to and interaction with services
## Access to and interaction with services
Provide contact details for the provision of specialist advice if a person has received care for neurogenic lower urinary tract dysfunction in a specialised setting (for example, in a spinal injury unit or a paediatric urology unit). The contact details should be given to the person, and their family members and carers, and to the non-specialist medical and nursing staff involved in their care.
Provide people with neurogenic lower urinary tract dysfunction, and their family members and carers, with written information that includes:
a list of key healthcare professionals involved in their care, a description of their role and their contact details
copies of all clinical correspondence
a list of prescribed medications and equipment. This information should also be sent to the person's GP.
NICE has produced guidance on the components of good patient experience in adult NHS services. All healthcare professionals should follow the recommendations in the NICE guideline on patient experience in adult NHS services, particularly relating to:
tailoring healthcare services for each patient
continuity of care and relationships.
## Transfer from child to adult services
When managing the transition of a person from paediatric services to adult services for ongoing care of neurogenic lower urinary tract dysfunction:
formulate a clear structured care pathway at an early stage and involve the person and their parents and carers
involve the young person's parents and carers when preparing transfer documentation with the young person's consent
provide a full summary of the person's clinical history, investigation results and details of treatments for the person and receiving clinician
integrate information from the multidisciplinary health team into the transfer documentation
identify and plan the urological services that will need to be continued after the transition of care
formally transfer care to a named individual(s).
When receiving a person from paediatric services to adult services for ongoing care of neurogenic lower urinary tract dysfunction:
review the transfer documentation and liaise with the other adult services involved in ongoing care (for example, adult neuro-rehabilitation services)
provide the person with details of the service to which care is being transferred, including contact details of key personnel, such as the urologist and specialist nurses
ensure that urological services are being provided after transition to adult services.
Consider establishing regular multidisciplinary team meetings for paediatric and adult specialists to discuss the management of neurogenic lower urinary tract dysfunction in children and young people during the years leading up to transition and after entering adult services.
# Terms used in this guideline
## Alpha-blocking agents
Drugs that inhibit the response to sympathetic impulses by blocking the alpha receptor sites of effector organs. Because they inhibit the contraction of non-vascular smooth muscle such as that found at the bladder neck and within the prostate, alpha-blockers are commonly used to treat bladder outflow obstruction in men with normally innervated urinary tracts. Also known as 'alpha adrenergic blocking agents' or 'alpha adrenergic antagonists'.
## Antimuscarinic drugs
An anticholinergic agent that specifically blocks the muscarinic form of the cholinergic receptor. Because they decrease the responsiveness of the bladder wall muscle to stimulating nerve impulses, antimuscarinic drugs are used in the management of the overactive bladder.
## Augmentation cystoplasty
Surgical reconstruction of the bladder using an isolated intestinal segment to augment bladder capacity.
## Autologous fascial sling surgery
A procedure to treat stress urinary incontinence, in which a harvested strip of rectus fascia is used to provide support to the urethra. Also see urethral tape and sling surgery.
## Behavioural management programmes
Behavioural therapies are usually used to treat urge urinary incontinence and mixed urinary incontinence. Such therapies include:
Timed voiding where the person is asked to void at set time intervals, rather than in response to a sense of bladder filling.
Bladder retraining where intervals between voids are progressively increased, or the patient is asked to delay voiding for a specific time when they experience the need to void.
Habit retraining involves identifying an incontinent person's toileting pattern and developing an individualised toileting schedule in order to pre-empt episodes of incontinence.
## Biofeedback
The process of becoming aware of various physiological functions using instruments that provide information on the activity of those same systems, with a goal of being able to manipulate them at will.
## Bladder retraining
See behavioural management programmes.
## Bladder stone
Stone found in the urinary bladder formed by crystallisation and concretion of salts from the urine and containing phosphate and oxalate salts of calcium or ammonium. Stones typically form in conjunction with bacterial colonisation of the urine, for example, when an indwelling catheter is present, or bladder emptying is incomplete.
## Cauda equina compression
A serious condition caused by compression of the nerve roots in the lower portion of the spinal canal that supply the lower limbs and the bladder and urethral sphincter.
## Cystectomy
Surgical removal of all or part of the urinary bladder.
## Filling cystometry
Part of urodynamic testing in which the bladder is slowly filled with liquid while pressure and volume measurements are taken in order to assess bladder function.
## Habit retraining
See behavioural management programmes.
## Hydronephrosis
Distension and dilation of the renal pelvis and calyces, usually caused by obstruction of the free flow of urine from the kidney. Untreated, it leads to progressive atrophy of the kidney as a result of back pressure.
## Ileal conduit diversion
Surgical technique for the diversion of urine after a patient has had their bladder removed. Urine is transported from the ureters (the tubes draining urine from the kidneys) to a stoma on the abdominal wall using an isolated segment of small intestine.
## Neurogenic
Originating in the nerves or nervous tissue.
## Neuromuscular electrical stimulation
Procedure used to strengthen healthy muscles or to maintain muscle mass during or following periods of enforced inactivity. This helps to maintain or gain range of motion, to facilitate voluntary motor control, and temporarily reduces spasticity when the nerve supply to the muscle is intact. This procedure involves sending small electrical impulses through the skin to the underlying nerves and muscles to create an involuntary muscle contraction.
## Overactive bladder
Produces symptoms of urinary urgency, with or without urge incontinence, usually with an increased frequency of micturition. The strong, sudden need to urinate is usually caused by involuntary contractions of the bladder or 'bladder spasms'.
## Pelvic floor muscle training
Daily training programme to strengthen the muscles that support the uterus, bladder and other pelvic organs and help prevent accidental urine leakage. Also called Kegel exercises or pelvic muscle rehabilitation.
## Pelvic floor prolapse
Loss of muscle tone and/or ligamentous elasticity resulting in the descent of the uterus or other pelvic organs into the vagina. If severe, the prolapse can protrude out of the vaginal orifice.
## Pressure-flow studies
Simultaneous measurement of bladder pressure and flow rate during the voiding phase of the micturition cycle. The test is used to assess the process of bladder emptying. For example, bladder outflow obstruction can be diagnosed if there is a low urinary flow rate in conjunction with a raised bladder pressure during voiding.
## Prompted voiding
A behavioural management programme that is used to encourage people to initiate their own toileting. It usually involves positive reinforcement and education of both the person with incontinence and their carer(s).
## Renal scintigraphy
Photographic recording, using a gamma camera, of the distribution of a radioisotope (radioactive substance) given by injection. The radioisotope accumulates in the kidneys, allowing pictures to be produced showing details of both kidney structure and function.
## Sacral agenesis
A condition that exists when either part or all of the sacrum is absent due to a failure of the sacral spine to develop normally. In many cases, some or all of the nerves that supply the pelvic organs will also have failed to develop normally.
## Spina bifida
A condition in which the bones of the spine do not close due to a failure of normal development in the fetus. In cases of myelomeningocele, the bony abnormality is accompanied by abnormal development of the spinal cord or nerves and their covering membranes, which leads to abnormalities in the nerve supply to the lower limbs and pelvic organs.
## Spinal dysraphism
A general term that encompasses a number of different developmental abnormalities of the spine and spinal cord, of which spina bifida is an example.
## Stress incontinence
Stress urinary incontinence describes a symptom, a sign and a diagnosis, although it is only following urodynamic investigation that a diagnosis of urodynamic stress incontinence can be made. This condition is defined as 'the involuntary leakage of urine during increased abdominal pressure in the absence of a detrusor contraction'.
## Timed voiding
See behavioural management programmes.
## Urethral tape and sling surgery
A procedure that restores bladder control for people who lose urine when they cough or exercise. The urethral tape procedure involves positioning an artificial tape under the urethra, which is the tube that runs from the bladder through which you urinate. The tape will then rest like a hammock under the urethra, giving support and maintaining continence. A urethral tape consists of a thin mesh ribbon that is placed in order to provide support to the urethra. Urethral sling surgery involves placing a sling around the urethra to lift it back into a normal position and to exert pressure on the urethra to aid urine retention. The sling is attached to the abdominal wall. Also see autologous fascial sling surgery.
## Urodynamic investigations
Investigation of the function of the lower urinary tract (the bladder and urethra) using physical measurements such as urine pressure and flow rate, as well as clinical assessment. Video-urodynamic investigations involve using a dye to fill the bladder enabling X-rays of the lower urinary tract to be taken during filling and emptying of the bladder.# Recommendations for research
The guideline development group has made the following recommendations for research.
# Safety and efficacy of antimuscarinics
What is the safety and efficacy of more recently developed antimuscarinics compared with (a) placebo/usual care and (b) other antimuscarinics in the treatment of neurogenic lower urinary tract dysfunction?
## Why this is important
No high-quality clinical trials looking at the use of the newer antimuscarinic drugs in people with neurogenic lower urinary tract dysfunction have been carried out. Both placebo-controlled and comparative studies are lacking. This is important because the more recently developed medications are of unknown efficacy, are more expensive and claim (in the non-neurogenic population) to have fewer adverse effects. The adverse effects of antimuscarinics are mostly due to their action at sites other than the bladder (for example, causing a dry mouth) but there is now increasing concern that antimuscarinic effects on the central nervous system may adversely affect cognitive function in both children with brain damage (caused by cerebral palsy or hydrocephalus) and adults with impaired cognition (caused by cerebral involvement in multiple sclerosis or neurodegenerative diseases).
# Safety and efficacy of botulinum toxin
What is the safety and efficacy of botulinum toxin compared with (a) usual care, (b) antimuscarinics and (c) augmentation cystoplasty in people with neurogenic lower urinary tract dysfunction?
## Why this is important
Further research is needed to determine whether repeated intradetrusor injections of botulinum toxin type A have long-term efficacy. The efficacy in terms of continence and upper urinary tract preservation should be studied.
Botulinum toxin injection into the detrusor is an effective means of managing incontinence and improves urodynamic measures of bladder storage with the potential to protect the kidneys from the effects of high intravesical pressures. It is well tolerated in a spectrum of conditions and ages. However, the longer-term efficacy over many injections has not been established.
A clinical trial is needed to study the outcome in terms of continence and renal preservation over many cycles of repeated injection. Quality of life is an important outcome. A trial should enrol children and adults. The indications for botulinum toxin need not be modified for inclusion, but entrants into a trial must have anatomically normal kidneys (on imaging) and normal renal function.
What is the safety and efficacy of botulinum toxin compared with (a) usual care, (b) antimuscarinics and (c) augmentation cystoplasty in people with primary cerebral conditions with lower urinary tract dysfunction?
## Why this is important
The effects of intradetrusor botulinum toxin type A injection should be investigated in groups of people with underlying cerebral conditions that are associated with lower urinary tract dysfunction, as well as those with spinal cord injury, spina bifida and multiple sclerosis. Reports of its use in other conditions are limited to small numbers of patients within case series studies that include heterogeneous groups of patients. Potential benefits of successful treatment in cerebral disease may include the avoidance of cognitive impairment, which can be seen as a side effect of antimuscarinic medication.
A trial should include people with primary cerebral conditions including (but not restricted to) stroke, head injury and cerebral palsy, but excluding multiple sclerosis. Children and adults should be recruited. Tolerability and acceptability are important outcomes, as well as the primary outcomes of continence, preservation of the upper urinary tracts and quality of life. Measurement of carer burden and quality of life is also important.
# Management strategies to reduce the risk of symptomatic urinary tract infections
In people with neurogenic lower urinary tract dysfunction, which management strategies (including the use of prophylactic antibiotics and various invasive and non-invasive techniques to aid bladder drainage) reduce the risk of symptomatic urinary tract infections?
## Why this is important
Recurrent urinary tract infections in people with neurogenic bladder dysfunction are a cause of considerable morbidity. Urinary tract infections may exacerbate incontinence, cause symptoms of malaise and may progress to involve the upper urinary tract with possible loss of renal function. In the population with neurological diseases such as multiple sclerosis, Parkinson's disease and dementia, the rise in temperature with urinary tract infections can cause deterioration in neurological function and even a relapse of multiple sclerosis. There are therefore numerous reasons why people with neurogenic lower urinary tract dysfunction should avoid urinary tract infections.
The causes for the high prevalence of urinary tract infections in such people include loss of physiological bladder function and high intravesical pressures. Intermittent or permanent catheterisation inevitably exacerbate the problem, but incomplete bladder emptying is also a predisposing factor for urinary tract infections.
Research in this area is faced with methodological difficulties, not least because it may be difficult to distinguish between bladder colonisation (asymptomatic bacteriuria) and true infection.
In view of the considerable clinical burden of urinary tract infections and the global problem of antibiotic resistance, it is important to establish whether or not any infection prevention strategies, including patient training or the provision of information relating to prophylactic antibiotics are effective in reducing symptomatic urinary tract infections.
# Bladder management strategies
What are the long-term risks and effects on quality of life of different bladder management strategies for lower urinary tract dysfunction in people with neurological disease?
## Why this is important
The range of bladder management strategies available to manage lower urinary tract dysfunction in neurological disease includes permanent urethral catheterisation and suprapubic catheterisation, intermittent self-catheterisation, penile sheath collection systems and pads. However, there is very sparse evidence about which strategies are most acceptable to patients and their family members and carers. The current research base relates mainly to the spinal injury population but may be relevant to people with other neurological diseases.
Bladder management strategies are a long-term treatment with implications for maintaining health and quality of life. In order to make informed choices about the most appropriate method of bladder management, patients and their family members and carers require information about the risks and benefits of the available options. There is currently little evidence about which methods are most likely to produce long-term complications (renal impairment, urinary stones and infections, hydronephrosis, bladder malignancy). The effect on quality of life for patients and their family members and carers of different bladder management strategies is not known. There are methodological difficulties due to the heterogeneity of the population with neurological disease, the long-time course of treatments and the presence of cognitive impairment in some sub-populations.
Proposed studies could include prospective cohort studies of disease-specific populations examining the effect of each method on quality of life using both generic and disease-specific assessment methods. In addition, prospective screening for complications including renal impairment, stone formation and infection should be carried out and comparisons made for each bladder management method. Particular emphasis should be placed on quality-of-life outcomes for family members and carers, especially for those looking after people with cognitive impairment.
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{'Introduction': "The lower urinary tract consists of the urinary bladder and the urethra. Its function is to store and expel urine in a coordinated and controlled manner. The central and peripheral nervous systems regulate this activity. Urinary symptoms can arise due to neurological disease in the brain, the suprasacral spinal cord, the sacral spinal cord or the peripheral nervous system. Damage within each of these areas tends to produce characteristic patterns of bladder and sphincter dysfunction. The nature of the damage to the nervous system is also important. In children, the neurological damage is often the result of congenital defects such as spina bifida or sacral agenesis. Conditions may produce a relatively fixed or stable injury to the nervous system (for example, stroke, spinal cord injury and cauda equina compression) or progressive damage (for example, dementia, Parkinson's disease, multiple sclerosis and peripheral neuropathy). Table\xa01 groups neurological conditions based on the anatomical site of the resulting neurological lesion with the likelihood of disease progression.\n\n\n\n\n\nCongenital and perinatal conditions\n\nAcquired, stable conditions\n\nAcquired, progressive or degenerative conditions\n\nBrain conditions\n\nCerebral palsy\n\nStroke\n\nHead injury\n\nMultiple sclerosis\n\nParkinson's disease\n\nDementia\n\nMultiple system atrophy\n\nSuprasacral spinal cord conditions\n\nSpinal dysraphism (such as myelomeningocele)\n\nSpinal cord injury\n\nMultiple sclerosis\n\nCervical spondylosis with myelopathy\n\nSacral spinal cord or peripheral nerve conditions\n\nSpinal dysraphism\n\nSacral agenesis\n\nAnorectal anomalies\n\nCauda equina syndrome\n\nSpinal cord injury\n\nPeripheral nerve injury from radical pelvic surgery\n\nPeripheral neuropathy\n\n\n\nThe proximity of the neurological centres controlling bowel and sexual functions to those involved in lower urinary tract function means that many people with neurological disease will have a combination of urinary, bowel and sexual dysfunction. The clinical team should not treat lower urinary tract problems in isolation but should address associated problems in other systems using a holistic approach.\n\nSymptoms of neurogenic lower urinary tract dysfunction may relate to impaired urine storage and/or bladder emptying difficulties. Symptoms of impaired storage include increased frequency of urination and urinary incontinence. Urinary tract symptoms have a significant impact on quality of life, for example, they can cause embarrassment, lead to social isolation and impair activities of daily living. Incontinence is particularly problematic and can arise as a result of an overactive bladder, dysfunction of the urethral sphincters or a combination of the\xa02.\n\nSecondary effects can also arise as a result of neurogenic lower urinary tract dysfunction. For example, there is a marked increase in the risk of urinary tract infection in people with neurogenic lower urinary tract dysfunction and kidney function can be lost as a result of abnormally high pressures within the bladder, from the effects of urinary tract infection and as a result of kidney stones.\n\nMedical interventions often do not restore normal urinary function, and quality of life may be affected by the medical management of neurogenic lower urinary tract dysfunction. Many patients will have to cope with the side effects of medication, the social and psychological consequences of using intermittent self-catheterisation, the impact of indwelling catheterisation and the continuing use of pads or appliances. These may also have an impact on quality of life for family members and carers, and there may be issues related to the physical demands of caring for a person with neurological disease and urinary problems, as well as psychological, relationship and social pressures.\n\nThe economic cost of managing neurogenic lower urinary tract dysfunction is considerable. There are major costs associated with the use of pads, appliances, catheters, drug treatments and surgical interventions. A further financial burden arises from the person's requirements for carer, nursing and medical support. A person's ability to work can be affected by their neurogenic lower urinary tract dysfunction. Further significant expenditure is associated with the follow-up of patients, some of whom are placed on long-term urinary tract surveillance.\n\nAn overview of the clinical approach that is used when dealing with neurogenic lower urinary tract dysfunction is provided in 3\xa0algorithms that are included in the full guideline.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.\n\nThis guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's good practice in prescribing and managing medicines and devices for further information. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Assessment of lower urinary tract dysfunction in patients with neurological conditions\n\nAssessment applies to new people, those with changing symptoms and those needing periodic reassessment of their urinary tract management. The interval between routine assessments will be guided by the person's particular circumstances (for example, their age, diagnosis and type of management) but should not exceed 3\xa0years.\n\nThese recommendations on assessment apply to people who have a neurological condition. If the assessment shows the incontinence to be non-neurogenic, see the NICE guidelines on lower urinary tract symptoms in men and urinary incontinence and pelvic organ prolapse in women for guidance on management.\n\n## Clinical assessment\n\nWhen assessing lower urinary tract dysfunction in a person with neurological disease, take a clinical history, including information about:\n\nurinary tract symptoms\n\nneurological symptoms and diagnosis (if known)\n\nclinical course of the neurological disease\n\nbowel symptoms\n\nsexual function\n\ncomorbidities\n\nuse of prescription and other medication and therapies.\n\nAssess the impact of the underlying neurological disease on factors that will affect how lower urinary tract dysfunction can be managed, such as:\n\nmobility\n\nhand function\n\ncognitive function\n\nsocial support\n\nlifestyle.\n\nUndertake a general physical examination that includes:\n\nmeasuring blood pressure\n\nan abdominal examination\n\nan external genitalia examination\n\na vaginal or rectal examination if clinically indicated (for example, to look for evidence of pelvic floor prolapse, faecal loading or alterations in anal tone).\n\nCarry out a focused neurological examination, which may need to include assessment of:\n\ncognitive function\n\nambulation and mobility\n\nhand function\n\nlumbar and sacral spinal segment function.\n\nUndertake a urine dipstick test using an appropriately collected sample to test for the presence of blood, glucose, protein, leukocytes and nitrites. Appropriate urine samples include clean-catch midstream samples, samples taken from a freshly inserted intermittent sterile catheter and samples taken from a catheter port. Do not take samples from leg bags.\n\nIf the dipstick test result and person's symptoms suggest an infection, arrange a urine bacterial culture and antibiotic sensitivity test before starting antibiotic treatment. Treatment need not be delayed but may be adapted when results are available.\n\nBe aware that bacterial colonisation will be present in people using a catheter and so urine dipstick testing and bacterial culture may be unreliable for diagnosing active infection.\n\nAsk people and their family members and carers to complete a 'fluid input/urine output chart' to record fluid intake, frequency of urination and volume of urine passed for a minimum of 3\xa0days.\n\nConsider measuring the urinary flow rate in people who are able to void voluntarily.\n\nMeasure the post-void residual urine volume by ultrasound, preferably using a portable scanner, and consider taking further measurements on different occasions to establish how bladder emptying varies at different times and in different circumstances.\n\nConsider making a referral for a renal ultrasound scan in people who are at high risk of renal complications such as those with spina bifida or spinal cord injury.\n\nRefer people for urgent investigation if they have any of the following 'red flag' signs and symptoms:\n\nhaematuria\n\nrecurrent urinary tract infections (for example, 3\xa0or more infections in the last 6\xa0months)\n\nloin pain\n\nrecurrent catheter blockages (for example, catheters blocking within 6\xa0weeks of being changed)\n\nhydronephrosis or kidney stones on imaging\n\nbiochemical evidence of renal deterioration.\n\nBe aware that unexplained changes in neurological symptoms (for example, confusion or worsening spasticity) can be caused by urinary tract disease, and consider further urinary tract investigation and treatment if this is suspected.\n\nRefer people with changes in urinary function that may be due to new or progressing neurological disease needing specialist investigation (for example, syringomyelia, hydrocephalus, multiple system atrophy or cauda equina syndrome).\n\nAssess the impact of lower urinary tract symptoms on the person's family members and carers and consider ways of reducing any adverse impact. If it is suspected that severe stress is leading to abuse, follow local safeguarding procedures.\n\n## Urodynamic investigations\n\nDo not offer urodynamic investigations (such as filling cystometry and pressure-flow studies) routinely to people who are known to have a low risk of renal complications (for example, most people with multiple sclerosis).\n\nOffer video-urodynamic investigations to people who are known to have a high risk of renal complications (for example, people with spina bifida, spinal cord injury or anorectal abnormalities).\n\nOffer urodynamic investigations before performing surgical treatments for neurogenic lower urinary tract dysfunction.\n\n# Information and support\n\nOffer people with neurogenic urinary tract dysfunction, their family members and carers specific information and training. Ensure that people who are starting to use, or are using, a bladder management system that involves the use of catheters, appliances or pads:\n\nreceive training, support and review from healthcare professionals who are trained to provide support in the relevant bladder management systems and are knowledgeable about the range of products available\n\nhave access to a range of products that meet their needs\n\nhave their products reviewed, at a maximum of 2\xa0yearly intervals.\n\nTailor information and training to the person's physical condition and cognitive function to promote their active participation in care and self-management.\n\nInform people how to access further support and information from a healthcare professional about their urinary tract management.\n\nNICE has produced guidance on the components of good patient experience in adult NHS services. All healthcare professionals should follow the recommendations in the\xa0NICE guideline on patient experience in adult NHS services. Recommendations on shared decision making and information enabling people to actively participate in their care can be found in the NICE guidelines on shared decision making and patient experience in adult NHS services.\n\n# Treatment to improve bladder storage\n\n## Behavioural treatments\n\nConsider a behavioural management programme (for example, timed voiding, bladder retraining or habit retraining) for people with neurogenic lower urinary tract dysfunction:\n\nonly after assessment by a healthcare professional trained in the assessment of people with neurogenic lower urinary tract dysfunction\xa0and\n\nin conjunction with education about lower urinary tract function for the person and/or their family members and carers.\n\nWhen choosing a behavioural management programme, take into account that prompted voiding and habit retraining are particularly suitable for people with cognitive impairment.\n\n## Antimuscarinics\n\nIn August 2012, not all antimuscarinics had a UK marketing authorisation for the indications in recommendations 1.3.3 to 1.3.5 or for use in both adults and children. See NICE's information on prescribing medicines.\n\nOffer antimuscarinic drugs to people with:\n\nspinal cord disease (for example, spinal cord injury or multiple sclerosis) and\n\nsymptoms of an overactive bladder such as increased frequency, urgency and incontinence.\n\nConsider antimuscarinic drug treatment in people with:\n\nconditions affecting the brain (for example, cerebral palsy, head injury or stroke) and\n\nsymptoms of an overactive bladder.\n\nConsider antimuscarinic drug treatment in people with urodynamic investigations showing impaired bladder storage.\n\nMonitor residual urine volume in people who are not using intermittent or indwelling catheterisation after starting antimuscarinic treatment.\n\nWhen prescribing antimuscarinics, take into account that:\n\nantimuscarinics known to cross the blood-brain barrier (for example, oxybutynin) have the potential to cause central nervous system-related side effects (such as confusion)\n\nantimuscarinic treatment can reduce bladder emptying, which may increase the risk of urinary tract infections\n\nantimuscarinic treatment may precipitate or exacerbate constipation.\n\n## Botulinum toxin type\xa0A\n\nIn August 2012, botulinum toxin type\xa0A did not have a UK marketing authorisation for the indications in recommendations 1.3.8 to 1.3.11. See NICE's information on prescribing medicines.\n\nOffer bladder wall injection with botulinum toxin type\xa0A to adults:\n\nwith spinal cord disease (for example, spinal cord injury or multiple sclerosis) and\n\nwith symptoms of an overactive bladder and\n\nin whom antimuscarinic drugs have proved to be ineffective or poorly tolerated.\n\nConsider bladder wall injection with botulinum toxin type\xa0A for children and young people:\n\nwith spinal cord disease and\n\nwith symptoms of an overactive bladder and\n\nin whom antimuscarinic drugs have proved to be ineffective or poorly tolerated.\n\nOffer bladder wall injection with botulinum toxin type\xa0A to adults:\n\nwith spinal cord disease and\n\nwith urodynamic investigations showing impaired bladder storage and\n\nin whom antimuscarinic drugs have proved to be ineffective or poorly tolerated.\n\nConsider bladder wall injection with botulinum toxin type\xa0A for children and young people:\n\nwith spinal cord disease and\n\nwith urodynamic investigations showing impaired bladder storage and\n\nin whom antimuscarinic drugs have proved to be ineffective or poorly tolerated.\n\nBefore offering bladder wall injection with botulinum toxin type\xa0A:\n\nexplain to the person and/or their family members and carers that a catheterisation regimen is needed in most people with neurogenic lower urinary tract dysfunction after treatment, and\n\nensure that they are able and willing to manage such a regimen should urinary retention develop after the treatment.\n\nMonitor residual urine volume in people who are not using a catheterisation regimen during treatment with botulinum toxin type\xa0A.\n\nMonitor the upper urinary tract in people who are judged to be at risk of renal complications (for example, those with high intravesical pressures on filling cystometry) during treatment with botulinum toxin type\xa0A.\n\nEnsure that people who have been offered continuing treatment with repeated botulinum toxin type\xa0A injections have prompt access to repeat injections when symptoms return.\n\n## Augmentation cystoplasty\n\nConsider augmentation cystoplasty using an intestinal segment for people:\n\nwith non-progressive neurological disorders and\n\ncomplications of impaired bladder storage (for example, hydronephrosis or incontinence) and\n\nonly after a thorough clinical and urodynamic assessment and discussion with the patient and/or their family members and carers about complications, risks and alternative treatments.\n\nOffer patients life-long follow-up after augmentation cystoplasty because of the risk of long-term complications. Potential complications include metabolic effects, such as the development of vitamin\xa0B12 deficiency and the development of bladder cancer.\n\n# Treatment for stress incontinence\n\n## Pelvic floor muscle training\n\nConsider pelvic floor muscle training for people with:\n\nlower urinary tract dysfunction due to multiple sclerosis or stroke or\n\nother neurological conditions where the potential to voluntarily contract the pelvic floor is preserved. Select patients for this training after specialist pelvic floor assessment and consider combining treatment with biofeedback and/or electrical stimulation of the pelvic floor.\n\n## Urethral tape and sling surgery\n\nConsider autologous fascial sling surgery for people with neurogenic stress incontinence.\n\nDo not routinely use synthetic tapes and slings in people with neurogenic stress incontinence because of the risk of urethral erosion.\n\n## Artificial urinary sphincter\n\nConsider surgery to insert an artificial urinary sphincter for people with neurogenic stress incontinence only if an alternative procedure, such as insertion of an autologous fascial sling, is less likely to control incontinence.\n\nWhen considering inserting an artificial urinary sphincter:\n\ndiscuss with the person and/or their family members and carers the risks associated with the device, the possible need for repeat operations and alternative procedures\n\nensure that the bladder has adequate low-pressure storage capacity.\n\nMonitor the upper urinary tract after artificial urinary sphincter surgery (for example, using annual ultrasound scans), as bladder storage function can deteriorate in some people after treatment of their neurogenic stress incontinence.\n\n# Treatment to improve bladder emptying\n\n## Alpha-blockers\n\nDo not offer alpha-blockers to people as a treatment for bladder emptying problems caused by neurological disease.\n\n# Management with catheter valves\n\nIn people for whom it is appropriate a catheter valve may be used as an alternative to a drainage bag.[This recommendation is from the NICE guideline on healthcare-associated infections: prevention and control in primary and community care]\n\nTo ensure that a catheter valve is appropriate, take into consideration the person's preference, family member and carer support, manual dexterity, cognitive ability, and lower urinary tract function when offering a catheter valve as an alternative to continuous drainage into a bag.\n\nConsider the need for continuing upper urinary tract surveillance in people who have impaired bladder storage (for example, due to reduced bladder compliance).\n\n# Management with ileal conduit diversion\n\nFor people with neurogenic lower urinary tract dysfunction who have intractable, major problems with urinary tract management, such as incontinence or renal deterioration:\n\nconsider ileal conduit diversion (urostomy) and\n\ndiscuss with the person the option of simultaneous cystectomy as prophylaxis against pyocystis.\n\n# Treatment to prevent urinary tract infection\n\nDo not routinely use antibiotic prophylaxis for urinary tract infections in people with neurogenic lower urinary tract dysfunction.\n\nConsider antibiotic prophylaxis for people who have a recent history of frequent or severe urinary tract infections.\n\nBefore prescribing antibiotic prophylaxis for urinary tract infection:\n\ninvestigate the urinary tract for an underlying treatable cause (such as urinary tract stones or incomplete bladder emptying)\n\ntake into account and discuss with the person the risks and benefits of prophylaxis\n\nrefer to local protocols approved by a microbiologist or discuss suitable regimens with a microbiologist.\n\nEnsure that the need for ongoing prophylaxis in all people who are receiving antibiotic prophylaxis is regularly reviewed.\n\nWhen changing catheters in patients with a long-term indwelling urinary catheter:\n\ndo not offer antibiotic prophylaxis routinely\n\nconsider antibiotic prophylaxis for patients who:\n\n\n\nhave a history of symptomatic urinary tract infection after catheter change or\n\nexperience trauma during catheterisation (trauma defined as frank haematuria after catheterisation or 2\xa0or more attempts of catheterisation).In August 2012, no antibiotics had a UK marketing authorisation for this indication. See NICE's information on prescribing medicines.[This recommendation is from the NICE guideline on healthcare-associated infections: prevention and control in primary and community care.]\n\n\n\n# Monitoring and surveillance protocols\n\nDo not rely on serum creatinine and estimated glomerular filtration rate in isolation for monitoring renal function in people with neurogenic lower urinary tract dysfunction. For more information on the measurement of kidney function, see the NICE guideline on chronic kidney disease.\n\nConsider using isotopic glomerular filtration rate when an accurate measurement of glomerular filtration rate is required (for example, if imaging of the kidneys suggests that renal function might be compromised). For more information on the measurement of kidney function, see the NICE guideline on chronic kidney disease.\n\nOffer lifelong ultrasound surveillance of the kidneys to people who are judged to be at high risk of renal complications (for example, consider surveillance ultrasound scanning at annual or 2\xa0yearly intervals). Those at high risk include people with spinal cord injury or spina bifida and those with adverse features on urodynamic investigations such as impaired bladder compliance, detrusor-sphincter dyssynergia or vesico-ureteric reflux.\n\nDo not use plain abdominal radiography for routine surveillance in people with neurogenic lower urinary tract dysfunction.\n\nConsider urodynamic investigations as part of a surveillance regimen for people at high risk of urinary tract complications (for example, people with spina bifida, spinal cord injury or anorectal abnormalities).\n\nDo not use cystoscopy for routine surveillance in people with neurogenic lower urinary tract dysfunction.\n\nDo not use renal scintigraphy for routine surveillance in people with neurogenic lower urinary tract dysfunction.\n\n# Potential complications: providing information and initial management\n\n## Renal impairment\n\nDiscuss with the person, and their family members and carers, the increased risk of renal complications (such as kidney stones, hydronephrosis and scarring) in people with neurogenic urinary tract dysfunction (in particular those with spina bifida or spinal cord injury). Tell them the symptoms to look out for (such as loin pain, urinary tract infection and haematuria) and when to see a healthcare professional.\n\nWhen discussing treatment options, tell the person that indwelling urethral catheters may be associated with higher risks of renal complications (such as kidney stones and scarring) than other forms of bladder management (such as intermittent self-catheterisation).\n\nUse renal imaging to investigate symptoms that suggest upper urinary tract disease.\n\n## Bladder stones\n\nDiscuss with the person, and their family members and carers, the increased risk of bladder stones in people with neurogenic lower urinary tract dysfunction. Tell them the symptoms to look out for that mean they should see a healthcare professional (for example, recurrent infection, recurrent catheter blockages or haematuria).\n\nDiscuss with the person, and their family members and carers, that indwelling catheters (urethral and suprapubic) are associated with a higher incidence of bladder stones compared with other forms of bladder management. Tell them the symptoms to look out for that mean they should see a healthcare professional (for example, recurrent infection, recurrent catheter blockages or haematuria).\n\nRefer people with symptoms that suggest the presence of bladder stones (for example, recurrent catheter blockages, recurrent urinary tract infection or haematuria) for cystoscopy.\n\n## Bladder cancer\n\nDiscuss with the person, and their family members and carers, that there may be an increased risk of bladder cancer in people with neurogenic lower urinary tract dysfunction, in particular those with a long history of neurogenic lower urinary tract dysfunction and complicating factors, such as recurrent urinary tract infections. Tell them the symptoms to look out for (especially haematuria) that mean they should see a healthcare professional.\n\nArrange urgent (within 2\xa0weeks) investigation with urinary tract imaging and cystoscopy for people with:\n\nvisible haematuria or\n\nincreased frequency of urinary tract infections or\n\nother unexplained lower urinary tract symptoms.\n\n# Access to and interaction with services\n\n## Access to and interaction with services\n\nProvide contact details for the provision of specialist advice if a person has received care for neurogenic lower urinary tract dysfunction in a specialised setting (for example, in a spinal injury unit or a paediatric urology unit). The contact details should be given to the person, and their family members and carers, and to the non-specialist medical and nursing staff involved in their care.\n\nProvide people with neurogenic lower urinary tract dysfunction, and their family members and carers, with written information that includes:\n\na list of key healthcare professionals involved in their care, a description of their role and their contact details\n\ncopies of all clinical correspondence\n\na list of prescribed medications and equipment. This information should also be sent to the person's GP.\n\nNICE has produced guidance on the components of good patient experience in adult NHS services. All healthcare professionals should follow the recommendations in the\xa0NICE guideline on patient experience in adult NHS services, particularly relating to:\n\ntailoring healthcare services for each patient\n\ncontinuity of care and relationships.\n\n## Transfer from child to adult services\n\nWhen managing the transition of a person from paediatric services to adult services for ongoing care of neurogenic lower urinary tract dysfunction:\n\nformulate a clear structured care pathway at an early stage and involve the person and their parents and carers\n\ninvolve the young person's parents and carers when preparing transfer documentation with the young person's consent\n\nprovide a full summary of the person's clinical history, investigation results and details of treatments for the person and receiving clinician\n\nintegrate information from the multidisciplinary health team into the transfer documentation\n\nidentify and plan the urological services that will need to be continued after the transition of care\n\nformally transfer care to a named individual(s).\n\nWhen receiving a person from paediatric services to adult services for ongoing care of neurogenic lower urinary tract dysfunction:\n\nreview the transfer documentation and liaise with the other adult services involved in ongoing care (for example, adult neuro-rehabilitation services)\n\nprovide the person with details of the service to which care is being transferred, including contact details of key personnel, such as the urologist and specialist nurses\n\nensure that urological services are being provided after transition to adult services.\n\nConsider establishing regular multidisciplinary team meetings for paediatric and adult specialists to discuss the management of neurogenic lower urinary tract dysfunction in children and young people during the years leading up to transition and after entering adult services.\n\n# Terms used in this guideline\n\n## Alpha-blocking agents\n\nDrugs that inhibit the response to sympathetic impulses by blocking the alpha receptor sites of effector organs. Because they inhibit the contraction of non-vascular smooth muscle such as that found at the bladder neck and within the prostate, alpha-blockers are commonly used to treat bladder outflow obstruction in men with normally innervated urinary tracts. Also known as 'alpha adrenergic blocking agents' or 'alpha adrenergic antagonists'.\n\n## Antimuscarinic drugs\n\nAn anticholinergic agent that specifically blocks the muscarinic form of the cholinergic receptor. Because they decrease the responsiveness of the bladder wall muscle to stimulating nerve impulses, antimuscarinic drugs are used in the management of the overactive bladder.\n\n## Augmentation cystoplasty\n\nSurgical reconstruction of the bladder using an isolated intestinal segment to augment bladder capacity.\n\n## Autologous fascial sling surgery\n\nA procedure to treat stress urinary incontinence, in which a harvested strip of rectus fascia is used to provide support to the urethra. Also see urethral tape and sling surgery.\n\n## Behavioural management programmes\n\nBehavioural therapies are usually used to treat urge urinary incontinence and mixed urinary incontinence. Such therapies include:\n\nTimed voiding where the person is asked to void at set time intervals, rather than in response to a sense of bladder filling.\n\nBladder retraining where intervals between voids are progressively increased, or the patient is asked to delay voiding for a specific time when they experience the need to void.\n\nHabit retraining involves identifying an incontinent person's toileting pattern and developing an individualised toileting schedule in order to pre-empt episodes of incontinence.\n\n## Biofeedback\n\nThe process of becoming aware of various physiological functions using instruments that provide information on the activity of those same systems, with a goal of being able to manipulate them at will.\n\n## Bladder retraining\n\nSee behavioural management programmes.\n\n## Bladder stone\n\nStone found in the urinary bladder formed by crystallisation and concretion of salts from the urine and containing phosphate and oxalate salts of calcium or ammonium. Stones typically form in conjunction with bacterial colonisation of the urine, for example, when an indwelling catheter is present, or bladder emptying is incomplete.\n\n## Cauda equina compression\n\nA serious condition caused by compression of the nerve roots in the lower portion of the spinal canal that supply the lower limbs and the bladder and urethral sphincter.\n\n## Cystectomy\n\nSurgical removal of all or part of the urinary bladder.\n\n## Filling cystometry\n\nPart of urodynamic testing in which the bladder is slowly filled with liquid while pressure and volume measurements are taken in order to assess bladder function.\n\n## Habit retraining\n\nSee behavioural management programmes.\n\n## Hydronephrosis\n\nDistension and dilation of the renal pelvis and calyces, usually caused by obstruction of the free flow of urine from the kidney. Untreated, it leads to progressive atrophy of the kidney as a result of back pressure.\n\n## Ileal conduit diversion\n\nSurgical technique for the diversion of urine after a patient has had their bladder removed. Urine is transported from the ureters (the tubes draining urine from the kidneys) to a stoma on the abdominal wall using an isolated segment of small intestine.\n\n## Neurogenic\n\nOriginating in the nerves or nervous tissue.\n\n## Neuromuscular electrical stimulation\n\nProcedure used to strengthen healthy muscles or to maintain muscle mass during or following periods of enforced inactivity. This helps to maintain or gain range of motion, to facilitate voluntary motor control, and temporarily reduces spasticity when the nerve supply to the muscle is intact. This procedure involves sending small electrical impulses through the skin to the underlying nerves and muscles to create an involuntary muscle contraction.\n\n## Overactive bladder\n\nProduces symptoms of urinary urgency, with or without urge incontinence, usually with an increased frequency of micturition. The strong, sudden need to urinate is usually caused by involuntary contractions of the bladder or 'bladder spasms'.\n\n## Pelvic floor muscle training\n\nDaily training programme to strengthen the muscles that support the uterus, bladder and other pelvic organs and help prevent accidental urine leakage. Also called Kegel exercises or pelvic muscle rehabilitation.\n\n## Pelvic floor prolapse\n\nLoss of muscle tone and/or ligamentous elasticity resulting in the descent of the uterus or other pelvic organs into the vagina. If severe, the prolapse can protrude out of the vaginal orifice.\n\n## Pressure-flow studies\n\nSimultaneous measurement of bladder pressure and flow rate during the voiding phase of the micturition cycle. The test is used to assess the process of bladder emptying. For example, bladder outflow obstruction can be diagnosed if there is a low urinary flow rate in conjunction with a raised bladder pressure during voiding.\n\n## Prompted voiding\n\nA behavioural management programme that is used to encourage people to initiate their own toileting. It usually involves positive reinforcement and education of both the person with incontinence and their carer(s).\n\n## Renal scintigraphy\n\nPhotographic recording, using a gamma camera, of the distribution of a radioisotope (radioactive substance) given by injection. The radioisotope accumulates in the kidneys, allowing pictures to be produced showing details of both kidney structure and function.\n\n## Sacral agenesis\n\nA condition that exists when either part or all of the sacrum is absent due to a failure of the sacral spine to develop normally. In many cases, some or all of the nerves that supply the pelvic organs will also have failed to develop normally.\n\n## Spina bifida\n\nA condition in which the bones of the spine do not close due to a failure of normal development in the fetus. In cases of myelomeningocele, the bony abnormality is accompanied by abnormal development of the spinal cord or nerves and their covering membranes, which leads to abnormalities in the nerve supply to the lower limbs and pelvic organs.\n\n## Spinal dysraphism\n\nA general term that encompasses a number of different developmental abnormalities of the spine and spinal cord, of which spina bifida is an example.\n\n## Stress incontinence\n\nStress urinary incontinence describes a symptom, a sign and a diagnosis, although it is only following urodynamic investigation that a diagnosis of urodynamic stress incontinence can be made. This condition is defined as 'the involuntary leakage of urine during increased abdominal pressure in the absence of a detrusor contraction'.\n\n## Timed voiding\n\nSee behavioural management programmes.\n\n## Urethral tape and sling surgery\n\nA procedure that restores bladder control for people who lose urine when they cough or exercise. The urethral tape procedure involves positioning an artificial tape under the urethra, which is the tube that runs from the bladder through which you urinate. The tape will then rest like a hammock under the urethra, giving support and maintaining continence. A urethral tape consists of a thin mesh ribbon that is placed in order to provide support to the urethra. Urethral sling surgery involves placing a sling around the urethra to lift it back into a normal position and to exert pressure on the urethra to aid urine retention. The sling is attached to the abdominal wall. Also see autologous fascial sling surgery.\n\n## Urodynamic investigations\n\nInvestigation of the function of the lower urinary tract (the bladder and urethra) using physical measurements such as urine pressure and flow rate, as well as clinical assessment. Video-urodynamic investigations involve using a dye to fill the bladder enabling X-rays of the lower urinary tract to be taken during filling and emptying of the bladder.", 'Recommendations for research': "The guideline development group has made the following recommendations for research.\n\n# Safety and efficacy of antimuscarinics\n\nWhat is the safety and efficacy of more recently developed antimuscarinics compared with (a) placebo/usual care and (b) other antimuscarinics in the treatment of neurogenic lower urinary tract dysfunction?\n\n## Why this is important\n\nNo high-quality clinical trials looking at the use of the newer antimuscarinic drugs in people with neurogenic lower urinary tract dysfunction have been carried out. Both placebo-controlled and comparative studies are lacking. This is important because the more recently developed medications are of unknown efficacy, are more expensive and claim (in the non-neurogenic population) to have fewer adverse effects. The adverse effects of antimuscarinics are mostly due to their action at sites other than the bladder (for example, causing a dry mouth) but there is now increasing concern that antimuscarinic effects on the central nervous system may adversely affect cognitive function in both children with brain damage (caused by cerebral palsy or hydrocephalus) and adults with impaired cognition (caused by cerebral involvement in multiple sclerosis or neurodegenerative diseases).\n\n# Safety and efficacy of botulinum toxin\n\nWhat is the safety and efficacy of botulinum toxin compared with (a) usual care, (b) antimuscarinics and (c) augmentation cystoplasty in people with neurogenic lower urinary tract dysfunction?\n\n## Why this is important\n\nFurther research is needed to determine whether repeated intradetrusor injections of botulinum toxin type\xa0A have long-term efficacy. The efficacy in terms of continence and upper urinary tract preservation should be studied.\n\nBotulinum toxin injection into the detrusor is an effective means of managing incontinence and improves urodynamic measures of bladder storage with the potential to protect the kidneys from the effects of high intravesical pressures. It is well tolerated in a spectrum of conditions and ages. However, the longer-term efficacy over many injections has not been established.\n\nA clinical trial is needed to study the outcome in terms of continence and renal preservation over many cycles of repeated injection. Quality of life is an important outcome. A trial should enrol children and adults. The indications for botulinum toxin need not be modified for inclusion, but entrants into a trial must have anatomically normal kidneys (on imaging) and normal renal function.\n\nWhat is the safety and efficacy of botulinum toxin compared with (a) usual care, (b) antimuscarinics and (c) augmentation cystoplasty in people with primary cerebral conditions with lower urinary tract dysfunction?\n\n## Why this is important\n\nThe effects of intradetrusor botulinum toxin type\xa0A injection should be investigated in groups of people with underlying cerebral conditions that are associated with lower urinary tract dysfunction, as well as those with spinal cord injury, spina bifida and multiple sclerosis. Reports of its use in other conditions are limited to small numbers of patients within case series studies that include heterogeneous groups of patients. Potential benefits of successful treatment in cerebral disease may include the avoidance of cognitive impairment, which can be seen as a side effect of antimuscarinic medication.\n\nA trial should include people with primary cerebral conditions including (but not restricted to) stroke, head injury and cerebral palsy, but excluding multiple sclerosis. Children and adults should be recruited. Tolerability and acceptability are important outcomes, as well as the primary outcomes of continence, preservation of the upper urinary tracts and quality of life. Measurement of carer burden and quality of life is also important.\n\n# Management strategies to reduce the risk of symptomatic urinary tract infections\n\nIn people with neurogenic lower urinary tract dysfunction, which management strategies (including the use of prophylactic antibiotics and various invasive and non-invasive techniques to aid bladder drainage) reduce the risk of symptomatic urinary tract infections?\n\n## Why this is important\n\nRecurrent urinary tract infections in people with neurogenic bladder dysfunction are a cause of considerable morbidity. Urinary tract infections may exacerbate incontinence, cause symptoms of malaise and may progress to involve the upper urinary tract with possible loss of renal function. In the population with neurological diseases such as multiple sclerosis, Parkinson's disease and dementia, the rise in temperature with urinary tract infections can cause deterioration in neurological function and even a relapse of multiple sclerosis. There are therefore numerous reasons why people with neurogenic lower urinary tract dysfunction should avoid urinary tract infections.\n\nThe causes for the high prevalence of urinary tract infections in such people include loss of physiological bladder function and high intravesical pressures. Intermittent or permanent catheterisation inevitably exacerbate the problem, but incomplete bladder emptying is also a predisposing factor for urinary tract infections.\n\nResearch in this area is faced with methodological difficulties, not least because it may be difficult to distinguish between bladder colonisation (asymptomatic bacteriuria) and true infection.\n\nIn view of the considerable clinical burden of urinary tract infections and the global problem of antibiotic resistance, it is important to establish whether or not any infection prevention strategies, including patient training or the provision of information relating to prophylactic antibiotics are effective in reducing symptomatic urinary tract infections.\n\n# Bladder management strategies\n\nWhat are the long-term risks and effects on quality of life of different bladder management strategies for lower urinary tract dysfunction in people with neurological disease?\n\n## Why this is important\n\nThe range of bladder management strategies available to manage lower urinary tract dysfunction in neurological disease includes permanent urethral catheterisation and suprapubic catheterisation, intermittent self-catheterisation, penile sheath collection systems and pads. However, there is very sparse evidence about which strategies are most acceptable to patients and their family members and carers. The current research base relates mainly to the spinal injury population but may be relevant to people with other neurological diseases.\n\nBladder management strategies are a long-term treatment with implications for maintaining health and quality of life. In order to make informed choices about the most appropriate method of bladder management, patients and their family members and carers require information about the risks and benefits of the available options. There is currently little evidence about which methods are most likely to produce long-term complications (renal impairment, urinary stones and infections, hydronephrosis, bladder malignancy). The effect on quality of life for patients and their family members and carers of different bladder management strategies is not known. There are methodological difficulties due to the heterogeneity of the population with neurological disease, the long-time course of treatments and the presence of cognitive impairment in some sub-populations.\n\nProposed studies could include prospective cohort studies of disease-specific populations examining the effect of each method on quality of life using both generic and disease-specific assessment methods. In addition, prospective screening for complications including renal impairment, stone formation and infection should be carried out and comparisons made for each bladder management method. Particular emphasis should be placed on quality-of-life outcomes for family members and carers, especially for those looking after people with cognitive impairment."}
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https://www.nice.org.uk/guidance/cg148
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This guideline covers assessing and managing urinary incontinence in children, young people and adults with neurological disease. It aims to improve care by recommending specific treatments based on what symptoms and neurological conditions people have.
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15cfc720d337dbd66a516b13ce833eaa754b1c83
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nice
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Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism
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Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism
Evidence-based recommendations on rivaroxaban (Xarelto) for treating deep vein thrombosis and preventing a pulmonary embolism or another deep vein thrombosis in adults.
# Guidance
Rivaroxaban is recommended as an option for treating deep vein thrombosis and preventing recurrent deep vein thrombosis and pulmonary embolism after a diagnosis of acute deep vein thrombosis in adults.# The technology
Rivaroxaban (Xarelto, Bayer) is indicated for the 'treatment of deep vein thrombosis (DVT), and prevention of recurrent DVT and pulmonary embolism (PE) following an acute DVT in adults'. For the initial treatment of acute deep vein thrombosis, the recommended dosage of rivaroxaban is 15 mg twice daily for the first 21 days followed by 20 mg once daily for continued treatment and prevention of recurrence.
The duration of treatment recommended in the summary of product characteristics depends on bleeding risk and other clinical criteria: short-term treatment (3 months) is recommended for those with transient risk factors such as recent surgery and trauma, and longer treatment for permanent risk factors or idiopathic (unprovoked) deep vein thrombosis. The summary of product characteristics further states that experience with rivaroxaban in this indication for more than 12 months is limited. A reduced dosage of 15 mg twice daily for 21 days followed by 15 mg once daily should be used in people with moderate (creatinine clearance 30–49 ml/min) or severe (creatinine clearance 15–29 ml/min) renal impairment. For full details of side effects and contraindications, see the summary of product characteristics.
Rivaroxaban costs £2.10 per 15 mg or 20 mg tablet. The cost of treatment is estimated to be £235.86, £427.61 and £811.13 for 3, 6 and 12 months of treatment respectively. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rivaroxaban and a review of this submission by the Evidence Review Group (ERG; appendix B).
The key clinical evidence in the manufacturer's submission came from 2 trials (EINSTEIN-DVT and EINSTEIN-Ext). EINSTEIN-DVT was an open-label non-inferiority study that compared rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for 3, 6 or 12 months) with enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for treating patients with acute symptomatic deep vein thrombosis without any symptoms of pulmonary embolism, and for preventing recurrent deep vein thrombosis and pulmonary embolism. Enoxaparin was given until a vitamin K antagonist had brought the international normalised ratio (INR) into the target range, and was then stopped. Based on individual patient risk factors, patients were either assigned to 3, 6 or 12 months of treatment as determined by the treating physician. EINSTEIN-Ext was a randomised placebo-controlled superiority trial that compared rivaroxaban (20 mg once daily; n=602) with placebo once daily (n=594) in patients with confirmed symptomatic deep vein thrombosis or pulmonary embolism that had been treated for 6 or 12 months with a vitamin K antagonist (warfarin or acenocoumarol) or rivaroxaban up to the moment of randomisation. Patients were recruited if the risks and benefits of further anticoagulation were finely balanced, that is, there was 'clinical equipoise' for the decision to continue anticoagulation.
The manufacturer's submission noted that about 60% of patients recruited into EINSTEIN-Ext were assigned to 6 months of treatment, about 40% were assigned to 12 months of treatment and 28% had previously used rivaroxaban. The manufacturer also noted that some people were excluded from the EINSTEIN-DVT and EINSTEIN-Ext trials, such as those with a creatinine clearance of less than 30 ml/min, clinically significant liver disease, high blood pressure (systolic more than 180 mmHg or diastolic more than 110 mmHg), active bleeding or at high risk of bleeding.
The primary efficacy endpoint was a composite of deep vein thrombosis or pulmonary embolism (symptomatic, recurrent venous thromboembolism). Pulmonary embolism included both fatal and non-fatal pulmonary embolism. The primary safety endpoint was a composite of major bleeding and other clinically relevant non-major bleeding ('clinically relevant bleeding') for EINSTEIN-DVT and major bleeding for EINSTEIN-Ext. A range of secondary composite endpoints were also included.
In EINSTEIN-DVT, the primary efficacy endpoint of symptomatic recurrent venous thromboembolism occurred in 2.1% (n=36) of patients in the rivaroxaban group compared with 3.0% (n=51) in the enoxaparin and vitamin K antagonist group (hazard ratio 0.68; 95% confidence interval 0.44 to 1.04, p<0.001 for non-inferiority and p=0.076 for superiority). The overall HR for rivaroxaban was 0.97 (95% CI 0.76 to 1.22, p=0.77) for the primary safety endpoint of clinically relevant bleeding and 0.67 (95% CI 0.44 to 1.02, p=0.06) for death from all causes. Recurrent deep vein thrombosis occurred less frequently in patients treated with rivaroxaban than with enoxaparin and a vitamin K antagonist (14 compared with 28). Pulmonary embolisms (fatal and non-fatal) did not differ between treatment groups.
The manufacturer reported a time in therapeutic range for the comparator enoxaparin and a vitamin K antagonist of 57.7% across all centres and 59.7% in western European centres. The manufacturer highlighted that guidelines from the National Patient Safety Agency and the Scottish Executive Health Department recommend a time in therapeutic range of at least 60%. It also noted there was no statistical interaction observed in EINSTEIN-DVT between time in therapeutic range and treatment effect.
In EINSTEIN-Ext, patients taking rivaroxaban experienced fewer recurrences of venous thromboembolism (1.3%, n=8) than patients taking placebo (7.1%, n=42) (HR 0.18, 95% CI 0.09 to 0.39, p<0.0001). The numbers of clinically relevant non-major bleeding events were significantly higher in the rivaroxaban arm than in the placebo arm (32 patients compared with 7 patients , p<0.001). There were more major bleeding events in patients taking rivaroxaban (4 patients compared with no patients), although this did not reach statistical significance.
The manufacturer reported a mixed treatment comparison for the subgroup of patients with cancer. This compared the relative effectiveness of rivaroxaban with dual low molecular weight heparin (LMWH) and a vitamin K antagonist, long-term LMWH compared with LMWH and a vitamin K antagonist, and rivaroxaban compared with long-term LMWH. The manufacturer provided 3 analyses. The primary analysis used data from a systematic review of long-term anticoagulation in patients with cancer reported by Akl et al. (2011) and from the whole EINSTEIN-DVT trial population. Secondary analysis 1 used data from a trial by Lee et al. (2003) evaluating the LMWH dalteparin for the prevention of recurrent venous thromboembolism in patients with cancer and the data from the whole EINSTEIN-DVT trial population. Similarly, secondary analysis 2 used data from Akl et al. (2011) and effectiveness data from the cancer subgroup of EINSTEIN-DVT.
Results from the primary analysis indicated that for patients with active cancer, the venous thromboembolism recurrence hazard ratio for rivaroxaban compared with long-term LMWH was 1.44 (95% credible intervals 0.07 to 31.4). Secondary analysis 2 showed that rivaroxaban was less effective than LMWH at preventing venous thromboembolism recurrence (HR 1.32, 95% credible intervals 0.06 to 32.3) but induced fewer major bleeding events (odds ratio 0.24, 95% credible intervals 0.00 to 9.44). However, the manufacturer noted that the mixed treatment comparison had credible intervals with wide margins for the efficacy and safety of rivaroxaban compared with long-term LMWH.
The manufacturer reported adverse events from EINSTEIN-DVT and EINSTEIN-Ext that were experienced in at least 4% of any treatment group. The most common adverse events across both EINSTEIN trials were headache, pain in extremity, nasopharyngitis and nosebleed. The reported incidences of post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension were low in both arms of EINSTEIN-DVT and EINSTEIN-Ext.
The manufacturer's submission used a Markov-based model for the economic evaluation of rivaroxaban within its licensed indication for treating deep vein thrombosis and preventing recurrent thromboembolic events. Two analyses were presented: a primary analysis comparing rivaroxaban with LMWH and a vitamin K antagonist over 3, 6 and 12 months, and a cost-minimisation analysis for patients with active cancer, which used dalteparin (a LMWH) as the comparator. The manufacturer also presented a further exploratory cost-effectiveness analysis for patients with active cancer at the request of the ERG.
The Markov model comprised 11 health and treatment states and patients entered the model after a diagnosis of deep vein thrombosis. The model relied on the control arm of EINSTEIN-DVT to derive the probabilities of recurrent venous thromboembolism, bleeding and discontinuation rates. The probabilities in the rivaroxaban arm were calculated by applying the appropriate hazard ratio or risk ratio to the probability in the control arm. The 3-month discontinuation rate was assumed to be 1.9%. Probabilities for long-term complications and risk of mortality were taken from both EINSTEIN-DVT and literature reviews. Drug and resource costs were derived from relevant UK sources ('British national formulary' , NHS Reference Costs 2009–10 and Personal Social Services Research Unit 2010) and generally reflected UK clinical practice. The model did not include monitoring for patients treated with rivaroxaban or LMWH. It assumed 9 visits in the first 3 months, followed by 5 visits thereafter (every 3 months) for patients treated with a vitamin K antagonist. It also assumed that 66% of visits for INR monitoring would take place in primary care and 34% in secondary care. For primary care, the manufacturer assumed INR monitoring would be delivered equally by a GP and a nurse (50/50 split). The estimated annual cost of INR monitoring, including transport costs, was £656 in the first year and £540 thereafter.
A validated preference-based measure of quality of life was not used in the EINSTEIN-DVT trial, so the economic model submitted by the manufacturer used utility values sourced from literature reviews. The manufacturer assigned a baseline utility value of 0.825 to all patients with deep vein thrombosis entering the model, which was taken from a survey of the UK general population using a visual analogue scale rating (Kind et al. 1998) and adjusted with disutility values for deep vein thrombosis, pulmonary embolism, extracranial bleed, intracranial bleed and post-thrombotic syndrome.
The base-case results included all the drug acquisition costs, resources associated with monitoring, and costs associated with adverse events (that is, bleeding events) and were presented by intended treatment durations (3, 6 and 12 months). Treatment with rivaroxaban dominated treatment with LMWH and a vitamin K antagonist across all treatment durations, that is, rivaroxaban was less costly and more effective compared with LMWH and a vitamin K antagonist (0.02 incremental QALYs for all treatment durations and cost savings of £163 at 3 months, £124 at 6 months and £33 at 12 months).
The manufacturer undertook a series of univariate and multivariate deterministic sensitivity analyses to test the robustness of the results by varying most of the parameters used in the economic evaluation. The results were generally sensitive to the cost of monitoring and the hazard ratio for venous thromboembolism. The manufacturer also provided probabilistic sensitivity analyses. These showed that there was a 94.2–98.9% probability of rivaroxaban being cost effective at £20,000 per QALY gained for all treatment durations. The treatment duration of 3 months produced the most cost savings and increased incremental QALYs. The probability of rivaroxaban being the dominant treatment option was 97.1% in patients having 3 months of anticoagulation, 83.9% in those having 6 months and 53.0% in those having 12 months.
The manufacturer presented a cost minimisation analysis evaluating rivaroxaban in patients with cancer. Patients with cancer were assumed to be treated for 6 months. The cost of rivaroxaban was £4.20 per day for the first 21 days (2 tablets daily), followed by £2.10 per day (1 tablet daily). The cost of dalteparin was £8.47 per day for the first month and £7.06 per day for subsequent months. The total cost saving associated with rivaroxaban compared with LMWH (dalteparin) was £903 for patients with cancer.
The manufacturer also presented an exploratory cost-effectiveness analysis of the subgroup of patients with cancer. Using treatment effects from the mixed treatment comparison, assuming no INR monitoring cost and using a 6-month treatment duration, rivaroxaban dominated dalteparin (0.0013 incremental QALYs and cost savings of £1085).
The ERG raised concerns about the applicability of the EINSTEIN trials to UK clinical practice, including that the trials did not fully reflect the UK population with deep vein thrombosis because a number of important patient groups were excluded from both trials. These included patients with high risk of bleeding, creatinine clearance less than 30 ml/min (but not less than 15 ml/min), clinically significant liver disease, high blood pressure (systolic more than 180 mmHg or diastolic more than 110 mmHg) and non-proximal deep vein thrombosis. Specifically, the ERG noted that there are no data to inform decisions about patients with increased risk of bleeding. The ERG also noted that the EINSTEIN trials did not include patients for whom vitamin K antagonists are not appropriate, other than patients with cancer. It noted the population recruited into the EINSTEIN trials excluded a number of important groups relevant to the decision problem.
The ERG and its clinical advisers considered the comparator (enoxaparin) used by the manufacturer to be appropriate, although the dosage used in the EINSTEIN trials (1 mg/kg twice daily) was not in line with UK clinical practice (1.5 mg/kg once daily). Using the twice-daily dosage may have been unfavourable to rivaroxaban.
The manufacturer assumed the maximum treatment duration was 12 months for idiopathic deep vein thrombosis or in the presence of permanent risk factors. However, the clinical advisers to the ERG questioned this assumption and stated that it is now common for treatment to extend beyond 12 months, depending on patient characteristics and risk factors. The ERG's clinical advisers estimated that around 20% of people with deep vein thrombosis would have long-term treatment because of an ongoing risk of recurrence of venous thromboembolism.
The ERG raised concerns about the robustness of the mixed treatment comparison in the cancer subgroup and the way the evidence was synthesised. The ERG noted that the included trials varied in the length of follow-up, and choice and dosage of LMWH also varied across studies. The ERG concluded that the mixed treatment comparison did not provide good estimates of the uncertainty associated with the true treatment effect, but found the point estimate to be reasonable.
The ERG presented exploratory analyses that corrected certain errors in the model and took into account a less intensive INR monitoring strategy comprising 6 INR monitoring visits in the first 3 months and 3 visits every 3 months thereafter. The results indicated that enoxaparin and a vitamin K antagonist were dominated by rivaroxaban for the 3-month duration group (0.02 incremental QALYs and a cost saving of £51). Compared with enoxaparin and a vitamin K antagonist, the incremental cost-effectiveness ratio (ICER) of rivaroxaban was £3247 per QALY gained for the 6-month treatment duration and £14,902 per QALY gained for the 12-month treatment duration.
The ERG revised the manufacturer's exploratory analysis in cancer patients to take into account what it considered to be a more plausible – and smaller – distribution of between-study standard deviations (as opposed to the alternative distributions used by the manufacturer). This found rivaroxaban to be less effective than LMWH at preventing venous thromboembolism recurrence. The ERG raised concerns with the limited evidence available in the cancer subgroup, and with the modelling assumptions in the exploratory analysis. The ERG concluded any reliance on the results of the mixed treatment comparison may lead to inaccurate estimates of mean ICERs because they are based on inflated expected values.
# Additional manufacturer analyses
After consultation, the manufacturer submitted additional analyses on the cost effectiveness of rivaroxaban in people in whom long-term anticoagulation is intended; that is, people who need anticoagulation for longer than 12 months. The manufacturer also commented further on the characteristics of patients in the 3, 6, and 12 month treatment duration groups in the EINSTEIN-DVT trial.
The manufacturer's new economic model for long-term use of rivaroxaban used event rates for venous thromboembolism recurrence and bleeding from the 12-month duration group of EINSTEIN-DVT for people treated with a LMWH and a vitamin K antagonist. The long-term risk of venous thromboembolism recurrence (after 1 year) was taken from a meta-analysis review, and results from the whole trial population of EINSTEIN-DVT were used to estimate the treatment effects. The manufacturer presented 2 scenarios. One took into account the manufacturer's assumed INR frequency of 9 visits in the first 3 months followed by 5 visits every 3 months thereafter (first-year costs £656). The other adopted a less intensive INR monitoring programme of 6 visits in the first 3 months followed by 3 visits every 3 months thereafter (first-year cost of £413). The model assumed a discontinuation rate of 3.6% every 3 months based on a review of long-term statin therapy because evidence on adherence to rivaroxaban for longer than 12 months of treatment was not available. The model also included a sensitivity analysis in which the 3-month discontinuation rate was varied from 1.9% to 6.9%.
The model applied a disutility of 0.012 to warfarin, which was sourced from a study by Marchetti et al. (2001) involving a small group of patients (n=48) attending an anticoagulation clinic. The manufacturer noted that a disutility would not apply to rivaroxaban, citing reasons that included raised levels of treatment satisfaction in comparison with LMWH and a vitamin K antagonist, and that no clinically important adverse events were associated with rivaroxaban that had not already been taken into account in the model. The manufacturer also referred to 'Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation' (NICE technology appraisal 249), in which a disutility was applied to dabigatran to account for dyspepsia, an adverse event not associated with rivaroxaban.
The results from the long-term anticoagulation model showed that the ICER for rivaroxaban compared with LMWH and a vitamin K antagonist was £6037 per QALY gained under the manufacturer's assumed INR monitoring cost of £656 (0.16 incremental QALYs and additional cost of £953). Assuming a lower INR monitoring cost of £413, an ICER of £15,847 per QALY gained (0.16 incremental QALYs and additional cost of £2502) was reported by the manufacturer. The probabilistic sensitivity analysis based on reduced INR monitoring showed that there was a 58% probability that rivaroxaban was cost effective at £20,000 per QALY gained and a 25% probability that rivaroxaban was dominant (more effective and less costly).
The ERG was generally satisfied with the assumptions made in the manufacturer's long-term economic model but noted that it is uncertain whether the treatment effects assumed in the model would remain fixed over a lifetime. The ERG explored several scenarios based on variations to the manufacturer's long-term anticoagulation model:
Assuming treatment effect from the whole trial population over a lifetime horizon.
Assuming a lower INR cost of £320 for the first year followed by £248 annually thereafter, based on a reduced frequency of visits (6 visits in the first 3 months and then 3 visits every 3 months thereafter with a different GP/nurse consultation ratio than the one used by the manufacturer).
Varying the 3-month discontinuation rate for rivaroxaban from 3.6% as assumed in the manufacturer's long-term model to 1.9% as assumed by the manufacturer in the original submission.
Applying a 0.012 decrement in utility for warfarin and no decrement for rivaroxaban; 0.012 decrement in utility for warfarin and 0.006 decrement in utility for rivaroxaban; and assuming no decrement in utility for both warfarin and rivaroxaban.
Taking into account the above assumptions, the results from the ERG's exploratory analyses yielded ICERs ranging from £19,381 to £38,837 per QALY gained. A deterministic calculation based on a whole-trial treatment effect, the lower cost of INR monitoring, and a utility decrement for warfarin only, indicated an ICER of £19,381 per QALY gained, assuming the same 3-month discontinuation rate of 3.6% for warfarin and rivaroxaban. The equivalent ICER when the discontinuation rate for rivaroxaban was lowered to 1.9%, while keeping the warfarin discontinuation rate at 3.6%, was £25,076 per QALY gained.
Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA261# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rivaroxaban, having considered evidence on the nature of venous thromboembolism and the value placed on the benefits of rivaroxaban by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee heard from the clinical specialists that currently venous thromboembolism is initially treated with a LMWH (such as enoxaparin, dalteparin or tinzaparin) for rapid anticoagulation, overlapped with warfarin until an effective INR is achieved. The Committee also heard that treatment duration is based on an assessment of the benefit of continued anticoagulation compared with the risk of bleeding. The clinical specialists stated that treatment is often started with an expected duration of therapy, but that increasingly, a clinical re-evaluation is carried out at 3 or 6 months and a decision is made whether or not to continue therapy. The clinical specialists stated that in current UK practice, most people receive anticoagulation treatment for 6 months, which corresponds to the largest group in the EINSTEIN-DVT trial. However, the Committee heard that a NICE clinical guideline in development on venous thromboembolic diseases is expected to recommend anticoagulation for 3 months in people with transient risk factors for deep vein thrombosis, and to recommend longer-term treatment in people with permanent risk factors and unprovoked deep vein thrombosis, taking into account individual risk factors such as risk of bleeding. The Committee concluded that although 6 months is currently the commonest duration of treatment in UK practice, this could change in light of the NICE clinical guideline on venous thromboembolic diseases.
The Committee noted the written evidence from patient experts, which stated that many people find taking warfarin to be stressful, because of the necessary regular monitoring with blood tests, dosing adjustments, and because people must be careful about their diet because of warfarin's interaction with certain foods. The Committee heard from clinical specialists who agreed that warfarin is associated with a wide range of important and potentially dangerous drug interactions, and that warfarin can also negatively impact people's quality of life by preventing travel and other freedoms because of the need for regular monitoring. The Committee also heard from the patient experts that rivaroxaban may improve the quality of life of people who currently take warfarin by removing the need for constant monitoring, frequent blood tests and visits to an anticoagulation clinic. It also heard that rivaroxaban is likely to benefit people who are needle phobic or who want to resume normal patterns of life without having to worry about the disruption associated with attending clinics. The use of rivaroxaban would also relieve the concern that people may have about not being on the correct warfarin dose to keep their INR well controlled. Additional advantages of rivaroxaban are the lack of need for INR monitoring, which could reduce the need for support services, and its oral formulation compared with LMWH, which is injected.
# Clinical effectiveness
The Committee discussed the clinical-effectiveness data from the EINSTEIN-DVT trial, which compared rivaroxaban with enoxaparin and a vitamin K antagonist in people with venous thromboembolism. The Committee heard from the clinical specialists that enoxaparin and a vitamin K antagonist is the key comparator. The Committee discussed whether the dosage of enoxaparin used in the EINSTEIN-DVT trial is relevant to UK clinical practice. The Committee heard from the clinical specialists that the dosage used in the UK (1.5 mg/kg once daily) and the dosage used in the EINSTEIN-DVT trial (1 mg/kg twice daily) are similar in efficacy and the difference is not expected to have affected the results of the trial. The Committee concluded that the difference in dosage did not appear to be clinically significant and was satisfied that the comparators used in the trial represented routine and best practice in the NHS.
The Committee considered the time in therapeutic range in the warfarin arm of the trial. It noted that the mean time in therapeutic range was 58%, which is lower than might be expected in routine UK clinical practice. However, the Committee heard from the clinical experts that control of INR is more difficult when warfarin is first started and before stabilisation on longer-term treatment. The Committee therefore concluded that for this patient population, the data from the warfarin arm in the trial was applicable to routine UK practice.
The Committee considered the trial design and results of EINSTEIN-DVT. The Committee noted that EINSTEIN-DVT was a non-inferiority trial that compared rivaroxaban with enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol). The Committee heard that patients recruited into the trial were allocated to 3, 6 and 12 month treatment durations by the treating physician, based on individual patient risk factors, before randomisation. The Committee noted that, for the whole trial population, rivaroxaban was at least as effective as the enoxaparin and a vitamin K antagonist regimen with respect to the primary efficacy endpoint of symptomatic recurrent venous thromboembolism and to the primary safety endpoint of clinically relevant bleeding. The Committee concluded that rivaroxaban was as effective as enoxaparin followed by a vitamin K antagonist for preventing recurrent venous thromboembolism, and did not have the disadvantages of an injected treatment followed by an oral treatment with the need for regular monitoring with blood tests.
The Committee considered the baseline characteristics of the EINSTEIN-DVT trial population and the results of the pre-specified subgroup analyses presented by the manufacturer. The Committee noted that rivaroxaban appeared to be more effective in people with a previous episode of deep vein thrombosis or pulmonary embolism, and that the effect of rivaroxaban varied between the subgroups allocated to the 3 different intended treatment durations. The Committee noted that the subgroup analysis by intended treatment duration suggested that rivaroxaban might be less effective than enoxaparin and warfarin in patients for whom 3 months of treatment was intended. The Committee noted the heterogeneity of the trial population in terms of underlying risk factors for deep vein thrombosis, and noted that no individually identifiable clinical group was included in only 1 treatment duration subgroup. The Committee also heard from the manufacturer that there were no specific clinical criteria or algorithms used to allocate people into the different intended treatment duration groups, and that there was no apparent biological or clinical plausibility for the differential effectiveness of rivaroxaban across the intended treatment duration subgroups. A similar view was taken by the clinical specialists, who noted that they were not aware of any clinical reasons why rivaroxaban would be less effective than LMWH and a vitamin K antagonist in people who received 3 months of treatment, while being more effective in the 6 and 12 months groups. The Committee also heard from the ERG that the lower efficacy in the patient group treated for 3 months only was based on a small number of events in both arms and the majority of events occurred in the 6 and 12 month groups. The Committee accepted that there is insufficient evidence to demonstrate that rivaroxaban had a substantially different effectiveness across treatment durations, and was not aware of any biological reason to expect a differential effect in the first 3 months. The Committee therefore concluded that evidence of treatment effect should be based on the whole trial population of EINSTEIN-DVT.
The Committee questioned whether the pre-specified intended treatment duration used in the EINSTEIN-DVT trial reflects clinical practice. It noted that the clinical advisers to the ERG estimated that approximately 20% of people with deep vein thrombosis may need treatment for longer than 12 months. The Committee heard from the clinical specialists that the average duration of treatment is currently 6 months, at which time further treatment, including life-long treatment, would be considered if the person's risk of a recurrence remained high. However, the Committee noted that the summary of product characteristics for rivaroxaban states that experience with rivaroxaban in this indication for more than 12 months is limited. The manufacturer informed the Committee that there is a risk management plan agreed with the European Medicines Agency that involves the non-interventional XALIA study. The study will recruit people with a diagnosis of acute deep vein thrombosis and aims to estimate the recurrence of venous thromboembolism, incidence of major bleeding and mortality over the longer term. The Committee concluded that it may not be realistic to assume that people stop treatment once the pre-specified treatment period has ended and some people with ongoing risk factors for recurrence would need ongoing treatment, possibly for many years or lifelong.
The Committee discussed the results from the EINSTEIN-Ext trial. It noted that the trial inclusion criteria included people defined to be in 'clinical equipoise'. The manufacturer defined this as people for whom the decision to treat with anticoagulants was finely balanced. However, the Committee heard from the clinical specialists that in UK practice people who are to be treated for up to 12 months, as in the EINSTEIN-Ext trial, would generally not fall under this definition because they would have a strong clinical reason for further anticoagulation. It therefore agreed that the population in the EINSTEIN-DVT trial was more relevant for appraising rivaroxaban in venous thromboembolism for up to 12 months of treatment.
The Committee considered the adverse events reported in the EINSTEIN-DVT and EINSTEIN-Ext trials. The Committee noted that patients treated with rivaroxaban experienced a comparable number of clinically relevant bleeding episodes to those treated with enoxaparin and a vitamin K antagonist in EINSTEIN-DVT. The Committee noted that patients treated with rivaroxaban in the extension study experienced a higher rate of clinically relevant non-major bleeding but that the comparator was placebo and not active control. The Committee concluded that treatment with rivaroxaban had an acceptable adverse event profile compared with the combination of LMWH and warfarin.
# Cost effectiveness
The Committee considered the cost effectiveness of rivaroxaban for up to 12 months of treatment. The Committee noted that the economic model used clinical-effectiveness data from the EINSTEIN-DVT trial and that the results were presented by treatment duration. It noted that rivaroxaban dominated treatment with enoxaparin and a vitamin K antagonist in the manufacturer's deterministic analysis, that is, rivaroxaban was less costly and more effective across all 3 treatment durations (3, 6 and 12 months). The manufacturer's model assumed a first-year INR monitoring cost of £656, and £540 in subsequent years. The Committee was mindful of the QALY increment for people treated with rivaroxaban but considered that the estimate of INR costs was too high and was not likely to reflect the actual cost in UK clinical practice. The Committee could therefore not accept the results of the manufacturer's base-case analysis as the estimate of cost effectiveness.
The Committee discussed the estimate of the cost of INR monitoring. The Committee acknowledged the multiple models of provision for INR monitoring across the UK and the uncertainty about the costs. It noted that estimates of INR monitoring costs varied greatly, and some community-based monitoring programmes appeared to be much cheaper than the manufacturer's estimate. The Committee considered the ERG's critique of the base-case economic model for up to 12 months of treatment. The ERG assumed a less intensive INR monitoring programme of 6 visits in the first 3 months followed by 3 visits every 3 months thereafter, and assumed different provisions for INR monitoring than did the manufacturer. The ERG's estimate of the cost of INR monitoring was £320 in the first year and £248 thereafter. It noted that the ERG estimate appeared to be in the region of the estimated INR costs used in NICE technology appraisal 249. The Committee heard from the clinical specialists that the population eligible for treatment with rivaroxaban is not likely to need significantly more frequent INR monitoring than people being started on anticoagulation therapy for other indications. Comments from consultees also indicated that the manufacturer's estimate of INR monitoring costs was higher than was plausible for UK practice. The Committee therefore concluded that the ERG's alternative assumptions and estimate of £320 for INR monitoring in the first year of treatment were reasonable and relevant for this appraisal.
The Committee considered the results of the ERG's economic evaluation of rivaroxaban treatment for up to 12 months. The ERG's estimate used clinical-effectiveness data from the whole trial population of EINSTEIN-DVT and the ERG's lower estimate for INR monitoring. The results indicated that rivaroxaban dominated therapy with LMWH and a vitamin K antagonist in the 3-month treatment duration group. The ICER for rivaroxaban was £3200 per QALY gained for the 6-month treatment duration and £14,900 per QALY gained for the 12-month treatment duration. The Committee agreed that these cost-effectiveness results for up to 12 months of treatment using the ERG estimate for the cost of INR monitoring were more plausible than those provided by the manufacturer. The Committee concluded that treatment with rivaroxaban represented a clinical and cost-effective option in people in whom treatment for up to 12 months is indicated.
The Committee then discussed the manufacturer's submission for rivaroxaban in those who need long-term anticoagulation; that is, beyond 12 months of treatment. It noted that the manufacturer's economic model included a decrement in utility of 0.012 for people on warfarin only, which was taken from a small study by Marchetti et al. The Committee heard from the patient experts that warfarin has an impact on quality of life (see section 4.3). The Committee considered that although treatment with rivaroxaban could be associated with a small disutility, it was satisfied that treatment with warfarin was associated with a higher disutility than treatment with rivaroxaban, and the relative difference in disutility could be even higher than 0.012 for people who may have to take it for many years or lifelong. The Committee concluded that although it was not convinced that the utility decrement used by the manufacturer was supported by strong evidence, it was of the opinion that the relative difference in disutility was at least as great as the value used by the manufacturer in its long-term model.
The Committee discussed the discontinuation rates in the economic evaluation of rivaroxaban in those who need ongoing anticoagulation. It noted that the manufacturer had used a discontinuation rate of 3.6% for every 3-month period for both treatments, which was taken from a study on long-term statin therapy. The Committee acknowledged the lack of evidence for the long-term adherence of people treated with rivaroxaban in venous thromboembolism, but noted there was no strong evidence to suggest that the people treated with rivaroxaban should have different rates of discontinuation compared with warfarin. The Committee concluded that it was satisfied that equal or near-equal discontinuation rates should be applied to both treatment arms.
The Committee then considered the results of the cost-effectiveness analysis of rivaroxaban for long-term anticoagulation. It noted the results from the manufacturer's long-term model which incorporated INR monitoring costs of £656 and a disutility of 0.012 applied to warfarin only, resulting in an ICER of £6000 per QALY gained for rivaroxaban compared with enoxaparin and a vitamin K antagonist. The Committee noted that the equivalent ICER, when a less intensive INR monitoring cost of £413 was assumed, was £15,800 per QALY. The Committee also noted the ERG's exploratory analysis, which provided a range of estimates of the ICERs for ongoing anticoagulation under the scenarios outlined in 3.27. This gave ICERs ranging from £19,400 to £38,800 per QALY gained. The Committee noted that the INR monitoring costs assumed by the manufacturer were higher than are considered to be reasonable and therefore considered the ERG's analysis to be more appropriate. The Committee was satisfied that the differential disutility for warfarin compared with rivaroxaban, although uncertain, was at least 0.012 when long-term or lifelong treatment is needed (see section 4.16). Assuming an equal discontinuation rate, a differential disutility of more than 0.012 would bring the ICER down to below £19,400 per QALY gained. The Committee also explored the scenario incorporating a discontinuation rate for rivaroxaban of just over half the warfarin discontinuation rate which, if a differential disutility of 0.012 was applied, gave an ICER of £25,100 per QALY gained. However, the Committee was not convinced that the discontinuation rate would be different, and felt that the ICER estimate of £25,100 was too high (see section 4.17). The Committee therefore concluded that £19,400 per QALY gained was a plausible estimate, and that rivaroxaban was a cost-effective treatment option for people who need anticoagulation treatment for longer than 12 months.
The Committee discussed the effectiveness of rivaroxaban in people with cancer. It considered the manufacturer's mixed-treatment analyses, and found the manufacturer's secondary analysis 2 (see section 3.7) to be the most relevant because it used data from the cancer subgroup. It noted that this analysis indicated that rivaroxaban was less effective than dalteparin at preventing venous thromboembolism recurrence but induced fewer major bleeding events. It also noted that the credible intervals around these estimates were wide. The Committee acknowledged that the ERG did not find the cancer subgroup analyses to be robust and had concerns with the limited evidence and with how the mixed-treatment comparison was conducted and implemented. The Committee heard from the clinical specialists that the current standard care in treating venous thromboembolism in people with cancer is LMWH alone, which the evidence suggests provides benefits greater than warfarin. This seems to be a cancer-specific effect. The clinical specialists further stated that there is no direct trial evidence demonstrating that rivaroxaban is superior to a LMWH in people with cancer, and so would not expect the availability of rivaroxaban to change UK clinical practice in this population. The Committee heard from the patient experts that people with cancer would welcome a non-invasive treatment option such as rivaroxaban, particularly people receiving palliative care, as long as the treatment is safe and does not interact with the cancer treatment. Given the lack of clinical evidence for this group, the Committee was unable to make specific recommendations on the use of rivaroxaban in people with cancer but recognised the disadvantages of the currently available treatment, which involves regular injections, and which some people might choose to decline. The Committee concluded that rivaroxaban should not be excluded as a treatment option for preventing venous thromboembolism in people with cancer.
# Summary of Appraisal Committee's key conclusions
TA261
Appraisal title: Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism
Section
Key conclusion
Rivaroxaban is recommended as an option for treating deep vein thrombosis and preventing recurrent deep vein thrombosis and pulmonary embolism after a diagnosis of acute deep vein thrombosis in adults.
The Committee considered the cost-effectiveness result for up to 12 months of treatment using the ERG's estimate for INR monitoring. The results indicated that rivaroxaban dominated therapy with LMWH and a vitamin K antagonist in the 3-month duration group. The ICER was £3200 per QALY gained for the 6-month treatment duration and £14,900 per QALY gained for the 12-month treatment duration. The Committee concluded that treatment with rivaroxaban represented a clinical and cost-effective option in people in whom treatment for up to 12 months is indicated.
The Committee considered the results of the cost-effectiveness analysis of rivaroxaban for long-term anticoagulation. The Committee concluded that £19,400 per QALY gained was a plausible estimate, and that rivaroxaban was a cost-effective treatment for people who need anticoagulation treatment for longer than 12 months.
Current
practice
Clinical need of patients, including the availability of alternative treatments
Current management of venous thromboembolism is initiated with an LMWH (such as enoxaparin, which is the most commonly used LMWH in the UK) for rapid anticoagulation, and overlapped with warfarin until an effective dose is achieved. Treatment duration is based on the benefit of anticoagulation compared with the risk of bleeding. The main concerns with long-term anticoagulation with warfarin are the impact on people's lifestyle, and resource use associated with regular INR monitoring. Current UK practice indicates that the average treatment duration is 6 months.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The clinical specialists noted that warfarin is associated with a number of difficulties, including dietary restrictions and possible drug interactions. Patient experts noted that people find taking warfarin stressful because of the need for constant monitoring with blood tests, dosing adjustments and because of warfarin's interactions with certain foods and drugs. The Committee acknowledged the limitations of warfarin therapy, and recognised the advantages of rivaroxaban that include its oral formulation and lack of need for INR monitoring, which could reduce the need for support services.
What is the position of the treatment in the pathway of care for the condition?
Rivaroxaban is indicated for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism after an acute deep vein thrombosis in adults.
Adverse reactions
The Committee noted that rivaroxaban had comparable rates of clinically relevant bleeding when compared with enoxaparin and a vitamin K antagonist, but was associated with higher bleeding events when compared with placebo in the extension study.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The EINSTEIN-DVT trial was the key trial supporting the clinical effectiveness of rivaroxaban in the manufacturer's submission.
Relevance to general clinical practice in the NHS
The Committee considered the trial to reflect UK clinical practice.
Uncertainties generated by the evidence
The Committee considered the baseline characteristics of the EINSTEIN-DVT trial population, and wished to explore the biological plausibility of any differential effectiveness in the subgroups. The Committee noted that no individually identifiable clinical group was included in only 1 treatment duration subgroup, and heard from the manufacturer and clinical experts that no specific clinical criteria were used or biological rationale existed that explain a differential effectiveness across the intended treatment duration groups. The Committee concluded that evidence of treatment effect should be based on the whole trial population of EINSTEIN-DVT.
The Committee heard that there is no direct trial evidence demonstrating that rivaroxaban is superior to a LMWH in patients with cancer. Given the lack of clinical evidence for this group of patients, the Committee was unable to make specific recommendations on the use of rivaroxaban in people with cancer but recognised the disadvantages of the currently available treatment, which involves regular injections, and which some patients might choose to decline.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee considered the subgroup results presented by the manufacturer, which showed that rivaroxaban appeared to be less effective in certain groups of patients, including those for whom 3 months of treatment was clinically indicated. However, the Committee concluded that there was no biological plausibility that would explain the differential effectiveness and accepted that evidence of treatment effect should be based on the whole trial population of EINSTEIN-DVT.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
Compared with enoxaparin and a vitamin K antagonist, rivaroxaban was associated with a hazard ratio of 0.68 for prevention of venous thromboembolism. The Committee concluded that rivaroxaban was as effective as enoxaparin followed by a vitamin K antagonist for preventing venous thromboembolism recurrences.
Evidence for cost effectiveness
Availability and nature of evidence
The manufacturer presented a Markov model using effectiveness data from the trial population of EINSTEIN-DVT (that is, for up to 12 months of treatment) and provided analyses on the cost effectiveness of rivaroxaban in people in whom long-term anticoagulation is intended; that is, beyond 12 months of treatment.
The manufacturer also provided a cost minimisation analysis and an exploratory cost-effectiveness analysis, evaluating the benefits of rivaroxaban in patients with cancer.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee recognised the various provisions for INR monitoring across the UK but found the manufacturer's estimate for INR monitoring of £656 in the first year to be high. The Committee heard from clinical specialists that the treatment population for rivaroxaban are not likely to need significantly more frequent INR monitoring than people being started on anticoagulation therapy for other indications, and found the ERG estimate of £320 for INR monitoring to be more appropriate and in line with the recent NICE guidance on dabigatran in atrial fibrillation (NICE technology appraisal guidance 249). The Committee concluded that the appropriate estimate for INR monitoring is £320 in the first year.
The Committee noted that the discontinuation rates used in the economic evaluation of rivaroxaban in those who need ongoing anticoagulation were based on a review of long-term statin therapy, and acknowledged the lack of evidence for long-term adherence of patients treated with rivaroxaban in venous thromboembolism. However, the Committee noted there was no strong evidence to suggest that the people treated with rivaroxaban should have different rates of discontinuation compared with warfarin, and therefore accepted that equal or near-equal discontinuation rates should be applied to both rivaroxaban and warfarin.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The manufacturer's economic model for up to 12 months of treatment used utility values sourced from the literature.
The manufacturer also included a decrement in utility of 0.012 for people taking warfarin in the economic model. The Committee heard from clinical specialists and patient experts who confirmed the impact warfarin has on a person's quality of life in terms of fear that INR may not be optimally controlled, the need for constant monitoring and how warfarin has several food and drug interactions. The Committee was satisfied that warfarin was associated with a higher disutility than rivaroxaban, and accepted that the difference in disutility was at least as great as the point estimate (0.012) used by the manufacturer.
Are there specific groups of people for whom the technology is particularly cost effective?
Not applicable.
What are the key drivers of cost effectiveness?
INR monitoring costs. The Committee noted that the INR monitoring costs assumed by the manufacturer were higher than were considered to be reasonable and therefore accepted the ERG's analysis which assumed lower INR costs to be more appropriate.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee noted that rivaroxaban dominated therapy with a LMWH and a vitamin K antagonist in the 3-month group; the ICER for rivaroxaban was £3200 per QALY gained for the 6-month treatment duration and £14,900 per QALY gained for the 12-month treatment duration.
The ICER for rivaroxaban was £19,400 per QALY gained for people who need anticoagulation beyond 12 months of treatment.
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable.
End-of-life considerations
End-of-life considerations were not discussed.
Equalities considerations and social value judgements
Not applicable.
# Recommendations for further research
Further research on the clinical effectiveness of rivaroxaban compared with LMWH in patients with active cancer should be conducted.# Related NICE guidance
Published
Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. NICE clinical guideline 144 (2012)
Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation. NICE technology appraisal guidance 249 (2012).
Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults. NICE technology appraisal guidance 245 (2012).
Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital. NICE clinical guideline 92 (2010).
Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults. NICE technology appraisal guidance 170 (2009).
Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. NICE technology appraisal guidance 157 (2008).
Under development
NICE is developing the following guidance (details available from www.nice.org.uk):
Publication expected June 2012.
Dabigatran etexilate for the treatment of acute venous thromboembolic events. NICE technology appraisal. Publication date to be confirmed.# Review of guidance
The guidance on this technology will be considered for review in May 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveJune 2012# Changes after publication
February 2014:
minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Rivaroxaban is recommended as an option for treating deep vein thrombosis and preventing recurrent deep vein thrombosis and pulmonary embolism after a diagnosis of acute deep vein thrombosis in adults.', 'The technology ': "Rivaroxaban (Xarelto, Bayer) is indicated for the 'treatment of deep vein thrombosis (DVT), and prevention of recurrent DVT and pulmonary embolism (PE) following an acute DVT in adults'. For the initial treatment of acute deep vein thrombosis, the recommended dosage of rivaroxaban is 15\xa0mg twice daily for the first 21\xa0days followed by 20\xa0mg once daily for continued treatment and prevention of recurrence.\n\nThe duration of treatment recommended in the summary of product characteristics depends on bleeding risk and other clinical criteria: short-term treatment (3\xa0months) is recommended for those with transient risk factors such as recent surgery and trauma, and longer treatment for permanent risk factors or idiopathic (unprovoked) deep vein thrombosis. The summary of product characteristics further states that experience with rivaroxaban in this indication for more than 12\xa0months is limited. A reduced dosage of 15\xa0mg twice daily for 21\xa0days followed by 15\xa0mg once daily should be used in people with moderate (creatinine clearance 30–49\xa0ml/min) or severe (creatinine clearance 15–29\xa0ml/min) renal impairment. For full details of side effects and contraindications, see the summary of product characteristics.\n\nRivaroxaban costs £2.10 per 15\xa0mg or 20\xa0mg tablet. The cost of treatment is estimated to be £235.86, £427.61 and £811.13 for 3, 6\xa0and 12\xa0months of treatment respectively. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rivaroxaban and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe key clinical evidence in the manufacturer's submission came from 2 trials (EINSTEIN-DVT and EINSTEIN-Ext). EINSTEIN-DVT was an open-label non-inferiority study that compared rivaroxaban (15\xa0mg twice daily for 3\xa0weeks, then 20\xa0mg once daily for 3, 6 or 12\xa0months) with enoxaparin followed by a vitamin\xa0K antagonist (either warfarin or acenocoumarol) for treating patients with acute symptomatic deep vein thrombosis without any symptoms of pulmonary embolism, and for preventing recurrent deep vein thrombosis and pulmonary embolism. Enoxaparin was given until a vitamin\xa0K antagonist had brought the international normalised ratio (INR) into the target range, and was then stopped. Based on individual patient risk factors, patients were either assigned to 3, 6 or 12\xa0months of treatment as determined by the treating physician. EINSTEIN-Ext was a randomised placebo-controlled superiority trial that compared rivaroxaban (20\xa0mg once daily; n=602) with placebo once daily (n=594) in patients with confirmed symptomatic deep vein thrombosis or pulmonary embolism that had been treated for 6\xa0or 12\xa0months with a vitamin\xa0K antagonist (warfarin or acenocoumarol) or rivaroxaban up to the moment of randomisation. Patients were recruited if the risks and benefits of further anticoagulation were finely balanced, that is, there was 'clinical equipoise' for the decision to continue anticoagulation.\n\nThe manufacturer's submission noted that about 60% of patients recruited into EINSTEIN-Ext were assigned to 6\xa0months of treatment, about 40% were assigned to 12\xa0months of treatment and 28% had previously used rivaroxaban. The manufacturer also noted that some people were excluded from the EINSTEIN-DVT and EINSTEIN-Ext trials, such as those with a creatinine clearance of less than 30\xa0ml/min, clinically significant liver disease, high blood pressure (systolic more than 180\xa0mmHg or diastolic more than 110\xa0mmHg), active bleeding or at high risk of bleeding.\n\nThe primary efficacy endpoint was a composite of deep vein thrombosis or pulmonary embolism (symptomatic, recurrent venous thromboembolism). Pulmonary embolism included both fatal and non-fatal pulmonary embolism. The primary safety endpoint was a composite of major bleeding and other clinically relevant non-major bleeding ('clinically relevant bleeding') for EINSTEIN-DVT and major bleeding for EINSTEIN-Ext. A range of secondary composite endpoints were also included.\n\nIn EINSTEIN-DVT, the primary efficacy endpoint of symptomatic recurrent venous thromboembolism occurred in 2.1% (n=36) of patients in the rivaroxaban group compared with 3.0% (n=51) in the enoxaparin and vitamin\xa0K antagonist group (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.44 to 1.04, p<0.001 for non-inferiority and p=0.076 for superiority). The overall HR for rivaroxaban was 0.97 (95% CI 0.76 to 1.22, p=0.77) for the primary safety endpoint of clinically relevant bleeding and 0.67 (95% CI 0.44 to 1.02, p=0.06) for death from all causes. Recurrent deep vein thrombosis occurred less frequently in patients treated with rivaroxaban than with enoxaparin and a vitamin\xa0K antagonist (14 compared with 28). Pulmonary embolisms (fatal and non-fatal) did not differ between treatment groups.\n\nThe manufacturer reported a time in therapeutic range for the comparator enoxaparin and a vitamin\xa0K antagonist of 57.7% across all centres and 59.7% in western European centres. The manufacturer highlighted that guidelines from the National Patient Safety Agency and the Scottish Executive Health Department recommend a time in therapeutic range of at least 60%. It also noted there was no statistical interaction observed in EINSTEIN-DVT between time in therapeutic range and treatment effect.\n\nIn EINSTEIN-Ext, patients taking rivaroxaban experienced fewer recurrences of venous thromboembolism (1.3%, n=8) than patients taking placebo (7.1%, n=42) (HR 0.18, 95% CI 0.09 to 0.39, p<0.0001). The numbers of clinically relevant non-major bleeding events were significantly higher in the rivaroxaban arm than in the placebo arm (32 patients [5.3%] compared with 7\xa0patients [1.2%], p<0.001). There were more major bleeding events in patients taking rivaroxaban (4 patients compared with no patients), although this did not reach statistical significance.\n\nThe manufacturer reported a mixed treatment comparison for the subgroup of patients with cancer. This compared the relative effectiveness of rivaroxaban with dual low molecular weight heparin (LMWH) and a vitamin\xa0K antagonist, long-term LMWH compared with LMWH and a vitamin\xa0K antagonist, and rivaroxaban compared with long-term LMWH. The manufacturer provided 3 analyses. The primary analysis used data from a systematic review of long-term anticoagulation in patients with cancer reported by Akl et al. (2011) and from the whole EINSTEIN-DVT trial population. Secondary analysis 1 used data from a trial by Lee et al. (2003) evaluating the LMWH dalteparin for the prevention of recurrent venous thromboembolism in patients with cancer and the data from the whole EINSTEIN-DVT trial population. Similarly, secondary analysis 2 used data from Akl et al. (2011) and effectiveness data from the cancer subgroup of EINSTEIN-DVT.\n\nResults from the primary analysis indicated that for patients with active cancer, the venous thromboembolism recurrence hazard ratio for rivaroxaban compared with long-term LMWH was 1.44 (95% credible intervals 0.07 to 31.4). Secondary analysis 2 showed that rivaroxaban was less effective than LMWH at preventing venous thromboembolism recurrence (HR 1.32, 95% credible intervals 0.06 to 32.3) but induced fewer major bleeding events (odds ratio 0.24, 95% credible intervals 0.00 to 9.44). However, the manufacturer noted that the mixed treatment comparison had credible intervals with wide margins for the efficacy and safety of rivaroxaban compared with long-term LMWH.\n\nThe manufacturer reported adverse events from EINSTEIN-DVT and EINSTEIN-Ext that were experienced in at least 4% of any treatment group. The most common adverse events across both EINSTEIN trials were headache, pain in extremity, nasopharyngitis and nosebleed. The reported incidences of post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension were low in both arms of EINSTEIN-DVT and EINSTEIN-Ext.\n\nThe manufacturer's submission used a Markov-based model for the economic evaluation of rivaroxaban within its licensed indication for treating deep vein thrombosis and preventing recurrent thromboembolic events. Two analyses were presented: a primary analysis comparing rivaroxaban with LMWH and a vitamin\xa0K antagonist over 3, 6 and 12\xa0months, and a cost-minimisation analysis for patients with active cancer, which used dalteparin (a LMWH) as the comparator. The manufacturer also presented a further exploratory cost-effectiveness analysis for patients with active cancer at the request of the ERG.\n\nThe Markov model comprised 11 health and treatment states and patients entered the model after a diagnosis of deep vein thrombosis. The model relied on the control arm of EINSTEIN-DVT to derive the probabilities of recurrent venous thromboembolism, bleeding and discontinuation rates. The probabilities in the rivaroxaban arm were calculated by applying the appropriate hazard ratio or risk ratio to the probability in the control arm. The 3-month discontinuation rate was assumed to be 1.9%. Probabilities for long-term complications and risk of mortality were taken from both EINSTEIN-DVT and literature reviews. Drug and resource costs were derived from relevant UK sources ('British national formulary' [BNF], NHS Reference Costs 2009–10 and Personal Social Services Research Unit [PSSRU] 2010) and generally reflected UK clinical practice. The model did not include monitoring for patients treated with rivaroxaban or LMWH. It assumed 9 visits in the first 3\xa0months, followed by 5 visits thereafter (every 3\xa0months) for patients treated with a vitamin\xa0K antagonist. It also assumed that 66% of visits for INR monitoring would take place in primary care and 34% in secondary care. For primary care, the manufacturer assumed INR monitoring would be delivered equally by a GP and a nurse (50/50 split). The estimated annual cost of INR monitoring, including transport costs, was £656 in the first year and £540 thereafter.\n\nA validated preference-based measure of quality of life was not used in the EINSTEIN-DVT trial, so the economic model submitted by the manufacturer used utility values sourced from literature reviews. The manufacturer assigned a baseline utility value of 0.825 to all patients with deep vein thrombosis entering the model, which was taken from a survey of the UK general population using a visual analogue scale rating (Kind et al. 1998) and adjusted with disutility values for deep vein thrombosis, pulmonary embolism, extracranial bleed, intracranial bleed and post-thrombotic syndrome.\n\nThe base-case results included all the drug acquisition costs, resources associated with monitoring, and costs associated with adverse events (that is, bleeding events) and were presented by intended treatment durations (3, 6 and 12\xa0months). Treatment with rivaroxaban dominated treatment with LMWH and a vitamin\xa0K antagonist across all treatment durations, that is, rivaroxaban was less costly and more effective compared with LMWH and a vitamin\xa0K antagonist (0.02 incremental QALYs for all treatment durations and cost savings of £163 at 3\xa0months, £124 at 6\xa0months and £33 at 12\xa0months).\n\nThe manufacturer undertook a series of univariate and multivariate deterministic sensitivity analyses to test the robustness of the results by varying most of the parameters used in the economic evaluation. The results were generally sensitive to the cost of monitoring and the hazard ratio for venous thromboembolism. The manufacturer also provided probabilistic sensitivity analyses. These showed that there was a 94.2–98.9% probability of rivaroxaban being cost effective at £20,000 per QALY gained for all treatment durations. The treatment duration of 3\xa0months produced the most cost savings and increased incremental QALYs. The probability of rivaroxaban being the dominant treatment option was 97.1% in patients having 3\xa0months of anticoagulation, 83.9% in those having 6\xa0months and 53.0% in those having 12\xa0months.\n\nThe manufacturer presented a cost minimisation analysis evaluating rivaroxaban in patients with cancer. Patients with cancer were assumed to be treated for 6\xa0months. The cost of rivaroxaban was £4.20 per\xa0day for the first 21\xa0days (2 tablets daily), followed by £2.10 per\xa0day (1 tablet daily). The cost of dalteparin was £8.47 per\xa0day for the first\xa0month and £7.06 per\xa0day for subsequent\xa0months. The total cost saving associated with rivaroxaban compared with LMWH (dalteparin) was £903 for patients with cancer.\n\nThe manufacturer also presented an exploratory cost-effectiveness analysis of the subgroup of patients with cancer. Using treatment effects from the mixed treatment comparison, assuming no INR monitoring cost and using a 6-month treatment duration, rivaroxaban dominated dalteparin (0.0013 incremental QALYs and cost savings of £1085).\n\nThe ERG raised concerns about the applicability of the EINSTEIN trials to UK clinical practice, including that the trials did not fully reflect the UK population with deep vein thrombosis because a number of important patient groups were excluded from both trials. These included patients with high risk of bleeding, creatinine clearance less than\xa030\xa0ml/min (but not less than 15\xa0ml/min), clinically significant liver disease, high blood pressure (systolic more than\xa0180\xa0mmHg or diastolic more than\xa0110\xa0mmHg) and non-proximal deep vein thrombosis. Specifically, the ERG noted that there are no data to inform decisions about patients with increased risk of bleeding. The ERG also noted that the EINSTEIN trials did not include patients for whom vitamin\xa0K antagonists are not appropriate, other than patients with cancer. It noted the population recruited into the EINSTEIN trials excluded a number of important groups relevant to the decision problem.\n\nThe ERG and its clinical advisers considered the comparator (enoxaparin) used by the manufacturer to be appropriate, although the dosage used in the EINSTEIN trials (1\xa0mg/kg twice daily) was not in line with UK clinical practice (1.5\xa0mg/kg once daily). Using the twice-daily dosage may have been unfavourable to rivaroxaban.\n\nThe manufacturer assumed the maximum treatment duration was 12\xa0months for idiopathic deep vein thrombosis or in the presence of permanent risk factors. However, the clinical advisers to the ERG questioned this assumption and stated that it is now common for treatment to extend beyond 12\xa0months, depending on patient characteristics and risk factors. The ERG's clinical advisers estimated that around 20% of people with deep vein thrombosis would have long-term treatment because of an ongoing risk of recurrence of venous thromboembolism.\n\nThe ERG raised concerns about the robustness of the mixed treatment comparison in the cancer subgroup and the way the evidence was synthesised. The ERG noted that the included trials varied in the length of follow-up, and choice and dosage of LMWH also varied across studies. The ERG concluded that the mixed treatment comparison did not provide good estimates of the uncertainty associated with the true treatment effect, but found the point estimate to be reasonable.\n\nThe ERG presented exploratory analyses that corrected certain errors in the model and took into account a less intensive INR monitoring strategy comprising 6 INR monitoring visits in the first 3\xa0months and 3 visits every 3\xa0months thereafter. The results indicated that enoxaparin and a vitamin\xa0K antagonist were dominated by rivaroxaban for the 3-month duration group (0.02 incremental QALYs and a cost saving of £51). Compared with enoxaparin and a vitamin\xa0K antagonist, the incremental cost-effectiveness ratio (ICER) of rivaroxaban was £3247 per QALY gained for the 6-month treatment duration and £14,902 per QALY gained for the 12-month treatment duration.\n\nThe ERG revised the manufacturer's exploratory analysis in cancer patients to take into account what it considered to be a more plausible – and smaller – distribution of between-study standard deviations (as opposed to the alternative distributions used by the manufacturer). This found rivaroxaban to be less effective than LMWH at preventing venous thromboembolism recurrence. The ERG raised concerns with the limited evidence available in the cancer subgroup, and with the modelling assumptions in the exploratory analysis. The ERG concluded any reliance on the results of the mixed treatment comparison may lead to inaccurate estimates of mean ICERs because they are based on inflated expected values.\n\n# Additional manufacturer analyses\n\nAfter consultation, the manufacturer submitted additional analyses on the cost effectiveness of rivaroxaban in people in whom long-term anticoagulation is intended; that is, people who need anticoagulation for longer than 12\xa0months. The manufacturer also commented further on the characteristics of patients in the 3, 6, and 12\xa0month treatment duration groups in the EINSTEIN-DVT trial.\n\nThe manufacturer's new economic model for long-term use of rivaroxaban used event rates for venous thromboembolism recurrence and bleeding from the 12-month duration group of EINSTEIN-DVT for people treated with a LMWH and a vitamin\xa0K antagonist. The long-term risk of venous thromboembolism recurrence (after 1\xa0year) was taken from a meta-analysis review, and results from the whole trial population of EINSTEIN-DVT were used to estimate the treatment effects. The manufacturer presented 2 scenarios. One took into account the manufacturer's assumed INR frequency of 9 visits in the first 3\xa0months followed by 5 visits every 3\xa0months thereafter (first-year costs £656). The other adopted a less intensive INR monitoring programme of 6 visits in the first 3\xa0months followed by 3 visits every 3\xa0months thereafter (first-year cost of £413). The model assumed a discontinuation rate of 3.6% every 3\xa0months based on a review of long-term statin therapy because evidence on adherence to rivaroxaban for longer than 12\xa0months of treatment was not available. The model also included a sensitivity analysis in which the 3-month discontinuation rate was varied from 1.9% to 6.9%.\n\nThe model applied a disutility of 0.012 to warfarin, which was sourced from a study by Marchetti et al. (2001) involving a small group of patients (n=48) attending an anticoagulation clinic. The manufacturer noted that a disutility would not apply to rivaroxaban, citing reasons that included raised levels of treatment satisfaction in comparison with LMWH and a vitamin\xa0K antagonist, and that no clinically important adverse events were associated with rivaroxaban that had not already been taken into account in the model. The manufacturer also referred to 'Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation' (NICE technology appraisal 249), in which a disutility was applied to dabigatran to account for dyspepsia, an adverse event not associated with rivaroxaban.\n\nThe results from the long-term anticoagulation model showed that the ICER for rivaroxaban compared with LMWH and a vitamin\xa0K antagonist was £6037 per QALY gained under the manufacturer's assumed INR monitoring cost of £656 (0.16 incremental QALYs and additional cost of £953). Assuming a lower INR monitoring cost of £413, an ICER of £15,847 per QALY gained (0.16 incremental QALYs and additional cost of £2502) was reported by the manufacturer. The probabilistic sensitivity analysis based on reduced INR monitoring showed that there was a 58% probability that rivaroxaban was cost effective at £20,000 per QALY gained and a 25% probability that rivaroxaban was dominant (more effective and less costly).\n\nThe ERG was generally satisfied with the assumptions made in the manufacturer's long-term economic model but noted that it is uncertain whether the treatment effects assumed in the model would remain fixed over a lifetime. The ERG explored several scenarios based on variations to the manufacturer's long-term anticoagulation model:\n\nAssuming treatment effect from the whole trial population over a lifetime horizon.\n\nAssuming a lower INR cost of £320 for the first year followed by £248 annually thereafter, based on a reduced frequency of visits (6 visits in the first 3\xa0months and then 3 visits every 3\xa0months thereafter with a different GP/nurse consultation ratio than the one used by the manufacturer).\n\nVarying the 3-month discontinuation rate for rivaroxaban from 3.6% as assumed in the manufacturer's long-term model to 1.9% as assumed by the manufacturer in the original submission.\n\nApplying a 0.012 decrement in utility for warfarin and no decrement for rivaroxaban; 0.012 decrement in utility for warfarin and 0.006 decrement in utility for rivaroxaban; and assuming no decrement in utility for both warfarin and rivaroxaban.\n\nTaking into account the above assumptions, the results from the ERG's exploratory analyses yielded ICERs ranging from £19,381 to £38,837 per QALY gained. A deterministic calculation based on a whole-trial treatment effect, the lower cost of INR monitoring, and a utility decrement for warfarin only, indicated an ICER of £19,381 per QALY gained, assuming the same 3-month discontinuation rate of 3.6% for warfarin and rivaroxaban. The equivalent ICER when the discontinuation rate for rivaroxaban was lowered to 1.9%, while keeping the warfarin discontinuation rate at 3.6%, was £25,076 per QALY gained.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA261", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rivaroxaban, having considered evidence on the nature of venous thromboembolism and the value placed on the benefits of rivaroxaban by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee heard from the clinical specialists that currently venous thromboembolism is initially treated with a LMWH (such as enoxaparin, dalteparin or tinzaparin) for rapid anticoagulation, overlapped with warfarin until an effective INR is achieved. The Committee also heard that treatment duration is based on an assessment of the benefit of continued anticoagulation compared with the risk of bleeding. The clinical specialists stated that treatment is often started with an expected duration of therapy, but that increasingly, a clinical re-evaluation is carried out at 3 or 6\xa0months and a decision is made whether or not to continue therapy. The clinical specialists stated that in current UK practice, most people receive anticoagulation treatment for 6\xa0months, which corresponds to the largest group in the EINSTEIN-DVT trial. However, the Committee heard that a NICE clinical guideline in development on venous thromboembolic diseases is expected to recommend anticoagulation for 3\xa0months in people with transient risk factors for deep vein thrombosis, and to recommend longer-term treatment in people with permanent risk factors and unprovoked deep vein thrombosis, taking into account individual risk factors such as risk of bleeding. The Committee concluded that although 6\xa0months is currently the commonest duration of treatment in UK practice, this could change in light of the NICE clinical guideline on venous thromboembolic diseases.\n\nThe Committee noted the written evidence from patient experts, which stated that many people find taking warfarin to be stressful, because of the necessary regular monitoring with blood tests, dosing adjustments, and because people must be careful about their diet because of warfarin's interaction with certain foods. The Committee heard from clinical specialists who agreed that warfarin is associated with a wide range of important and potentially dangerous drug interactions, and that warfarin can also negatively impact people's quality of life by preventing travel and other freedoms because of the need for regular monitoring. The Committee also heard from the patient experts that rivaroxaban may improve the quality of life of people who currently take warfarin by removing the need for constant monitoring, frequent blood tests and visits to an anticoagulation clinic. It also heard that rivaroxaban is likely to benefit people who are needle phobic or who want to resume normal patterns of life without having to worry about the disruption associated with attending clinics. The use of rivaroxaban would also relieve the concern that people may have about not being on the correct warfarin dose to keep their INR well controlled. Additional advantages of rivaroxaban are the lack of need for INR monitoring, which could reduce the need for support services, and its oral formulation compared with LMWH, which is injected.\n\n# Clinical effectiveness\n\nThe Committee discussed the clinical-effectiveness data from the EINSTEIN-DVT trial, which compared rivaroxaban with enoxaparin and a vitamin\xa0K antagonist in people with venous thromboembolism. The Committee heard from the clinical specialists that enoxaparin and a vitamin\xa0K antagonist is the key comparator. The Committee discussed whether the dosage of enoxaparin used in the EINSTEIN-DVT trial is relevant to UK clinical practice. The Committee heard from the clinical specialists that the dosage used in the UK (1.5\xa0mg/kg once daily) and the dosage used in the EINSTEIN-DVT trial (1\xa0mg/kg twice daily) are similar in efficacy and the difference is not expected to have affected the results of the trial. The Committee concluded that the difference in dosage did not appear to be clinically significant and was satisfied that the comparators used in the trial represented routine and best practice in the NHS.\n\nThe Committee considered the time in therapeutic range in the warfarin arm of the trial. It noted that the mean time in therapeutic range was 58%, which is lower than might be expected in routine UK clinical practice. However, the Committee heard from the clinical experts that control of INR is more difficult when warfarin is first started and before stabilisation on longer-term treatment. The Committee therefore concluded that for this patient population, the data from the warfarin arm in the trial was applicable to routine UK practice.\n\nThe Committee considered the trial design and results of EINSTEIN-DVT. The Committee noted that EINSTEIN-DVT was a non-inferiority trial that compared rivaroxaban with enoxaparin followed by a vitamin\xa0K antagonist (either warfarin or acenocoumarol). The Committee heard that patients recruited into the trial were allocated to 3, 6 and 12\xa0month treatment durations by the treating physician, based on individual patient risk factors, before randomisation. The Committee noted that, for the whole trial population, rivaroxaban was at least as effective as the enoxaparin and a vitamin\xa0K antagonist regimen with respect to the primary efficacy endpoint of symptomatic recurrent venous thromboembolism and to the primary safety endpoint of clinically relevant bleeding. The Committee concluded that rivaroxaban was as effective as enoxaparin followed by a vitamin\xa0K antagonist for preventing recurrent venous thromboembolism, and did not have the disadvantages of an injected treatment followed by an oral treatment with the need for regular monitoring with blood tests.\n\nThe Committee considered the baseline characteristics of the EINSTEIN-DVT trial population and the results of the pre-specified subgroup analyses presented by the manufacturer. The Committee noted that rivaroxaban appeared to be more effective in people with a previous episode of deep vein thrombosis or pulmonary embolism, and that the effect of rivaroxaban varied between the subgroups allocated to the 3 different intended treatment durations. The Committee noted that the subgroup analysis by intended treatment duration suggested that rivaroxaban might be less effective than enoxaparin and warfarin in patients for whom 3\xa0months of treatment was intended. The Committee noted the heterogeneity of the trial population in terms of underlying risk factors for deep vein thrombosis, and noted that no individually identifiable clinical group was included in only 1 treatment duration subgroup. The Committee also heard from the manufacturer that there were no specific clinical criteria or algorithms used to allocate people into the different intended treatment duration groups, and that there was no apparent biological or clinical plausibility for the differential effectiveness of rivaroxaban across the intended treatment duration subgroups. A similar view was taken by the clinical specialists, who noted that they were not aware of any clinical reasons why rivaroxaban would be less effective than LMWH and a vitamin\xa0K antagonist in people who received 3\xa0months of treatment, while being more effective in the 6 and 12\xa0months groups. The Committee also heard from the ERG that the lower efficacy in the patient group treated for 3\xa0months only was based on a small number of events in both arms and the majority of events occurred in the 6 and 12\xa0month groups. The Committee accepted that there is insufficient evidence to demonstrate that rivaroxaban had a substantially different effectiveness across treatment durations, and was not aware of any biological reason to expect a differential effect in the first 3\xa0months. The Committee therefore concluded that evidence of treatment effect should be based on the whole trial population of EINSTEIN-DVT.\n\nThe Committee questioned whether the pre-specified intended treatment duration used in the EINSTEIN-DVT trial reflects clinical practice. It noted that the clinical advisers to the ERG estimated that approximately 20% of people with deep vein thrombosis may need treatment for longer than 12\xa0months. The Committee heard from the clinical specialists that the average duration of treatment is currently 6\xa0months, at which time further treatment, including life-long treatment, would be considered if the person's risk of a recurrence remained high. However, the Committee noted that the summary of product characteristics for rivaroxaban states that experience with rivaroxaban in this indication for more than 12\xa0months is limited. The manufacturer informed the Committee that there is a risk management plan agreed with the European Medicines Agency that involves the non-interventional XALIA study. The study will recruit people with a diagnosis of acute deep vein thrombosis and aims to estimate the recurrence of venous thromboembolism, incidence of major bleeding and mortality over the longer term. The Committee concluded that it may not be realistic to assume that people stop treatment once the pre-specified treatment period has ended and some people with ongoing risk factors for recurrence would need ongoing treatment, possibly for many years or lifelong.\n\nThe Committee discussed the results from the EINSTEIN-Ext trial. It noted that the trial inclusion criteria included people defined to be in 'clinical equipoise'. The manufacturer defined this as people for whom the decision to treat with anticoagulants was finely balanced. However, the Committee heard from the clinical specialists that in UK practice people who are to be treated for up to 12\xa0months, as in the EINSTEIN-Ext trial, would generally not fall under this definition because they would have a strong clinical reason for further anticoagulation. It therefore agreed that the population in the EINSTEIN-DVT trial was more relevant for appraising rivaroxaban in venous thromboembolism for up to 12\xa0months of treatment.\n\nThe Committee considered the adverse events reported in the EINSTEIN-DVT and EINSTEIN-Ext trials. The Committee noted that patients treated with rivaroxaban experienced a comparable number of clinically relevant bleeding episodes to those treated with enoxaparin and a vitamin\xa0K antagonist in EINSTEIN-DVT. The Committee noted that patients treated with rivaroxaban in the extension study experienced a higher rate of clinically relevant non-major bleeding but that the comparator was placebo and not active control. The Committee concluded that treatment with rivaroxaban had an acceptable adverse event profile compared with the combination of LMWH and warfarin.\n\n# Cost effectiveness\n\nThe Committee considered the cost effectiveness of rivaroxaban for up to 12\xa0months of treatment. The Committee noted that the economic model used clinical-effectiveness data from the EINSTEIN-DVT trial and that the results were presented by treatment duration. It noted that rivaroxaban dominated treatment with enoxaparin and a vitamin\xa0K antagonist in the manufacturer's deterministic analysis, that is, rivaroxaban was less costly and more effective across all 3 treatment durations (3, 6 and 12\xa0months). The manufacturer's model assumed a first-year INR monitoring cost of £656, and £540 in subsequent years. The Committee was mindful of the QALY increment for people treated with rivaroxaban but considered that the estimate of INR costs was too high and was not likely to reflect the actual cost in UK clinical practice. The Committee could therefore not accept the results of the manufacturer's base-case analysis as the estimate of cost effectiveness.\n\nThe Committee discussed the estimate of the cost of INR monitoring. The Committee acknowledged the multiple models of provision for INR monitoring across the UK and the uncertainty about the costs. It noted that estimates of INR monitoring costs varied greatly, and some community-based monitoring programmes appeared to be much cheaper than the manufacturer's estimate. The Committee considered the ERG's critique of the base-case economic model for up to 12\xa0months of treatment. The ERG assumed a less intensive INR monitoring programme of 6\xa0visits in the first 3\xa0months followed by 3 visits every 3\xa0months thereafter, and assumed different provisions for INR monitoring than did the manufacturer. The ERG's estimate of the cost of INR monitoring was £320 in the first year and £248 thereafter. It noted that the ERG estimate appeared to be in the region of the estimated INR costs used in NICE technology appraisal 249. The Committee heard from the clinical specialists that the population eligible for treatment with rivaroxaban is not likely to need significantly more frequent INR monitoring than people being started on anticoagulation therapy for other indications. Comments from consultees also indicated that the manufacturer's estimate of INR monitoring costs was higher than was plausible for UK practice. The Committee therefore concluded that the ERG's alternative assumptions and estimate of £320 for INR monitoring in the first year of treatment were reasonable and relevant for this appraisal.\n\nThe Committee considered the results of the ERG's economic evaluation of rivaroxaban treatment for up to 12\xa0months. The ERG's estimate used clinical-effectiveness data from the whole trial population of EINSTEIN-DVT and the ERG's lower estimate for INR monitoring. The results indicated that rivaroxaban dominated therapy with LMWH and a vitamin\xa0K antagonist in the 3-month treatment duration group. The ICER for rivaroxaban was £3200 per QALY gained for the 6-month treatment duration and £14,900 per QALY gained for the 12-month treatment duration. The Committee agreed that these cost-effectiveness results for up to 12\xa0months of treatment using the ERG estimate for the cost of INR monitoring were more plausible than those provided by the manufacturer. The Committee concluded that treatment with rivaroxaban represented a clinical and cost-effective option in people in whom treatment for up to 12\xa0months is indicated.\n\nThe Committee then discussed the manufacturer's submission for rivaroxaban in those who need long-term anticoagulation; that is, beyond 12\xa0months of treatment. It noted that the manufacturer's economic model included a decrement in utility of 0.012 for people on warfarin only, which was taken from a small study by Marchetti et al. The Committee heard from the patient experts that warfarin has an impact on quality of life (see section 4.3). The Committee considered that although treatment with rivaroxaban could be associated with a small disutility, it was satisfied that treatment with warfarin was associated with a higher disutility than treatment with rivaroxaban, and the relative difference in disutility could be even higher than 0.012 for people who may have to take it for many years or lifelong. The Committee concluded that although it was not convinced that the utility decrement used by the manufacturer was supported by strong evidence, it was of the opinion that the relative difference in disutility was at least as great as the value used by the manufacturer in its long-term model.\n\nThe Committee discussed the discontinuation rates in the economic evaluation of rivaroxaban in those who need ongoing anticoagulation. It noted that the manufacturer had used a discontinuation rate of 3.6% for every 3-month period for both treatments, which was taken from a study on long-term statin therapy. The Committee acknowledged the lack of evidence for the long-term adherence of people treated with rivaroxaban in venous thromboembolism, but noted there was no strong evidence to suggest that the people treated with rivaroxaban should have different rates of discontinuation compared with warfarin. The Committee concluded that it was satisfied that equal or near-equal discontinuation rates should be applied to both treatment arms.\n\nThe Committee then considered the results of the cost-effectiveness analysis of rivaroxaban for long-term anticoagulation. It noted the results from the manufacturer's long-term model which incorporated INR monitoring costs of £656 and a disutility of 0.012 applied to warfarin only, resulting in an ICER of £6000 per QALY gained for rivaroxaban compared with enoxaparin and a vitamin\xa0K antagonist. The Committee noted that the equivalent ICER, when a less intensive INR monitoring cost of £413 was assumed, was £15,800 per QALY. The Committee also noted the ERG's exploratory analysis, which provided a range of estimates of the ICERs for ongoing anticoagulation under the scenarios outlined in 3.27. This gave ICERs ranging from £19,400 to £38,800 per QALY gained. The Committee noted that the INR monitoring costs assumed by the manufacturer were higher than are considered to be reasonable and therefore considered the ERG's analysis to be more appropriate. The Committee was satisfied that the differential disutility for warfarin compared with rivaroxaban, although uncertain, was at least 0.012 when long-term or lifelong treatment is needed (see section 4.16). Assuming an equal discontinuation rate, a differential disutility of more than 0.012 would bring the ICER down to below £19,400 per QALY gained. The Committee also explored the scenario incorporating a discontinuation rate for rivaroxaban of just over half the warfarin discontinuation rate which, if a differential disutility of 0.012 was applied, gave an ICER of £25,100 per QALY gained. However, the Committee was not convinced that the discontinuation rate would be different, and felt that the ICER estimate of £25,100 was too high (see section 4.17). The Committee therefore concluded that £19,400 per QALY gained was a plausible estimate, and that rivaroxaban was a cost-effective treatment option for people who need anticoagulation treatment for longer than 12\xa0months.\n\nThe Committee discussed the effectiveness of rivaroxaban in people with cancer. It considered the manufacturer's mixed-treatment analyses, and found the manufacturer's secondary analysis 2 (see section 3.7) to be the most relevant because it used data from the cancer subgroup. It noted that this analysis indicated that rivaroxaban was less effective than dalteparin at preventing venous thromboembolism recurrence but induced fewer major bleeding events. It also noted that the credible intervals around these estimates were wide. The Committee acknowledged that the ERG did not find the cancer subgroup analyses to be robust and had concerns with the limited evidence and with how the mixed-treatment comparison was conducted and implemented. The Committee heard from the clinical specialists that the current standard care in treating venous thromboembolism in people with cancer is LMWH alone, which the evidence suggests provides benefits greater than warfarin. This seems to be a cancer-specific effect. The clinical specialists further stated that there is no direct trial evidence demonstrating that rivaroxaban is superior to a LMWH in people with cancer, and so would not expect the availability of rivaroxaban to change UK clinical practice in this population. The Committee heard from the patient experts that people with cancer would welcome a non-invasive treatment option such as rivaroxaban, particularly people receiving palliative care, as long as the treatment is safe and does not interact with the cancer treatment. Given the lack of clinical evidence for this group, the Committee was unable to make specific recommendations on the use of rivaroxaban in people with cancer but recognised the disadvantages of the currently available treatment, which involves regular injections, and which some people might choose to decline. The Committee concluded that rivaroxaban should not be excluded as a treatment option for preventing venous thromboembolism in people with cancer.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA261\n\nAppraisal title: Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism\n\nSection\n\nKey conclusion\n\nRivaroxaban is recommended as an option for treating deep vein thrombosis and preventing recurrent deep vein thrombosis and pulmonary embolism after a diagnosis of acute deep vein thrombosis in adults.\n\nThe Committee considered the cost-effectiveness result for up to 12\xa0months of treatment using the ERG's estimate for INR monitoring. The results indicated that rivaroxaban dominated therapy with LMWH and a vitamin\xa0K antagonist in the 3-month duration group. The ICER was £3200 per QALY gained for the 6-month treatment duration and £14,900 per QALY gained for the 12-month treatment duration. The Committee concluded that treatment with rivaroxaban represented a clinical and cost-effective option in people in whom treatment for up to 12\xa0months is indicated.\n\nThe Committee considered the results of the cost-effectiveness analysis of rivaroxaban for long-term anticoagulation. The Committee concluded that £19,400 per QALY gained was a plausible estimate, and that rivaroxaban was a cost-effective treatment for people who need anticoagulation treatment for longer than 12\xa0months.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nCurrent\n practice\n\nClinical need of patients, including the availability of alternative treatments\n\nCurrent management of venous thromboembolism is initiated with an LMWH (such as enoxaparin, which is the most commonly used LMWH in the UK) for rapid anticoagulation, and overlapped with warfarin until an effective dose is achieved. Treatment duration is based on the benefit of anticoagulation compared with the risk of bleeding. The main concerns with long-term anticoagulation with warfarin are the impact on people's lifestyle, and resource use associated with regular INR monitoring. Current UK practice indicates that the average treatment duration is 6\xa0months.\n\n, 4.3\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe clinical specialists noted that warfarin is associated with a number of difficulties, including dietary restrictions and possible drug interactions. Patient experts noted that people find taking warfarin stressful because of the need for constant monitoring with blood tests, dosing adjustments and because of warfarin's interactions with certain foods and drugs. The Committee acknowledged the limitations of warfarin therapy, and recognised the advantages of rivaroxaban that include its oral formulation and lack of need for INR monitoring, which could reduce the need for support services.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nRivaroxaban is indicated for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism after an acute deep vein thrombosis in adults.\n\n\n\nAdverse reactions\n\nThe Committee noted that rivaroxaban had comparable rates of clinically relevant bleeding when compared with enoxaparin and a vitamin\xa0K antagonist, but was associated with higher bleeding events when compared with placebo in the extension study.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe EINSTEIN-DVT trial was the key trial supporting the clinical effectiveness of rivaroxaban in the manufacturer's submission.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee considered the trial to reflect UK clinical practice.\n\n, 4.5\n\nUncertainties generated by the evidence\n\nThe Committee considered the baseline characteristics of the EINSTEIN-DVT trial population, and wished to explore the biological plausibility of any differential effectiveness in the subgroups. The Committee noted that no individually identifiable clinical group was included in only 1 treatment duration subgroup, and heard from the manufacturer and clinical experts that no specific clinical criteria were used or biological rationale existed that explain a differential effectiveness across the intended treatment duration groups. The Committee concluded that evidence of treatment effect should be based on the whole trial population of EINSTEIN-DVT.\n\nThe Committee heard that there is no direct trial evidence demonstrating that rivaroxaban is superior to a LMWH in patients with cancer. Given the lack of clinical evidence for this group of patients, the Committee was unable to make specific recommendations on the use of rivaroxaban in people with cancer but recognised the disadvantages of the currently available treatment, which involves regular injections, and which some patients might choose to decline.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee considered the subgroup results presented by the manufacturer, which showed that rivaroxaban appeared to be less effective in certain groups of patients, including those for whom 3\xa0months of treatment was clinically indicated. However, the Committee concluded that there was no biological plausibility that would explain the differential effectiveness and accepted that evidence of treatment effect should be based on the whole trial population of EINSTEIN-DVT.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nCompared with enoxaparin and a vitamin\xa0K antagonist, rivaroxaban was associated with a hazard ratio of 0.68 for prevention of venous thromboembolism. The Committee concluded that rivaroxaban was as effective as enoxaparin followed by a vitamin\xa0K antagonist for preventing venous thromboembolism recurrences.\n\n, 4.6\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer presented a Markov model using effectiveness data from the trial population of EINSTEIN-DVT (that is, for up to 12\xa0months of treatment) and provided analyses on the cost effectiveness of rivaroxaban in people in whom long-term anticoagulation is intended; that is, beyond 12\xa0months of treatment.\n\nThe manufacturer also provided a cost minimisation analysis and an exploratory cost-effectiveness analysis, evaluating the benefits of rivaroxaban in patients with cancer.\n\n\n\n\n\n\n\n\n\n\n\n\n\n, 3.16\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee recognised the various provisions for INR monitoring across the UK but found the manufacturer's estimate for INR monitoring of £656 in the first year to be high. The Committee heard from clinical specialists that the treatment population for rivaroxaban are not likely to need significantly more frequent INR monitoring than people being started on anticoagulation therapy for other indications, and found the ERG estimate of £320 for INR monitoring to be more appropriate and in line with the recent NICE guidance on dabigatran in atrial fibrillation (NICE technology appraisal guidance 249). The Committee concluded that the appropriate estimate for INR monitoring is £320 in the first year.\n\nThe Committee noted that the discontinuation rates used in the economic evaluation of rivaroxaban in those who need ongoing anticoagulation were based on a review of long-term statin therapy, and acknowledged the lack of evidence for long-term adherence of patients treated with rivaroxaban in venous thromboembolism. However, the Committee noted there was no strong evidence to suggest that the people treated with rivaroxaban should have different rates of discontinuation compared with warfarin, and therefore accepted that equal or near-equal discontinuation rates should be applied to both rivaroxaban and warfarin.\n\n\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe manufacturer's economic model for up to 12\xa0months of treatment used utility values sourced from the literature.\n\nThe manufacturer also included a decrement in utility of 0.012 for people taking warfarin in the economic model. The Committee heard from clinical specialists and patient experts who confirmed the impact warfarin has on a person's quality of life in terms of fear that INR may not be optimally controlled, the need for constant monitoring and how warfarin has several food and drug interactions. The Committee was satisfied that warfarin was associated with a higher disutility than rivaroxaban, and accepted that the difference in disutility was at least as great as the point estimate (0.012) used by the manufacturer.\n\n\n\n\n\n\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nINR monitoring costs. The Committee noted that the INR monitoring costs assumed by the manufacturer were higher than were considered to be reasonable and therefore accepted the ERG's analysis which assumed lower INR costs to be more appropriate.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee noted that rivaroxaban dominated therapy with a LMWH and a vitamin\xa0K antagonist in the 3-month group; the ICER for rivaroxaban was £3200 per QALY gained for the 6-month treatment duration and £14,900 per QALY gained for the 12-month treatment duration.\n\nThe ICER for rivaroxaban was £19,400 per QALY gained for people who need anticoagulation beyond 12\xa0months of treatment.\n\n\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n\n\nEnd-of-life considerations\n\nEnd-of-life considerations were not discussed.\n\n\n\nEqualities considerations and social value judgements\n\nNot applicable.\n\n", 'Recommendations for further research ': 'Further research on the clinical effectiveness of rivaroxaban compared with LMWH in patients with active cancer should be conducted.', 'Related NICE guidance': 'Published\n\nVenous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. NICE clinical guideline 144 (2012)\n\nDabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation. NICE technology appraisal guidance 249 (2012).\n\nApixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults. NICE technology appraisal guidance 245 (2012).\n\nVenous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital. NICE clinical guideline 92 (2010).\n\nRivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults. NICE technology appraisal guidance 170 (2009).\n\nDabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. NICE technology appraisal guidance 157 (2008).\n\nUnder development\n\nNICE is developing the following guidance (details available from www.nice.org.uk):\n\nPublication expected June 2012.\n\nDabigatran etexilate for the treatment of acute venous thromboembolic events. NICE technology appraisal. Publication date to be confirmed.', 'Review of guidance': 'The guidance on this technology will be considered for review in May 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveJune 2012', 'Changes after publication': 'February 2014:\n minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta261
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Evidence-based recommendations on rivaroxaban (Xarelto) for treating deep vein thrombosis and preventing a pulmonary embolism or another deep vein thrombosis in adults.
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ff4f94c2f66b91ed827153ad1aabbc534a15b106
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nice
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Endovascular stent insertion for intracranial atherosclerotic disease
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Endovascular stent insertion for intracranial atherosclerotic disease
# Guidance
This document replaces previous guidance on endovascular stent insertion for intracranial atherosclerotic disease (interventional procedure guidance 233).
Current evidence on the efficacy of endovascular stent insertion for intracranial atherosclerotic disease shows no substantial differences in clinical outcomes compared with medical treatment after 1–2 years. Evidence on its safety shows that there is a significant risk of periprocedural stroke and death. Therefore, this procedure should only be used in the context of research. Research should clearly define patient selection and be designed to provide outcome data based on follow-up of at least 2 years.# The procedure
# Indications and current treatments
Intracranial atherosclerotic disease is the narrowing or obstruction of arteries within the skull that supply blood to the brain. It is caused by atheromatous plaques, which can reduce blood flow and may be associated with thrombosis or embolism, leading to transient ischaemic attacks (TIA), stroke or death. Intracranial atherosclerotic disease is usually diagnosed only after a patient has presented with a TIA or stroke.
Symptomatic intracranial atherosclerotic disease is usually treated with antiplatelet medication together with a statin and attention to risk factors for atherosclerosis such as smoking, hypertension and diabetes.
Direct intervention to treat intracranial atherosclerotic disease is not commonly used. It involves balloon angioplasty to dilate diseased arteries, which may then be followed by stent insertion, with the aim of improving patency compared with balloon angioplasty alone.
# Outline of the procedure
The procedure is carried out with the patient under general or local anaesthesia. Under fluoroscopic control, a catheter is introduced percutaneously through an artery in the arm or leg and guided into the affected intracranial artery. Balloon angioplasty of the target lesion is normally done to dilate it before inserting a stent. It is possible to insert more than 1 stent or to treat more than 1 lesion in a treatment session.
Two main types of stent have been used – balloon expandable and self-expanding. Some studies have also used drug-eluting stents. The technology has evolved over the past decade and continues to do so.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
The efficacy outcomes described below include stroke or death occurring more than 30 days after the procedure (unless specified otherwise). Stroke or death occurring on or before 30 days is considered to be a safety outcome.
A randomised controlled trial of 451 patients treated by angioplasty and stent insertion or medical management alone reported ischaemic stroke in the area of the brain supplied by the artery with the index lesion more than 30 days after enrolment in 6% of patients in both groups (13/224 and 13/227, respectively, p value not stated) at a mean follow-up of 12 months. A case series of 213 patients reported lesion-related ischaemic stroke more than 30 days after the procedure in 3% (7/213) of patients, at a mean follow-up of 27 months. A case series of 158 patients reported that 20% (22/110) of patients had a stroke or TIA between 30 days and 12 months after the procedure.
The randomised controlled trial of 451 patients treated by angioplasty and stent insertion or medical management alone reported a death rate of 3% in both groups (7/224 and 7/227, respectively, p=0.95) at a mean follow-up of 12 months.
A systematic review comparing 36 studies of angioplasty and endovascular stent insertion with 33 studies of angioplasty alone reported stroke and/or death in 12% (123/1070) and 17% (125/731) of patients respectively at 1-year follow-up (p=0.0002).
The case series of 213 patients reported an overall restenosis rate of 19% (19/99) identified on follow-up angiography at a mean follow-up of 9 months. A case series of 189 patients reported recurrent stenosis in 25% (43/174) of lesions identified on angiography at a mean follow-up of 4 months. A case series of 113 patients reported an overall restenosis rate of 18% (16/89; identified by transcranial doppler ultrasound or angiography) at a mean follow-up of 29 months.
The Specialist Advisers listed key efficacy outcomes as reduction in TIA or stroke frequency.
# Safety
The randomised controlled trial of 451 patients treated by angioplasty and stent insertion or by medical management alone reported stroke or death within 30 days of enrolment in 15% (33/224) and 6% (13/227) of patients, respectively (p=0.002). There were 5 stroke-related deaths in the stent group and 1 non-stroke-related death in the medical management group. The systematic review comparing 36 studies of angioplasty and endovascular stent insertion with 33 studies of angioplasty alone reported stroke and/or death in 8% (104/1291) and 9% (91/1027) of patients respectively at 1-month follow-up (p=0.49).
Stent occlusion occurred in 4% (2/53) of patients treated by endovascular stent insertion in a non-randomised comparative study. One occlusion occurred 2 days after stent insertion and the patient had extracranial-intracranial bypass surgery because of recurrent TIAs. The second occlusion occurred 9 days after stent insertion in a patient who was not receiving antiplatelet medication because of a gastrointestinal haemorrhage; the patient had a stroke and died.
Vessel rupture during stent navigation was reported in 2% (2/113) of patients in the case series of 113 patients; 1 patient died of massive subarachnoid haemorrhage, and the other was treated by emergency craniotomy and surgical clipping of the middle cerebral artery. One patient died after vessel rupture during the procedure in the case series of 189 patients.
Fatal intracerebral haemorrhage was reported in 1 patient in the case series of 189 patients (timing not reported). There were haemorrhages in 3 other patients; 1 intracerebral haemorrhage 6 days after the procedure (resolved within 30 days) and 2 subarachnoid haemorrhages (1 resolved without treatment and the other was successfully treated by coil occlusion). Bilateral intracerebral haemorrhage was reported in 1 patient in the case series of 113 patients, 2 weeks after the procedure (no other details provided). Symptomatic subarachnoid haemorrhage (not otherwise described) was reported in 1% (2/213) of patients and symptomatic brain haemorrhage (not otherwise described) was reported in 1 patient, within 30 days of the procedure, in the case series of 213 patients.
Specialist Advisers listed anecdotal adverse events as basilar artery rupture resulting in death, disabling thalamic infarction, and reperfusion haemorrhage. They stated that theoretical adverse events included vessel dissection, embolisation, myocardial infarction, groin haematoma and contrast reactions.
# Other comments
The Committee noted that a number of different devices have been used for endovascular stent insertion for intracranial atherosclerotic disease and that technical evolution of devices is continuing.
The Committee also noted that medical management is variable and continues to evolve. This complicates interpretation of studies that compare the procedure with medical treatment.# Further information
For related NICE guidance see www.nice.org.uk.
Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedures guidance process.
It updates and replaces NICE interventional procedure guidance 233.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
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{'Guidance': 'This document replaces previous guidance on endovascular stent insertion for intracranial atherosclerotic disease (interventional procedure guidance 233).\n\nCurrent evidence on the efficacy of endovascular stent insertion for intracranial atherosclerotic disease shows no substantial differences in clinical outcomes compared with medical treatment after 1–2\xa0years. Evidence on its safety shows that there is a significant risk of periprocedural stroke and death. Therefore, this procedure should only be used in the context of research. Research should clearly define patient selection and be designed to provide outcome data based on follow-up of at least 2\xa0years.', 'The procedure': '# Indications and current treatments\n\nIntracranial atherosclerotic disease is the narrowing or obstruction of arteries within the skull that supply blood to the brain. It is caused by atheromatous plaques, which can reduce blood flow and may be associated with thrombosis or embolism, leading to transient ischaemic attacks (TIA), stroke or death. Intracranial atherosclerotic disease is usually diagnosed only after a patient has presented with a TIA or stroke.\n\nSymptomatic intracranial atherosclerotic disease is usually treated with antiplatelet medication together with a statin and attention to risk factors for atherosclerosis such as smoking, hypertension and diabetes.\n\nDirect intervention to treat intracranial atherosclerotic disease is not commonly used. It involves balloon angioplasty to dilate diseased arteries, which may then be followed by stent insertion, with the aim of improving patency compared with balloon angioplasty alone.\n\n# Outline of the procedure\n\nThe procedure is carried out with the patient under general or local anaesthesia. Under fluoroscopic control, a catheter is introduced percutaneously through an artery in the arm or leg and guided into the affected intracranial artery. Balloon angioplasty of the target lesion is normally done to dilate it before inserting a stent. It is possible to insert more than 1 stent or to treat more than 1 lesion in a treatment session.\n\nTwo main types of stent have been used – balloon expandable and self-expanding. Some studies have also used drug-eluting stents. The technology has evolved over the past decade and continues to do so.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nThe efficacy outcomes described below include stroke or death occurring more than 30\xa0days after the procedure (unless specified otherwise). Stroke or death occurring on or before 30\xa0days is considered to be a safety outcome.\n\nA randomised controlled trial of 451\xa0patients treated by angioplasty and stent insertion or medical management alone reported ischaemic stroke in the area of the brain supplied by the artery with the index lesion more than 30\xa0days after enrolment in 6% of patients in both groups (13/224 and 13/227, respectively, p value not stated) at a mean follow-up of 12\xa0months. A case series of 213\xa0patients reported lesion-related ischaemic stroke more than 30\xa0days after the procedure in 3% (7/213) of patients, at a mean follow-up of 27\xa0months. A case series of 158\xa0patients reported that 20% (22/110) of patients had a stroke or TIA between 30\xa0days and 12\xa0months after the procedure.\n\nThe randomised controlled trial of 451\xa0patients treated by angioplasty and stent insertion or medical management alone reported a death rate of 3% in both groups (7/224 and 7/227, respectively, p=0.95) at a mean follow-up of 12\xa0months.\n\nA systematic review comparing 36\xa0studies of angioplasty and endovascular stent insertion with 33\xa0studies of angioplasty alone reported stroke and/or death in 12% (123/1070) and 17% (125/731) of patients respectively at 1-year follow-up (p=0.0002).\n\nThe case series of 213\xa0patients reported an overall restenosis rate of 19% (19/99) identified on follow-up angiography at a mean follow-up of 9\xa0months. A case series of 189\xa0patients reported recurrent stenosis in 25% (43/174) of lesions identified on angiography at a mean follow-up of 4\xa0months. A case series of 113\xa0patients reported an overall restenosis rate of 18% (16/89; identified by transcranial doppler ultrasound or angiography) at a mean follow-up of 29\xa0months.\n\nThe Specialist Advisers listed key efficacy outcomes as reduction in TIA or stroke frequency.\n\n# Safety\n\nThe randomised controlled trial of 451\xa0patients treated by angioplasty and stent insertion or by medical management alone reported stroke or death within 30\xa0days of enrolment in 15% (33/224) and 6% (13/227) of patients, respectively (p=0.002). There were 5 stroke-related deaths in the stent group and 1 non-stroke-related death in the medical management group. The systematic review comparing 36\xa0studies of angioplasty and endovascular stent insertion with 33\xa0studies of angioplasty alone reported stroke and/or death in 8% (104/1291) and 9% (91/1027) of patients respectively at 1-month follow-up (p=0.49).\n\nStent occlusion occurred in 4% (2/53) of patients treated by endovascular stent insertion in a non-randomised comparative study. One occlusion occurred 2\xa0days after stent insertion and the patient had extracranial-intracranial bypass surgery because of recurrent TIAs. The second occlusion occurred 9\xa0days after stent insertion in a patient who was not receiving antiplatelet medication because of a gastrointestinal haemorrhage; the patient had a stroke and died.\n\nVessel rupture during stent navigation was reported in 2% (2/113) of patients in the case series of 113\xa0patients; 1\xa0patient died of massive subarachnoid haemorrhage, and the other was treated by emergency craniotomy and surgical clipping of the middle cerebral artery. One patient died after vessel rupture during the procedure in the case series of 189\xa0patients.\n\nFatal intracerebral haemorrhage was reported in 1\xa0patient in the case series of 189\xa0patients (timing not reported). There were haemorrhages in 3 other patients; 1 intracerebral haemorrhage 6\xa0days after the procedure (resolved within 30 days) and 2\xa0subarachnoid haemorrhages (1 resolved without treatment and the other was successfully treated by coil occlusion). Bilateral intracerebral haemorrhage was reported in 1\xa0patient in the case series of 113\xa0patients, 2\xa0weeks after the procedure (no other details provided). Symptomatic subarachnoid haemorrhage (not otherwise described) was reported in 1% (2/213) of patients and symptomatic brain haemorrhage (not otherwise described) was reported in 1\xa0patient, within 30\xa0days of the procedure, in the case series of 213\xa0patients.\n\nSpecialist Advisers listed anecdotal adverse events as basilar artery rupture resulting in death, disabling thalamic infarction, and reperfusion haemorrhage. They stated that theoretical adverse events included vessel dissection, embolisation, myocardial infarction, groin haematoma and contrast reactions.\n\n# Other comments\n\nThe Committee noted that a number of different devices have been used for endovascular stent insertion for intracranial atherosclerotic disease and that technical evolution of devices is continuing.\n\nThe Committee also noted that medical management is variable and continues to evolve. This complicates interpretation of studies that compare the procedure with medical treatment.', 'Further information': "For related NICE guidance see www.nice.org.uk.\n\nInformation for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 233.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n\n033 7780'}
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https://www.nice.org.uk/guidance/ipg429
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ce38250452b5f9358aa2df4c956d160060669fdf
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nice
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Partial replacement of the meniscus of the knee using a biodegradable scaffold
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Partial replacement of the meniscus of the knee using a biodegradable scaffold
# Guidance
Current evidence on partial replacement of the meniscus of the knee using a biodegradable scaffold raises no major safety concerns. Evidence for any advantage of the procedure over standard surgery, for symptom relief in the short term, or for any reduction in further operations in the long term, is limited in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake partial replacement of the meniscus of the knee using a biodegradable scaffold should take the following actions.
Inform the clinical governance leads in their Trusts.
Ensure that patients understand that there are uncertainties about any possible long-term advantage over other surgical options and that considerable rehabilitation is required after this procedure. Clinicians should provide patients with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.
Audit and review clinical outcomes of all patients having partial replacement of the meniscus of the knee using a biodegradable scaffold (see section 3.1).
The procedure should only be carried out by surgeons who are highly experienced in arthroscopic meniscal surgery.
NICE encourages further research and data collection on partial replacement of the meniscus of the knee using a biodegradable scaffold. This should include clear descriptions of patient selection and adjunctive treatments. Outcome measures should include symptom relief and functional ability in the short term and the need for further treatment in the longer term.# The procedure
# Indications and current treatments
The menisci are semi-lunar wedge-shaped fibrocartilaginous structures which act as shock absorbers, spreading the load on the articular surfaces of the knee.
The menisci can be damaged (often a tear) as a result of acute injury or degeneration, which may cause pain and/or locking of the knee. It is believed that meniscal damage is associated with a higher risk of knee osteoarthritis in the longer term. Minor meniscal damage can be treated conservatively (including rest and physical therapies). For more severe cases, treatment usually involves removal of the damaged part of the meniscus (partial meniscectomy).
Meniscal repair is possible only in a minority of patients. This depends on the proximity of the damage to the peripheral vascular region of the meniscus (where good blood supply allows meniscal healing), the pattern of the damage and whether there is damage to other knee joint structures.
# Outline of the procedure
Implantation of a scaffold for partial replacement of the meniscus of the knee aims to support the body's own physiological pathways for healing by providing a 3-dimensional matrix for cell adhesion and vascular ingrowth, when attached to the vascular portion of the meniscus. In the short term the procedure aims to restore the load-bearing and shock-absorbing functions of the damaged meniscus, contributing to pain relief and restoring functional mobility. In the long term it aims to lower the risk of osteoarthritis and the need for further operations. A strict rehabilitation regime is usually employed after the procedure, which may include several weeks of restricted weight bearing and temporary bracing to limit knee movement.
The procedure may be done with the patient under general or regional anaesthesia. Using an arthroscope, damaged sections of the meniscus are excised, leaving a residual meniscal rim in the vascular zone. The size of the defect is measured and the implant is trimmed to match it. The implant is then introduced into the joint via one of the portals and sutured to the remaining meniscal rim. This may require extra skin incisions to provide sufficient access.
The types of scaffolds available for this procedure include those made of synthetic polyurethane and of collagen derived from animal sources.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A randomised controlled trial (RCT) of 311 patients divided patients into two groups, depending on whether they had prior surgery on the affected meniscus. Each group was randomised to treatment by partial replacement of the meniscus with a biodegradable implant or to partial meniscectomy alone. Pain scores were reported as a mean change from baseline (assessed at rest, during activities of daily living and at the highest level of activity, on a visual analogue scale; 0–100, higher score indicates greater pain) at mean follow-up of 59 months. The first group of 157 patients had no prior surgery on the affected meniscus. Patients treated by the procedure (n=75) had a mean pain score of 16 compared with 21 for those treated by partial meniscectomy (n=82; reported as not significant, p-values not reported). The second group of 151 patients, who had had prior surgery on the affected meniscus (85 treated by the procedure and 69 treated by partial meniscectomy) had mean pain scores of 18 for both groups (reported as not significant, p-values not reported).
An RCT of 60 patients, which included 30 patients treated by the procedure and high tibial osteotomy (there was a high dropout rate in the comparator arm of tibial osteotomy alone) reported that the 23 patients followed for 8–18 months had Lysholm scores (0–100, higher score corresponds to better function) which improved from a baseline of 65 to 94 (p-value not reported).
In a case series of 52 patients treated by partial replacement of the meniscus with a polyurethane scaffold, treatment failure (defined as an additional surgical procedure on the involved meniscus) was reported in 15% (8/52) of patients (treatment failure related to infection was excluded) and the overall treatment failure was 17% (9/52). Three cases were definitely related to the implant, 3 were not related to the implant, 1 was possibly related to the implant, 1 was unknown and 1 treatment failure (infection) was not related to the implant. Timing to the need for further intervention ranged from 1 week to 24 months.
A non-randomised comparative study of 33 patients treated by partial replacement of the medial meniscus (n=17) or by partial medial meniscectomy (n=16) reported mean quality of life scores measured bySF-36 physical health and mental health indices (scale of 0–100, higher score indicates better functioning). For the SF-36 physical health index, scores were 54 and 44 for the implant and the partial meniscectomy groups respectively, at a mean follow-up of 11 years (p=0.026). For the mental health index, scores were 55 and 44 for the implant and the partial meniscectomy groups respectively at mean follow-up of 11 years (p=0.004).
The RCT of 311 patients reported reoperation rates, defined as an additional surgical procedure (outside the protocol) on the knee as a result of disabling or persistent pain and/or mechanical symptoms that could possibly involve the meniscus. The reoperation rates were 10% and 23% for the implant and the partial meniscectomy groups respectively, at 5 years (denominators not reported; significance not reported). Reasons for reoperation included pain, swelling and instability.
The Specialist Advisers listed the following key efficacy outcomes: pain reduction, functional improvement, reduction in risk of further degeneration of the articular cartilage lining of the knee, early failure (further surgery) and early failure (symptoms or patient-related outcome measures).
# Safety
Dislocation of the implant was reported in 1 patient out of 30 treated by partial replacement of the meniscus combined with high tibial osteotomy in the RCT of 60 patients. The implant was removed but the timing of this was not reported.
Implant failure (defined as infection caused by the collagen implant or mechanical failure of the implant) was reported in 8% (2/25) of the patients in a case series of 25 patients during follow-up of 10 to 13 years. Postoperative infection (unrelated to the polyurethane scaffold) was reported in 1 patient in the case series of 52 patients at 1 week after the index surgery (resolved with treatment; no further details reported).
Swelling, effusion and redness were reported in 4 patients treated by the procedure and in 1 patient treated by partial meniscectomy in the RCT of 311 patients (timing of assessment was unclear; denominator not reported). Knee swelling was reported in 32% (7/22) of the patients in the case series of 25 patients (timing of assessment was unclear; further details not reported).
The Specialist Advisers listed the following theoretical safety outcomes: reaction to foreign material, lack of repair/healing with subsequent tearing or displacement, infection or standard related risks for any knee surgery operation.
# Other comments
The Committee noted the lack of clear criteria for patient selection for partial replacement of the meniscus of the knee using a biodegradable scaffold. It also noted that there are two main patient groups, young active patients and older patients with meniscal degeneration. It considered that the needs and outcomes of these two groups may be different.# Further information
This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
For related NICE guidance see www.nice.org.uk
Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedures guidance process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
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{'Guidance': "Current evidence on partial replacement of the meniscus of the knee using a biodegradable scaffold raises no major safety concerns. Evidence for any advantage of the procedure over standard surgery, for symptom relief in the short term, or for any reduction in further operations in the long term, is limited in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake partial replacement of the meniscus of the knee using a biodegradable scaffold should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand that there are uncertainties about any possible long-term advantage over other surgical options and that considerable rehabilitation is required after this procedure. Clinicians should provide patients with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having partial replacement of the meniscus of the knee using a biodegradable scaffold (see section 3.1).\n\nThe procedure should only be carried out by surgeons who are highly experienced in arthroscopic meniscal surgery.\n\nNICE encourages further research and data collection on partial replacement of the meniscus of the knee using a biodegradable scaffold. This should include clear descriptions of patient selection and adjunctive treatments. Outcome measures should include symptom relief and functional ability in the short term and the need for further treatment in the longer term.", 'The procedure': "# Indications and current treatments\n\nThe menisci are semi-lunar wedge-shaped fibrocartilaginous structures which act as shock absorbers, spreading the load on the articular surfaces of the knee.\n\nThe menisci can be damaged (often a tear) as a result of acute injury or degeneration, which may cause pain and/or locking of the knee. It is believed that meniscal damage is associated with a higher risk of knee osteoarthritis in the longer term. Minor meniscal damage can be treated conservatively (including rest and physical therapies). For more severe cases, treatment usually involves removal of the damaged part of the meniscus (partial meniscectomy).\n\nMeniscal repair is possible only in a minority of patients. This depends on the proximity of the damage to the peripheral vascular region of the meniscus (where good blood supply allows meniscal healing), the pattern of the damage and whether there is damage to other knee joint structures.\n\n# Outline of the procedure\n\nImplantation of a scaffold for partial replacement of the meniscus of the knee aims to support the body's own physiological pathways for healing by providing a 3-dimensional matrix for cell adhesion and vascular ingrowth, when attached to the vascular portion of the meniscus. In the short term the procedure aims to restore the load-bearing and shock-absorbing functions of the damaged meniscus, contributing to pain relief and restoring functional mobility. In the long term it aims to lower the risk of osteoarthritis and the need for further operations. A strict rehabilitation regime is usually employed after the procedure, which may include several weeks of restricted weight bearing and temporary bracing to limit knee movement.\n\nThe procedure may be done with the patient under general or regional anaesthesia. Using an arthroscope, damaged sections of the meniscus are excised, leaving a residual meniscal rim in the vascular zone. The size of the defect is measured and the implant is trimmed to match it. The implant is then introduced into the joint via one of the portals and sutured to the remaining meniscal rim. This may require extra skin incisions to provide sufficient access.\n\nThe types of scaffolds available for this procedure include those made of synthetic polyurethane and of collagen derived from animal sources.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 311\xa0patients divided patients into two groups, depending on whether they had prior surgery on the affected meniscus. Each group was randomised to treatment by partial replacement of the meniscus with a biodegradable implant or to partial meniscectomy alone. Pain scores were reported as a mean change from baseline (assessed at rest, during activities of daily living and at the highest level of activity, on a visual analogue scale; 0–100, higher score indicates greater pain) at mean follow-up of 59\xa0months. The first group of 157\xa0patients had no prior surgery on the affected meniscus. Patients treated by the procedure (n=75) had a mean pain score of 16 compared with 21 for those treated by partial meniscectomy (n=82; reported as not significant, p-values not reported). The second group of 151\xa0patients, who had had prior surgery on the affected meniscus (85 treated by the procedure and 69 treated by partial meniscectomy) had mean pain scores of 18 for both groups (reported as not significant, p-values not reported).\n\nAn RCT of 60\xa0patients, which included 30\xa0patients treated by the procedure and high tibial osteotomy (there was a high dropout rate in the comparator arm of tibial osteotomy alone) reported that the 23\xa0patients followed for 8–18\xa0months had Lysholm scores (0–100, higher score corresponds to better function) which improved from a baseline of 65 to 94 (p-value not reported).\n\nIn a case series of 52\xa0patients treated by partial replacement of the meniscus with a polyurethane scaffold, treatment failure (defined as an additional surgical procedure on the involved meniscus) was reported in 15% (8/52) of patients (treatment failure related to infection was excluded) and the overall treatment failure was 17% (9/52). Three cases were definitely related to the implant, 3 were not related to the implant, 1 was possibly related to the implant, 1 was unknown and 1 treatment failure (infection) was not related to the implant. Timing to the need for further intervention ranged from 1\xa0week to 24\xa0months.\n\nA non-randomised comparative study of 33\xa0patients treated by partial replacement of the medial meniscus (n=17) or by partial medial meniscectomy (n=16) reported mean quality of life scores measured bySF-36 physical health and mental health indices (scale of 0–100, higher score indicates better functioning). For the SF-36 physical health index, scores were 54 and 44 for the implant and the partial meniscectomy groups respectively, at a mean follow-up of 11\xa0years (p=0.026). For the mental health index, scores were 55 and 44 for the implant and the partial meniscectomy groups respectively at mean follow-up of 11\xa0years (p=0.004).\n\nThe RCT of 311\xa0patients reported reoperation rates, defined as an additional surgical procedure (outside the protocol) on the knee as a result of disabling or persistent pain and/or mechanical symptoms that could possibly involve the meniscus. The reoperation rates were 10% and 23% for the implant and the partial meniscectomy groups respectively, at 5\xa0years (denominators not reported; significance not reported). Reasons for reoperation included pain, swelling and instability.\n\nThe Specialist Advisers listed the following key efficacy outcomes: pain reduction, functional improvement, reduction in risk of further degeneration of the articular cartilage lining of the knee, early failure (further surgery) and early failure (symptoms or patient-related outcome measures).\n\n# Safety\n\nDislocation of the implant was reported in 1\xa0patient out of 30 treated by partial replacement of the meniscus combined with high tibial osteotomy in the RCT of 60\xa0patients. The implant was removed but the timing of this was not reported.\n\nImplant failure (defined as infection caused by the collagen implant or mechanical failure of the implant) was reported in 8% (2/25) of the patients in a case series of 25\xa0patients during follow-up of 10 to 13\xa0years. Postoperative infection (unrelated to the polyurethane scaffold) was reported in 1\xa0patient in the case series of 52\xa0patients at 1\xa0week after the index surgery (resolved with treatment; no further details reported).\n\nSwelling, effusion and redness were reported in 4\xa0patients treated by the procedure and in 1\xa0patient treated by partial meniscectomy in the RCT of 311\xa0patients (timing of assessment was unclear; denominator not reported). Knee swelling was reported in 32% (7/22) of the patients in the case series of 25\xa0patients (timing of assessment was unclear; further details not reported).\n\nThe Specialist Advisers listed the following theoretical safety outcomes: reaction to foreign material, lack of repair/healing with subsequent tearing or displacement, infection or standard related risks for any knee surgery operation.\n\n# Other comments\n\nThe Committee noted the lack of clear criteria for patient selection for partial replacement of the meniscus of the knee using a biodegradable scaffold. It also noted that there are two main patient groups, young active patients and older patients with meniscal degeneration. It considered that the needs and outcomes of these two groups may be different.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see www.nice.org.uk\n\nInformation for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}
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https://www.nice.org.uk/guidance/ipg430
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Botulinum toxin type A for the prevention of headaches in adults with chronic migraine
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Botulinum toxin type A for the prevention of headaches in adults with chronic migraine
Evidence-based recommendations on botulinum toxin type A (Botox) for preventing headaches in adults with chronic migraine.
# Guidance
Botulinum toxin type A is recommended as an option for the prophylaxis of headaches in adults with chronic migraine (defined as headaches on at least 15 days per month of which at least 8 days are with migraine):
that has not responded to at least three prior pharmacological prophylaxis therapies and
whose condition is appropriately managed for medication overuse.
Treatment with botulinum toxin type A that is recommended according to 1.1 should be stopped in people whose condition:
is not adequately responding to treatment (defined as less than a 30% reduction in headache days per month after two treatment cycles) or
has changed to episodic migraine (defined as fewer than 15 headache days per month) for three consecutive months.
People currently receiving botulinum toxin type A that is not recommended according to 1.1 and 1.2 should have the option to continue treatment until they and their clinician consider it appropriate to stop.# The technology
Botulinum toxin type A (Botox, Allergan) is a purified neurotoxin complex, which is derived from the bacterium Clostridium botulinum. It has neuromuscular transmitter blocking effects. It has a UK marketing authorisation 'for the prophylaxis of headaches in adults with chronic migraine (headaches on at least 15 days per month of which at least 8 days are with migraine)'. The recommended reconstituted dose is 155–195 units, administered intramuscularly as 0.1 ml (5 units) injections to between 31 and 39 sites around the head and back of the neck. The recommended re-treatment schedule is every 12 weeks (see the summary of product characteristics).
The summary of product characteristics lists the following common adverse reactions that may be associated with botulinum toxin type A treatment: headache, migraine, facial paresis, eyelid ptosis, pruritus, rash, neck pain, myalgia, musculoskeletal pain, musculoskeletal stiffness, muscle spasms, muscle tightness, muscular weakness, and injection site pain. It states that 'in general, adverse reactions occur within the first few days following injection and while generally transient, may have a duration of several months or, in rare cases, longer'. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The net price of a 200 unit vial is £276.40 (excluding VAT; 'British national formulary' edition 63). The manufacturer estimates that the administration cost is £73 per treatment, based on a total treatment time of less than 30 minutes. The total cost for treatment and administration of treatment per 12 week cycle, assuming no vial sharing, is therefore expected by the manufacturer to be £349.40. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of botulinum toxin type A and a review of this submission by the Evidence Review Group (ERG; appendix B).
The decision problem defined in the scope asked whether botulinum toxin type A is clinically and cost effective in adults whose chronic migraine has failed to respond to at least three prior pharmacological prophylaxis therapies and whose medication overuse has been appropriately managed, compared with standard management without botulinum toxin type A excluding invasive procedures. The manufacturer addressed this decision problem in its submission by carrying out a sensitivity analysis.
# Clinical effectiveness
To establish the efficacy of botulinum toxin type A, the manufacturer performed a systematic review to identify randomised controlled trials comparing botulinum toxin type A with placebo. The manufacturer identified seven relevant trials, of which four were against an active comparator and were excluded from consideration. Of the three remaining trials, two were large phase III trials and were the focus of the manufacturer's submission. The third was a small trial (n=60) that was excluded from further discussion because of concerns regarding its quality and relevance to the decision problem.
Evidence from the two randomised controlled trials, PREEMPT 1 and PREEMPT 2 (phase III trials evaluating migraine preventive therapy), was presented, as well as the pooled results from these trials. The trials were identically designed with a 56-week treatment period. In total, 688 people were recruited into the botulinum toxin type A arms of the trials and 696 into the placebo arms. Patients were stratified by their use of acute headache pain medication at baseline. The first phase of the trial was a 24-week double-blind phase, in which patients received a series of 31–39 intramuscular injections of botulinum toxin type A or placebo (saline), at day 0 and week 12. In the second phase of the trial, from week 24 to 56, patients entered into a 32-week, open-label phase in which all patients continuing in the trials received botulinum toxin type A at weeks 24, 36 and 48.
The PREEMPT trials enrolled people aged 18 to 65 years who had chronic migraine. All patients had to have had at least 15 headache days in the 28 days before week 0, and at least 50% of headache days had to be migraine or probable migraine days. Most people in the trials received at least one prior preventive treatment (approximately 64%), and approximately 35% of the patients had received three or more prior preventive treatments. Most people in the trials overused acute pain medication (more than 64%). The PREEMPT trials recruited people from North America and Europe, including from the UK. Patients were excluded if they used headache preventive medications within 4 weeks of the start of baseline, or if their headache was attributed to other disorders such as medication overuse. However, chronic migraine patients with protocol-defined overuse of acute medications were included and this was a stratification factor at randomisation.
The characteristics of the patients in the trials were similar, with no statistically significant differences between baseline characteristics in the PREEMPT 2 trial. In PREEMPT 1, most differences between groups were statistically non-significant, except for mean headache episodes and mean migraine episodes, which were lower in the botulinum toxin type A group compared with the placebo group, and the number of cumulative headache hours, which were higher in the botulinum toxin type A group compared with the placebo group.
All efficacy analyses from the two trials used the intention-to-treat population, which included all randomised patients. The reduction in frequency of headache days (the primary endpoint) was statistically significant in both trials. In PREEMPT 1, there was a reduction of 7.8 headache days from 20.0 (per 28 days) at baseline for patients treated with botulinum toxin type A, compared with a reduction of 6.4 headache days from 19.8 at baseline for those in the placebo arm (p=0.006). In PREEMPT 2, there was a reduction of 9.0 headache days from a baseline of 19.9 in the botulinum toxin type A arm, compared with a reduction of 6.7 headache days from a baseline of 19.7 days for those in the placebo arm (p<0.001). The difference between the two arms of the trials for the frequency of headache episodes was not statistically significant in the PREEMPT 1 trial, but was statistically significant in the PREEMPT 2 trial. The following were statistically significantly lower in the botulinum toxin type A arm compared with the placebo arm in both trials: total cumulative hours of headache on headache days; the frequency of migraine days, and moderate to severe headache days. There was no difference in the intake of acute pain medication between the arms in both studies, although there was statistically significant lower triptan use in the botulinum toxin type A arm. The pooled results of the two trials were consistent with the results from the individual studies: for the outcome of frequency of headache days (per 28 days), the pooled botulinum toxin type A group had a statistically significant reduction of 8.4 headache days from 19.9 days at baseline, compared with a reduction of 6.6 headache days from 19.8 days in the pooled placebo group (p<0.001).
The PREEMPT trials measured health-related quality of life, using the headache impact test 6 (HIT-6) and the migraine-specific quality of life questionnaire (MSQ). The HIT-6 was developed for use in people with general headache whereas the MSQ was developed specifically for people with chronic migraine. At 24 weeks, there were statistically significant improvements from baseline in quality of life as measured by the HIT-6 and the MSQ for people in the botulinum toxin type A arm compared with those in the placebo arm in both trials.
The most frequently reported adverse reactions occurring at a higher incidence in the pooled botulinum toxin type A group than in the pooled placebo group were: neck pain, headache, migraine, eyelid ptosis, musculoskeletal stiffness and muscular weakness. Of these, neck pain was the only one to occur at a rate of 5% or more in the pooled botulinum toxin type A arm compared with the pooled placebo arm.
A subgroup analysis was conducted for people who had previously received three or more headache preventive medications, for the outcome of frequency of headache days (per 28 days), using the pooled data from the PREEMPT trials (231 people in the botulinum toxin type A arm and 248 in the placebo arm). The pooled botulinum toxin type A group had a statistically significant reduction of 7.4 headache days from 20.0 days at baseline, compared with a reduction of 4.7 headache days from 20.2 days at baseline in the pooled placebo group (p<0.001). Treatment efficacy for frequency of headache days was similar for the subgroup of people who had previously received three or more preventive treatments, those who had previously received two preventive treatments, and those who had previously received one or more preventive treatments.
# Cost effectiveness
## Original submission
The manufacturer carried out a systematic review for economic evaluations of botulinum toxin type A for people with chronic migraine, but no relevant published studies were identified.
The manufacturer developed a Markov model using the pooled data from the two PREEMPT trials, comparing botulinum toxin type A with placebo. Only approximately 35% of the population met the criteria set out in the NICE scope (people whose condition has failed to respond to three or more prior pharmacological prophylaxis therapies). Because of the similarity in efficacy, (see section 3.9) the manufacturer used the population whose condition had failed to respond to one or more pharmacological therapies, which was approximately 64% of the trial population, in order to increase the statistical power.
Six health states were defined in the model according to the number of headache days per month: 0–3 (health state 1), 4–9 (health state 2), 10–14 (health state 3), 15–19 (health state 4), 20–23 (health state 5) and 24 or more (health state 6). Patients could enter the model in any of the three chronic migraine states (health states 4,5 or 6); chronic migraine was defined as 15 headache days or more per 28 days. The cycle length was 12 weeks, which is the same as the frequency of administration of botulinum toxin type A in the trials. The model used the transition probabilities observed in the clinical trials, which include the transitions between the six health states as well as an additional transition to discontinuation of therapy. For the placebo arm, the second cycle transition probability was repeatedly applied after week 24. For the botulinum toxin type A arm, the same transitional probability matrix was applied for the third, fourth and fifth cycles; this figure was calculated by averaging these three cycles. For people continuing on treatment in cycles 6–9, the same average figure was used. The time horizon used in the model was 2 years, in line with the manufacturer's expected maximum treatment duration with botulinum toxin type A. For the first of the 2 years, trial data were used if possible, with extrapolation used for the second year, using the last observations from the trial.
As well as using the discontinuation data from the clinical trials in the model, two treatment (dis)continuation rules were applied. A negative stopping rule was applied at week 24 for people whose condition responded insufficiently to botulinum toxin type A. Insufficient response was defined as people having an improvement of less than two health states (a reduction of between 5 and 10 headache days per 28 days depending on both the number of headache days and the corresponding health state at the start of treatment) after two successive cycles of treatment. After discontinuation, they moved between health states using the transition probabilities for placebo treatment, but did not incur treatment costs. A positive stopping rule was applied at week 48 for people whose condition had changed to episodic migraine (fewer than 15 headache days per 28 days). The model assumed that after 1 year, people whose condition had changed to episodic migraine stopped treatment with botulinum toxin type A and remained stable in the episodic migraine health states thereafter.
Two mapping equations were derived to map the MSQ data (as collected during the trials) to EQ-5D utility, so that utilities could be attached to each health state. One equation was used to predict utilities for people in the chronic migraine health states, and the other was used for predicting utilities in the episodic health states. Utility was different for each health state in this model and also between treatments within the same health state, the latter being justified on the grounds that treatment with botulinum toxin type A was shown to affect a broad range of relevant outcomes such as the severity and intensity of headaches, as well as the number of headache days. Utility was predicted for each health state using the patient-level data from the trials. This was done by grouping patients by health state and calculating the mean utility per treatment group. Utility values used in the model ranged between 0.479 and 0.746 depending on the treatment and on the number of headaches experienced. Adverse events affecting health-related quality of life were captured in the model by applying discontinuation rates. There were assumed to be no additional costs relating to adverse events.
The manufacturer assumed that chronic migraine in the relevant patient population would be managed in a specialist setting, with associated consultant-related costs. Administration time was assumed to be 30 minutes, at a cost of £73.00. Cost of treatment was calculated based on one 200 unit vial of botulinum toxin type A at £276.40, with no vial sharing, leading to a total cost of £349.40 per 12 week cycle. For people in the placebo arm (standard care), the cost was assumed to be £36.50 per 12 weeks, which is based on a 15 minute appointment with a consultant every 24 weeks to optimise acute therapy. Costs for GP visits, accident and emergency attendance, hospitalisation and the cost of triptan were modelled for each health state but only three different costs were used; for health state 1, states 2–3 and states 4–6. These costs came from a poster by Bloudek et al. (2011) of Scottish resource use according to the International Burden of Migraine Study (IBMS). Costs and quality-adjusted life years (QALYs) were discounted at a rate of 3.5% per year.
For people whose condition failed to respond to at least three prior preventive medications, the total cost and QALYs for placebo were £1895 and 1.20 respectively, compared with a total cost of £2438 and 1.29 QALYs for botulinum toxin type A. This gave an incremental cost and incremental QALYs of £543 and 0.09 respectively and an ICER of £6083 per QALY gained for botulinum toxin type A compared with placebo. There was a 69.1% probability of botulinum toxin type A being cost effective if the maximum acceptable ICER was £20,000 per QALY gained. The manufacturer did not report a central estimate of the ICER calculated by probabilistic modelling. For the wider population, which included people whose condition had not responded to one or more prior preventive medications, the costs and QALYs were similar, with an ICER of £5828 per QALY gained for botulinum toxin type A compared with placebo.
The manufacturer presented a variety of sensitivity analyses, and for most of the cases the ICER for botulinum toxin type A compared with placebo stayed under £10,000 per QALY gained. Excluding the positive and negative stopping rules increased the ICER to £15,294 per QALY gained. Restricting the time horizon to 1 year increased the ICER to £14,098 per QALY gained.
The manufacturer identified an error in its analyses, in which the original ICERs were based on utilities derived from all people in the trials. It submitted revised ICERs using utilities from people whose condition failed to respond to at least three prior preventive medications. After correcting for the error, the ICER for botulinum toxin type A compared with placebo increased from £6083 to £6434 per QALY gained.
## ERG critique of original submission
The ERG noted that the trials were generally of good quality. The ERG pointed out that in the PREEMPT 1 trial, at baseline patients in the botulinum toxin type A group had a statistically significantly lower frequency of migraine episodes (11.5 compared with 12.7, p=0.006) and frequency of headache episodes (12.3 compared with 13.4, p=0.023), but had statistically significantly more cumulative hours of headache on headache days (295.7 compared with 274.9, p=0.022) than those in the placebo group. The original primary outcome in PREEMPT 1 was to have been frequency of headache episodes, but this was changed to headache days because of new guidelines for the conduct of clinical trials in chronic migraine. This was considered reasonable by the ERG.
The ERG found botulinum toxin type A to be effective regardless of the number of previous preventive medications taken. As the number of previous preventive medications rose, so did the relative effectiveness of botulinum toxin type A compared with placebo (reductions of 2.3 and 2.7 headache days per month for the one prior preventive medication and three or more prior preventive medications subgroups respectively). In addition, the ERG observed that the placebo effect decreased as the number of previous preventive medications increased.
The ERG stated that a noticeable feature of the trial data was the size of the improvement on placebo, which lasted for at least 24 weeks and was only modestly less than on active treatment. In addition the ERG pointed out that the efficacy of botulinum toxin type A was greatest with the first injection and that the second injection had much less effect, with similar efficacy to that of the second placebo injection. The ERG therefore queried whether a negative stopping rule could be applied after the first injection.
The ERG's main concern about the design of the PREEMPT trials was about whether blinding was maintained and if not, what the effect of this was on the results of the trials. The ERG pointed out that in previous botulinum toxin type A trials, 70% of patients receiving botulinum toxin type A correctly guessed what they had received, because of changes in muscle tone such as reduced wrinkling of the forehead. The ERG further explained that because unblinding is an important factor in controlled trials of preventive treatment of chronic migraines, the International Headache Society guidelines recommend that subjects and investigators should be questioned at the end of trials about whether they thought active or placebo was administered during the trial. This was not done in the PREEMPT trials.
The ERG considered the manufacturer's model to be reasonable for the decision problem. The ERG noted that the model and trial data sets for headache days per month at week 24 corresponded poorly and that this overestimated the net impact of botulinum toxin type A by 53%. Yet this overestimate had no direct impact on cost effectiveness because it was the distribution between health states that determined the costs and QALYs within the model. The ERG observed that within the validation data, the model and trial were reported by the manufacturer as having no patients in health states 5 and 6 at week 24 in the botulinum toxin type A arm. The ERG noted that this could be because of the negative stopping rule being applied in both sets of data, with these patients falling into the discontinuation category, but could not verify this. Uncertainty remained around this point and also the distribution between health states among those patients modelled as discontinuing because of the negative stopping rule, but who were followed up within the trial. The ERG noted that there were no clinical data to support the use of the two stopping rules. The ERG queried whether the negative stopping rule at 24 weeks in the model would apply in practice, and whether the requirement for an improvement could be based on either one or two health states. It found that an improvement of only one health state within two cycles increased the ICER for the three or more prior preventive medications subgroup from £6083 per QALY gained to £8354 per QALY gained. The ERG doubted that the positive stopping rule at week 48 was likely to be implemented. It queried how long people who had stopped treatment would remain stable before needing re-treatment, noting 2-year follow-up data from a published abstract by Rothrock et al. (2011), which estimated the duration of response to treatment with botulinum toxin type A based on a 50% reduction in the number of headache days per month. Of a total sample of 100 people whose chronic migraine responded to treatment with botulinum toxin type A, 68% maintained a good response to treatment with continued injections at a frequency of 3.2 months. A further 24% were able to stop treatment and maintain a good response for at least 6 months; and 8% relapsed back to chronic migraine. The ERG found that removing the positive stopping rule roughly doubled the ICER for the three or more prior preventive medications subgroup for botulinum toxin type A arm compared with placebo, from £6083 per QALY to £12,542 per QALY gained.
The ERG noted that there were wide disparities between the model inputs for resource use used in the economic model, which were based on the poster by Bloudek et al., and those reported in a published paper by Blumenfeld et al. (2011). The ERG noted that the two sources had reported results from the same international study, however Bloudek et al. appeared to include costs based on Scottish implementation, with no information on the number and ages of the patients, GP visits, hospital outpatient and accident and emergency attendances, hospital admissions or medication use. The ERG noted that because the higher costs for health states 4–6 were driven by hospital admission costs and were the same in each of the health states 4–6, details of the Bloudek et al. poster were important because it could be that the manufacturer's estimate of resource use was too high. It was for this reason that the ERG preferred the resource use detailed in Blumenfeld et al. which contained more detailed data. The ERG had concerns about the applicability of international data on hospital admission rates for chronic migraine to clinical practice in England and Wales, but recognised that Blumenfeld et al. contained the most detailed data available.
The ERG observed that utility values were calculated using MSQ estimations at 24 weeks, when the full effect of botulinum toxin type A had occurred. The ERG noted that the manufacturer's model generally assigned higher utility values for the botulinum toxin type A arm than the placebo arm for each health state and that this feature of the model accounted for about half of the anticipated QALY gain for botulinum toxin type A. It noted that for this to be valid, there would have to be a difference in other features such as: the number of headaches experienced during a headache day, the duration of these headaches, or the proportion of headaches that were migraines. The ERG noted that this was plausible, although it was unsure whether the substantial difference in utilities in each health state was justified given the small absolute differences in secondary endpoints in the PREEMPT trials. The ERG commented that the number of headache days per month was not included in the estimate of utilities, which instead relied on IBMS MSQ data. The manufacturer had outlined a regression analysis from the EQ-5D in the IBMS and found that the EQ-5D and the number of headache days per month were statistically significantly negatively correlated. The ERG used these data and showed very little difference in utilities between botulinum toxin type A and placebo in a given health state. The ERG queried whether the IBMS MSQ data could be used to estimate utilities given that the IBMS included a different population to that described in the decision problem. It noted that a more appropriate estimation of utilities would encompass both MSQ and HIT-6 data. The ERG also explained that there is non-monotonicity (an anomaly in which the utility values are not consistently increasing or decreasing) in the utility values in the botulinum toxin type A arm in which people in health state 5 (20–23 headache days per month) have a lower utility than those in health state 6 (24–28 headache days per month). The ERG commented that this may highlight some uncertainty between the mapping of MSQ data to utilities and correspondence with the model structure as defined by the number of headache days per month.
The ERG noted that the model included the cost of administering botulinum toxin type A and of placebo, based on 30 and 15 minutes of neurologist time respectively. The ERG stated that review of a patient and administration of botulinum toxin type A may take between 30 minutes and 1 hour, depending on the experience of the person injecting and the possibility of complications during administration. As a result the ERG commented that the cost of administering botulinum toxin type A based on 30 minutes of neurologist time may be too optimistic. It also noted that the appropriate cost of follow-up outpatient consultations should be the standard NHS neurological outpatient follow-up reference cost of £140. The ERG noted that administration of botulinum toxin type A was reported to be offset by cost saving because of reductions in GP visits, inpatient admissions and accident and emergency attendance, but it considered the amount of the cost saving to be overestimated.
The ERG explained that the model submitted by the manufacturer was non-linear, with a central probabilistic estimate of cost effectiveness more than double that of the deterministic estimate, based on ERG exploratory analyses. It stated that some elements of the probabilistic modelling seemed unwarranted; for example, treating the identity matrix as having an uninformed prior and modelling it probabilistically. The ERG found that removing these elements reduced the degree of non-linearity but did not eliminate it. The ICER for the three or more prior preventive medications subgroup increased from the manufacturer's deterministic ICER of £6083 per QALY gained to the probabilistic ICER of £11,447 per QALY gained if the ERG's revisions were applied. If the ERG's revisions were not applied the probabilistic ICER was estimated at £14,004 per QALY gained.
The ERG conducted a number of different exploratory sensitivity analyses. In these analyses, the ERG used the manufacturer's model with a number of modifications. The modifications included:
A neurologist outpatient face-to-face follow-up cost of £140 for botulinum toxin type A administration and placebo follow-up (instead of £73 administration cost of botulinum toxin type A administration and £36.50 follow-up placebo cost, based on 30 and 15 minutes of neurologist time respectively).
Placebo routine care costs incorporated for patients stopping therapy in the botulinum toxin type A arm (instead of no ongoing routine care costs).
Resource use estimates from Blumenfeld et al., who included all UK participants from the IBMS (instead of from Bloudek et al. who appeared to use costs based on Scottish implementation).
Transition probability matrices from the three or more prior preventive medications patient subgroup (instead of from the one prior preventive medication population).
An average accident and emergency cost of £77.33 (instead of £90.94).
The ERG reported that applying all the above modifications (using the manufacturer's utility values based on one prior preventive treatment) resulted in an increase in the ICERs for botulinum toxin type A compared with placebo to give a deterministic ICER of £10,257 per QALY gained and a probabilistic ICER of £16,165 per QALY gained. The ERG reported that using these assumptions there was a 67% probability of botulinum toxin type A being cost effective if the maximum acceptable ICER was £20,000 per QALY gained, and an 87% probability of botulinum toxin type A being cost effective if the maximum acceptable ICER was £30,000 per QALY gained.
The ERG also explored the impact on the deterministic ICER of varying the negative and positive stopping rules and applying the same utility values for each arm. In these analyses, all the modifications outlined in section 3.28 were applied and the utilities from the three or more prior preventive medications subgroup were used. The ERG also used 2-year follow-up data from the published abstract by Rothrock et al. (2011) (see section 3.23).
Applying the same utilities from the three or more prior preventive medications patient subgroup to both arms (based on the updated utility data from the manufacturer) resulted in lower QALYs for botulinum toxin type A with no change in costs, compared with the base case. When the manufacturer's base case with positive and negative stopping rules and different utilities were used, the deterministic ICER for botulinum toxin type A compared with placebo was £11,267 per QALY gained, compared with £20,324 per QALY gained when the same utilities were applied to both arms for each health state. When the positive stopping rule was excluded (compared with using the positive stopping rule for people who move from chronic to episodic migraine) the ICER for botulinum toxin type A compared with placebo increased from £11,267 to £19,483 per QALY gained when different utilities were used in the botulinum toxin type A and placebo arms. When a positive stopping rule was applied to 24% of people who had moved from a health state of chronic migraine to episodic migraine (based on the study by Rothrock et al.) the ICER for botulinum toxin type A compared with placebo increased from £11,267 to £17,438 per QALY gained when different utilities were used. The ERG also applied various negative stopping rules: no negative stopping rule, an improvement of at least one health state within the first cycle; improvement of at least one health state within two cycles; and the manufacturer's base case of an improvement of two health states in two cycles. When no negative stopping rule was applied and different utilities were used in the botulinum toxin type A and placebo arm, the ICER for botulinum toxin type A compared with placebo was £13,986 per QALY gained. When different negative stopping rules were applied, the ICER for botulinum toxin type A compared with placebo ranged from £9618 to £13,167 per QALY gained. The scenario that had the most impact on the model results for botulinum toxin type A compared with placebo was when no positive and negative stopping rules were applied. This led to an ICER of £24,387 per QALY gained if different utilities for the three or more prior preventive medications patient subgroup were applied to both arms, or £46,290 per QALY gained if the same utilities for the three or more prior preventive medications patient subgroup were applied to both arms. The ERG also remarked that applying separate estimates for the transition probabilities for cycles 3, 4 and 5 to be more in line with patient data would further increase the ICERs by 5–10%.
## Additional submission after consultation
The manufacturer provided additional analyses after consultation in response to NICE's request for a revised economic model based on the Committee's preferred assumptions, and some clarification of a number of issues relating to the calculation of utilities in the model, the large difference between the deterministic and probabilistic ICER, and resource use. The manufacturer presented:
a revised economic model (which incorporated the Committee's preferred assumptions when the same and different utilities were assumed within each health state for the botulinum toxin type A and placebo arms)
scenario analyses which explored the impact of varying the negative stopping rule and the use of UK resources
some clarification of the way that utilities had been calculated and the likely causes of the difference in the probabilistic and deterministic ICERs.
In addition the manufacturer provided analyses varying the time horizon and placebo effectiveness, and also the results of an Australian survey of 10 people who received treatment with botulinum toxin type A for their chronic migraine.
The revised manufacturer's model presented the cumulative deterministic results for each of the Committee's preferred assumptions on the manufacturer's original deterministic ICER of £6083 per QALY gained when different or the same utility values were applied for each arm:
Applying routine care costs in the placebo arm to people stopping treatment because of inadequate response with botulinum toxin type A resulted in an ICER of £7170 per QALY gained when different utility values were applied, and £13,110 per QALY gained when the same utility values were applied.
When the 24% positive stopping rule was applied, the ICER increased from £7170 to £12,355 per QALY gained when different utilities were applied, and from £13,110 to £22,572 per QALY gained when the same utilities were applied.
Including resource use estimates specified in Blumenfeld et al. increased the ICER further from £12,355 to £13,776 per QALY gained when different utilities were applied, and from £22,572 to £25,168 per QALY gained when the same utilities were applied.
A neurologist follow-up cost of £140 for botulinum toxin type A and placebo administration and follow-up decreased the ICER from £13,776 to £11,997 per QALY gained when different utilities were applied, and from £25,168 to £21,917 per QALY gained when the same utilities were applied.
An average accident and emergency cost of £77.33 increased the ICER from £11,997 to £12,047 per QALY gained when different utilities were applied, and from £21,917 to £22,008 per QALY gained when the same utilities were applied.
Calculating utility values from data from the three or more prior preventive medications subgroup of the PREEMPT trials increased the ICERs to £16,243 per QALY gained when different utilities were applied, and to £23,624 per QALY gained when the same utilities were applied. When the utility values in health states 5 and 6 were pooled to remove non-monotonicity in the utility values, it led to a utility of 0.480 for health states 5 and 6 in the botulinum toxin type A arm, and 0.507 for health states 5 and 6 in the placebo arm. Pooling the utility values for health states 5 and 6 decreased the ICER to £14,876 per QALY gained when different utilities were applied and increased it to £23,975 per QALY gained when the same utilities were applied. When transition probability matrices from the three or more prior preventive medications subgroup were applied, the ICER increased to £15,270 per QALY gained when different utilities were applied and to £24,540 per QALY gained when the same utilities were applied.
The manufacturer's revised cumulative results were based on a negative stopping rule of a two health state reduction in two cycles of treatment, as assumed in their original model. The manufacturer conducted one-way deterministic sensitivity analyses to assess the impact of different negative stopping rules on the ICER (from no negative stopping rule to a stopping rule of less than 50% reduction in headache days per month increasing in 5% or 10% increments from 0%). The ICER varied between £14,198 and £17,174 per QALY gained when different utilities were applied, and from £23,849 and £30,755 per QALY gained when the same utilities were applied. The ICER when no stopping rule was assumed was £19,508 per QALY gained when applying different utilities, and £35,637 per QALY gained when applying the same utilities. The manufacturer considered a negative stopping rule of a 30% response rate based on the reduction in the number of headache days per 28 days after two cycles of treatment to represent its new base case, based on evidence that it is used in clinical practice in the UK for the treatment of chronic migraine. When using the revised base-case assumptions and inputs (see section 3.33) and a 30% negative stopping rule, the revised base-case deterministic ICER was £14,999 per QALY gained when different utilities were applied, and £24,939 per QALY gained when the same utilities were applied.
The manufacturer explored the causes of the large difference between the deterministic and probabilistic results observed in the manufacturer's original submission and the ERG's original additional analyses. The manufacturer identified one reason for the difference to be the method used to sample the transition probabilities for the probabilistic sensitivity analysis. In their original submission, these were calculated using a Dirichlet based sampling. When the manufacturer recalculated the probabilistic values using a beta tree sampling method, the central probabilistic estimate and the deterministic estimate were broadly in line with one another. The manufacturer also identified an error in its application of a continuity correction. When using the revised base-case assumptions and inputs, a 30% negative stopping rule, beta tree sampling, and correcting for the continuity correction error, the probabilistic ICER was £14,959 per QALY gained (compared with a deterministic ICER of £14,999 per QALY gained) when different utilities were applied, and £25,242 per QALY gained (compared with a deterministic ICER of £24,939 per QALY gained), when the same utilities were applied.
In response to NICE's request after the first Committee meeting, the manufacturer provided additional clarification about the differences in resource use between Bloudek et al. and Blumenfeld et al. The manufacturer highlighted that the primary reason for the differences was the inclusion of data on Brazilian patients in Bloudek et al. The manufacturer also provided one-way deterministic sensitivity analysis using data from the UK subset of the IBMS. When using the revised base-case assumptions, inputs including a 30% negative stopping rule, and resource use data from the UK subset of the IBMS, the deterministic ICER reduced from £14,999 to £12,624 per QALY gained when different utilities were applied, and from £24,939 to £20,989 per QALY gained when the same utilities were applied. The manufacturer stated that the reduction in the ICER was caused mainly by the higher than average number of hospitalisations in the UK patients in the IBMS.
The manufacturer carried out additional sensitivity analyses that varied the time horizon and the effectiveness of placebo, assuming no retreatment. The cost effectiveness of botulinum toxin type A was sensitive to the time horizon, with the deterministic ICER ranging from £14,999 to £8825 per QALY gained when the time horizon ranged from 2 to 20 years, and when different utilities were applied. When the same utilities were applied, the deterministic ICER ranged from £24,939 to £11,700 per QALY gained when the time horizon ranged from 2 to 20 years. The manufacturer also performed a sensitivity analysis in which it was assumed that people in the placebo arm remained in their original health state throughout the trial. This was done because the placebo effect observed in the trials would not be expected to exist in clinical practice in people with chronic migraine who have tried three or more prior preventive headache medications. When no effectiveness in the placebo arm was assumed, the ICER reduced from £14,999 to £5677 per QALY gained when different utilities were applied, and from £24,939 to £6008 per QALY gained when the same utilities were applied to each arm.
In response to NICE's request for clarification on utilities, the manufacturer provided further details of the mapping algorithms used in its economic model, which were applied to the week 24 data of the PREEMPT trials in the three prior preventive medications group. The manufacturer also supplied mean values of the coefficients and of the parameter values of the week 24 data. The manufacturer stated that the rationale for applying different utility values to treatment arms comes from the results of the PREEMPT trials, which showed significant clinical and health-related quality of life benefits beyond the reduction in the number of headache days per 28 days.
The manufacturer provided results of an Australian survey of ten people with chronic migraine who had received botulinum toxin type A for up to 5 years. The survey indicated that treatment with botulinum toxin type A provides three main types of clinical benefit: reduced frequency of migraine and headache days; reduced severity of migraine; and reduced length or duration of migraine symptoms. Participants also identified additional benefits to treatment, such as reduced reliance on other treatment, less sick leave, fewer accident and emergency and GP visits, as well as overall improvements in personal, social and mental well-being.
## ERG critique of the additional submission
The ERG reviewed the manufacturer's consultation comments and revised economic model. The ERG noted that it might be more appropriate to assume a placebo administration cost of £70 based on 30 minutes of neurologist time compared with a cost of £140 based on 60 minutes of neurologist time, given that the latter cost and time would involve the administration of botulinum toxin type A as well as a consultation. The ERG also justified a lower cost for neurologist time for placebo administration, in view of the fact that patients whose chronic migraine has failed three prior prophylaxis therapies have regular follow-up in some but not all neurology clinics. The ERG's analyses showed that when a placebo administration cost of £70 was applied to the manufacturer's revised base case (including a 30% negative stopping rule) the deterministic ICER increased from £14,999 to £19,244 per QALY gained when different utilities were applied. No ICER was calculated for applying the same utilities to each arm.
The ERG noted that the utility mapping functions were constructed to pick up elements of the condition that are not captured by the frequency of headache days per 28 days (such as severity or intensity of headaches). Therefore given that health states are defined in terms of the number of headache days per 28 days, it was not surprising that there were non-monotonic utility values. The ERG explained that there are alternative methods for calculating utilities to those chosen by the manufacturer, such as restricting the individual MSQ dimensions to being monotonic or at least non-decreasing, which could reduce or avoid the non-monotonicity observed in the original utility values. It noted that the manufacturer's utility mapping functions have different non-MSQ parameter values between health states for botulinum toxin type A and placebo. The ERG stated that the manufacturer had not provided a rationale as to why these parameter values should be different. When the ERG equalised the non-MSQ parameter values in the mapping functions, less non-monotonicity was observed and the ICER was £18,895 per QALY gained when different utilities were applied to each health state. The ERG stated that when the individual MSQ dimensions were restricted to being monotonic or at least non-decreasing, the ICER ranged from £17,278 to £18,256 per QALY gained.
The ERG reviewed the manufacturer's scenario analysis in which people in the placebo arm remained in their original health state throughout the model. The ERG argued that the benefits of botulinum toxin type A include a large placebo effect, therefore it would be wrong to retain the placebo effect when receiving botulinum toxin type A but not when receiving the placebo. The ERG also reviewed the scenario analysis that varied the time horizon. It noted that no clinical trial data existed beyond 12 months, as observed in the PREEMPT trial, but a 2 year time horizon is plausible. It also reviewed the manufacturer's Australian survey of people (n=10) who received botulinum toxin type A for their chronic migraine. The ERG expressed concern that the study included a very small number of participants who were paid to take part, and who received botulinum toxin type A for up to 5 years, which indicates that a positive stopping rule was not applied. It noted that the survey participants reported a good response to treatment with a dose of 100 to 150 units of botulinum toxin type A.
The ERG reviewed the manufacturer's comments about resource use. The ERG expressed continuing concern that it is unclear how to interpret some of the resource use data from Blumenfeld et al. and Bloudek et al. When reviewing the resource use data for people from the UK with chronic migraine in the IBMS presented by the manufacturer, the ERG noted that the subset included a small number of people (n=57), and a significant number of outlying results (for patients whose resource use contributed to most of the total resource use observed). The ERG stated that the manufacturer should have explored the impact of excluding outlying results from its analyses, and that given the small number of people from the UK with chronic migraine in the IBMS, they considered the Blumenfeld et al. resource use data to be most applicable to the UK.
The ERG identified an update of the published abstract by Rothrock et al. (see section 3.23). The update, published by Hanlon et al. (2011), closely matched the results published by Rothrock et al., with 25% (compared with 24% in Rothrock et al.) of people able to stop treatment and maintain a good response for at least 6 months after stopping treatment. It noted that 24–25% was the most appropriate figure on which to base a positive stopping rule.
Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA260# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of botulinum toxin type A, having considered evidence on the nature of chronic migraine and the value placed on the benefits of botulinum toxin type A by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee considered the impact of chronic migraine on the everyday life of people with the condition. It heard from the patient experts that chronic migraine is accompanied by severe pain, which impacts greatly on people's quality of life, affecting their ability to work and participate in social activities. The patient experts also noted that people with chronic migraine often experience anxiety and depression related to their condition. The Committee considered chronic migraine to be a debilitating condition which significantly affects health-related quality of life.
The Committee considered current clinical practice for the treatment of chronic migraine. The Committee heard from the clinical specialists that it is important for people first presenting with chronic migraine to try a range of oral preventive treatment options before considering treatment with botulinum toxin type A. The clinical specialists stated that there is no one measure of response to treatment and that response is multifaceted. The Committee heard from the clinical specialists that a good response to treatment is typically considered to be a 30–50% reduction in the frequency of headache days or headache episodes. The Committee also noted that when a person's response to treatment is assessed, clinicians also take account of any improvement in the person's quality of life, and that improvements may not always be accompanied by substantial reductions in the number of headache days. It heard from clinical specialists that people considered for treatment with botulinum toxin type A are assessed for medication overuse before treatment starts, and that this is monitored during treatment. The Committee also heard from the patient experts that many people with chronic migraine would consider any degree of response to treatment to be valuable and that further treatment options were important.
The Committee considered the administration of botulinum toxin type A and monitoring of the potential benefit associated with treatment. It heard from clinical specialists that an initial consultation typically lasts between 45 minutes and 1 hour and includes administration of botulinum toxin type A, which can take between 15 and 30 minutes depending on the experience of the person administering the injection. After treatment patients are asked to keep a headache diary. The clinical specialists stated that the re-treatment interval with botulinum toxin type A varies in practice. Some clinical practices have routine follow-up about every 3 months. This will be either a telephone consultation with a consultant or headache specialist nurse, or a 30 minute clinic appointment with the consultant during which repeat injections may be administered. In other clinical practices there is no routine follow-up and patients must request an appointment to be considered for further treatment with botulinum toxin type A. The Committee concluded that the re-treatment interval with botulinum toxin type A is variable in practice, being 3 months in some patients, but at much longer intervals in others.
The Committee considered the evidence on the clinical effectiveness of botulinum toxin type A for the prevention of headaches in adults with chronic migraine from the PREEMPT trials, which compared botulinum toxin type A with placebo. The Committee noted that the pooled results for the intention-to-treat population indicated a statistically significant reduction in frequency of headache days per month, migraine days per month and cumulative headache hours with botulinum toxin type A compared with placebo, but considered the absolute numerical benefit of botulinum toxin type A over placebo to be modest. It also noted the statistically significant reduction in the frequency of headache episodes, migraine episodes and frequency of acute headache medication days with botulinum toxin type A compared with placebo, but that the absolute numerical differences between the treatments were small. The Committee observed that there was no statistically significant difference in how often acute pain medication was taken. Further, the Committee noted the large placebo effect seen in the trials. It was also aware that the incremental effect of botulinum toxin type A compared with placebo may have been increased by people in the active treatment arm realising that they were receiving botulinum toxin type A because of its side effects. The Committee noted that the duration of follow-up in the PREEMPT trials was short (1 year) and the study design, which meant that all patients received the active drug from week 24, could not exclude natural improvements in people's condition over time. The Committee heard from the clinical specialists that at baseline, patients in the clinical trials had fewer headache days per month (a mean of 19) than people with chronic migraine in secondary care in the UK (a mean of 25–26 headache days per month). The clinical specialists said that this might explain why the benefit observed in the trials was less than what they would expect to see in clinical practice. The Committee discussed the duration of the therapeutic effect of botulinum toxin type A and heard from the clinical specialists and patient experts that when a person's condition responds to botulinum toxin type A, the re-treatment interval varies, and that many patients need treatment for longer than 2 years. The Committee was aware of the difficulties of conducting clinical trials in people with chronic migraine, particularly with regard to the known significant placebo effect observed in such studies. It noted that the placebo comparator in the trial would not be given in clinical practice in the manner used in the trial. Although the absolute magnitude of benefit with botulinum toxin type A was modest, evidence from clinical specialists and patient experts suggested that the effect was clinically meaningful in people whose chronic migraine had failed to respond to three prior preventive treatments and whose condition responds (with at least a 30% reduction in the number of headache days per 28 days) to botulinum toxin type A treatment. The Committee therefore concluded that botulinum toxin type A was clinically effective in people with chronic migraine whose condition had not responded to three prior preventive treatments.
The Committee considered the clinical trial evidence in light of the views of the patient experts and clinical specialists. The Committee noted the improvements in quality of life for patients whose condition responded to botulinum toxin type A. The Committee then considered the use of botulinum toxin type A in clinical practice in the UK. The Committee heard from clinical specialists that if a person's chronic migraine was responding to botulinum toxin type A, the treatment would be continued until the number of headache days was reduced to fewer than 15 headache days per month (episodic migraine). The clinical specialists estimated that people would have at least two treatment cycles. They said that after this approximately 50% of people would continue on treatment, and of those 30% would need five cycles of treatment before their condition was reclassified as episodic migraine. The remaining patients would continue to receive treatment for longer than 2 years. Alternatively, if chronic migraine does not respond adequately to botulinum toxin type A after at least two cycles of treatment, and there is little benefit to the patient, treatment is discontinued and patients would receive standard care. The Committee noted that the clinical trial evidence on the effectiveness of botulinum toxin type A was for 1 year. The Committee was aware of the abstract by Rothrock et al. (2011) and the update by Hanlon et al. (2011), which estimated duration of response to treatment with botulinum toxin type A, with response to treatment defined as a 50% reduction in the number of headache days per month. The Committee noted that only 24% of the patients who responded to treatment were able to stop treatment and maintain a good response for at least 6 months. The Committee concluded that because there are no long-term clinical trial data, the estimates of Rothrock et al. and Hanlon et al. are likely to be the best current estimates of the duration of benefit for people who respond to botulinum toxin type A in clinical practice in the UK.
The Committee discussed the adverse reactions of treatment with botulinum toxin type A for chronic migraine. It noted the adverse reactions reported in the trials with botulinum toxin type A (see section 3.8). It heard from the patient experts that there is often pain around an injection site lasting a few days after treatment with botulinum toxin type A. However, people would be willing to tolerate the adverse reactions with botulinum toxin type A treatment to reduce the frequency or severity of their chronic migraine. The Committee concluded that botulinum toxin type A is generally well tolerated; a conclusion supported by the patient experts and clinical specialists.
The Committee considered the cost effectiveness of botulinum toxin type A compared with standard care, based on the manufacturer's economic model and the critique by the ERG, in the context of the decision problem. The Committee was aware that the scope specified that the population should include adults with chronic migraine whose condition has failed to respond to at least three prior pharmacological prophylaxis therapies, and whose medication overuse has been appropriately managed. The Committee was aware that the manufacturer had focused on this population in a sensitivity analysis and that its main submission compared botulinum toxin type A with placebo in people whose condition has failed to respond to at least one prior preventive medication. The Committee noted comments from the clinical specialists that people first presenting with chronic migraine will be prescribed a range of oral preventive medication options before treatment with botulinum toxin type A is considered. The Committee concluded that the main decision problem proposed by the manufacturer, comparing botulinum toxin type A with placebo in people whose condition has failed to respond to at least one prior preventive medication, did not reflect clinical practice. It concluded that it was only relevant for the Committee and the NHS to consider the clinical and cost effectiveness of botulinum toxin type A in people whose chronic migraine has failed to respond to at least three prior preventive medications and that the trial data from this subgroup should be used to calculate the transition probability matrices used in the economic model.
The Committee discussed the revised economic model submitted by the manufacturer as part of the response to consultation. The Committee noted that the revised model included their preferred assumptions and inputs. It was aware that the revised model included a negative stopping rule of a two health state reduction in two cycles of treatment. The Committee noted that the manufacturer's cumulative analyses on the impact of each of the Committee's preferred assumptions resulted in a revised deterministic ICER for botulinum toxin type A compared with placebo of £15,300 per QALY gained when different utilities are applied to each arm, and £24,500 per QALY gained when the same utilities are applied to each arm. The Committee noted that the revised probabilistic ICERs for botulinum toxin type A compared with placebo were similar to the deterministic ICERs. The Committee concluded that the large differences between the deterministic and probabilistic ICER in the original model were no longer apparent in the revised economic model.
The Committee considered the costs and resource use in the revised economic model. The Committee was satisfied that its request for the placebo follow-up cost to be the same as the administration cost of botulinum toxin type A had been resolved because the revised economic model had included a standard NHS neurological outpatient follow-up reference cost of £140 for the placebo follow-up cost. It noted that the routine care costs used in the placebo arm were applied to people who discontinue botulinum toxin type A because of lack of efficacy in the model, and an average accident and emergency cost of £77.33 was used by the manufacturer, as requested in the Committee's preliminary recommendations. The Committee considered the additional clarification on resource use supplied by the manufacturer. It noted the ERG's concern that the resource use data for people from the UK with chronic migraine in the IBMS presented by the manufacturer included a small number of people (n=57), and a significant number of outlying results (for patients whose resource use contributed to most of the total resource use observed). The Committee concluded the Blumenfeld et al. resource use data to be most appropriate given the small number of people from the UK with chronic migraine in the IBMS.
The Committee noted that its preliminary recommendations requested any revised economic model to incorporate a range of negative stopping rules based on the reduction in the number of headache days per 28 days after two cycles of treatment for people with chronic migraine. The Committee noted from comments received during consultation that there was agreement between the manufacturer and the clinical community that a 50% response rate is considered to be too high, and that a 30% response rate recommended by the British Association for the Study of Headache is used in clinical practice. The Committee noted that the manufacturer's revised base-case deterministic ICER (based on a negative stopping rule of less than 30% reduction in headache days per month) for botulinum toxin type A compared with placebo was £15,000 per QALY gained when applying different utilities, and £24,900 per QALY gained when applying the same utilities. The Committee concluded that a 30% response rate (that is, a 30% reduction in the number of headache days per month after two cycles of treatment) was the most clinically relevant and reasonable negative stopping rule on which to base its decision.
The Committee discussed the appropriate positive stopping rule. It noted the consultation comments that a positive stopping rule, in which patients stop treatment if their migraine has changed to episodic migraine and remained stable in episodic migraine for at least 3 months, is the most clinically appropriate. The Committee also noted that the marketing authorisation for botulinum toxin type A does not include use in people with episodic migraine. It therefore concluded that a positive stopping rule in which patients stop treatment if their condition has changed to episodic migraine (that is, fewer than 15 headache days per month) for three consecutive months is the most clinically relevant. However, the Committee recognised that according to the only published longer term follow-up of patients who responded to treatment with botulinum toxin type A, only 24–25% were able to stop treatment with botulinum toxin type A and maintain a good response for at least 6 months (Rothrock et al. and Hanlon et al.) The Committee concluded that these publications provided the most plausible estimate for the likely implementation of the positive stopping rule in clinical practice in England and Wales, with 24–25% being the most appropriate figure on which to base a positive stopping rule in the economic model.
The Committee considered the use of the same or different utilities within each health state in the botulinum toxin type A and placebo arms. The Committee noted comments from consultees and commentators that treatment with botulinum toxin type A is associated with a range of clinical and non-clinical benefits, which are not included in the reduction in the number of headache days per month. It considered data on botulinum toxin type A on improving secondary outcomes, including the number of headache episodes, the number of migraine or probable migraine days, the number of moderate or severe headache days, and the number of acute medication days from the pooled PREEMPT trial data and evidence given by the patient experts in writing and at the Committee meeting. The Committee was also aware of an online survey of 60 people with chronic migraine recently conducted by Migraine Action, which also provided supportive data. However, the Committee was aware of the absence of robust data supporting the size of the difference in utility values in each arm. The Committee concluded that although using different utility values within each health state in the botulinum toxin type A and the placebo arm was plausible and better than applying the same utility values within each health state to calculate the most appropriate ICER for considering cost effectiveness, there was still considerable uncertainty around the degree to which differential utilities existed within each health state.
The Committee was aware that its preliminary recommendations stated that any revised economic model should explore removing the non-monotonicity in the original model, that is, for the botulinum toxin type A arm, the utility in health state 5 (20–23 headache days per month) is lower than the utility in health state 6 (24–28 headache days per month). It heard from the manufacturer that the non-monotonicity in the utility values in the original model was caused by the small number of people in the three or more prior preventive treatment group. The Committee further noted the ERG's explanation that the non-monotonicity was not surprising given that health states were defined in terms of the number of headache days per 28 days, while the MSQ utility mapping functions were constructed so as to pick up other elements of the condition (such as severity or intensity of headaches). The Committee considered that this explanation was plausible and that removing the non-monotonicity had little impact on the ICERs. It concluded that there was no need to remove the non-monotonicity in the updated economic model.
The Committee considered the explanation from the manufacturer on the way that utilities had been calculated, noting the way in which utilities had been mapped from the MSQ. The Committee noted the ERG's concern that the non-MSQ parameter values were different in the botulinum toxin type A and placebo utility mapping functions. It agreed that the manufacturer had not provided a clear rationale as to why these parameter values should be different. The Committee noted that when the ERG equalised the non-MSQ parameter values, less non-monotonicity was observed, and the deterministic ICER was £18,900 per QALY gained when applying different utility values to each arm. The Committee concluded that this was the most plausible ICER because it incorporated the Committee's preferred inputs and assumptions including a 30% negative stopping rule, applied different utilities to treatment arms (within the Committee's reservations stated in section 4.13), and equalised the non-MSQ parameter values in the utility mapping functions.
The Committee discussed whether botulinum toxin type A was an appropriate use of NHS resources for the prevention of headaches in adults with chronic migraine. It noted that botulinum toxin type A is the only technology with a UK marketing authorisation for the prevention of headaches in adults with chronic migraine, and that the method of administration of botulinum toxin type A is novel compared with other preventative treatments used in the management of chronic migraine. The Committee accepted the plausibility of using different utility values in the botulinum toxin type A and placebo arms (within the reservations expressed in section 4.13), and considered that the utility values in the economic model encompass the major health-related quality of life benefits associated with treatment with botulinum toxin type A, including duration and intensity of migraine, reduction in symptoms, need for rescue treatment, and lower dose of acute medication. It therefore considered that all of the significant or substantial health benefits of botulinum toxin type A treatment had been included in the model. The Committee concluded that because the most plausible ICER presented was less than £20,000 per QALY gained, botulinum toxin type A could be considered an appropriate use of NHS resources for the prevention of headaches in adults with chronic migraine that has not responded to at least three prior pharmacological prophylaxis therapies and whose condition is appropriately managed for medication overuse.
The Committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its preliminary recommendations in any way. The Committee was aware that during scoping, consultees and commentators suggested that there is inequity in access to diagnosis and treatment of migraine for people whose first language is not English. It also noted that comments suggested that there is unequal access to treatment for chronic migraine for people with mental health issues and that greater recognition of chronic migraine as a significant clinical problem will help eliminate discrimination in the workplace. It heard from the patient expert and from consultation comments that chronic migraine is more prevalent in women than men. The Committee was aware that consultation comments also suggested that there is inequity in access to treatment with botulinum toxin type A for people on low income. The Committee did not consider access to treatment for people whose first language is not English to be relevant because the recommendations do not specify a particular English language based test for the diagnosis of chronic migraine. Further, because the recommendations do not differentiate between any groups of people, the Committee concluded that its recommendations did not limit access to the technology for any specific group compared with other groups.
# Summary of Appraisal Committee's key conclusions
TA260
Appraisal title: Botulinum toxin type A for the prevention of headaches in adults with chronic migraine
Section
Key conclusion
Botulinum toxin type A is recommended as an option for the prophylaxis of headaches in adults with chronic migraine according to 1.1, 1.2 and 1.3.
Although the clinical trial evidence demonstrated statistically significant benefits of botulinum toxin type A treatment compared with placebo for a number of outcomes, the absolute numerical differences were small to modest. Further, there was a large placebo effect seen in the clinical trials.
The Committee concluded that the most appropriate use of botulinum toxin type A in clinical practice would be in people whose chronic migraine has failed to respond to at least three prior preventive medications.
The Committee noted that the manufacturer's revised model included the Committee's preferred assumptions and inputs. The Committee considered botulinum toxin type A to be a cost effective use of NHS resources only if positive and negative stopping rules were applied as given in section 1.1 and 1.2. They also noted that the key cost drivers were the use of different utilities between the botulinum toxin type A and placebo arm for a given health state, and different positive and negative stopping rules.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee considered chronic migraine to be a debilitating condition which seriously affects health-related quality of life.
The Committee heard from the patient experts that many people with chronic migraine would consider any degree of response to treatment to be valuable and that therefore further treatment options were important.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee noted the improvements in quality of life for patients whose condition responded to botulinum toxin type A.
The Committee considered that the utility values in the economic model encompass the major health-related quality of life benefits associated with treatment with botulinum toxin type A, including duration and intensity of migraine, reduction in symptoms, need for rescue treatment, and lower dose of acute medication. It therefore considered that all of the significant or substantial health benefits of botulinum toxin type A treatment had been included in the model.
What is the position of the treatment in the pathway of care for the condition?
The decision problem proposed by the manufacturer, comparing botulinum toxin type A with placebo in people whose condition has failed to respond to at least one prior preventative medication did not reflect clinical practice. The Committee concluded that it was only relevant to consider the clinical and cost effectiveness of botulinum toxin type A in people whose chronic migraine has failed to respond to at least three prior preventive medications.
Adverse reactions
The Committee noted the adverse reactions reported in the trials with botulinum toxin type A. It heard from the patient experts that there is often pain around an injection site lasting a few days after treatment with botulinum toxin type A. However, people would be willing to tolerate the adverse reactions with botulinum toxin type A treatment to reduce the frequency or severity of their chronic migraine. The Committee concluded that botulinum toxin type A is generally well tolerated; a conclusion supported by the patient experts and clinical specialists.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee considered the evidence on the clinical effectiveness of botulinum toxin type A for the prevention of headaches in adults with chronic migraine from the PREEMPT trials, which compared botulinum toxin type A with placebo.
Relevance to general clinical practice in the NHS
At baseline, patients in the clinical trials had fewer headache days per month (a mean of 19) than people with chronic migraine in secondary care in the UK (a mean of 25–26 headache days per month).
The PREEMPT studies had a limited duration of follow-up (1 year).
Uncertainties generated by the evidence
The large placebo effect seen in the trials may have been increased by people in the active treatment arm realising that they were receiving botulinum toxin type A because of its side effects.
The duration of follow-up in the PREEMPT trials was short (1 year) and the study design, which meant that all patients received the active drug from week 24, could not exclude natural improvements in people's condition over time.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee did not consider there to be any relevant subgroups.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
Although the clinical trial evidence demonstrated statistically significant benefits of botulinum toxin type A treatment compared with placebo for a number of outcomes, the absolute numerical differences were small. Further, the Committee noted the large placebo effect seen in the trials.
Evidence for cost effectiveness
Availability and nature of evidence
There was no relevant published literature on the cost effectiveness of botulinum toxin type A for people with chronic migraine.
The Committee considered the cost effectiveness of botulinum toxin type A compared with standard care, based on the manufacturer's economic model and the critique by the ERG, in the context of the decision problem.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted that the revised model included the Committee's preferred assumptions and inputs.
The Committee concluded that although using different utility values within each health state in the botulinum toxin type A and the placebo arm was plausible and better than applying the same utility values within each health state to calculate the most appropriate ICER for considering cost effectiveness, there was still considerable uncertainty around the degree to which differential utilities existed within each health state.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
There was non-monotonicity in the utility values, that is, for the botulinum toxin type A arm, the utility in health state 5 (20–23 headache days per month) is lower than the utility in health state 6 (24–28 headache days per month).
The non-MSQ parameter values were different in the botulinum toxin type A and placebo utility mapping functions. The manufacturer had not provided a clear rationale as to why these parameter values should be different.
The Committee considered that all of the significant or substantial health benefits of botulinum toxin type A treatment had been included in the economic model.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee concluded that botulinum toxin type A could be considered an appropriate use of NHS resources for the prevention of headaches in adults with chronic migraine that has not responded to at least three prior pharmacological prophylaxis therapies.
What are the key drivers of cost effectiveness?
The Committee considered the key cost drivers to be:
different utilities between the botulinum toxin type A and placebo arm for a given health state
different positive and negative stopping rules.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee concluded that the most plausible ICER was £18,900 per QALY gained, because it incorporated the Committee's preferred inputs and assumptions including a 30% negative stopping rule, applied different utilities to treatment arms (within the Committee's reservations stated in 4.13), and equalised the non-MSQ parameter values in the utility mapping functions.
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable
End-of-life considerations
Not applicable
Equalities considerations and social value judgements
The Committee was aware that during scoping, consultees and commentators suggested that there is inequity in access to diagnosis and treatment for people whose first language is not English. It also noted that comments suggested that there is unequal access to treatment for chronic migraine for people with mental health issues and that greater recognition of chronic migraine as a significant clinical problem will help eliminate discrimination in the workplace. It heard from the patient expert that chronic migraine is more prevalent in women than men. The Committee was aware that consultation comments also suggested that there is inequity in access to treatment with botulinum toxin type A for people on low income. The Committee did not consider access to treatment for people whose first language is not English to be relevant because the recommendations do not specify a particular English language based test for the diagnosis of chronic migraine. It concluded that its recommendations do not limit access to the technology for any specific protected group compared with other groups.
# Related NICE guidance
# Published
Percutaneous closure of patent foramen ovale for recurrent migraine. NICE interventional procedure guidance 370 (2010).
Deep brain stimulation for intractable trigeminal autonomic cephalalgias. NICE interventional procedure guidance 381 (2011).
# Under development
NICE is developing the following guidance (details available from www.nice.org.uk):
Diagnosis and management of headaches in young people and adults. NICE clinical guideline. Expected date of publication September 2012.# Review of guidance
The guidance on this technology will be considered for review in June 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveJune 2012# Changes after publication
February 2014:
minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Botulinum toxin type\xa0A is recommended as an option for the prophylaxis of headaches in adults with chronic migraine (defined as headaches on at least 15\xa0days per\xa0month of which at least 8\xa0days are with migraine):\n\nthat has not responded to at least three prior pharmacological prophylaxis therapies and\n\nwhose condition is appropriately managed for medication overuse.\n\nTreatment with botulinum toxin type\xa0A that is recommended according to 1.1 should be stopped in people whose condition:\n\nis not adequately responding to treatment (defined as less than a 30% reduction in headache days per month after two treatment cycles) or\n\nhas changed to episodic migraine (defined as fewer than 15\xa0headache\xa0days per\xa0month) for three consecutive months.\n\nPeople currently receiving botulinum toxin type A that is not recommended according to 1.1 and 1.2 should have the option to continue treatment until they and their clinician consider it appropriate to stop.', 'The technology ': "Botulinum toxin type\xa0A (Botox, Allergan) is a purified neurotoxin complex, which is derived from the bacterium Clostridium botulinum. It has neuromuscular transmitter blocking effects. It has a UK marketing authorisation 'for the prophylaxis of headaches in adults with chronic migraine (headaches on at least 15\xa0days per\xa0month of which at least 8\xa0days are with migraine)'. The recommended reconstituted dose is 155–195 units, administered intramuscularly as 0.1\xa0ml (5\xa0units) injections to between 31 and 39\xa0sites around the head and back of the neck. The recommended re-treatment schedule is every 12\xa0weeks (see the summary of product characteristics).\n\nThe summary of product characteristics lists the following common adverse reactions that may be associated with botulinum toxin type\xa0A treatment: headache, migraine, facial paresis, eyelid ptosis, pruritus, rash, neck pain, myalgia, musculoskeletal pain, musculoskeletal stiffness, muscle spasms, muscle tightness, muscular weakness, and injection site pain. It states that 'in general, adverse reactions occur within the first few days following injection and while generally transient, may have a duration of several months or, in rare cases, longer'. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe net price of a 200\xa0unit vial is £276.40 (excluding VAT; 'British national formulary' [BNF] edition 63). The manufacturer estimates that the administration cost is £73 per treatment, based on a total treatment time of less than 30\xa0minutes. The total cost for treatment and administration of treatment per 12\xa0week cycle, assuming no vial sharing, is therefore expected by the manufacturer to be £349.40. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of botulinum toxin type\xa0A and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe decision problem defined in the scope asked whether botulinum toxin type\xa0A is clinically and cost effective in adults whose chronic migraine has failed to respond to at least three prior pharmacological prophylaxis therapies and whose medication overuse has been appropriately managed, compared with standard management without botulinum toxin type\xa0A excluding invasive procedures. The manufacturer addressed this decision problem in its submission by carrying out a sensitivity analysis.\n\n# Clinical effectiveness\n\nTo establish the efficacy of botulinum toxin type\xa0A, the manufacturer performed a systematic review to identify randomised controlled trials comparing botulinum toxin type\xa0A with placebo. The manufacturer identified seven relevant trials, of which four were against an active comparator and were excluded from consideration. Of the three remaining trials, two were large phase III trials and were the focus of the manufacturer's submission. The third was a small trial (n=60) that was excluded from further discussion because of concerns regarding its quality and relevance to the decision problem.\n\nEvidence from the two randomised controlled trials, PREEMPT 1 and PREEMPT 2 (phase III trials evaluating migraine preventive therapy), was presented, as well as the pooled results from these trials. The trials were identically designed with a 56-week treatment period. In total, 688\xa0people were recruited into the botulinum toxin type\xa0A arms of the trials and 696 into the placebo arms. Patients were stratified by their use of acute headache pain medication at baseline. The first phase of the trial was a 24-week double-blind phase, in which patients received a series of 31–39 intramuscular injections of botulinum toxin type\xa0A or placebo (saline), at day\xa00 and week\xa012. In the second phase of the trial, from week 24 to 56, patients entered into a 32-week, open-label phase in which all patients continuing in the trials received botulinum toxin type\xa0A at weeks\xa024, 36 and 48.\n\nThe PREEMPT trials enrolled people aged 18 to 65\xa0years who had chronic migraine. All patients had to have had at least 15\xa0headache\xa0days in the 28\xa0days before week\xa00, and at least 50% of headache days had to be migraine or probable migraine days. Most people in the trials received at least one prior preventive treatment (approximately 64%), and approximately 35% of the patients had received three or more prior preventive treatments. Most people in the trials overused acute pain medication (more than 64%). The PREEMPT trials recruited people from North America and Europe, including from the UK. Patients were excluded if they used headache preventive medications within 4\xa0weeks of the start of baseline, or if their headache was attributed to other disorders such as medication overuse. However, chronic migraine patients with protocol-defined overuse of acute medications were included and this was a stratification factor at randomisation.\n\nThe characteristics of the patients in the trials were similar, with no statistically significant differences between baseline characteristics in the PREEMPT 2 trial. In PREEMPT 1, most differences between groups were statistically non-significant, except for mean headache episodes and mean migraine episodes, which were lower in the botulinum toxin type\xa0A group compared with the placebo group, and the number of cumulative headache hours, which were higher in the botulinum toxin type\xa0A group compared with the placebo group.\n\nAll efficacy analyses from the two trials used the intention-to-treat population, which included all randomised patients. The reduction in frequency of headache days (the primary endpoint) was statistically significant in both trials. In PREEMPT 1, there was a reduction of 7.8\xa0headache\xa0days from 20.0 (per 28\xa0days) at baseline for patients treated with botulinum toxin type\xa0A, compared with a reduction of 6.4\xa0headache\xa0days from 19.8 at baseline for those in the placebo arm (p=0.006). In PREEMPT 2, there was a reduction of 9.0\xa0headache\xa0days from a baseline of 19.9 in the botulinum toxin type\xa0A arm, compared with a reduction of 6.7\xa0headache\xa0days from a baseline of 19.7\xa0days for those in the placebo arm (p<0.001). The difference between the two arms of the trials for the frequency of headache episodes was not statistically significant in the PREEMPT\xa01 trial, but was statistically significant in the PREEMPT\xa02 trial. The following were statistically significantly lower in the botulinum toxin type\xa0A arm compared with the placebo arm in both trials: total cumulative hours of headache on headache days; the frequency of migraine days, and moderate to severe headache days. There was no difference in the intake of acute pain medication between the arms in both studies, although there was statistically significant lower triptan use in the botulinum toxin type\xa0A arm. The pooled results of the two trials were consistent with the results from the individual studies: for the outcome of frequency of headache days (per 28\xa0days), the pooled botulinum toxin type\xa0A group had a statistically significant reduction of 8.4\xa0headache\xa0days from 19.9\xa0days at baseline, compared with a reduction of 6.6\xa0headache\xa0days from 19.8\xa0days in the pooled placebo group (p<0.001).\n\nThe PREEMPT trials measured health-related quality of life, using the headache impact test 6 (HIT-6) and the migraine-specific quality of life questionnaire (MSQ). The HIT-6 was developed for use in people with general headache whereas the MSQ was developed specifically for people with chronic migraine. At 24\xa0weeks, there were statistically significant improvements from baseline in quality of life as measured by the HIT-6 and the MSQ for people in the botulinum toxin type\xa0A arm compared with those in the placebo arm in both trials.\n\nThe most frequently reported adverse reactions occurring at a higher incidence in the pooled botulinum toxin type\xa0A group than in the pooled placebo group were: neck pain, headache, migraine, eyelid ptosis, musculoskeletal stiffness and muscular weakness. Of these, neck pain was the only one to occur at a rate of 5% or more in the pooled botulinum toxin type\xa0A arm compared with the pooled placebo arm.\n\nA subgroup analysis was conducted for people who had previously received three or more headache preventive medications, for the outcome of frequency of headache days (per 28\xa0days), using the pooled data from the PREEMPT trials (231\xa0people in the botulinum toxin type\xa0A arm and 248 in the placebo arm). The pooled botulinum toxin type\xa0A group had a statistically significant reduction of 7.4\xa0headache\xa0days from 20.0\xa0days at baseline, compared with a reduction of 4.7 headache\xa0days from 20.2\xa0days at baseline in the pooled placebo group (p<0.001). Treatment efficacy for frequency of headache days was similar for the subgroup of people who had previously received three or more preventive treatments, those who had previously received two preventive treatments, and those who had previously received one or more preventive treatments.\n\n# Cost effectiveness\n\n## Original submission\n\nThe manufacturer carried out a systematic review for economic evaluations of botulinum toxin type\xa0A for people with chronic migraine, but no relevant published studies were identified.\n\nThe manufacturer developed a Markov model using the pooled data from the two PREEMPT trials, comparing botulinum toxin type\xa0A with placebo. Only approximately 35% of the population met the criteria set out in the NICE scope (people whose condition has failed to respond to three or more prior pharmacological prophylaxis therapies). Because of the similarity in efficacy, (see section 3.9) the manufacturer used the population whose condition had failed to respond to one or more pharmacological therapies, which was approximately 64% of the trial population, in order to increase the statistical power.\n\nSix health states were defined in the model according to the number of headache days per month: 0–3 (health state 1), 4–9 (health state 2), 10–14 (health state 3), 15–19 (health state 4), 20–23 (health state 5) and 24 or more (health state 6). Patients could enter the model in any of the three chronic migraine states (health states 4,5 or 6); chronic migraine was defined as 15\xa0headache\xa0days or more per 28\xa0days. The cycle length was 12\xa0weeks, which is the same as the frequency of administration of botulinum toxin type\xa0A in the trials. The model used the transition probabilities observed in the clinical trials, which include the transitions between the six health states as well as an additional transition to discontinuation of therapy. For the placebo arm, the second cycle transition probability was repeatedly applied after week\xa024. For the botulinum toxin type\xa0A arm, the same transitional probability matrix was applied for the third, fourth and fifth cycles; this figure was calculated by averaging these three cycles. For people continuing on treatment in cycles 6–9, the same average figure was used. The time horizon used in the model was 2\xa0years, in line with the manufacturer's expected maximum treatment duration with botulinum toxin type\xa0A. For the first of the 2\xa0years, trial data were used if possible, with extrapolation used for the second year, using the last observations from the trial.\n\nAs well as using the discontinuation data from the clinical trials in the model, two treatment (dis)continuation rules were applied. A negative stopping rule was applied at week\xa024 for people whose condition responded insufficiently to botulinum toxin type\xa0A. Insufficient response was defined as people having an improvement of less than two health states (a reduction of between 5 and 10\xa0headache\xa0days per 28\xa0days depending on both the number of headache days and the corresponding health state at the start of treatment) after two successive cycles of treatment. After discontinuation, they moved between health states using the transition probabilities for placebo treatment, but did not incur treatment costs. A positive stopping rule was applied at week\xa048 for people whose condition had changed to episodic migraine (fewer than 15\xa0headache\xa0days per 28\xa0days). The model assumed that after 1\xa0year, people whose condition had changed to episodic migraine stopped treatment with botulinum toxin type\xa0A and remained stable in the episodic migraine health states thereafter.\n\nTwo mapping equations were derived to map the MSQ data (as collected during the trials) to EQ-5D utility, so that utilities could be attached to each health state. One equation was used to predict utilities for people in the chronic migraine health states, and the other was used for predicting utilities in the episodic health states. Utility was different for each health state in this model and also between treatments within the same health state, the latter being justified on the grounds that treatment with botulinum toxin type\xa0A was shown to affect a broad range of relevant outcomes such as the severity and intensity of headaches, as well as the number of headache days. Utility was predicted for each health state using the patient-level data from the trials. This was done by grouping patients by health state and calculating the mean utility per treatment group. Utility values used in the model ranged between 0.479 and 0.746 depending on the treatment and on the number of headaches experienced. Adverse events affecting health-related quality of life were captured in the model by applying discontinuation rates. There were assumed to be no additional costs relating to adverse events.\n\nThe manufacturer assumed that chronic migraine in the relevant patient population would be managed in a specialist setting, with associated consultant-related costs. Administration time was assumed to be 30\xa0minutes, at a cost of £73.00. Cost of treatment was calculated based on one 200\xa0unit vial of botulinum toxin type\xa0A at £276.40, with no vial sharing, leading to a total cost of £349.40 per 12\xa0week cycle. For people in the placebo arm (standard care), the cost was assumed to be £36.50 per 12\xa0weeks, which is based on a 15\xa0minute appointment with a consultant every 24\xa0weeks to optimise acute therapy. Costs for GP visits, accident and emergency attendance, hospitalisation and the cost of triptan were modelled for each health state but only three different costs were used; for health state 1, states 2–3 and states 4–6. These costs came from a poster by Bloudek et al. (2011) of Scottish resource use according to the International Burden of Migraine Study (IBMS). Costs and quality-adjusted life years (QALYs) were discounted at a rate of 3.5% per\xa0year.\n\nFor people whose condition failed to respond to at least three prior preventive medications, the total cost and QALYs for placebo were £1895 and 1.20 respectively, compared with a total cost of £2438 and 1.29 QALYs for botulinum toxin type\xa0A. This gave an incremental cost and incremental QALYs of £543 and 0.09 respectively and an ICER of £6083 per QALY gained for botulinum toxin type\xa0A compared with placebo. There was a 69.1% probability of botulinum toxin type\xa0A being cost effective if the maximum acceptable ICER was £20,000 per QALY gained. The manufacturer did not report a central estimate of the ICER calculated by probabilistic modelling. For the wider population, which included people whose condition had not responded to one or more prior preventive medications, the costs and QALYs were similar, with an ICER of £5828 per QALY gained for botulinum toxin type\xa0A compared with placebo.\n\nThe manufacturer presented a variety of sensitivity analyses, and for most of the cases the ICER for botulinum toxin type\xa0A compared with placebo stayed under £10,000 per QALY gained. Excluding the positive and negative stopping rules increased the ICER to £15,294 per QALY gained. Restricting the time horizon to 1\xa0year increased the ICER to £14,098 per QALY gained.\n\nThe manufacturer identified an error in its analyses, in which the original ICERs were based on utilities derived from all people in the trials. It submitted revised ICERs using utilities from people whose condition failed to respond to at least three prior preventive medications. After correcting for the error, the ICER for botulinum toxin type\xa0A compared with placebo increased from £6083 to £6434 per QALY gained.\n\n## ERG critique of original submission\n\nThe ERG noted that the trials were generally of good quality. The ERG pointed out that in the PREEMPT 1 trial, at baseline patients in the botulinum toxin type\xa0A group had a statistically significantly lower frequency of migraine episodes (11.5 compared with 12.7, p=0.006) and frequency of headache episodes (12.3 compared with 13.4, p=0.023), but had statistically significantly more cumulative hours of headache on headache days (295.7 compared with 274.9, p=0.022) than those in the placebo group. The original primary outcome in PREEMPT 1 was to have been frequency of headache episodes, but this was changed to headache days because of new guidelines for the conduct of clinical trials in chronic migraine. This was considered reasonable by the ERG.\n\nThe ERG found botulinum toxin type\xa0A to be effective regardless of the number of previous preventive medications taken. As the number of previous preventive medications rose, so did the relative effectiveness of botulinum toxin type\xa0A compared with placebo (reductions of 2.3 and 2.7\xa0headache\xa0days per\xa0month for the one prior preventive medication and three or more prior preventive medications subgroups respectively). In addition, the ERG observed that the placebo effect decreased as the number of previous preventive medications increased.\n\nThe ERG stated that a noticeable feature of the trial data was the size of the improvement on placebo, which lasted for at least 24\xa0weeks and was only modestly less than on active treatment. In addition the ERG pointed out that the efficacy of botulinum toxin type\xa0A was greatest with the first injection and that the second injection had much less effect, with similar efficacy to that of the second placebo injection. The ERG therefore queried whether a negative stopping rule could be applied after the first injection.\n\nThe ERG's main concern about the design of the PREEMPT trials was about whether blinding was maintained and if not, what the effect of this was on the results of the trials. The ERG pointed out that in previous botulinum toxin type\xa0A trials, 70% of patients receiving botulinum toxin type\xa0A correctly guessed what they had received, because of changes in muscle tone such as reduced wrinkling of the forehead. The ERG further explained that because unblinding is an important factor in controlled trials of preventive treatment of chronic migraines, the International Headache Society guidelines recommend that subjects and investigators should be questioned at the end of trials about whether they thought active or placebo was administered during the trial. This was not done in the PREEMPT trials.\n\nThe ERG considered the manufacturer's model to be reasonable for the decision problem. The ERG noted that the model and trial data sets for headache days per month at week\xa024 corresponded poorly and that this overestimated the net impact of botulinum toxin type\xa0A by 53%. Yet this overestimate had no direct impact on cost effectiveness because it was the distribution between health states that determined the costs and QALYs within the model. The ERG observed that within the validation data, the model and trial were reported by the manufacturer as having no patients in health states 5 and 6 at week\xa024 in the botulinum toxin type\xa0A arm. The ERG noted that this could be because of the negative stopping rule being applied in both sets of data, with these patients falling into the discontinuation category, but could not verify this. Uncertainty remained around this point and also the distribution between health states among those patients modelled as discontinuing because of the negative stopping rule, but who were followed up within the trial. The ERG noted that there were no clinical data to support the use of the two stopping rules. The ERG queried whether the negative stopping rule at 24\xa0weeks in the model would apply in practice, and whether the requirement for an improvement could be based on either one or two health states. It found that an improvement of only one health state within two cycles increased the ICER for the three or more prior preventive medications subgroup from £6083 per QALY gained to £8354 per QALY gained. The ERG doubted that the positive stopping rule at week\xa048 was likely to be implemented. It queried how long people who had stopped treatment would remain stable before needing re-treatment, noting 2-year follow-up data from a published abstract by Rothrock et al. (2011), which estimated the duration of response to treatment with botulinum toxin type\xa0A based on a 50% reduction in the number of headache days per month. Of a total sample of 100\xa0people whose chronic migraine responded to treatment with botulinum toxin type\xa0A, 68% maintained a good response to treatment with continued injections at a frequency of 3.2\xa0months. A further 24% were able to stop treatment and maintain a good response for at least 6\xa0months; and 8% relapsed back to chronic migraine. The ERG found that removing the positive stopping rule roughly doubled the ICER for the three or more prior preventive medications subgroup for botulinum toxin type\xa0A arm compared with placebo, from £6083 per QALY to £12,542 per QALY gained.\n\nThe ERG noted that there were wide disparities between the model inputs for resource use used in the economic model, which were based on the poster by Bloudek et al., and those reported in a published paper by Blumenfeld et al. (2011). The ERG noted that the two sources had reported results from the same international study, however Bloudek et al. appeared to include costs based on Scottish implementation, with no information on the number and ages of the patients, GP visits, hospital outpatient and accident and emergency attendances, hospital admissions or medication use. The ERG noted that because the higher costs for health states 4–6 were driven by hospital admission costs and were the same in each of the health states 4–6, details of the Bloudek et al. poster were important because it could be that the manufacturer's estimate of resource use was too high. It was for this reason that the ERG preferred the resource use detailed in Blumenfeld et al. which contained more detailed data. The ERG had concerns about the applicability of international data on hospital admission rates for chronic migraine to clinical practice in England and Wales, but recognised that Blumenfeld et al. contained the most detailed data available.\n\nThe ERG observed that utility values were calculated using MSQ estimations at 24\xa0weeks, when the full effect of botulinum toxin type\xa0A had occurred. The ERG noted that the manufacturer's model generally assigned higher utility values for the botulinum toxin type\xa0A arm than the placebo arm for each health state and that this feature of the model accounted for about half of the anticipated QALY gain for botulinum toxin type\xa0A. It noted that for this to be valid, there would have to be a difference in other features such as: the number of headaches experienced during a headache day, the duration of these headaches, or the proportion of headaches that were migraines. The ERG noted that this was plausible, although it was unsure whether the substantial difference in utilities in each health state was justified given the small absolute differences in secondary endpoints in the PREEMPT trials. The ERG commented that the number of headache days per month was not included in the estimate of utilities, which instead relied on IBMS MSQ data. The manufacturer had outlined a regression analysis from the EQ-5D in the IBMS and found that the EQ-5D and the number of headache days per month were statistically significantly negatively correlated. The ERG used these data and showed very little difference in utilities between botulinum toxin type\xa0A and placebo in a given health state. The ERG queried whether the IBMS MSQ data could be used to estimate utilities given that the IBMS included a different population to that described in the decision problem. It noted that a more appropriate estimation of utilities would encompass both MSQ and HIT-6 data. The ERG also explained that there is non-monotonicity (an anomaly in which the utility values are not consistently increasing or decreasing) in the utility values in the botulinum toxin type\xa0A arm in which people in health state 5 (20–23 headache\xa0days per\xa0month) have a lower utility than those in health state 6 (24–28 headache\xa0days per\xa0month). The ERG commented that this may highlight some uncertainty between the mapping of MSQ data to utilities and correspondence with the model structure as defined by the number of headache days per month.\n\nThe ERG noted that the model included the cost of administering botulinum toxin type\xa0A and of placebo, based on 30 and 15\xa0minutes of neurologist time respectively. The ERG stated that review of a patient and administration of botulinum toxin type\xa0A may take between 30\xa0minutes and 1\xa0hour, depending on the experience of the person injecting and the possibility of complications during administration. As a result the ERG commented that the cost of administering botulinum toxin type\xa0A based on 30\xa0minutes of neurologist time may be too optimistic. It also noted that the appropriate cost of follow-up outpatient consultations should be the standard NHS neurological outpatient follow-up reference cost of £140. The ERG noted that administration of botulinum toxin type\xa0A was reported to be offset by cost saving because of reductions in GP visits, inpatient admissions and accident and emergency attendance, but it considered the amount of the cost saving to be overestimated.\n\nThe ERG explained that the model submitted by the manufacturer was non-linear, with a central probabilistic estimate of cost effectiveness more than double that of the deterministic estimate, based on ERG exploratory analyses. It stated that some elements of the probabilistic modelling seemed unwarranted; for example, treating the identity matrix as having an uninformed prior and modelling it probabilistically. The ERG found that removing these elements reduced the degree of non-linearity but did not eliminate it. The ICER for the three or more prior preventive medications subgroup increased from the manufacturer's deterministic ICER of £6083 per QALY gained to the probabilistic ICER of £11,447 per QALY gained if the ERG's revisions were applied. If the ERG's revisions were not applied the probabilistic ICER was estimated at £14,004 per QALY gained.\n\nThe ERG conducted a number of different exploratory sensitivity analyses. In these analyses, the ERG used the manufacturer's model with a number of modifications. The modifications included:\n\nA neurologist outpatient face-to-face follow-up cost of £140 for botulinum toxin type\xa0A administration and placebo follow-up (instead of £73 administration cost of botulinum toxin type\xa0A administration and £36.50 follow-up placebo cost, based on 30 and 15\xa0minutes of neurologist time respectively).\n\nPlacebo routine care costs incorporated for patients stopping therapy in the botulinum toxin type\xa0A arm (instead of no ongoing routine care costs).\n\nResource use estimates from Blumenfeld et al., who included all UK participants from the IBMS (instead of from Bloudek et al. who appeared to use costs based on Scottish implementation).\n\nTransition probability matrices from the three or more prior preventive medications patient subgroup (instead of from the one prior preventive medication population).\n\nAn average accident and emergency cost of £77.33 (instead of £90.94).\n\nThe ERG reported that applying all the above modifications (using the manufacturer's utility values based on one prior preventive treatment) resulted in an increase in the ICERs for botulinum toxin type\xa0A compared with placebo to give a deterministic ICER of £10,257 per QALY gained and a probabilistic ICER of £16,165 per QALY gained. The ERG reported that using these assumptions there was a 67% probability of botulinum toxin type\xa0A being cost effective if the maximum acceptable ICER was £20,000 per QALY gained, and an 87% probability of botulinum toxin type\xa0A being cost effective if the maximum acceptable ICER was £30,000 per QALY gained.\n\nThe ERG also explored the impact on the deterministic ICER of varying the negative and positive stopping rules and applying the same utility values for each arm. In these analyses, all the modifications outlined in section 3.28 were applied and the utilities from the three or more prior preventive medications subgroup were used. The ERG also used 2-year follow-up data from the published abstract by Rothrock et al. (2011) (see section 3.23).\n\nApplying the same utilities from the three or more prior preventive medications patient subgroup to both arms (based on the updated utility data from the manufacturer) resulted in lower QALYs for botulinum toxin type\xa0A with no change in costs, compared with the base case. When the manufacturer's base case with positive and negative stopping rules and different utilities were used, the deterministic ICER for botulinum toxin type\xa0A compared with placebo was £11,267 per QALY gained, compared with £20,324 per QALY gained when the same utilities were applied to both arms for each health state. When the positive stopping rule was excluded (compared with using the positive stopping rule for people who move from chronic to episodic migraine) the ICER for botulinum toxin type\xa0A compared with placebo increased from £11,267 to £19,483 per QALY gained when different utilities were used in the botulinum toxin type\xa0A and placebo arms. When a positive stopping rule was applied to 24% of people who had moved from a health state of chronic migraine to episodic migraine (based on the study by Rothrock et al.) the ICER for botulinum toxin type\xa0A compared with placebo increased from £11,267 to £17,438 per QALY gained when different utilities were used. The ERG also applied various negative stopping rules: no negative stopping rule, an improvement of at least one health state within the first cycle; improvement of at least one health state within two cycles; and the manufacturer's base case of an improvement of two health states in two cycles. When no negative stopping rule was applied and different utilities were used in the botulinum toxin type\xa0A and placebo arm, the ICER for botulinum toxin type\xa0A compared with placebo was £13,986 per QALY gained. When different negative stopping rules were applied, the ICER for botulinum toxin type\xa0A compared with placebo ranged from £9618 to £13,167 per QALY gained. The scenario that had the most impact on the model results for botulinum toxin type\xa0A compared with placebo was when no positive and negative stopping rules were applied. This led to an ICER of £24,387 per QALY gained if different utilities for the three or more prior preventive medications patient subgroup were applied to both arms, or £46,290 per QALY gained if the same utilities for the three or more prior preventive medications patient subgroup were applied to both arms. The ERG also remarked that applying separate estimates for the transition probabilities for cycles 3, 4 and 5 to be more in line with patient data would further increase the ICERs by 5–10%.\n\n## Additional submission after consultation\n\nThe manufacturer provided additional analyses after consultation in response to NICE's request for a revised economic model based on the Committee's preferred assumptions, and some clarification of a number of issues relating to the calculation of utilities in the model, the large difference between the deterministic and probabilistic ICER, and resource use. The manufacturer presented:\n\na revised economic model (which incorporated the Committee's preferred assumptions when the same and different utilities were assumed within each health state for the botulinum toxin type\xa0A and placebo arms)\n\nscenario analyses which explored the impact of varying the negative stopping rule and the use of UK resources\n\nsome clarification of the way that utilities had been calculated and the likely causes of the difference in the probabilistic and deterministic ICERs.\n\nIn addition the manufacturer provided analyses varying the time horizon and placebo effectiveness, and also the results of an Australian survey of 10\xa0people who received treatment with botulinum toxin type A for their chronic migraine.\n\nThe revised manufacturer's model presented the cumulative deterministic results for each of the Committee's preferred assumptions on the manufacturer's original deterministic ICER of £6083 per QALY gained when different or the same utility values were applied for each arm:\n\nApplying routine care costs in the placebo arm to people stopping treatment because of inadequate response with botulinum toxin type\xa0A resulted in an ICER of £7170 per QALY gained when different utility values were applied, and £13,110 per QALY gained when the same utility values were applied.\n\nWhen the 24% positive stopping rule was applied, the ICER increased from £7170 to £12,355 per QALY gained when different utilities were applied, and from £13,110 to £22,572 per QALY gained when the same utilities were applied.\n\nIncluding resource use estimates specified in Blumenfeld et al. increased the ICER further from £12,355 to £13,776 per QALY gained when different utilities were applied, and from £22,572 to £25,168 per QALY gained when the same utilities were applied.\n\nA neurologist follow-up cost of £140 for botulinum toxin type\xa0A and placebo administration and follow-up decreased the ICER from £13,776 to £11,997 per QALY gained when different utilities were applied, and from £25,168 to £21,917 per QALY gained when the same utilities were applied.\n\nAn average accident and emergency cost of £77.33 increased the ICER from £11,997 to £12,047 per QALY gained when different utilities were applied, and from £21,917 to £22,008 per QALY gained when the same utilities were applied.\n\nCalculating utility values from data from the three or more prior preventive medications subgroup of the PREEMPT trials increased the ICERs to £16,243 per QALY gained when different utilities were applied, and to £23,624 per QALY gained when the same utilities were applied. When the utility values in health states 5 and 6 were pooled to remove non-monotonicity in the utility values, it led to a utility of 0.480 for health states 5 and 6 in the botulinum toxin type\xa0A arm, and 0.507 for health states 5 and 6 in the placebo arm. Pooling the utility values for health states 5 and 6 decreased the ICER to £14,876 per QALY gained when different utilities were applied and increased it to £23,975 per QALY gained when the same utilities were applied. When transition probability matrices from the three or more prior preventive medications subgroup were applied, the ICER increased to £15,270 per QALY gained when different utilities were applied and to £24,540 per QALY gained when the same utilities were applied.\n\nThe manufacturer's revised cumulative results were based on a negative stopping rule of a two health state reduction in two cycles of treatment, as assumed in their original model. The manufacturer conducted one-way deterministic sensitivity analyses to assess the impact of different negative stopping rules on the ICER (from no negative stopping rule to a stopping rule of less than 50% reduction in headache days per month increasing in 5% or 10% increments from 0%). The ICER varied between £14,198 and £17,174 per QALY gained when different utilities were applied, and from £23,849 and £30,755 per QALY gained when the same utilities were applied. The ICER when no stopping rule was assumed was £19,508 per QALY gained when applying different utilities, and £35,637 per QALY gained when applying the same utilities. The manufacturer considered a negative stopping rule of a 30% response rate based on the reduction in the number of headache days per 28\xa0days after two cycles of treatment to represent its new base case, based on evidence that it is used in clinical practice in the UK for the treatment of chronic migraine. When using the revised base-case assumptions and inputs (see section 3.33) and a 30% negative stopping rule, the revised base-case deterministic ICER was £14,999 per QALY gained when different utilities were applied, and £24,939 per QALY gained when the same utilities were applied.\n\nThe manufacturer explored the causes of the large difference between the deterministic and probabilistic results observed in the manufacturer's original submission and the ERG's original additional analyses. The manufacturer identified one reason for the difference to be the method used to sample the transition probabilities for the probabilistic sensitivity analysis. In their original submission, these were calculated using a Dirichlet based sampling. When the manufacturer recalculated the probabilistic values using a beta tree sampling method, the central probabilistic estimate and the deterministic estimate were broadly in line with one another. The manufacturer also identified an error in its application of a continuity correction. When using the revised base-case assumptions and inputs, a 30% negative stopping rule, beta tree sampling, and correcting for the continuity correction error, the probabilistic ICER was £14,959 per QALY gained (compared with a deterministic ICER of £14,999 per QALY gained) when different utilities were applied, and £25,242 per QALY gained (compared with a deterministic ICER of £24,939 per QALY gained), when the same utilities were applied.\n\nIn response to NICE's request after the first Committee meeting, the manufacturer provided additional clarification about the differences in resource use between Bloudek et al. and Blumenfeld et al. The manufacturer highlighted that the primary reason for the differences was the inclusion of data on Brazilian patients in Bloudek et al. The manufacturer also provided one-way deterministic sensitivity analysis using data from the UK subset of the IBMS. When using the revised base-case assumptions, inputs including a 30% negative stopping rule, and resource use data from the UK subset of the IBMS, the deterministic ICER reduced from £14,999 to £12,624 per QALY gained when different utilities were applied, and from £24,939 to £20,989 per QALY gained when the same utilities were applied. The manufacturer stated that the reduction in the ICER was caused mainly by the higher than average number of hospitalisations in the UK patients in the IBMS.\n\nThe manufacturer carried out additional sensitivity analyses that varied the time horizon and the effectiveness of placebo, assuming no retreatment. The cost effectiveness of botulinum toxin type\xa0A was sensitive to the time horizon, with the deterministic ICER ranging from £14,999 to £8825 per QALY gained when the time horizon ranged from 2 to 20\xa0years, and when different utilities were applied. When the same utilities were applied, the deterministic ICER ranged from £24,939 to £11,700 per QALY gained when the time horizon ranged from 2 to 20\xa0years. The manufacturer also performed a sensitivity analysis in which it was assumed that people in the placebo arm remained in their original health state throughout the trial. This was done because the placebo effect observed in the trials would not be expected to exist in clinical practice in people with chronic migraine who have tried three or more prior preventive headache medications. When no effectiveness in the placebo arm was assumed, the ICER reduced from £14,999 to £5677 per QALY gained when different utilities were applied, and from £24,939 to £6008 per QALY gained when the same utilities were applied to each arm.\n\nIn response to NICE's request for clarification on utilities, the manufacturer provided further details of the mapping algorithms used in its economic model, which were applied to the week\xa024 data of the PREEMPT trials in the three prior preventive medications group. The manufacturer also supplied mean values of the coefficients and of the parameter values of the week 24 data. The manufacturer stated that the rationale for applying different utility values to treatment arms comes from the results of the PREEMPT trials, which showed significant clinical and health-related quality of life benefits beyond the reduction in the number of headache days per 28\xa0days.\n\nThe manufacturer provided results of an Australian survey of ten people with chronic migraine who had received botulinum toxin type\xa0A for up to 5\xa0years. The survey indicated that treatment with botulinum toxin type\xa0A provides three main types of clinical benefit: reduced frequency of migraine and headache days; reduced severity of migraine; and reduced length or duration of migraine symptoms. Participants also identified additional benefits to treatment, such as reduced reliance on other treatment, less sick leave, fewer accident and emergency and GP visits, as well as overall improvements in personal, social and mental well-being.\n\n## ERG critique of the additional submission\n\nThe ERG reviewed the manufacturer's consultation comments and revised economic model. The ERG noted that it might be more appropriate to assume a placebo administration cost of £70 based on 30\xa0minutes of neurologist time compared with a cost of £140 based on 60\xa0minutes of neurologist time, given that the latter cost and time would involve the administration of botulinum toxin type\xa0A as well as a consultation. The ERG also justified a lower cost for neurologist time for placebo administration, in view of the fact that patients whose chronic migraine has failed three prior prophylaxis therapies have regular follow-up in some but not all neurology clinics. The ERG's analyses showed that when a placebo administration cost of £70 was applied to the manufacturer's revised base case (including a 30% negative stopping rule) the deterministic ICER increased from £14,999 to £19,244 per QALY gained when different utilities were applied. No ICER was calculated for applying the same utilities to each arm.\n\nThe ERG noted that the utility mapping functions were constructed to pick up elements of the condition that are not captured by the frequency of headache days per 28\xa0days (such as severity or intensity of headaches). Therefore given that health states are defined in terms of the number of headache days per 28\xa0days, it was not surprising that there were non-monotonic utility values. The ERG explained that there are alternative methods for calculating utilities to those chosen by the manufacturer, such as restricting the individual MSQ dimensions to being monotonic or at least non-decreasing, which could reduce or avoid the non-monotonicity observed in the original utility values. It noted that the manufacturer's utility mapping functions have different non-MSQ parameter values between health states for botulinum toxin type\xa0A and placebo. The ERG stated that the manufacturer had not provided a rationale as to why these parameter values should be different. When the ERG equalised the non-MSQ parameter values in the mapping functions, less non-monotonicity was observed and the ICER was £18,895 per QALY gained when different utilities were applied to each health state. The ERG stated that when the individual MSQ dimensions were restricted to being monotonic or at least non-decreasing, the ICER ranged from £17,278 to £18,256 per QALY gained.\n\nThe ERG reviewed the manufacturer's scenario analysis in which people in the placebo arm remained in their original health state throughout the model. The ERG argued that the benefits of botulinum toxin type\xa0A include a large placebo effect, therefore it would be wrong to retain the placebo effect when receiving botulinum toxin type\xa0A but not when receiving the placebo. The ERG also reviewed the scenario analysis that varied the time horizon. It noted that no clinical trial data existed beyond 12\xa0months, as observed in the PREEMPT trial, but a 2\xa0year time horizon is plausible. It also reviewed the manufacturer's Australian survey of people (n=10) who received botulinum toxin type\xa0A for their chronic migraine. The ERG expressed concern that the study included a very small number of participants who were paid to take part, and who received botulinum toxin type\xa0A for up to 5\xa0years, which indicates that a positive stopping rule was not applied. It noted that the survey participants reported a good response to treatment with a dose of 100 to 150\xa0units of botulinum toxin type\xa0A.\n\nThe ERG reviewed the manufacturer's comments about resource use. The ERG expressed continuing concern that it is unclear how to interpret some of the resource use data from Blumenfeld et al. and Bloudek et al. When reviewing the resource use data for people from the UK with chronic migraine in the IBMS presented by the manufacturer, the ERG noted that the subset included a small number of people (n=57), and a significant number of outlying results (for patients whose resource use contributed to most of the total resource use observed). The ERG stated that the manufacturer should have explored the impact of excluding outlying results from its analyses, and that given the small number of people from the UK with chronic migraine in the IBMS, they considered the Blumenfeld et al. resource use data to be most applicable to the UK.\n\nThe ERG identified an update of the published abstract by Rothrock et al. (see section 3.23). The update, published by Hanlon et al. (2011), closely matched the results published by Rothrock et al., with 25% (compared with 24% in Rothrock et al.) of people able to stop treatment and maintain a good response for at least 6\xa0months after stopping treatment. It noted that 24–25% was the most appropriate figure on which to base a positive stopping rule.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA260", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of botulinum toxin type\xa0A, having considered evidence on the nature of chronic migraine and the value placed on the benefits of botulinum toxin type\xa0A by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee considered the impact of chronic migraine on the everyday life of people with the condition. It heard from the patient experts that chronic migraine is accompanied by severe pain, which impacts greatly on people's quality of life, affecting their ability to work and participate in social activities. The patient experts also noted that people with chronic migraine often experience anxiety and depression related to their condition. The Committee considered chronic migraine to be a debilitating condition which significantly affects health-related quality of life.\n\nThe Committee considered current clinical practice for the treatment of chronic migraine. The Committee heard from the clinical specialists that it is important for people first presenting with chronic migraine to try a range of oral preventive treatment options before considering treatment with botulinum toxin type\xa0A. The clinical specialists stated that there is no one measure of response to treatment and that response is multifaceted. The Committee heard from the clinical specialists that a good response to treatment is typically considered to be a 30–50% reduction in the frequency of headache days or headache episodes. The Committee also noted that when a person's response to treatment is assessed, clinicians also take account of any improvement in the person's quality of life, and that improvements may not always be accompanied by substantial reductions in the number of headache days. It heard from clinical specialists that people considered for treatment with botulinum toxin type\xa0A are assessed for medication overuse before treatment starts, and that this is monitored during treatment. The Committee also heard from the patient experts that many people with chronic migraine would consider any degree of response to treatment to be valuable and that further treatment options were important.\n\nThe Committee considered the administration of botulinum toxin type\xa0A and monitoring of the potential benefit associated with treatment. It heard from clinical specialists that an initial consultation typically lasts between 45\xa0minutes and 1\xa0hour and includes administration of botulinum toxin type\xa0A, which can take between 15 and 30\xa0minutes depending on the experience of the person administering the injection. After treatment patients are asked to keep a headache diary. The clinical specialists stated that the re-treatment interval with botulinum toxin type\xa0A varies in practice. Some clinical practices have routine follow-up about every 3\xa0months. This will be either a telephone consultation with a consultant or headache specialist nurse, or a 30\xa0minute clinic appointment with the consultant during which repeat injections may be administered. In other clinical practices there is no routine follow-up and patients must request an appointment to be considered for further treatment with botulinum toxin type\xa0A. The Committee concluded that the re-treatment interval with botulinum toxin type\xa0A is variable in practice, being 3\xa0months in some patients, but at much longer intervals in others.\n\nThe Committee considered the evidence on the clinical effectiveness of botulinum toxin type\xa0A for the prevention of headaches in adults with chronic migraine from the PREEMPT trials, which compared botulinum toxin type\xa0A with placebo. The Committee noted that the pooled results for the intention-to-treat population indicated a statistically significant reduction in frequency of headache days per month, migraine days per month and cumulative headache hours with botulinum toxin type\xa0A compared with placebo, but considered the absolute numerical benefit of botulinum toxin type\xa0A over placebo to be modest. It also noted the statistically significant reduction in the frequency of headache episodes, migraine episodes and frequency of acute headache medication days with botulinum toxin type\xa0A compared with placebo, but that the absolute numerical differences between the treatments were small. The Committee observed that there was no statistically significant difference in how often acute pain medication was taken. Further, the Committee noted the large placebo effect seen in the trials. It was also aware that the incremental effect of botulinum toxin type\xa0A compared with placebo may have been increased by people in the active treatment arm realising that they were receiving botulinum toxin type\xa0A because of its side effects. The Committee noted that the duration of follow-up in the PREEMPT trials was short (1\xa0year) and the study design, which meant that all patients received the active drug from week\xa024, could not exclude natural improvements in people's condition over time. The Committee heard from the clinical specialists that at baseline, patients in the clinical trials had fewer headache days per month (a mean of\xa019) than people with chronic migraine in secondary care in the UK (a mean of 25–26\xa0headache days per month). The clinical specialists said that this might explain why the benefit observed in the trials was less than what they would expect to see in clinical practice. The Committee discussed the duration of the therapeutic effect of botulinum toxin type\xa0A and heard from the clinical specialists and patient experts that when a person's condition responds to botulinum toxin type\xa0A, the re-treatment interval varies, and that many patients need treatment for longer than 2\xa0years. The Committee was aware of the difficulties of conducting clinical trials in people with chronic migraine, particularly with regard to the known significant placebo effect observed in such studies. It noted that the placebo comparator in the trial would not be given in clinical practice in the manner used in the trial. Although the absolute magnitude of benefit with botulinum toxin type\xa0A was modest, evidence from clinical specialists and patient experts suggested that the effect was clinically meaningful in people whose chronic migraine had failed to respond to three prior preventive treatments and whose condition responds (with at least a 30% reduction in the number of headache days per 28\xa0days) to botulinum toxin type\xa0A treatment. The Committee therefore concluded that botulinum toxin type\xa0A was clinically effective in people with chronic migraine whose condition had not responded to three prior preventive treatments.\n\nThe Committee considered the clinical trial evidence in light of the views of the patient experts and clinical specialists. The Committee noted the improvements in quality of life for patients whose condition responded to botulinum toxin type\xa0A. The Committee then considered the use of botulinum toxin type\xa0A in clinical practice in the UK. The Committee heard from clinical specialists that if a person's chronic migraine was responding to botulinum toxin type\xa0A, the treatment would be continued until the number of headache days was reduced to fewer than 15\xa0headache\xa0days per\xa0month (episodic migraine). The clinical specialists estimated that people would have at least two treatment cycles. They said that after this approximately 50% of people would continue on treatment, and of those 30% would need five cycles of treatment before their condition was reclassified as episodic migraine. The remaining patients would continue to receive treatment for longer than 2\xa0years. Alternatively, if chronic migraine does not respond adequately to botulinum toxin type\xa0A after at least two cycles of treatment, and there is little benefit to the patient, treatment is discontinued and patients would receive standard care. The Committee noted that the clinical trial evidence on the effectiveness of botulinum toxin type\xa0A was for 1\xa0year. The Committee was aware of the abstract by Rothrock et al. (2011) and the update by Hanlon et al. (2011), which estimated duration of response to treatment with botulinum toxin type\xa0A, with response to treatment defined as a 50% reduction in the number of headache days per month. The Committee noted that only 24% of the patients who responded to treatment were able to stop treatment and maintain a good response for at least 6\xa0months. The Committee concluded that because there are no long-term clinical trial data, the estimates of Rothrock et al. and Hanlon et al. are likely to be the best current estimates of the duration of benefit for people who respond to botulinum toxin type\xa0A in clinical practice in the UK.\n\nThe Committee discussed the adverse reactions of treatment with botulinum toxin type\xa0A for chronic migraine. It noted the adverse reactions reported in the trials with botulinum toxin type\xa0A (see section 3.8). It heard from the patient experts that there is often pain around an injection site lasting a few days after treatment with botulinum toxin type\xa0A. However, people would be willing to tolerate the adverse reactions with botulinum toxin type\xa0A treatment to reduce the frequency or severity of their chronic migraine. The Committee concluded that botulinum toxin type\xa0A is generally well tolerated; a conclusion supported by the patient experts and clinical specialists.\n\nThe Committee considered the cost effectiveness of botulinum toxin type\xa0A compared with standard care, based on the manufacturer's economic model and the critique by the ERG, in the context of the decision problem. The Committee was aware that the scope specified that the population should include adults with chronic migraine whose condition has failed to respond to at least three prior pharmacological prophylaxis therapies, and whose medication overuse has been appropriately managed. The Committee was aware that the manufacturer had focused on this population in a sensitivity analysis and that its main submission compared botulinum toxin type\xa0A with placebo in people whose condition has failed to respond to at least one prior preventive medication. The Committee noted comments from the clinical specialists that people first presenting with chronic migraine will be prescribed a range of oral preventive medication options before treatment with botulinum toxin type\xa0A is considered. The Committee concluded that the main decision problem proposed by the manufacturer, comparing botulinum toxin type\xa0A with placebo in people whose condition has failed to respond to at least one prior preventive medication, did not reflect clinical practice. It concluded that it was only relevant for the Committee and the NHS to consider the clinical and cost effectiveness of botulinum toxin type\xa0A in people whose chronic migraine has failed to respond to at least three prior preventive medications and that the trial data from this subgroup should be used to calculate the transition probability matrices used in the economic model.\n\nThe Committee discussed the revised economic model submitted by the manufacturer as part of the response to consultation. The Committee noted that the revised model included their preferred assumptions and inputs. It was aware that the revised model included a negative stopping rule of a two health state reduction in two cycles of treatment. The Committee noted that the manufacturer's cumulative analyses on the impact of each of the Committee's preferred assumptions resulted in a revised deterministic ICER for botulinum toxin type\xa0A compared with placebo of £15,300 per QALY gained when different utilities are applied to each arm, and £24,500 per QALY gained when the same utilities are applied to each arm. The Committee noted that the revised probabilistic ICERs for botulinum toxin type\xa0A compared with placebo were similar to the deterministic ICERs. The Committee concluded that the large differences between the deterministic and probabilistic ICER in the original model were no longer apparent in the revised economic model.\n\nThe Committee considered the costs and resource use in the revised economic model. The Committee was satisfied that its request for the placebo follow-up cost to be the same as the administration cost of botulinum toxin type A had been resolved because the revised economic model had included a standard NHS neurological outpatient follow-up reference cost of £140 for the placebo follow-up cost. It noted that the routine care costs used in the placebo arm were applied to people who discontinue botulinum toxin type A because of lack of efficacy in the model, and an average accident and emergency cost of £77.33 was used by the manufacturer, as requested in the Committee's preliminary recommendations. The Committee considered the additional clarification on resource use supplied by the manufacturer. It noted the ERG's concern that the resource use data for people from the UK with chronic migraine in the IBMS presented by the manufacturer included a small number of people (n=57), and a significant number of outlying results (for patients whose resource use contributed to most of the total resource use observed). The Committee concluded the Blumenfeld et al. resource use data to be most appropriate given the small number of people from the UK with chronic migraine in the IBMS.\n\nThe Committee noted that its preliminary recommendations requested any revised economic model to incorporate a range of negative stopping rules based on the reduction in the number of headache days per 28\xa0days after two cycles of treatment for people with chronic migraine. The Committee noted from comments received during consultation that there was agreement between the manufacturer and the clinical community that a 50% response rate is considered to be too high, and that a 30% response rate recommended by the British Association for the Study of Headache is used in clinical practice. The Committee noted that the manufacturer's revised base-case deterministic ICER (based on a negative stopping rule of less than 30% reduction in headache days per month) for botulinum toxin type\xa0A compared with placebo was £15,000 per QALY gained when applying different utilities, and £24,900 per QALY gained when applying the same utilities. The Committee concluded that a 30% response rate (that is, a 30% reduction in the number of headache days per month after two cycles of treatment) was the most clinically relevant and reasonable negative stopping rule on which to base its decision.\n\nThe Committee discussed the appropriate positive stopping rule. It noted the consultation comments that a positive stopping rule, in which patients stop treatment if their migraine has changed to episodic migraine and remained stable in episodic migraine for at least 3\xa0months, is the most clinically appropriate. The Committee also noted that the marketing authorisation for botulinum toxin type\xa0A does not include use in people with episodic migraine. It therefore concluded that a positive stopping rule in which patients stop treatment if their condition has changed to episodic migraine (that is, fewer than 15\xa0headache\xa0days per\xa0month) for three consecutive months is the most clinically relevant. However, the Committee recognised that according to the only published longer term follow-up of patients who responded to treatment with botulinum toxin type A, only 24–25% were able to stop treatment with botulinum toxin type A and maintain a good response for at least 6\xa0months (Rothrock et al. and Hanlon et al.) The Committee concluded that these publications provided the most plausible estimate for the likely implementation of the positive stopping rule in clinical practice in England and Wales, with 24–25% being the most appropriate figure on which to base a positive stopping rule in the economic model.\n\nThe Committee considered the use of the same or different utilities within each health state in the botulinum toxin type\xa0A and placebo arms. The Committee noted comments from consultees and commentators that treatment with botulinum toxin type\xa0A is associated with a range of clinical and non-clinical benefits, which are not included in the reduction in the number of headache days per month. It considered data on botulinum toxin type\xa0A on improving secondary outcomes, including the number of headache episodes, the number of migraine or probable migraine days, the number of moderate or severe headache days, and the number of acute medication days from the pooled PREEMPT trial data and evidence given by the patient experts in writing and at the Committee meeting. The Committee was also aware of an online survey of 60\xa0people with chronic migraine recently conducted by Migraine Action, which also provided supportive data. However, the Committee was aware of the absence of robust data supporting the size of the difference in utility values in each arm. The Committee concluded that although using different utility values within each health state in the botulinum toxin type\xa0A and the placebo arm was plausible and better than applying the same utility values within each health state to calculate the most appropriate ICER for considering cost effectiveness, there was still considerable uncertainty around the degree to which differential utilities existed within each health state.\n\nThe Committee was aware that its preliminary recommendations stated that any revised economic model should explore removing the non-monotonicity in the original model, that is, for the botulinum toxin type\xa0A arm, the utility in health state 5 (20–23\xa0headache\xa0days per\xa0month) is lower than the utility in health state 6 (24–28\xa0headache\xa0days per\xa0month). It heard from the manufacturer that the non-monotonicity in the utility values in the original model was caused by the small number of people in the three or more prior preventive treatment group. The Committee further noted the ERG's explanation that the non-monotonicity was not surprising given that health states were defined in terms of the number of headache days per 28\xa0days, while the MSQ utility mapping functions were constructed so as to pick up other elements of the condition (such as severity or intensity of headaches). The Committee considered that this explanation was plausible and that removing the non-monotonicity had little impact on the ICERs. It concluded that there was no need to remove the non-monotonicity in the updated economic model.\n\nThe Committee considered the explanation from the manufacturer on the way that utilities had been calculated, noting the way in which utilities had been mapped from the MSQ. The Committee noted the ERG's concern that the non-MSQ parameter values were different in the botulinum toxin type\xa0A and placebo utility mapping functions. It agreed that the manufacturer had not provided a clear rationale as to why these parameter values should be different. The Committee noted that when the ERG equalised the non-MSQ parameter values, less non-monotonicity was observed, and the deterministic ICER was £18,900 per QALY gained when applying different utility values to each arm. The Committee concluded that this was the most plausible ICER because it incorporated the Committee's preferred inputs and assumptions including a 30% negative stopping rule, applied different utilities to treatment arms (within the Committee's reservations stated in section 4.13), and equalised the non-MSQ parameter values in the utility mapping functions.\n\nThe Committee discussed whether botulinum toxin type\xa0A was an appropriate use of NHS resources for the prevention of headaches in adults with chronic migraine. It noted that botulinum toxin type\xa0A is the only technology with a UK marketing authorisation for the prevention of headaches in adults with chronic migraine, and that the method of administration of botulinum toxin type\xa0A is novel compared with other preventative treatments used in the management of chronic migraine. The Committee accepted the plausibility of using different utility values in the botulinum toxin type\xa0A and placebo arms (within the reservations expressed in section 4.13), and considered that the utility values in the economic model encompass the major health-related quality of life benefits associated with treatment with botulinum toxin type\xa0A, including duration and intensity of migraine, reduction in symptoms, need for rescue treatment, and lower dose of acute medication. It therefore considered that all of the significant or substantial health benefits of botulinum toxin type\xa0A treatment had been included in the model. The Committee concluded that because the most plausible ICER presented was less than £20,000 per QALY gained, botulinum toxin type\xa0A could be considered an appropriate use of NHS resources for the prevention of headaches in adults with chronic migraine that has not responded to at least three prior pharmacological prophylaxis therapies and whose condition is appropriately managed for medication overuse.\n\nThe Committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its preliminary recommendations in any way. The Committee was aware that during scoping, consultees and commentators suggested that there is inequity in access to diagnosis and treatment of migraine for people whose first language is not English. It also noted that comments suggested that there is unequal access to treatment for chronic migraine for people with mental health issues and that greater recognition of chronic migraine as a significant clinical problem will help eliminate discrimination in the workplace. It heard from the patient expert and from consultation comments that chronic migraine is more prevalent in women than men. The Committee was aware that consultation comments also suggested that there is inequity in access to treatment with botulinum toxin type\xa0A for people on low income. The Committee did not consider access to treatment for people whose first language is not English to be relevant because the recommendations do not specify a particular English language based test for the diagnosis of chronic migraine. Further, because the recommendations do not differentiate between any groups of people, the Committee concluded that its recommendations did not limit access to the technology for any specific group compared with other groups.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA260\n\nAppraisal title: Botulinum toxin type\xa0A for the prevention of headaches in adults with chronic migraine\n\nSection\n\nKey conclusion\n\nBotulinum toxin type\xa0A is recommended as an option for the prophylaxis of headaches in adults with chronic migraine according to 1.1, 1.2 and 1.3.\n\n\n\n,1.2, 1.3\n\nAlthough the clinical trial evidence demonstrated statistically significant benefits of botulinum toxin type\xa0A treatment compared with placebo for a number of outcomes, the absolute numerical differences were small to modest. Further, there was a large placebo effect seen in the clinical trials.\n\n\n\n\n\n\n\nThe Committee concluded that the most appropriate use of botulinum toxin type\xa0A in clinical practice would be in people whose chronic migraine has failed to respond to at least three prior preventive medications.\n\n\n\n, 4.8\n\n\n\nThe Committee noted that the manufacturer's revised model included the Committee's preferred assumptions and inputs. The Committee considered botulinum toxin type A to be a cost effective use of NHS resources only if positive and negative stopping rules were applied as given in section 1.1 and 1.2. They also noted that the key cost drivers were the use of different utilities between the botulinum toxin type\xa0A and placebo arm for a given health state, and different positive and negative stopping rules.\n\n, 4.11–4.13, 4.15\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee considered chronic migraine to be a debilitating condition which seriously affects health-related quality of life.\n\n\n\n\n\nThe Committee heard from the patient experts that many people with chronic migraine would consider any degree of response to treatment to be valuable and that therefore further treatment options were important.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee noted the improvements in quality of life for patients whose condition responded to botulinum toxin type\xa0A.\n\n\n\n\n\nThe Committee considered that the utility values in the economic model encompass the major health-related quality of life benefits associated with treatment with botulinum toxin type\xa0A, including duration and intensity of migraine, reduction in symptoms, need for rescue treatment, and lower dose of acute medication. It therefore considered that all of the significant or substantial health benefits of botulinum toxin type\xa0A treatment had been included in the model.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe decision problem proposed by the manufacturer, comparing botulinum toxin type A with placebo in people whose condition has failed to respond to at least one prior preventative medication did not reflect clinical practice. The Committee concluded that it was only relevant to consider the clinical and cost effectiveness of botulinum toxin type\xa0A in people whose chronic migraine has failed to respond to at least three prior preventive medications.\n\n\n\nAdverse reactions\n\nThe Committee noted the adverse reactions reported in the trials with botulinum toxin type\xa0A. It heard from the patient experts that there is often pain around an injection site lasting a few days after treatment with botulinum toxin type\xa0A. However, people would be willing to tolerate the adverse reactions with botulinum toxin type\xa0A treatment to reduce the frequency or severity of their chronic migraine. The Committee concluded that botulinum toxin type\xa0A is generally well tolerated; a conclusion supported by the patient experts and clinical specialists.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee considered the evidence on the clinical effectiveness of botulinum toxin type\xa0A for the prevention of headaches in adults with chronic migraine from the PREEMPT trials, which compared botulinum toxin type\xa0A with placebo.\n\n\n\n\n\n\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\nAt baseline, patients in the clinical trials had fewer headache days per month (a mean of\xa019) than people with chronic migraine in secondary care in the UK (a mean of 25–26 headache days per month).\n\nThe PREEMPT studies had a limited duration of follow-up (1 year).\n\n\n\n\n\n\n\n\n\n\n\nUncertainties generated by the evidence\n\nThe large placebo effect seen in the trials may have been increased by people in the active treatment arm realising that they were receiving botulinum toxin type\xa0A because of its side effects.\n\n\n\n\n\n\n\nThe duration of follow-up in the PREEMPT trials was short (1\xa0year) and the study design, which meant that all patients received the active drug from week\xa024, could not exclude natural improvements in people's condition over time.\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee did not consider there to be any relevant subgroups.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nAlthough the clinical trial evidence demonstrated statistically significant benefits of botulinum toxin type\xa0A treatment compared with placebo for a number of outcomes, the absolute numerical differences were small. Further, the Committee noted the large placebo effect seen in the trials.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThere was no relevant published literature on the cost effectiveness of botulinum toxin type\xa0A for people with chronic migraine.\n\n\n\n\n\nThe Committee considered the cost effectiveness of botulinum toxin type\xa0A compared with standard care, based on the manufacturer's economic model and the critique by the ERG, in the context of the decision problem.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that the revised model included the Committee's preferred assumptions and inputs.\n\n, 4.10\n\nThe Committee concluded that although using different utility values within each health state in the botulinum toxin type\xa0A and the placebo arm was plausible and better than applying the same utility values within each health state to calculate the most appropriate ICER for considering cost effectiveness, there was still considerable uncertainty around the degree to which differential utilities existed within each health state.\n\n\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThere was non-monotonicity in the utility values, that is, for the botulinum toxin type\xa0A arm, the utility in health state 5 (20–23\xa0headache days per month) is lower than the utility in health state 6 (24–28\xa0headache days per month).\n\n\n\n\n\n\n\n\n\nThe non-MSQ parameter values were different in the botulinum toxin type\xa0A and placebo utility mapping functions. The manufacturer had not provided a clear rationale as to why these parameter values should be different.\n\n\n\n\n\n\n\nThe Committee considered that all of the significant or substantial health benefits of botulinum toxin type\xa0A treatment had been included in the economic model.\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee concluded that botulinum toxin type\xa0A could be considered an appropriate use of NHS resources for the prevention of headaches in adults with chronic migraine that has not responded to at least three prior pharmacological prophylaxis therapies.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee considered the key cost drivers to be:\n\ndifferent utilities between the botulinum toxin type\xa0A and placebo arm for a given health state\n\ndifferent positive and negative stopping rules.\n\n, 4.11–4.13, 4.15\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee concluded that the most plausible ICER was £18,900 per QALY gained, because it incorporated the Committee's preferred inputs and assumptions including a 30% negative stopping rule, applied different utilities to treatment arms (within the Committee's reservations stated in 4.13), and equalised the non-MSQ parameter values in the utility mapping functions.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable\n\n-\n\nEnd-of-life considerations\n\nNot applicable\n\n-\n\nEqualities considerations and social value judgements\n\nThe Committee was aware that during scoping, consultees and commentators suggested that there is inequity in access to diagnosis and treatment for people whose first language is not English. It also noted that comments suggested that there is unequal access to treatment for chronic migraine for people with mental health issues and that greater recognition of chronic migraine as a significant clinical problem will help eliminate discrimination in the workplace. It heard from the patient expert that chronic migraine is more prevalent in women than men. The Committee was aware that consultation comments also suggested that there is inequity in access to treatment with botulinum toxin type\xa0A for people on low income. The Committee did not consider access to treatment for people whose first language is not English to be relevant because the recommendations do not specify a particular English language based test for the diagnosis of chronic migraine. It concluded that its recommendations do not limit access to the technology for any specific protected group compared with other groups.\n\n", 'Related NICE guidance': '# Published\n\nPercutaneous closure of patent foramen ovale for recurrent migraine. NICE interventional procedure guidance 370 (2010).\n\nDeep brain stimulation for intractable trigeminal autonomic cephalalgias. NICE interventional procedure guidance 381 (2011).\n\n# Under development\n\nNICE is developing the following guidance (details available from www.nice.org.uk):\n\nDiagnosis and management of headaches in young people and adults. NICE clinical guideline. Expected date of publication September 2012.', 'Review of guidance': 'The guidance on this technology will be considered for review in June 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveJune 2012', 'Changes after publication': 'February 2014:\n minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta260
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Evidence-based recommendations on botulinum toxin type A (Botox) for preventing headaches in adults with chronic migraine.
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92f216d966c94f0d31c756a091a80700270a2e17
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nice
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Lapatinib or trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2
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Lapatinib or trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2
Evidence-based recommendations on lapatinib (Tyverb) and trastuzumab (Herceptin) for treating metastatic hormone receptor-positive breast cancer that overexpresses HER2 in adults.
# Guidance
Lapatinib in combination with an aromatase inhibitor is not recommended for first-line treatment in postmenopausal women with metastatic hormone-receptor-positive breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2).
Trastuzumab in combination with an aromatase inhibitor is not recommended for first-line treatment in postmenopausal women with metastatic hormone-receptor-positive breast cancer that overexpresses HER2.
Postmenopausal women currently receiving lapatinib or trastuzumab in combination with an aromatase inhibitor that is not recommended according to 1.1 or 1.2 should have the option to continue treatment until they and their clinicians consider it appropriate to stop.# Clinical need and practice
Breast cancer is the most common type of cancer among women in the UK. Women have a one in nine lifetime risk of developing breast cancer. The incidence of breast cancer increases with age, doubling every 10 years until menopause, after which the rate of increase slows down. In the UK, 45,972 people were diagnosed with breast cancer in 2007, of whom over 99% were women.
Metastatic breast cancer is an advanced stage of the disease when it has spread to other organs. An estimated 5% of patients present with metastatic breast cancer, and approximately 30% of people who present with localised breast cancer will later develop metastatic breast cancer. Common sites of metastasis include bone, liver, lung and brain.
When clinicians manage breast cancer they consider various prognostic factors, including hormone receptor status and HER2 status. Hormone receptors include oestrogen receptors and progesterone receptors. Tumours that express either oestrogen receptors or progesterone receptors are commonly referred to as being hormone receptor positive. It is estimated that 60% and 80% of all breast cancers in premenopausal and postmenopausal women respectively are hormone receptor positive. People with hormone-receptor-positive breast cancer generally have a better prognosis than those with hormone-receptor-negative breast cancer.
Tumours that overexpress the HER2 protein (HER2+) grow and divide more quickly, so women with HER2+ tumours generally have a worse prognosis than women with HER2 negative tumours. Approximately 20–30% of people with metastatic breast cancer have HER2+ tumours, of which about 50% will also be hormone receptor positive. In this appraisal, estimates from consultees and clinical specialists for the number of women per year with newly diagnosed metastatic breast cancer who have tumours that are HER2+ and hormone receptor positive ranged from 50 to 2000.
The aim of treatment in metastatic breast cancer is to palliate symptoms, prolong survival and maintain a good quality of life with minimal adverse events. Choice of treatment depends on previous therapy, hormone receptor status, HER2 status and the extent of the disease. 'Advanced breast cancer: diagnosis and treatment' (NICE clinical guideline 81) recommends that if the disease is not imminently life threatening, or does not need early relief of symptoms because of significant visceral organ involvement, women who are postmenopausal and have hormone-receptor-positive breast cancer should be offered an aromatase inhibitor such as anastrozole or letrozole. There is variation in clinical practice for people with tumours that are both HER2+ and hormone receptor positive.# The technologies
Lapatinib (Tyverb, GlaxoSmithKline) is a protein kinase inhibitor that blocks the tyrosine kinase components of the epidermal growth factor receptors (ErbB1 and ErbB2), which are implicated in the growth of various tumours. Lapatinib has conditional marketing authorisation (that is, further evidence on this medicinal product is being awaited) in the UK. Lapatinib is 'indicated for the treatment of patients with breast cancer, whose tumours overexpress HER2 (ErbB2); in combination with an aromatase inhibitor for postmenopausal women with hormone receptor positive metastatic disease, not currently intended for chemotherapy'. The summary of product characteristics (SPC) states that 'patients in the registration study were not previously treated with trastuzumab or an aromatase inhibitor'.
The SPC states that the most common adverse reactions during therapy with lapatinib are diarrhoea, nausea, vomiting and rash. For full details of adverse reactions and contraindications, see the SPC.
Lapatinib is administered orally at a dosage of 1500 mg (six tablets) per day. The net price per pack of 84 tablets is £965.16 (excluding VAT; British national formulary , edition 62). The acquisition cost for a lifetime of treatment with lapatinib plus the aromatase inhibitor letrozole is £28,212 (£27,024 for lapatinib and £1188 for letrozole), assuming a mean treatment duration of 55.2 weeks and excluding administration costs. Costs may vary in different settings because of negotiated procurement discounts.
Trastuzumab (Herceptin, Roche Products) is a recombinant humanised IgG1 monoclonal antibody directed against HER2. Trastuzumab is indicated for the treatment of patients with HER2+ metastatic breast cancer 'in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone-receptor positive metastatic breast cancer, not previously treated with trastuzumab'.
The SPC states that the most common adverse reactions associated with trastuzumab in combination with chemotherapy are cardiotoxicity, infusion-related reactions, haematotoxicity (in particular neutropenia) and pulmonary events. In the clinical trials, patients receiving trastuzumab had to have a left ventricular ejection fraction of at least 55% and to have cardiac monitoring every 4 months. For full details of adverse reactions and contraindications, see the SPC.
The recommended dosage of trastuzumab is either a loading dose of 4 mg/kg by intravenous infusion followed by a weekly maintenance dose of 2 mg/kg until disease progression, or a loading dose of 8 mg/kg by intravenous infusion followed by 3-weekly maintenance doses of 6 mg/kg until disease progression. The net price per 150 mg vial is £407.40 (excluding VAT; BNF 62). Assuming an average patient weight of 67 kg, a mean treatment period of 15 months and excluding administration, monitoring and wastage costs, the acquisition cost for a lifetime of treatment with trastuzumab plus anastrozole is £26,018 (£24,852 for trastuzumab and £1166 for anastrozole) for a weekly schedule and £26,832 (£25,666 for trastuzumab and £1166 for anastrozole) for a 3-weekly schedule. Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
# Clinical effectiveness
Three randomised controlled trials were identified that considered lapatinib or trastuzumab used within their licensed indications. The studies compared:
lapatinib plus letrozole with letrozole alone (the EGF30008 trial)
trastuzumab plus anastrozole with anastrozole alone (the TAnDEM trial)
trastuzumab plus letrozole with letrozole alone (the eLEcTRA trial). All three trials were multicentre, multinational trials that included postmenopausal women receiving first-line treatment for metastatic breast cancer. In all three trials, patients received treatment until disease progression.
Lapatinib
The EGF30008 trial compared lapatinib plus letrozole with letrozole alone. All patients in the trial (n=1286, the intention-to-treat population ) had hormone-receptor-positive metastatic breast cancer but only 219 out of 1286 had HER2+ breast cancer. The trial excluded patients considered by the investigators to have rapidly progressing or life-threatening disease. The median age of patients in the ITT population was 62 years for the lapatinib plus letrozole group and 63 years for the letrozole group (the ages were 60 years and 59 years respectively for patients with HER2+ breast cancer). The two treatment groups were broadly similar in Eastern Cooperative Oncology Group (ECOG) performance status. In the lapatinib plus letrozole group, 58% had an ECOG performance status of 0, compared with 54% in the letrozole alone group; the proportions were 53% and 47% respectively for patients with HER2+ breast cancer. The median number of metastatic sites was two in both treatment groups, including patients with HER2+ breast cancer. The proportion of patients with metastases only to bone was 15% in the lapatinib plus letrozole group and 13% in the letrozole alone group (14% and 17% respectively in patients with HER2+ breast cancer). The remainder had visceral or soft tissue metastases. Patients were randomised to either lapatinib plus letrozole (n=642, which included 111 patients with HER2+ breast cancer) or to letrozole alone (n=644, which included 108 patients with HER2+ breast cancer).
The primary efficacy endpoint was investigator evaluated progression-free survival in the HER2+ population. Secondary outcomes included overall survival, time to progression and overall response rate in the HER2+, intention-to-treat and HER2 negative populations. For patients with hormone-receptor-positive and HER2+ breast cancer, median progression-free survival was 8.2 months for the lapatinib plus letrozole group and 3.0 months for the letrozole alone group (hazard ratio for progression 0.71, 95% confidence interval 0.53 to 0.96, p=0.019). A Cox regression analysis was performed to adjust for known baseline prognostic factors. These factors included treatment group, site of disease, previous adjuvant endocrine therapy, performance status, number of metastatic sites and serum HER2 extracellular domain levels at baseline. From this analysis, the hazard ratio for progression was 0.65 (95% CI 0.47 to 0.89, p=0.008). For the ITT population, progression-free survival was 11.9 months for the lapatinib plus letrozole group and 10.8 months for the letrozole alone group (HR for progression 0.86; 95% CI 0.76 to 0.98; p=0.026).
Median overall survival for patients with hormone-receptor-positive and HER2+ breast cancer was 33.3 months for the lapatinib plus letrozole group and 32.3 months for the letrozole alone group (HR for death 0.74, 95% CI 0.49 to 1.12, p=0.113). Overall survival results for the ITT population were not reported. The overall response rate for patients with hormone-receptor-positive and HER2+ breast cancer was 28% for the lapatinib plus letrozole group and 15% for the letrozole alone group (odds ratio 0.4, 95% CI 0.2 to 0.9, p=0.021). The overall response rate for the ITT population was 33% in the lapatinib plus letrozole group and 32% in the letrozole alone group (OR not reported, p=0.726).
Quality of life was assessed using the Functional Assessment of Cancer Therapy – Breast (FACT-B) questionnaire. Quality of life scores for patients with HER2+ breast cancer were reported to be generally constant over time in both treatment groups. The difference between the two groups was not statistically significant.
Patients who received lapatinib plus letrozole were more likely to experience adverse events, although serious adverse events were rare in both treatment groups. In the ITT population, the incidence of diarrhoea, rash and nausea was statistically significantly greater in the lapatinib plus letrozole group (64%, 45% and 31% respectively) compared with the letrozole alone group (20%, 13% and 21% respectively, p<0.05).
Trastuzumab
The TAnDEM trial (n=207) compared trastuzumab plus anastrozole with anastrozole alone. Patients included in the trial were postmenopausal women with hormone-receptor-positive and HER2+ metastatic breast cancer with an ECOG performance status of 0 or 1. The median age of patients was 56 years in the trastuzumab plus anastrozole group and 54 years in the anastrozole alone group. The median number of metastatic sites was two and 56% of patients had bone metastases. Patients were randomised to either trastuzumab plus anastrozole (n=103) or to anastrozole alone (n=104). At disease progression, 73 patients in the anastrozole alone group received second-line therapy including trastuzumab.
The primary outcome was progression-free survival. The secondary outcomes included overall survival, time to progression and overall response rate. Progression-free survival results were presented according to the ITT population, and in a subgroup in whom hormone-receptor positivity was centrally confirmed and updated results were provided at a later cut-off point (April 2008). For the ITT population, median progression-free survival was 4.8 months (95% CI 3.7 to 7.0) for the trastuzumab plus anastrozole group and 2.4 months (95% CI 2.0 to 4.6) for the anastrozole alone group (HR for progression 0.63, 95% CI 0.47 to 0.84, p=0.002). For the centrally confirmed results, median progression-free survival was 5.6 months (95% CI 3.8 to 8.3) for the trastuzumab plus anastrozole group and 3.8 months (95% CI 2.0 to 6.3) for the anastrozole alone group (HR for progression 0.62, 95% CI not reported, p=0.006). For the updated results, the median progression-free survival was 5.8 months (95% CI 4.6 to 8.3) for the trastuzumab plus anastrozole group and 2.9 months (95% CI 2.1 to 4.5) for the anastrozole alone group (HR for progression 0.55, 95% CI 0.41 to 0.74, p<0.001).
Overall survival results were presented according to the ITT population and the centrally confirmed hormone-receptor-positive population, and results were adjusted for patients who had crossed over from the aromatase inhibitor group to receive trastuzumab. For the ITT population, the median overall survival was 28.5 months (95% CI 22.8 to 42.4) for the trastuzumab plus anastrozole group and 23.9 months (95% CI 18.2 to 37.4) for the anastrozole alone group (HR for death 0.84, 95% CI 0.59 to 1.20, p=0.33). For the centrally confirmed results, the median overall survival was 34.1 months (95% CI 23.9 to 52.0) for the trastuzumab plus anastrozole group and 28.6 months (95% CI 17.4 to 40.0) for the anastrozole alone group (HR for death 0.85, 95% CI not reported, p=0.45).
The manufacturer attempted to account for crossover by conducting a post-hoc analysis of overall survival. The 'rank preserving structural failure time' approach was used to account for crossover (70% of the patients randomised to anastrozole alone subsequently received trastuzumab). In this analysis, the manufacturer reported that the overall survival was 28.52 months (95% CI not reported) for the trastuzumab plus anastrozole group and 21.98 months (95% CI not reported) for the anastrozole alone group (HR for death 0.73, 95% CI 0.51 to 1.04, p value not reported). The Assessment Group commented that no pre-planned statistical methods were described to address the issue of crossover and there was no agreement about the best method to use. It stated that the 'rank preserving structural failure time' approach might not be appropriate when imbalances occur after randomisation, such as when there is an unequal distribution of patients receiving second-line treatment across the groups. The Assessment Group noted that in the TAnDEM trial, the proportion of patients who crossed over was relatively high, and this increased the likelihood of bias. The Assessment Group stated that, ideally, different methods for accounting for crossover should have been tested.
Patient utility data were not collected in the TAnDEM trial. Patients who received trastuzumab plus anastrozole were more likely to experience adverse events compared with patients who received anastrozole alone (87% compared with 65%), including serious adverse events (23% compared with 6%). Fatigue, diarrhoea and vomiting were among the most common adverse events (21%, 20% and 21% respectively in the trastuzumab plus anastrozole group compared with 10%, 8% and 5% in the anastrozole alone group).
The eLEcTRA trial aimed to compare trastuzumab plus letrozole with letrozole alone. However, only 92 patients with hormone-receptor-positive metastatic breast cancer were enrolled (out of a planned 370 patients) before the study was stopped early because of slow recruitment.
Indirect
comparisons
The manufacturer of lapatinib (GlaxoSmithKline) performed adjusted indirect comparisons in which data from five studies were incorporated: EGF30008, TAnDEM, one study comparing letrozole with tamoxifen and two studies comparing anastrozole with tamoxifen. The eLEcTRA study was not included because only an abstract had been published. Overall survival data suggested that the hazard ratio for death with lapatinib plus letrozole was 0.85 (95% CI 0.47 to 1.54) when compared with trastuzumab plus anastrozole, 0.77 (95% CI 0.52 to 1.14) when compared with letrozole alone, 0.71 (95% CI 0.45 to 1.14) when compared with anastrozole alone and 0.74 (95% CI 0.49 to 1.12) when compared with tamoxifen.
GlaxoSmithKline reported that the hazard ratio for progression with lapatinib plus letrozole was 0.89 (95% CI 0.54 to 1.47) when compared with trastuzumab plus anastrozole, 0.65 (95% CI 0.47 to 0.89) when compared with letrozole alone, 0.53 (95% CI 0.36 to 0.80) when compared with anastrozole alone and 0.45 (95% CI 0.32 to 0.65) when compared with tamoxifen.
The manufacturer of trastuzumab (Roche) performed an indirect network meta-analysis with a number of different analyses for overall survival (12 trials) and progression-free survival (seven trials). Roche used the overall survival findings from the TAnDEM trial, adjusting for crossover and assuming that aromatase inhibitors have a 'class effect' (that is, letrozole is equivalent to anastrozole). In the base case, Roche reported that the hazard ratio for death with trastuzumab plus aromatase inhibitors was 0.98 (95% CI 0.58 to 1.67) when compared with lapatinib plus aromatase inhibitors and 0.73 (95% CI 0.51 to 1.04) when compared with aromatase inhibitors. The hazard ratio for death with lapatinib plus aromatase inhibitors compared with aromatase inhibitors was 0.74 (95% CI 0.50 to 1.10). When the results were not adjusted for crossover, the hazard ratio for death with trastuzumab plus aromatase inhibitors was 1.13 (95% CI 0.67 to 1.92) compared with lapatinib plus aromatase inhibitors and 0.84 (95% CI 0.59 to 1.19) compared with aromatase inhibitors. The hazard ratio for death with lapatinib plus aromatase inhibitors compared with aromatase inhibitors was 0.74 (95% CI 0.50 to 1.10).
The hazard ratio for progression of trastuzumab plus aromatase inhibitors was 0.78 (95% CI 0.52 to 1.18) when compared with lapatinib plus aromatase inhibitors and 0.55 (95% CI 0.42 to 0.74) when compared with aromatase inhibitors. The hazard ratio for progression of lapatinib plus aromatase inhibitors compared with aromatase inhibitors was 0.71 (95% CI 0.53 to 0.95).
The Assessment Group considered that the findings of the indirect comparisons presented by the two manufacturers should be treated with caution. It stated that the populations in the EGF30008 and TAnDEM trials differed substantially and that neither of the manufacturers' indirect comparisons met the basic requirement for indirect comparisons – that is, exchangeability of relative treatment effect between trials could not be assumed. The Assessment Group noted that the proportion of patients with hormone-receptor positive and HER2+ metastatic breast cancer included in the other trials in the indirect comparisons was unclear. It also noted that the length of follow-up and the proportion of patients receiving first-line treatment differed between trials.
# Cost effectiveness
The Assessment Group did not identify any published economic analyses that were considered relevant to the appraisal. The manufacturer of trastuzumab identified one study that it considered to be relevant. This was a poster by Hastings et al. presented in June 2010 at the annual meeting of the American Society of Clinical Oncology. The poster described analysis of an indirect comparison of the cost effectiveness of lapatinib plus letrozole and trastuzumab plus anastrozole in postmenopausal women with hormone-receptor positive and HER2+ metastatic breast cancer who had not received previous treatment. The Assessment Group considered that the studies that made up the evidence network addressed different populations and the analysis could not provide a reliable estimate of relative cost effectiveness.
Both manufacturers provided economic analyses to support their submissions in which the technologies under assessment were compared with each other and with letrozole and anastrozole as monotherapies.
GlaxoSmithKline (lapatinib plus an aromatase inhibitor)
The manufacturer's economic model had three states: alive and no disease progression, alive with progression, and dead. The model had a time horizon of 10 years and both costs and benefits were discounted at 3.5% per year. The analysis was carried out from the perspective of the NHS and personal social services. The key clinical data comparing lapatinib plus letrozole with letrozole alone came from the EGF30008 trial. To compare lapatinib plus letrozole with other technologies, the manufacturer used the results of the indirect comparison. The manufacturer's model generated 431 and 269 progression-free survival days with lapatinib and an aromatase inhibitor respectively. This gave a gain of 162 pre-progression survival days with lapatinib. The model generated 810 and 759 post-progression survival days with lapatinib and an aromatase inhibitor respectively; a gain of 51 post-progression days with lapatinib. The manufacturer estimated 1241 overall survival days with lapatinib and 1028 overall survival days with an aromatase inhibitor, a gain of 213 overall survival days with lapatinib treatment.
The utility value for the 'alive and no disease progression' state was estimated using data from the FACT-B questionnaire administered during the EGF30008 trial. The utility value for the 'alive with progression' state was taken from the results of a study by Lloyd et al. (2006) of societal preferences for different stages of metastatic breast cancer in the UK. The utility value used for the 'alive and no disease progression' state was 0.86 and the value for 'alive with progression' was 0.62. The utility decrements applied in the economic model included: nausea (0.1); vomiting (0.1); diarrhoea (0.1); alopecia (0.11); asthenia, fatigue or lethargy (0.12); skin and nail disorders (0.15).
In the base case, the incremental cost of lapatinib plus letrozole compared with letrozole alone was £34,737 and the incremental quality-adjusted life year (QALY) gain was 0.467. This generated an incremental cost-effectiveness ratio (ICER) of £74,448 per QALY gained. The ICER for lapatinib plus letrozole compared with trastuzumab plus anastrozole was £21,836 per QALY gained (incremental cost of £5513 and incremental QALY gain of 0.252) while the ICER for lapatinib plus letrozole compared with anastrozole alone was £59,895 per QALY gained (incremental cost of £35,995 and incremental QALY gain of 0.601).
The manufacturer examined 51 scenarios in deterministic sensitivity analyses. The analyses showed that the ICERs were most sensitive to the utility value for the 'alive and no disease progression' health state, the discount rate for costs and outcomes and the time horizon. Using different assumptions, the ICER for lapatinib plus letrozole compared with letrozole alone ranged from £41,877 per QALY gained to lapatinib plus letrozole being dominated by letrozole alone (that is, letrozole alone was more effective and less costly). The ICER for lapatinib plus letrozole compared with anastrozole alone ranged from £38,170 to £378,674 per QALY gained. The ICER for lapatinib plus letrozole compared with trastuzumab plus anastrozole ranged from lapatinib plus letrozole dominating the comparator to £45,106 per QALY gained. The manufacturer also performed a probabilistic sensitivity analysis. The results showed that at £30,000 for an additional QALY, the probability of lapatinib plus letrozole being cost effective was less than 25% when compared with any aromatase inhibitor, and about 50% when compared with trastuzumab plus anastrozole.
Roche (trastuzumab plus an aromatase inhibitor)
The manufacturer's economic model had three states: progression-free survival, progressive disease and death. The model had a time horizon of 15 years and discounted both costs and benefits at 3.5% per year. The key clinical data used for trastuzumab plus anastrozole compared with anastrozole alone were taken from the TAnDEM trial. All model inputs were from the latest data available, with an April 2008 cut-off point. Based on the results from the indirect comparison it was assumed that letrozole and anastrozole have a 'class effect' and therefore the progression-free survival and overall survival curves for anastrozole were used for letrozole. The clinical estimates for lapatinib plus letrozole came from the EGF30008 trial. The manufacturer's model generated 434 and 190 progression-free survival days with trastuzumab and an aromatase inhibitor respectively. This gave a gain of 244 pre-progression survival days with trastuzumab. The model generated 810 and 737 post-progression survival days with trastuzumab and an aromatase inhibitor respectively. This gave a gain of 73 post-progression days with trastuzumab. The manufacturer estimated 1245 overall survival days with trastuzumab and 931 overall survival days with an aromatase inhibitor, giving a gain of 314 overall survival days with trastuzumab treatment.
The manufacturer used utility values reported by Cooper et al. (2003) that assigned a utility of 0.73 to progression-free survival and 0.45 to progressive disease. Only grade 3 or 4 adverse events were considered in the model and disutilities resulting from adverse events were not modelled.
The manufacturer presented the results based on an incremental analysis. In the base case, it was reported that trastuzumab plus anastrozole compared with anastrozole alone gave an incremental QALY gain of 0.58 at an incremental cost of £31,408, giving an ICER of £54,312 per QALY gained. The manufacturer also reported the results of a pairwise analysis with the remaining two comparisons. In comparison with letrozole alone the ICER was £54,336 per QALY gained (an incremental QALY gain of 0.58 and an incremental cost of £31,422). In comparison with lapatinib plus letrozole the ICER was £18,347 per QALY gained (an incremental QALY gain of 0.16 and an incremental cost of £2866).
A univariate sensitivity analysis showed that the ICERs were most sensitive to the utility value for progression-free survival. When the base-case utility value of 0.73 was varied between 0.803 and 0.657 the ICER ranged from £50,099 to £59,355 per QALY gained for trastuzumab plus anastrozole compared with anastrozole alone. The manufacturer also described three multivariate scenario analyses. In these analyses, when the hazard ratios for progression and for death from the indirect comparisons were used in the model, anastrozole represented a cost-effective treatment option up to £3594 for an additional QALY; letrozole was the most cost-effective treatment option from £3594 to £57,773 per QALY gained; and trastuzumab plus anastrozole was the most cost-effective treatment option above £57,773 per QALY gained.
The manufacturer conducted a probabilistic sensitivity analysis. This analysis showed that at £30,000 for an additional QALY, the combination therapies were not cost effective. At £55,000 for an additional QALY, trastuzumab plus anastrozole was cost effective in approximately 35% of simulations.
Following consultation, the manufacturer updated the base case to include the utility values used by the Assessment Group. The manufacturer also removed the indirect comparison and only used the comparison of trastuzumab plus anastrozole compared with anastrozole alone. The effect of this was to decrease the ICER to £50,975 per QALY gained (incremental cost £31,400 and incremental QALY gain 0.62) for trastuzumab. The manufacturer noted that they had not accounted for the effects of second-line therapy in this analysis.
Independent economic assessment by the Assessment Group
Because of potential differences between the EGF30008 and TAnDEM trials in the baseline characteristics of patients, the Assessment Group performed two separate cost-effectiveness analyses. These analyses used directly observed progression-free survival and post-progression survival data from the trials to generate expected overall survival. The analyses had common parameter values, but took effectiveness data from a single randomised controlled trial (either TAnDEM or EGF30008). Days spent in 'progression-free survival' and 'progressive disease' from the trials were used to calculate health service costs and expected QALY gains. Costs and outcomes were discounted at 3.5% per year.
Assessment Group model for lapatinib plus letrozole compared with letrozole alone
The Assessment Group calculated the mean progression-free survival by applying the difference between the Kaplan–Meier area under the curve estimates up to the time of convergence (505 days) and then applying a single exponential model of progression-free survival to both the intervention and the comparator. This generated 266 progression-free survival days for lapatinib plus letrozole and 199 progression-free survival days for letrozole alone, giving a progression-free survival gain of 67 days per patient attributable to lapatinib. The Assessment Group reported that, following disease progression, patients in both groups of the trial were at the same risk of death, which appeared to be constant over time. The model generated 765 days post-progression survival for both groups. Overall survival was calculated as progression-free survival plus post-progression survival. After adjusting post-progression survival to exclude patients who died at or before disease progression, the overall survival was 983 days for lapatinib plus letrozole and 928 days for letrozole alone, resulting in an overall survival gain of 55 days per patient attributable to lapatinib.
Based on a study by Lloyd et al. (2006), slightly different utility values for the 'progression-free survival' state were assigned to the lapatinib plus letrozole group (0.766) and to the letrozole alone group (0.762). A utility of 0.496 was assigned to the 'post-progression survival' state. Disutility of adverse events was not included in the base case but was examined in a sensitivity analysis.
In the base case, the Assessment Group stated that lapatinib plus letrozole provided less than 0.12 additional QALYs at an additional cost of more than £26,150 per patient compared with letrozole alone, resulting in an ICER in excess of £220,000 per QALY gained. The results from deterministic sensitivity analysis showed that the ICER is most sensitive to the health state utility values, and to the cost of lapatinib. The Assessment Group conducted a probabilistic sensitivity analysis, which estimated the ICER to be in excess of £2,000,000 per QALY gained.
In response to consultation comments, the Assessment Group in its deterministic sensitivity analysis revised the estimates of survival and the ICER for lapatinib. The revised estimates of pre-progression survival were 343 days and 255 days for lapatinib and an aromatase inhibitor respectively, giving a gain of 89 days of pre-progression survival with lapatinib treatment. The revised estimates of post-progression survival were 717 days and 742 days for lapatinib and an aromatase inhibitor respectively, giving a loss of 25 days of post-progression survival with lapatinib treatment. Overall survival was estimated to be 1061 days with lapatinib and 997 days with an aromatase inhibitor, giving an increase of 64 days with lapatinib treatment. The corresponding ICER remained in excess of £225,000 per QALY gained. Also in response to consultation comments, the Assessment Group corrected its model for all the issues raised by the manufacturer of lapatinib. The revised probabilistic ICER was £228,913 per QALY gained.
Assessment Group model for trastuzumab plus anastrozole compared with anastrozole alone
The mean progression-free survival was calculated using the Kaplan–Meier area under the curve estimate up to the last recorded event in each group, and then adding the area under the projected long-term Weibull curve. The number of days in progression-free survival and post-progression survival were reported in the Assessment Group report but were corrected following consultation on the model. The corrected values for progression-free survival were 515 days for trastuzumab plus anastrozole and 190 days for anastrozole alone, giving a gain of 325 progression-free survival days attributable to trastuzumab. Mean post-progression survival was calculated using the Kaplan–Meier area under the curve estimate up to the last recorded event in each group, and then adding the area under the projected long-term Weibull model as applied for progression-free survival. The corrected values for post-progression survival were 810 days for trastuzumab plus anastrozole and 870 days for anastrozole alone, making a loss of 60 post-progression survival days attributable to trastuzumab. The estimate for overall survival was obtained by combining estimates of mean progression-free survival and mean post-progression survival in each group, and adjusting for the patients who died at or before progression. This generated 1030 overall survival days for trastuzumab plus anastrozole and 810 overall survival days for anastrozole alone, with a gain of 220 overall survival days attributable to trastuzumab.
Based on the study by Lloyd et al. (2006), slightly different utility values for progression-free survival were assigned to the trastuzumab plus anastrozole group (0.769 ) and to the anastrozole alone group (0.764 ). A health state utility value of 0.496 (standard error 0.160) was assigned to the post-progression survival state. Disutility of adverse events was not included in the base case, but was examined in a sensitivity analysis.
In the base case, the Assessment Group reported that there was a mean health gain per patient of 0.51 QALYs at an additional cost of about £37,500 per patient. The resulting ICER exceeded £73,000 per QALY gained for trastuzumab plus anastrozole compared with anastrozole alone. A sensitivity analysis showed that the ICER is most sensitive to the utility values for the different states, the cost of trastuzumab and discounting rates. A probabilistic sensitivity analysis was undertaken using the base-case scenario over a 20-year time horizon. This showed no measurable probability of trastuzumab plus anastrozole being cost effective at £40,000 for an additional QALY, and a 3.2% probability of being cost effective at £50,000 for an additional QALY.
In response to consultation comments, the Assessment Group revised the estimates of survival and the ICER for trastuzumab, correcting for an error in the number of patients who died at or before progression in the trastuzumab group. The revised estimates of pre-progression survival were 510 days and 194 days for trastuzumab and an aromatase inhibitor respectively, giving a gain of 316 days pre-progression survival with trastuzumab treatment. The revised estimates of post-progression survival were 612 days and 672 days for trastuzumab and an aromatase inhibitor respectively, giving a loss of 60 days pre-progression survival with trastuzumab treatment. Overall survival was estimated to be 1122 days with trastuzumab and 866 days with an aromatase inhibitor, giving an increase of 256 days with trastuzumab treatment. The corresponding ICER was £69,514 per QALY gained.
# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of lapatinib and trastuzumab, having considered evidence on the nature of metastatic hormone-receptor-positive and HER2+ breast cancer and the value placed on the benefits of lapatinib and trastuzumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee considered the population for whom the two combination technologies would be used. It discussed current clinical practice in the UK in the treatment of metastatic hormone-receptor-positive and HER2+ breast cancer and the position of lapatinib and trastuzumab in the treatment pathway. The Committee heard from clinical specialists that in current UK clinical practice, women with metastatic HER2+ breast cancer are more likely to receive trastuzumab plus chemotherapy than an aromatase inhibitor. Aromatase inhibitors alone are currently offered to women who prefer not to receive chemotherapy, who are not fit enough to receive chemotherapy or in whom it is contraindicated. The clinical specialists stated that the combination of lapatinib or trastuzumab plus an aromatase inhibitor would therefore be likely to be offered to these women. The clinical specialists stated that lapatinib or trastuzumab plus an aromatase inhibitor might be preferred for some women in whom chemotherapy would currently be offered because these combinations have a better adverse reaction profile than chemotherapy. The Committee heard from patient experts that for some women, chemotherapy was particularly difficult to cope with and treatment with lapatinib or trastuzumab in combination with an aromatase inhibitor may make carrying on with their lives easier. The Committee also noted comments from patient experts that women wish to have access to the newer therapies because these may increase progression-free survival, and that this benefit outweighed concerns about potential adverse reactions associated with adding these agents to aromatase inhibitor monotherapy. The Committee therefore concluded that lapatinib or trastuzumab plus an aromatase inhibitor are likely to be used in women who, in consultation with their clinicians, consider that chemotherapy is not the best option for first-line treatment of metastatic disease.
The Committee considered the clinical trial evidence for the two technologies under consideration. It noted that the trial results suggested a greater difference between treatment and comparators in median progression-free survival in the lapatinib trial than in the trastuzumab trial (that is, a difference of 5.2 months in EGF30008, compared with 2.4 months in the TAnDEM trial). However, the results over the duration of the trials suggested a greater gain in median overall survival with trastuzumab than with lapatinib. In EGF30008, the percentage of people alive without progression was the same between the treatment and comparator arms at 16 months, and remained the same for the remainder of the trial, indicating no gain in progression-free survival with lapatinib after 16 months. However, in TAnDEM the percentage of people alive without progression in the treatment arm remained higher than that in the comparator arm throughout the duration of the trial. The Committee noted that the curves showing the percentages of people alive without progression for the treatment arms were similar to each other between the trials. It understood from clinical specialists that this would be expected in clinical practice (that is, that there would be no difference in the clinical effectiveness of lapatinib and trastuzumab). The Committee noted the comments received during consultation on the post-appeal appraisal consultation document and discussed the difficulties with comparing the trials. The Committee discussed the inclusion criteria of the trials (the baseline characteristics including hormone receptor status, the number and location of metastatic sites, and time from diagnosis to inclusion in the trials) and whether the two trial populations were comparable. The Committee also discussed crossover, differences in post-progression treatments, randomisation, the size of the trial populations, and whether the use of different aromatase inhibitors in the trials was relevant. Taking all these factors into consideration, the Committee was uncertain to what extent the trials could be compared. The Committee heard from the clinical specialist that the trials did not provide robust evidence for or against a real difference between the two agents.
The Committee noted the mixed treatment comparisons presented by the manufacturers. It heard that the Assessment Group believed it was not possible to combine the EGF30008 and TAnDEM trials in a meta-analysis because of the different populations included in the trials, and that the results of the manufacturer's meta-analyses should be interpreted with caution. The Committee noted that the Assessment Group had not compared the clinical and cost effectiveness of lapatinib plus an aromatase inhibitor with trastuzumab plus an aromatase inhibitor in one model. The Committee accepted that it would need to consider the clinical and cost effectiveness of lapatinib plus an aromatase inhibitor and trastuzumab plus an aromatase inhibitor independently, at least in the first instance.
Lapatinib plus an aromatase inhibitor
The Committee considered the clinical effectiveness of treatment with lapatinib plus an aromatase inhibitor. It first considered the progression-free survival outcomes from EGF30008. It noted a statistically significant difference of 5.2 months in median progression-free survival with lapatinib plus letrozole when compared with letrozole alone. The Committee considered the overall survival outcomes. In the subgroup of HER2+ patients there was a non-statistically significant median increase of 1 month in overall survival for patients receiving lapatinib plus an aromatase inhibitor. The Committee concluded that lapatinib plus an aromatase inhibitor offered a benefit in progression-free survival but only a small and uncertain overall survival gain.
The Committee considered the manufacturer's and Assessment Group's economic models for lapatinib plus an aromatase inhibitor. The Committee understood that the manufacturer had estimated overall survival as a single entity using projective modelling from the trial data whereas the Assessment Group had projected progression-free survival and post-progression survival separately and combined these to obtain an estimate of overall survival. The Committee noted that there were some differences between the Assessment Group's and the manufacturer's estimates of progression-free survival and post-progression survival.
The Committee considered the estimates of progression-free survival in the manufacturer and Assessment Group's models. It noted that for the lapatinib plus an aromatase inhibitor treatment group, the manufacturer's estimate of progression-free survival was 431 days and the Assessment Group's estimate was 343 days. The Committee heard from the Assessment Group that its (the Assessment Group's) model may have underestimated the longer term progression-free survival gain with lapatinib plus an aromatase inhibitor. The Committee therefore concluded that the manufacturer's estimate of progression-free survival was acceptable. The Committee accepted the manufacturer's estimate of progression-free survival for the aromatase inhibitor arm, because the estimates of the manufacturer's model (269 days) and the Assessment Group's model (255 days) were similar.
The Committee then considered the modelled estimates of post-progression survival. The Committee understood that patients would have stopped treatment with lapatinib plus an aromatase inhibitor at this stage. It noted that the Assessment Group's model resulted in a lower estimate for lapatinib plus an aromatase inhibitor (717 days) than for the aromatase inhibitor alone (742 days). This resulted in a negative number of days gain in post-progression survival (−25 days) with lapatinib plus an aromatase inhibitor treatment. The Committee further noted that the manufacturer's model resulted in a higher estimate of post-progression survival for lapatinib plus an aromatase inhibitor (810 days) than for an aromatase inhibitor alone (759 days). This resulted in a positive number of days gained during post-progression survival following lapatinib plus an aromatase inhibitor treatment (51 days). The Committee heard from clinical specialists that there is no reason why the addition of lapatinib to an aromatase inhibitor before progression should result in either a shorter or longer duration of post-progression survival. The Committee concluded that it was possible that a longer time in progression-free survival might reduce the time in post-progression survival, but that uncertainty remained around this.
The Committee considered the ICERs for lapatinib plus an aromatase inhibitor. It noted that the manufacturer presented an ICER of £74,400 per QALY gained (representing incremental costs of £34,700 and incremental QALYs gained of 0.47). The Assessment Group presented a deterministic ICER in excess of £225,000 per QALY gained (incremental costs of £26,200 and incremental QALYs gained of less than 0.12). After consultation the Committee noted the Assessment Group's revised estimate of £228,900 per QALY gained for the mean probabilistic ICER. The Committee considered that the Assessment Group's estimates were likely to be an overestimate of the most plausible ICER for lapatinib plus an aromatase inhibitor on the basis of previous discussions in which the Committee had agreed that the progression-free survival had been underestimated (section 4.3.7) by the Assessment Group. The Committee discussed the manufacturer's estimate of the ICER. On the basis of previous discussions regarding post-progression survival (section 4.3.8) the Committee concluded that the most plausible ICER would be nearer £74,000 per QALY gained.
Trastuzumab plus an aromatase inhibitor
The Committee considered the clinical effectiveness of treatment with trastuzumab plus an aromatase inhibitor. It first considered the progression-free survival outcomes from TAnDEM. It noted a statistically significant difference of 2.4 months in median survival with trastuzumab plus anastrozole compared with anastrozole alone. The Committee then considered the overall survival outcomes. The Committee was aware that the manufacturer of trastuzumab had presented an analysis that adjusted for patients who had crossed over from the aromatase inhibitor group to receive trastuzumab plus an aromatase inhibitor, which it considered to be the most appropriate analysis. It noted that this gave a non-statistically significant gain of 6.5 months in overall survival. The Committee concluded that trastuzumab plus an aromatase inhibitor is associated with a statistically significant increase in median progression-free survival but that the trial did not demonstrate a statistically significant increase in overall survival.
The Committee considered the estimates of progression-free survival in the manufacturer and Assessment Group's models. It noted that the manufacturer's estimate of progression-free survival with trastuzumab treatment was 434 days and the Assessment Group's estimate was 510 days. The Committee accepted the manufacturer's estimate of progression-free survival for trastuzumab because it was based on a complete dataset.
The Committee considered the modelled estimates of post-progression survival. It noted the large differences in the estimates produced by the manufacturer and the Assessment Group's models. In particular it noted that the Assessment Group's model resulted in a negative value of −60 days in post-progression survival for trastuzumab plus an aromatase inhibitor compared with an aromatase inhibitor. The Committee noted comments from the manufacturer of trastuzumab that it would seem wrong that treatment with trastuzumab causes a shortened life expectancy following disease progression. The Committee heard from clinical specialists that there is no reason why the addition of trastuzumab to an aromatase inhibitor before progression should result in either a shorter or longer duration of post-progression survival. The Committee concluded that it was unable to fully explain this finding. It noted the Assessment Group's opinion that the finding relates to data in the control arm of the trial and the manufacturer's view that other pivotal trials of trastuzumab all showed prolonged post-progression survival. The Committee concluded that there was a considerable lack of clarity around the relationship between progression-free survival and post-progression survival.
The Committee considered the ICERs for trastuzumab plus anastrozole compared with anastrozole alone. It understood that the manufacturer's revised base-case ICER (£51,000 per QALY) gained was based on the Assessment Group's original estimate (£73,100 per QALY gained), adjusted to correct the number of patients who died at or before progression, minus £6500 (the difference in drug costs between the manufacturer's and the Assessment Group's model) and using the higher utility values used in the Assessment Group's model. The Committee also noted that the Assessment Group's revised estimate of the ICER was £69,500 per QALY gained. The Committee concluded that the most plausible ICER for trastuzumab plus an aromatase inhibitor would be at least £51,000 per QALY gained.
Supplementary advice to the Committee for end-of-life conditions
The Committee considered the supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that:
the estimates of the extension to life are robust and can be shown or reasonably inferred from either progression-free survival or overall survival (taking account of trials in which crossover has occurred and has been accounted for in the effectiveness review) and
the assumptions used in the reference case of the economic modelling are plausible, objective and robust.
Trastuzumab plus an aromatase inhibitor
The Committee considered whether trastuzumab met the criterion for a small population. The Committee examined the estimates provided by the manufacturer of the number of patients diagnosed annually with conditions for which trastuzumab is indicated. It noted that the total number (7158) had previously been accepted as fulfilling the criterion for a small population by another Committee. It also noted that on that occasion, the other Committee had accepted that patients in clinical trials could be excluded from the calculation of population size. The Committee was not persuaded that a population of over 7000 was small, or that it was valid to exclude patients in clinical trials from the calculation of population size. The Committee recognised that these different conclusions from those of a previous Committee were matters of judgement. However in the interest of fairness to this patient population, the Committee agreed not to differ from the other Committee's conclusion on this occasion. On this basis the Committee accepted that trastuzumab plus an aromatase inhibitor fulfilled the small population criterion.
The Committee considered the criterion for short life expectancy. The Committee reviewed all the evidence for life expectancy in this group of patients, including historical published data and estimates of overall survival in the aromatase inhibitor arms of the trials. It considered that the best estimate of expected survival using current standard NHS treatment was demonstrated in the control arms of the trials. The Committee noted that a range of overall survival estimates were presented, from the median survival in the ITT population of 23.9 months, median survival in the centrally confirmed population of 28.6 months and the Assessment Group and manufacturer's estimates of mean survival of 29 and 31 months respectively. The Committee was aware that, in distributions of survival times that are asymmetrical and skewed to the right (that is, most patients are alive in the first few months and then a few patients survive for much longer), the median would always underestimate the mean. The Committee noted that when an attempt was made to remove the effect of crossover (rank preserving structural failure time analysis) the median survival was 22 months, but considered that in clinical practice patients may be offered further treatment on progression. The Committee also noted that additional information on survival with standard NHS treatment was available from the aromatase inhibitor arm of the EGF30008 trial in which median overall survival was 32 months. The Committee concluded that, taken together, the balance of evidence on survival indicated that patients receiving current standard NHS treatment would have an expected survival of greater than 24 months. The Committee therefore concluded that the life expectancy of patients exceeded 24 months and that trastuzumab plus an aromatase inhibitor did not fulfil the criterion for short life expectancy.
The Committee discussed the extension to life criterion. The Committee discussed whether a 3-month survival gain could be reasonably inferred from the data provided and it decided that as trastuzumab did not meet the end-of-life criterion for life expectancy it was not necessary to make a decision about the extension to life criterion.
On the basis of these discussions (sections 4.3.15–4.3.17) the Committee concluded that treatment with trastuzumab plus an aromatase inhibitor did not fulfil all of the criteria for special consideration under the supplementary advice from NICE. The Committee also considered that even if all the criteria had been satisfied, the ICERs were too high to consider trastuzumab plus an aromatase inhibitor a cost-effective use of NHS resources.
Lapatinib plus an aromatase inhibitor
The Committee considered whether lapatinib plus an aromatase inhibitor for the treatment of metastatic hormone-receptor-positive and HER2+ metastatic breast cancer fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee discussed the first criterion and noted that the evidence for life expectancy in this group of patients exceeded 24 months (see section 4.3.16). The Committee concluded that lapatinib plus an aromatase inhibitor did not fulfil the criterion for short life expectancy.
The Committee considered the second criterion. The Committee considered that no robust evidence had been presented to indicate that lapatinib plus an aromatase inhibitor compared with an aromatase inhibitor alone offered a 3-month survival gain and concluded that lapatinib plus an aromatase inhibitor did not meet this criterion.
The Committee considered that the potential population covered by the marketing authorisation for lapatinib would not be as large as for trastuzumab (see 4.3.15) because lapatinib does not have a marketing authorisation for early breast cancer or for gastric cancer. The Committee concluded that lapatinib did fulfil the small population criterion.
On the basis of these discussions (sections 4.3.19–4.3.21) the Committee concluded that lapatinib did not fulfil all the criteria for special consideration under the supplementary advice from NICE. The Committee also concluded that even if all the criteria had been satisfied, the ICERs were too high to consider lapatinib plus an aromatase inhibitor a cost-effective use of NHS resources.
The Committee considered the clinical and cost effectiveness of lapatinib plus an aromatase inhibitor and trastuzumab plus an aromatase inhibitor in light of the submitted evidence and the comments of the clinical specialists, the commissioning expert and the patient experts. The Committee agreed that the cost-effectiveness estimates for both technologies were high and subject to uncertainties which would increase, rather than decrease, the manufacturers' ICERs. The Committee concluded that neither lapatinib nor trastuzumab would be a cost-effective use of NHS resources when combined with an aromatase inhibitor for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2 compared with an aromatase inhibitor alone.
The Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. The Committee discussed comments from consultees indicating that a small population of older patients who are not fit enough to receive chemotherapy may not have access to an alternative treatment and so may be disadvantaged. The Committee agreed that this was not an issue of age discrimination because other factors can also affect whether people are fit enough to receive chemotherapy, such as comorbidities. The Committee also noted that the cost-effectiveness estimates had been based on the comparison with an aromatase inhibitor alone and not with chemotherapy, and that neither lapatinib nor trastuzumab plus an aromatase inhibitor were cost effective relative to an aromatase inhibitor alone. The Committee concluded that there was no need to change or add to its recommendations.
# Summary of Appraisal Committee's key conclusions
TA257
Appraisal title: Lapatinib or trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2
Section
Key conclusion
Lapatinib in combination with an aromatase inhibitor is not recommended for first-line treatment in postmenopausal women with metastatic hormone-receptor-positive breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2).
Trastuzumab in combination with an aromatase inhibitor is not recommended for first-line treatment in postmenopausal women with metastatic hormone-receptor-positive breast cancer that overexpresses HER2.
The end-of-life supplementary advice was not accepted for either technology.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee heard from clinical specialists that in current UK clinical practice, women with metastatic HER2+ breast cancer are more likely to receive trastuzumab plus chemotherapy than an aromatase inhibitor. The Committee concluded that lapatinib or trastuzumab plus an aromatase inhibitor would be most likely to be used in women who, in consultation with their clinicians, consider that chemotherapy is not the best option for first-line treatment of metastatic disease.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
Clinical specialists stated that lapatinib or trastuzumab plus an aromatase inhibitor might be preferred for some women in whom chemotherapy would currently be offered because the combination has a better adverse reaction profile than chemotherapy.
The Committee heard from patient experts that for some women, chemotherapy was particularly difficult to cope with and treatment with lapatinib or trastuzumab in combination with an aromatase inhibitor may make carrying on with their lives easier.
What is the position of the treatment in the pathway of care for the condition?
The Committee concluded that lapatinib or trastuzumab plus an aromatase inhibitor are likely to be used in women who, in consultation with their clinicians, consider that chemotherapy is not the best option for first-line treatment of metastatic disease.
Adverse reactions
Clinical specialists stated that that lapatinib or trastuzumab plus an aromatase inhibitor might be preferred for some women in whom chemotherapy would currently be offered because the combination has a better adverse reaction profile than chemotherapy.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee heard from the Assessment Group that it was not possible to combine the EGF30008 and TAnDEM trials in a meta-analysis because of the different populations included in the trials, and that the results of the manufacturer's meta-analyses should be interpreted with caution. The Committee accepted that it would need to consider the clinical effectiveness of lapatinib plus an aromatase inhibitor and trastuzumab plus an aromatase inhibitor independently, at least in the first instance.
Relevance to general clinical practice in the NHS
The Committee understood from the clinical specialists that no difference in the clinical effectiveness of lapatinib and trastuzumab plus an aromatase inhibitor would be expected in clinical practice. It also heard that the trials did not provide robust evidence for or against a real difference between the two agents.
Uncertainties generated by the evidence
The Committee concluded that lapatinib plus an aromatase inhibitor offered a benefit in progression-free survival but only a small and uncertain overall survival gain.
The Committee concluded that trastuzumab plus an aromatase inhibitor is associated with a statistically significant increase in median progression-free survival but that the evidence did not demonstrate a statistically significant increase in overall survival.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
No subgroups were identified in this appraisal.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee noted that the trial results suggested a greater difference between treatment and comparators in median progression-free survival in the lapatinib and trastuzumab trials (that is, a difference of 5.2 months in EGF30008, compared with 2.4 months in the TAnDEM trial).
Evidence of an overall survival gain was not demonstrated conclusively for either drug.
Evidence for cost effectiveness
Availability and nature of evidence
The Assessment Group did not identify any published economic analyses that were considered relevant to the appraisal. The manufacturer of trastuzumab identified one study that it considered to be relevant. This was a poster by Hastings et al. presented in June 2010 at the annual meeting of the American Society of Clinical Oncology.
Uncertainties around and plausibility of assumptions and inputs in the economic model
In the Assessment Group's models, the estimates of additional post-progression survival with treatment with either lapatinib or trastuzumab plus an aromatase inhibitor were negative. Conversely, in both the manufacturer's models, the gain was a positive number. The Committee heard from clinical specialists that there is no reason why the addition of lapatinib or trastuzumab to an aromatase inhibitor before progression should result in either a shorter or longer duration of post-progression survival.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee did not discuss the incorporation of health-related quality of life benefits or utility values.
Are there specific groups of people for whom the technology is particularly cost effective?
No subgroups were identified in this appraisal.
What are the key drivers of cost effectiveness?
The Committee considered that the differences in the ICERs were mainly because of different incremental QALYs that resulted from the different progression-free and post-progression survival estimates.
and 4.3.13
Most likely cost-effectiveness estimate (given as an ICER)
The Committee concluded that the most plausible ICER for lapatinib plus an aromatase inhibitor would be near to £74,000 per QALY gained.
The Committee concluded that the most plausible ICER for trastuzumab plus an aromatase inhibitor would be at least £51,000 per QALY gained.
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable to this appraisal.
End-of-life considerations
Trastuzumab
The Committee noted that the total number (7158) of patients diagnosed annually with conditions for which trastuzumab is indicated had been accepted by another Committee. The Committee was not persuaded that a population of over 7000 was small, or that it was valid to exclude patients in clinical trials from the calculation of population size. The Committee recognised that these different conclusions from that of a previous Committee were matters of judgement. However in the interest of fairness to this patient population, the Committee agreed not to differ from the other Committee's conclusion on this occasion. It therefore concluded that trastuzumab plus an aromatase inhibitor fulfilled the small population criterion.
The Committee noted that a range of survival estimates were presented and that all the evidence indicated that patients receiving current standard NHS treatment would have an expected survival greater than 24 months. The Committee concluded that trastuzumab did not fulfil the criterion for short life expectancy.
The Committee discussed whether a 3-month survival gain could be reasonably inferred from the data provided and it decided that as trastuzumab did not meet the end-of-life criteria for life expectancy it was not required to make a decision for the extension to life criterion. The Committee concluded that treatment with trastuzumab plus an aromatase inhibitor did not fulfil all of the criteria for special consideration under the supplementary advice from NICE.
Lapatinib
The Committee noted that the mean overall survival in the aromatase inhibitor monotherapy arm of the EGF30008 trial and in the ITT population of the TAnDEM trial exceeded 24 months. The Committee concluded that lapatinib plus an aromatase inhibitor did not fulfil the criterion for short life expectancy.
The Committee considered that no robust evidence had been presented to indicate that lapatinib plus an aromatase inhibitor compared with an aromatase inhibitor alone offered a 3-month survival gain and concluded that lapatinib plus an aromatase inhibitor did not meet this criterion.
The Committee concluded that lapatinib did fulfil the small population criterion. However, because lapatinib had failed to meet the first and second criteria for consideration as a life-extending end-of-life treatment, the Committee concluded that lapatinib did not fulfil all the criteria for special consideration under the supplementary advice from NICE.
Equalities considerations and social value judgements
Comments from consultees indicated that a small population of older patients who are not fit enough to receive chemotherapy may not have access to an alternative treatment and so may be disadvantaged. The Committee agreed that this was not an issue of age discrimination because other factors can also affect whether people are fit enough to receive chemotherapy, such as comorbidities. The Committee concluded that there was no need to change or add to its recommendations.
# Related NICE guidance
Advanced breast cancer: diagnosis and treatment. NICE clinical guideline 81 (2009).
Familial breast cancer: the classification and care of women at risk of familial breast cancer in primary, secondary and tertiary care. NICE clinical guideline 41 (2006).
Guidance on the use of trastuzumab for the treatment of advanced breast cancer. NICE technology appraisal guidance 34 (2002).
Guidance on the use of eribulin for the treatment of locally advanced or metastatic breast cancer. NICE technology appraisal guidance 250 (2012).# Review of guidance
The guidance on this technology will be considered for review by the Guidance Executive in June 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveJune 2012# Changes after publication
February 2014:
minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE multiple technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Lapatinib in combination with an aromatase inhibitor is not recommended for first-line treatment in postmenopausal women with metastatic hormone-receptor-positive breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2).\n\nTrastuzumab in combination with an aromatase inhibitor is not recommended for first-line treatment in postmenopausal women with metastatic hormone-receptor-positive breast cancer that overexpresses HER2.\n\nPostmenopausal women currently receiving lapatinib or trastuzumab in combination with an aromatase inhibitor that is not recommended according to 1.1 or 1.2 should have the option to continue treatment until they and their clinicians consider it appropriate to stop.', 'Clinical need and practice': "Breast cancer is the most common type of cancer among women in the UK. Women have a one in nine lifetime risk of developing breast cancer. The incidence of breast cancer increases with age, doubling every 10\xa0years until menopause, after which the rate of increase slows down. In the UK, 45,972\xa0people were diagnosed with breast cancer in 2007, of whom over 99% were women.\n\nMetastatic breast cancer is an advanced stage of the disease when it has spread to other organs. An estimated 5% of patients present with metastatic breast cancer, and approximately 30% of people who present with localised breast cancer will later develop metastatic breast cancer. Common sites of metastasis include bone, liver, lung and brain.\n\nWhen clinicians manage breast cancer they consider various prognostic factors, including hormone receptor status and HER2 status. Hormone receptors include oestrogen receptors and progesterone receptors. Tumours that express either oestrogen receptors or progesterone receptors are commonly referred to as being hormone receptor positive. It is estimated that 60% and 80% of all breast cancers in premenopausal and postmenopausal women respectively are hormone receptor positive. People with hormone-receptor-positive breast cancer generally have a better prognosis than those with hormone-receptor-negative breast cancer.\n\nTumours that overexpress the HER2 protein (HER2+) grow and divide more quickly, so women with HER2+ tumours generally have a worse prognosis than women with HER2 negative tumours. Approximately 20–30% of people with metastatic breast cancer have HER2+ tumours, of which about 50% will also be hormone receptor positive. In this appraisal, estimates from consultees and clinical specialists for the number of women per year with newly diagnosed metastatic breast cancer who have tumours that are HER2+ and hormone receptor positive ranged from 50 to 2000.\n\nThe aim of treatment in metastatic breast cancer is to palliate symptoms, prolong survival and maintain a good quality of life with minimal adverse events. Choice of treatment depends on previous therapy, hormone receptor status, HER2 status and the extent of the disease. 'Advanced breast cancer: diagnosis and treatment' (NICE clinical guideline 81) recommends that if the disease is not imminently life threatening, or does not need early relief of symptoms because of significant visceral organ involvement, women who are postmenopausal and have hormone-receptor-positive breast cancer should be offered an aromatase inhibitor such as anastrozole or letrozole. There is variation in clinical practice for people with tumours that are both HER2+ and hormone receptor positive.", 'The technologies': "Lapatinib (Tyverb, GlaxoSmithKline) is a protein kinase inhibitor that blocks the tyrosine kinase components of the epidermal growth factor receptors (ErbB1 and ErbB2), which are implicated in the growth of various tumours. Lapatinib has conditional marketing authorisation (that is, further evidence on this medicinal product is being awaited) in the UK. Lapatinib is 'indicated for the treatment of patients with breast cancer, whose tumours overexpress HER2 (ErbB2); in combination with an aromatase inhibitor for postmenopausal women with hormone receptor positive metastatic disease, not currently intended for chemotherapy'. The summary of product characteristics (SPC) states that 'patients in the registration study were not previously treated with trastuzumab or an aromatase inhibitor'.\n\nThe SPC states that the most common adverse reactions during therapy with lapatinib are diarrhoea, nausea, vomiting and rash. For full details of adverse reactions and contraindications, see the SPC.\n\nLapatinib is administered orally at a dosage of 1500\xa0mg (six tablets) per day. The net price per pack of 84\xa0tablets is £965.16 (excluding VAT; British national formulary [BNF], edition 62). The acquisition cost for a lifetime of treatment with lapatinib plus the aromatase inhibitor letrozole is £28,212 (£27,024 for lapatinib and £1188 for letrozole), assuming a mean treatment duration of 55.2\xa0weeks and excluding administration costs. Costs may vary in different settings because of negotiated procurement discounts.\n\nTrastuzumab (Herceptin, Roche Products) is a recombinant humanised IgG1 monoclonal antibody directed against HER2. Trastuzumab is indicated for the treatment of patients with HER2+ metastatic breast cancer 'in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone-receptor positive metastatic breast cancer, not previously treated with trastuzumab'.\n\nThe SPC states that the most common adverse reactions associated with trastuzumab in combination with chemotherapy are cardiotoxicity, infusion-related reactions, haematotoxicity (in particular neutropenia) and pulmonary events. In the clinical trials, patients receiving trastuzumab had to have a left ventricular ejection fraction of at least 55% and to have cardiac monitoring every 4\xa0months. For full details of adverse reactions and contraindications, see the SPC.\n\nThe recommended dosage of trastuzumab is either a loading dose of 4\xa0mg/kg by intravenous infusion followed by a weekly maintenance dose of 2\xa0mg/kg until disease progression, or a loading dose of 8\xa0mg/kg by intravenous infusion followed by 3-weekly maintenance doses of 6\xa0mg/kg until disease progression. The net price per 150\xa0mg vial is £407.40 (excluding VAT; BNF\xa062). Assuming an average patient weight of 67\xa0kg, a mean treatment period of 15\xa0months and excluding administration, monitoring and wastage costs, the acquisition cost for a lifetime of treatment with trastuzumab plus anastrozole is £26,018 (£24,852 for trastuzumab and £1166 for anastrozole) for a weekly schedule and £26,832 (£25,666 for trastuzumab and £1166 for anastrozole) for a 3-weekly schedule. Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nThree randomised controlled trials were identified that considered lapatinib or trastuzumab used within their licensed indications. The studies compared:\n\nlapatinib plus letrozole with letrozole alone (the EGF30008 trial)\n\ntrastuzumab plus anastrozole with anastrozole alone (the TAnDEM trial)\n\ntrastuzumab plus letrozole with letrozole alone (the eLEcTRA trial). All three trials were multicentre, multinational trials that included postmenopausal women receiving first-line treatment for metastatic breast cancer. In all three trials, patients received treatment until disease progression.\n\nLapatinib\n\nThe EGF30008 trial compared lapatinib plus letrozole with letrozole alone. All patients in the trial (n=1286, the intention-to-treat population [ITT]) had hormone-receptor-positive metastatic breast cancer but only 219 out of 1286 had HER2+ breast cancer. The trial excluded patients considered by the investigators to have rapidly progressing or life-threatening disease. The median age of patients in the ITT population was 62\xa0years for the lapatinib plus letrozole group and 63\xa0years for the letrozole group (the ages were 60\xa0years and 59\xa0years respectively for patients with HER2+ breast cancer). The two treatment groups were broadly similar in Eastern Cooperative Oncology Group (ECOG) performance status. In the lapatinib plus letrozole group, 58% had an ECOG performance status of 0, compared with 54% in the letrozole alone group; the proportions were 53% and 47% respectively for patients with HER2+ breast cancer. The median number of metastatic sites was two in both treatment groups, including patients with HER2+ breast cancer. The proportion of patients with metastases only to bone was 15% in the lapatinib plus letrozole group and 13% in the letrozole alone group (14% and 17% respectively in patients with HER2+ breast cancer). The remainder had visceral or soft tissue metastases. Patients were randomised to either lapatinib plus letrozole (n=642, which included 111\xa0patients with HER2+ breast cancer) or to letrozole alone (n=644, which included 108\xa0patients with HER2+ breast cancer).\n\nThe primary efficacy endpoint was investigator evaluated progression-free survival in the HER2+ population. Secondary outcomes included overall survival, time to progression and overall response rate in the HER2+, intention-to-treat and HER2 negative populations. For patients with hormone-receptor-positive and HER2+ breast cancer, median progression-free survival was 8.2\xa0months for the lapatinib plus letrozole group and 3.0\xa0months for the letrozole alone group (hazard ratio [HR] for progression 0.71, 95% confidence interval [CI] 0.53 to 0.96, p=0.019). A Cox regression analysis was performed to adjust for known baseline prognostic factors. These factors included treatment group, site of disease, previous adjuvant endocrine therapy, performance status, number of metastatic sites and serum HER2 extracellular domain levels at baseline. From this analysis, the hazard ratio for progression was 0.65 (95%\xa0CI 0.47 to 0.89, p=0.008). For the ITT population, progression-free survival was 11.9\xa0months for the lapatinib plus letrozole group and 10.8\xa0months for the letrozole alone group (HR\xa0for progression 0.86; 95%\xa0CI 0.76 to 0.98; p=0.026).\n\nMedian overall survival for patients with hormone-receptor-positive and HER2+ breast cancer was 33.3\xa0months for the lapatinib plus letrozole group and 32.3\xa0months for the letrozole alone group (HR\xa0for death 0.74, 95%\xa0CI 0.49 to 1.12, p=0.113). Overall survival results for the ITT population were not reported. The overall response rate for patients with hormone-receptor-positive and HER2+ breast cancer was 28% for the lapatinib plus letrozole group and 15% for the letrozole alone group (odds ratio [OR] 0.4, 95%\xa0CI 0.2 to 0.9, p=0.021). The overall response rate for the ITT population was 33% in the lapatinib plus letrozole group and 32% in the letrozole alone group (OR not reported, p=0.726).\n\nQuality of life was assessed using the Functional Assessment of Cancer Therapy – Breast (FACT-B) questionnaire. Quality of life scores for patients with HER2+ breast cancer were reported to be generally constant over time in both treatment groups. The difference between the two groups was not statistically significant.\n\nPatients who received lapatinib plus letrozole were more likely to experience adverse events, although serious adverse events were rare in both treatment groups. In the ITT population, the incidence of diarrhoea, rash and nausea was statistically significantly greater in the lapatinib plus letrozole group (64%, 45% and 31% respectively) compared with the letrozole alone group (20%, 13% and 21% respectively, p<0.05).\n\nTrastuzumab\n\nThe TAnDEM trial (n=207) compared trastuzumab plus anastrozole with anastrozole alone. Patients included in the trial were postmenopausal women with hormone-receptor-positive and HER2+ metastatic breast cancer with an ECOG performance status of 0 or 1. The median age of patients was 56\xa0years in the trastuzumab plus anastrozole group and 54\xa0years in the anastrozole alone group. The median number of metastatic sites was two and 56% of patients had bone metastases. Patients were randomised to either trastuzumab plus anastrozole (n=103) or to anastrozole alone (n=104). At disease progression, 73 patients in the anastrozole alone group received second-line therapy including trastuzumab.\n\nThe primary outcome was progression-free survival. The secondary outcomes included overall survival, time to progression and overall response rate. Progression-free survival results were presented according to the ITT population, and in a subgroup in whom hormone-receptor positivity was centrally confirmed and updated results were provided at a later cut-off point (April 2008). For the ITT population, median progression-free survival was 4.8\xa0months (95%\xa0CI 3.7 to 7.0) for the trastuzumab plus anastrozole group and 2.4\xa0months (95%\xa0CI 2.0 to 4.6) for the anastrozole alone group (HR\xa0for progression 0.63, 95%\xa0CI 0.47 to 0.84, p=0.002). For the centrally confirmed results, median progression-free survival was 5.6\xa0months (95%\xa0CI 3.8 to 8.3) for the trastuzumab plus anastrozole group and 3.8\xa0months (95%\xa0CI 2.0 to 6.3) for the anastrozole alone group (HR\xa0for progression 0.62, 95%\xa0CI not reported, p=0.006). For the updated results, the median progression-free survival was 5.8\xa0months (95%\xa0CI 4.6 to 8.3) for the trastuzumab plus anastrozole group and 2.9\xa0months (95% CI 2.1 to 4.5) for the anastrozole alone group (HR for progression\xa00.55, 95%\xa0CI 0.41 to 0.74, p<0.001).\n\nOverall survival results were presented according to the ITT population and the centrally confirmed hormone-receptor-positive population, and results were adjusted for patients who had crossed over from the aromatase inhibitor group to receive trastuzumab. For the ITT population, the median overall survival was 28.5\xa0months (95%\xa0CI 22.8 to 42.4) for the trastuzumab plus anastrozole group and 23.9\xa0months (95%\xa0CI 18.2 to 37.4) for the anastrozole alone group (HR for death 0.84, 95%\xa0CI 0.59 to 1.20, p=0.33). For the centrally confirmed results, the median overall survival was 34.1\xa0months (95%\xa0CI 23.9 to 52.0) for the trastuzumab plus anastrozole group and 28.6\xa0months (95%\xa0CI 17.4 to 40.0) for the anastrozole alone group (HR for death 0.85, 95%\xa0CI not reported, p=0.45).\n\nThe manufacturer attempted to account for crossover by conducting a post-hoc analysis of overall survival. The 'rank preserving structural failure time' approach was used to account for crossover (70% of the patients randomised to anastrozole alone subsequently received trastuzumab). In this analysis, the manufacturer reported that the overall survival was 28.52\xa0months (95%\xa0CI not reported) for the trastuzumab plus anastrozole group and 21.98\xa0months (95%\xa0CI not reported) for the anastrozole alone group (HR for death 0.73, 95%\xa0CI 0.51 to 1.04, p value not reported). The Assessment Group commented that no pre-planned statistical methods were described to address the issue of crossover and there was no agreement about the best method to use. It stated that the 'rank preserving structural failure time' approach might not be appropriate when imbalances occur after randomisation, such as when there is an unequal distribution of patients receiving second-line treatment across the groups. The Assessment Group noted that in the TAnDEM trial, the proportion of patients who crossed over was relatively high, and this increased the likelihood of bias. The Assessment Group stated that, ideally, different methods for accounting for crossover should have been tested.\n\nPatient utility data were not collected in the TAnDEM trial. Patients who received trastuzumab plus anastrozole were more likely to experience adverse events compared with patients who received anastrozole alone (87% compared with 65%), including serious adverse events (23% compared with 6%). Fatigue, diarrhoea and vomiting were among the most common adverse events (21%, 20% and 21% respectively in the trastuzumab plus anastrozole group compared with 10%, 8% and 5% in the anastrozole alone group).\n\nThe eLEcTRA trial aimed to compare trastuzumab plus letrozole with letrozole alone. However, only 92\xa0patients with hormone-receptor-positive metastatic breast cancer were enrolled (out of a planned 370\xa0patients) before the study was stopped early because of slow recruitment.\n\nIndirect\n comparisons\n\nThe manufacturer of lapatinib (GlaxoSmithKline) performed adjusted indirect comparisons in which data from five studies were incorporated: EGF30008, TAnDEM, one study comparing letrozole with tamoxifen and two studies comparing anastrozole with tamoxifen. The eLEcTRA study was not included because only an abstract had been published. Overall survival data suggested that the hazard ratio for death with lapatinib plus letrozole was 0.85 (95%\xa0CI 0.47 to 1.54) when compared with trastuzumab plus anastrozole, 0.77 (95% CI 0.52 to 1.14) when compared with letrozole alone, 0.71 (95% CI 0.45 to 1.14) when compared with anastrozole alone and 0.74 (95% CI 0.49 to 1.12) when compared with tamoxifen.\n\nGlaxoSmithKline reported that the hazard ratio for progression with lapatinib plus letrozole was 0.89 (95% CI 0.54 to 1.47) when compared with trastuzumab plus anastrozole, 0.65 (95% CI 0.47 to 0.89) when compared with letrozole alone, 0.53 (95% CI 0.36 to 0.80) when compared with anastrozole alone and 0.45 (95% CI 0.32 to 0.65) when compared with tamoxifen.\n\nThe manufacturer of trastuzumab (Roche) performed an indirect network meta-analysis with a number of different analyses for overall survival (12 trials) and progression-free survival (seven trials). Roche used the overall survival findings from the TAnDEM trial, adjusting for crossover and assuming that aromatase inhibitors have a 'class effect' (that is, letrozole is equivalent to anastrozole). In the base case, Roche reported that the hazard ratio for death with trastuzumab plus aromatase inhibitors was\xa00.98 (95% CI 0.58 to 1.67) when compared with lapatinib plus aromatase inhibitors and 0.73 (95% CI 0.51 to 1.04) when compared with aromatase inhibitors. The hazard ratio for death with lapatinib plus aromatase inhibitors compared with aromatase inhibitors was 0.74 (95% CI 0.50 to 1.10). When the results were not adjusted for crossover, the hazard ratio for death with trastuzumab plus aromatase inhibitors was 1.13 (95% CI 0.67 to 1.92) compared with lapatinib plus aromatase inhibitors and 0.84 (95% CI 0.59 to 1.19) compared with aromatase inhibitors. The hazard ratio for death with lapatinib plus aromatase inhibitors compared with aromatase inhibitors was 0.74 (95% CI 0.50 to 1.10).\n\nThe hazard ratio for progression of trastuzumab plus aromatase inhibitors was 0.78 (95% CI 0.52 to 1.18) when compared with lapatinib plus aromatase inhibitors and 0.55 (95% CI 0.42 to 0.74) when compared with aromatase inhibitors. The hazard ratio for progression of lapatinib plus aromatase inhibitors compared with aromatase inhibitors was 0.71 (95% CI 0.53 to 0.95).\n\nThe Assessment Group considered that the findings of the indirect comparisons presented by the two manufacturers should be treated with caution. It stated that the populations in the EGF30008 and TAnDEM trials differed substantially and that neither of the manufacturers' indirect comparisons met the basic requirement for indirect comparisons – that is, exchangeability of relative treatment effect between trials could not be assumed. The Assessment Group noted that the proportion of patients with hormone-receptor positive and HER2+ metastatic breast cancer included in the other trials in the indirect comparisons was unclear. It also noted that the length of follow-up and the proportion of patients receiving first-line treatment differed between trials.\n\n# Cost effectiveness\n\nThe Assessment Group did not identify any published economic analyses that were considered relevant to the appraisal. The manufacturer of trastuzumab identified one study that it considered to be relevant. This was a poster by Hastings et al. presented in June 2010 at the annual meeting of the American Society of Clinical Oncology. The poster described analysis of an indirect comparison of the cost effectiveness of lapatinib plus letrozole and trastuzumab plus anastrozole in postmenopausal women with hormone-receptor positive and HER2+ metastatic breast cancer who had not received previous treatment. The Assessment Group considered that the studies that made up the evidence network addressed different populations and the analysis could not provide a reliable estimate of relative cost effectiveness.\n\nBoth manufacturers provided economic analyses to support their submissions in which the technologies under assessment were compared with each other and with letrozole and anastrozole as monotherapies.\n\nGlaxoSmithKline (lapatinib plus an aromatase inhibitor)\n\nThe manufacturer's economic model had three states: alive and no disease progression, alive with progression, and dead. The model had a time horizon of 10\xa0years and both costs and benefits were discounted at 3.5% per year. The analysis was carried out from the perspective of the NHS and personal social services. The key clinical data comparing lapatinib plus letrozole with letrozole alone came from the EGF30008 trial. To compare lapatinib plus letrozole with other technologies, the manufacturer used the results of the indirect comparison. The manufacturer's model generated 431 and 269 progression-free survival days with lapatinib and an aromatase inhibitor respectively. This gave a gain of 162 pre-progression survival days with lapatinib. The model generated 810 and 759 post-progression survival days with lapatinib and an aromatase inhibitor respectively; a gain of 51 post-progression days with lapatinib. The manufacturer estimated 1241 overall survival days with lapatinib and 1028 overall survival days with an aromatase inhibitor, a gain of 213 overall survival days with lapatinib treatment.\n\nThe utility value for the 'alive and no disease progression' state was estimated using data from the FACT-B questionnaire administered during the EGF30008 trial. The utility value for the 'alive with progression' state was taken from the results of a study by Lloyd et al. (2006) of societal preferences for different stages of metastatic breast cancer in the UK. The utility value used for the 'alive and no disease progression' state was 0.86 and the value for 'alive with progression' was 0.62. The utility decrements applied in the economic model included: nausea (0.1); vomiting (0.1); diarrhoea (0.1); alopecia (0.11); asthenia, fatigue or lethargy (0.12); skin and nail disorders (0.15).\n\nIn the base case, the incremental cost of lapatinib plus letrozole compared with letrozole alone was £34,737 and the incremental quality-adjusted life year (QALY) gain was 0.467. This generated an incremental cost-effectiveness ratio (ICER) of £74,448 per QALY gained. The ICER for lapatinib plus letrozole compared with trastuzumab plus anastrozole was £21,836 per QALY gained (incremental cost of £5513 and incremental QALY gain of 0.252) while the ICER for lapatinib plus letrozole compared with anastrozole alone was £59,895 per QALY gained (incremental cost of £35,995 and incremental QALY gain of 0.601).\n\nThe manufacturer examined 51 scenarios in deterministic sensitivity analyses. The analyses showed that the ICERs were most sensitive to the utility value for the 'alive and no disease progression' health state, the discount rate for costs and outcomes and the time horizon. Using different assumptions, the ICER for lapatinib plus letrozole compared with letrozole alone ranged from £41,877 per QALY gained to lapatinib plus letrozole being dominated by letrozole alone (that is, letrozole alone was more effective and less costly). The ICER for lapatinib plus letrozole compared with anastrozole alone ranged from £38,170 to £378,674 per QALY gained. The ICER for lapatinib plus letrozole compared with trastuzumab plus anastrozole ranged from lapatinib plus letrozole dominating the comparator to £45,106 per QALY gained. The manufacturer also performed a probabilistic sensitivity analysis. The results showed that at £30,000 for an additional QALY, the probability of lapatinib plus letrozole being cost effective was less than 25% when compared with any aromatase inhibitor, and about 50% when compared with trastuzumab plus anastrozole.\n\nRoche (trastuzumab plus an aromatase inhibitor)\n\nThe manufacturer's economic model had three states: progression-free survival, progressive disease and death. The model had a time horizon of 15\xa0years and discounted both costs and benefits at 3.5% per year. The key clinical data used for trastuzumab plus anastrozole compared with anastrozole alone were taken from the TAnDEM trial. All model inputs were from the latest data available, with an April 2008 cut-off point. Based on the results from the indirect comparison it was assumed that letrozole and anastrozole have a 'class effect' and therefore the progression-free survival and overall survival curves for anastrozole were used for letrozole. The clinical estimates for lapatinib plus letrozole came from the EGF30008 trial. The manufacturer's model generated 434 and 190 progression-free survival days with trastuzumab and an aromatase inhibitor respectively. This gave a gain of 244 pre-progression survival days with trastuzumab. The model generated 810 and 737 post-progression survival days with trastuzumab and an aromatase inhibitor respectively. This gave a gain of 73 post-progression days with trastuzumab. The manufacturer estimated 1245 overall survival days with trastuzumab and 931 overall survival days with an aromatase inhibitor, giving a gain of 314 overall survival days with trastuzumab treatment.\n\nThe manufacturer used utility values reported by Cooper et al. (2003) that assigned a utility of 0.73 to progression-free survival and 0.45 to progressive disease. Only grade 3 or 4 adverse events were considered in the model and disutilities resulting from adverse events were not modelled.\n\nThe manufacturer presented the results based on an incremental analysis. In the base case, it was reported that trastuzumab plus anastrozole compared with anastrozole alone gave an incremental QALY gain of 0.58 at an incremental cost of £31,408, giving an ICER of £54,312 per QALY gained. The manufacturer also reported the results of a pairwise analysis with the remaining two comparisons. In comparison with letrozole alone the ICER was £54,336 per QALY gained (an incremental QALY gain of 0.58 and an incremental cost of £31,422). In comparison with lapatinib plus letrozole the ICER was £18,347 per QALY gained (an incremental QALY gain of 0.16 and an incremental cost of £2866).\n\nA univariate sensitivity analysis showed that the ICERs were most sensitive to the utility value for progression-free survival. When the base-case utility value of 0.73 was varied between 0.803 and 0.657 the ICER ranged from £50,099 to £59,355 per QALY gained for trastuzumab plus anastrozole compared with anastrozole alone. The manufacturer also described three multivariate scenario analyses. In these analyses, when the hazard ratios for progression and for death from the indirect comparisons were used in the model, anastrozole represented a cost-effective treatment option up to £3594 for an additional QALY; letrozole was the most cost-effective treatment option from £3594 to £57,773 per QALY gained; and trastuzumab plus anastrozole was the most cost-effective treatment option above £57,773 per QALY gained.\n\nThe manufacturer conducted a probabilistic sensitivity analysis. This analysis showed that at £30,000 for an additional QALY, the combination therapies were not cost effective. At £55,000 for an additional QALY, trastuzumab plus anastrozole was cost effective in approximately 35% of simulations.\n\nFollowing consultation, the manufacturer updated the base case to include the utility values used by the Assessment Group. The manufacturer also removed the indirect comparison and only used the comparison of trastuzumab plus anastrozole compared with anastrozole alone. The effect of this was to decrease the ICER to £50,975 per QALY gained (incremental cost £31,400 and incremental QALY gain 0.62) for trastuzumab. The manufacturer noted that they had not accounted for the effects of second-line therapy in this analysis.\n\nIndependent economic assessment by the Assessment Group\n\nBecause of potential differences between the EGF30008 and TAnDEM trials in the baseline characteristics of patients, the Assessment Group performed two separate cost-effectiveness analyses. These analyses used directly observed progression-free survival and post-progression survival data from the trials to generate expected overall survival. The analyses had common parameter values, but took effectiveness data from a single randomised controlled trial (either TAnDEM or EGF30008). Days spent in 'progression-free survival' and 'progressive disease' from the trials were used to calculate health service costs and expected QALY gains. Costs and outcomes were discounted at 3.5% per year.\n\nAssessment Group model for lapatinib plus letrozole compared with letrozole alone\n\nThe Assessment Group calculated the mean progression-free survival by applying the difference between the Kaplan–Meier area under the curve estimates up to the time of convergence (505\xa0days) and then applying a single exponential model of progression-free survival to both the intervention and the comparator. This generated 266 progression-free survival days for lapatinib plus letrozole and 199 progression-free survival days for letrozole alone, giving a progression-free survival gain of 67\xa0days per patient attributable to lapatinib. The Assessment Group reported that, following disease progression, patients in both groups of the trial were at the same risk of death, which appeared to be constant over time. The model generated 765\xa0days post-progression survival for both groups. Overall survival was calculated as progression-free survival plus post-progression survival. After adjusting post-progression survival to exclude patients who died at or before disease progression, the overall survival was 983\xa0days for lapatinib plus letrozole and 928\xa0days for letrozole alone, resulting in an overall survival gain of 55\xa0days per patient attributable to lapatinib.\n\nBased on a study by Lloyd et al. (2006), slightly different utility values for the 'progression-free survival' state were assigned to the lapatinib plus letrozole group (0.766) and to the letrozole alone group (0.762). A utility of 0.496 was assigned to the 'post-progression survival' state. Disutility of adverse events was not included in the base case but was examined in a sensitivity analysis.\n\nIn the base case, the Assessment Group stated that lapatinib plus letrozole provided less than 0.12 additional QALYs at an additional cost of more than £26,150 per patient compared with letrozole alone, resulting in an ICER in excess of £220,000 per QALY gained. The results from deterministic sensitivity analysis showed that the ICER is most sensitive to the health state utility values, and to the cost of lapatinib. The Assessment Group conducted a probabilistic sensitivity analysis, which estimated the ICER to be in excess of £2,000,000 per QALY gained.\n\nIn response to consultation comments, the Assessment Group in its deterministic sensitivity analysis revised the estimates of survival and the ICER for lapatinib. The revised estimates of pre-progression survival were 343\xa0days and 255\xa0days for lapatinib and an aromatase inhibitor respectively, giving a gain of 89\xa0days of pre-progression survival with lapatinib treatment. The revised estimates of post-progression survival were 717\xa0days and 742\xa0days for lapatinib and an aromatase inhibitor respectively, giving a loss of 25\xa0days of post-progression survival with lapatinib treatment. Overall survival was estimated to be 1061\xa0days with lapatinib and 997\xa0days with an aromatase inhibitor, giving an increase of 64\xa0days with lapatinib treatment. The corresponding ICER remained in excess of £225,000 per QALY gained. Also in response to consultation comments, the Assessment Group corrected its model for all the issues raised by the manufacturer of lapatinib. The revised probabilistic ICER was £228,913 per QALY gained.\n\nAssessment Group model for trastuzumab plus anastrozole compared with anastrozole alone\n\nThe mean progression-free survival was calculated using the Kaplan–Meier area under the curve estimate up to the last recorded event in each group, and then adding the area under the projected long-term Weibull curve. The number of days in progression-free survival and post-progression survival were reported in the Assessment Group report but were corrected following consultation on the model. The corrected values for progression-free survival were 515\xa0days for trastuzumab plus anastrozole and 190\xa0days for anastrozole alone, giving a gain of 325 progression-free survival days attributable to trastuzumab. Mean post-progression survival was calculated using the Kaplan–Meier area under the curve estimate up to the last recorded event in each group, and then adding the area under the projected long-term Weibull model as applied for progression-free survival. The corrected values for post-progression survival were 810\xa0days for trastuzumab plus anastrozole and 870\xa0days for anastrozole alone, making a loss of 60 post-progression survival days attributable to trastuzumab. The estimate for overall survival was obtained by combining estimates of mean progression-free survival and mean post-progression survival in each group, and adjusting for the patients who died at or before progression. This generated 1030 overall survival days for trastuzumab plus anastrozole and 810 overall survival days for anastrozole alone, with a gain of 220 overall survival days attributable to trastuzumab.\n\nBased on the study by Lloyd et al. (2006), slightly different utility values for progression-free survival were assigned to the trastuzumab plus anastrozole group (0.769 [standard error 0.113]) and to the anastrozole alone group (0.764 [standard error 0.114]). A health state utility value of 0.496 (standard error 0.160) was assigned to the post-progression survival state. Disutility of adverse events was not included in the base case, but was examined in a sensitivity analysis.\n\nIn the base case, the Assessment Group reported that there was a mean health gain per patient of 0.51\xa0QALYs at an additional cost of about £37,500 per patient. The resulting ICER exceeded £73,000 per QALY gained for trastuzumab plus anastrozole compared with anastrozole alone. A sensitivity analysis showed that the ICER is most sensitive to the utility values for the different states, the cost of trastuzumab and discounting rates. A probabilistic sensitivity analysis was undertaken using the base-case scenario over a 20-year time horizon. This showed no measurable probability of trastuzumab plus anastrozole being cost effective at £40,000 for an additional QALY, and a 3.2% probability of being cost effective at £50,000 for an additional QALY.\n\nIn response to consultation comments, the Assessment Group revised the estimates of survival and the ICER for trastuzumab, correcting for an error in the number of patients who died at or before progression in the trastuzumab group. The revised estimates of pre-progression survival were 510\xa0days and 194\xa0days for trastuzumab and an aromatase inhibitor respectively, giving a gain of 316\xa0days pre-progression survival with trastuzumab treatment. The revised estimates of post-progression survival were 612\xa0days and 672\xa0days for trastuzumab and an aromatase inhibitor respectively, giving a loss of 60\xa0days pre-progression survival with trastuzumab treatment. Overall survival was estimated to be 1122\xa0days with trastuzumab and 866\xa0days with an aromatase inhibitor, giving an increase of 256\xa0days with trastuzumab treatment. The corresponding ICER was £69,514 per QALY gained.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of lapatinib and trastuzumab, having considered evidence on the nature of metastatic hormone-receptor-positive and HER2+ breast cancer and the value placed on the benefits of lapatinib and trastuzumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee considered the population for whom the two combination technologies would be used. It discussed current clinical practice in the UK in the treatment of metastatic hormone-receptor-positive and HER2+ breast cancer and the position of lapatinib and trastuzumab in the treatment pathway. The Committee heard from clinical specialists that in current UK clinical practice, women with metastatic HER2+ breast cancer are more likely to receive trastuzumab plus chemotherapy than an aromatase inhibitor. Aromatase inhibitors alone are currently offered to women who prefer not to receive chemotherapy, who are not fit enough to receive chemotherapy or in whom it is contraindicated. The clinical specialists stated that the combination of lapatinib or trastuzumab plus an aromatase inhibitor would therefore be likely to be offered to these women. The clinical specialists stated that lapatinib or trastuzumab plus an aromatase inhibitor might be preferred for some women in whom chemotherapy would currently be offered because these combinations have a better adverse reaction profile than chemotherapy. The Committee heard from patient experts that for some women, chemotherapy was particularly difficult to cope with and treatment with lapatinib or trastuzumab in combination with an aromatase inhibitor may make carrying on with their lives easier. The Committee also noted comments from patient experts that women wish to have access to the newer therapies because these may increase progression-free survival, and that this benefit outweighed concerns about potential adverse reactions associated with adding these agents to aromatase inhibitor monotherapy. The Committee therefore concluded that lapatinib or trastuzumab plus an aromatase inhibitor are likely to be used in women who, in consultation with their clinicians, consider that chemotherapy is not the best option for first-line treatment of metastatic disease.\n\nThe Committee considered the clinical trial evidence for the two technologies under consideration. It noted that the trial results suggested a greater difference between treatment and comparators in median progression-free survival in the lapatinib trial than in the trastuzumab trial (that is, a difference of 5.2\xa0months in EGF30008, compared with 2.4\xa0months in the TAnDEM trial). However, the results over the duration of the trials suggested a greater gain in median overall survival with trastuzumab than with lapatinib. In EGF30008, the percentage of people alive without progression was the same between the treatment and comparator arms at 16\xa0months, and remained the same for the remainder of the trial, indicating no gain in progression-free survival with lapatinib after 16\xa0months. However, in TAnDEM the percentage of people alive without progression in the treatment arm remained higher than that in the comparator arm throughout the duration of the trial. The Committee noted that the curves showing the percentages of people alive without progression for the treatment arms were similar to each other between the trials. It understood from clinical specialists that this would be expected in clinical practice (that is, that there would be no difference in the clinical effectiveness of lapatinib and trastuzumab). The Committee noted the comments received during consultation on the post-appeal appraisal consultation document and discussed the difficulties with comparing the trials. The Committee discussed the inclusion criteria of the trials (the baseline characteristics including hormone receptor status, the number and location of metastatic sites, and time from diagnosis to inclusion in the trials) and whether the two trial populations were comparable. The Committee also discussed crossover, differences in post-progression treatments, randomisation, the size of the trial populations, and whether the use of different aromatase inhibitors in the trials was relevant. Taking all these factors into consideration, the Committee was uncertain to what extent the trials could be compared. The Committee heard from the clinical specialist that the trials did not provide robust evidence for or against a real difference between the two agents.\n\nThe Committee noted the mixed treatment comparisons presented by the manufacturers. It heard that the Assessment Group believed it was not possible to combine the EGF30008 and TAnDEM trials in a meta-analysis because of the different populations included in the trials, and that the results of the manufacturer's meta-analyses should be interpreted with caution. The Committee noted that the Assessment Group had not compared the clinical and cost effectiveness of lapatinib plus an aromatase inhibitor with trastuzumab plus an aromatase inhibitor in one model. The Committee accepted that it would need to consider the clinical and cost effectiveness of lapatinib plus an aromatase inhibitor and trastuzumab plus an aromatase inhibitor independently, at least in the first instance.\n\nLapatinib plus an aromatase inhibitor\n\nThe Committee considered the clinical effectiveness of treatment with lapatinib plus an aromatase inhibitor. It first considered the progression-free survival outcomes from EGF30008. It noted a statistically significant difference of 5.2\xa0months in median progression-free survival with lapatinib plus letrozole when compared with letrozole alone. The Committee considered the overall survival outcomes. In the subgroup of HER2+ patients there was a non-statistically significant median increase of 1\xa0month in overall survival for patients receiving lapatinib plus an aromatase inhibitor. The Committee concluded that lapatinib plus an aromatase inhibitor offered a benefit in progression-free survival but only a small and uncertain overall survival gain.\n\nThe Committee considered the manufacturer's and Assessment Group's economic models for lapatinib plus an aromatase inhibitor. The Committee understood that the manufacturer had estimated overall survival as a single entity using projective modelling from the trial data whereas the Assessment Group had projected progression-free survival and post-progression survival separately and combined these to obtain an estimate of overall survival. The Committee noted that there were some differences between the Assessment Group's and the manufacturer's estimates of progression-free survival and post-progression survival.\n\nThe Committee considered the estimates of progression-free survival in the manufacturer and Assessment Group's models. It noted that for the lapatinib plus an aromatase inhibitor treatment group, the manufacturer's estimate of progression-free survival was 431\xa0days and the Assessment Group's estimate was 343\xa0days. The Committee heard from the Assessment Group that its (the Assessment Group's) model may have underestimated the longer term progression-free survival gain with lapatinib plus an aromatase inhibitor. The Committee therefore concluded that the manufacturer's estimate of progression-free survival was acceptable. The Committee accepted the manufacturer's estimate of progression-free survival for the aromatase inhibitor arm, because the estimates of the manufacturer's model (269\xa0days) and the Assessment Group's model (255\xa0days) were similar.\n\nThe Committee then considered the modelled estimates of post-progression survival. The Committee understood that patients would have stopped treatment with lapatinib plus an aromatase inhibitor at this stage. It noted that the Assessment Group's model resulted in a lower estimate for lapatinib plus an aromatase inhibitor (717\xa0days) than for the aromatase inhibitor alone (742\xa0days). This resulted in a negative number of days gain in post-progression survival (−25\xa0days) with lapatinib plus an aromatase inhibitor treatment. The Committee further noted that the manufacturer's model resulted in a higher estimate of post-progression survival for lapatinib plus an aromatase inhibitor (810\xa0days) than for an aromatase inhibitor alone (759\xa0days). This resulted in a positive number of days gained during post-progression survival following lapatinib plus an aromatase inhibitor treatment (51\xa0days). The Committee heard from clinical specialists that there is no reason why the addition of lapatinib to an aromatase inhibitor before progression should result in either a shorter or longer duration of post-progression survival. The Committee concluded that it was possible that a longer time in progression-free survival might reduce the time in post-progression survival, but that uncertainty remained around this.\n\nThe Committee considered the ICERs for lapatinib plus an aromatase inhibitor. It noted that the manufacturer presented an ICER of £74,400 per QALY gained (representing incremental costs of £34,700 and incremental QALYs gained of 0.47). The Assessment Group presented a deterministic ICER in excess of £225,000 per QALY gained (incremental costs of £26,200 and incremental QALYs gained of less than 0.12). After consultation the Committee noted the Assessment Group's revised estimate of £228,900 per QALY gained for the mean probabilistic ICER. The Committee considered that the Assessment Group's estimates were likely to be an overestimate of the most plausible ICER for lapatinib plus an aromatase inhibitor on the basis of previous discussions in which the Committee had agreed that the progression-free survival had been underestimated (section 4.3.7) by the Assessment Group. The Committee discussed the manufacturer's estimate of the ICER. On the basis of previous discussions regarding post-progression survival (section 4.3.8) the Committee concluded that the most plausible ICER would be nearer £74,000 per QALY gained.\n\nTrastuzumab plus an aromatase inhibitor\n\nThe Committee considered the clinical effectiveness of treatment with trastuzumab plus an aromatase inhibitor. It first considered the progression-free survival outcomes from TAnDEM. It noted a statistically significant difference of 2.4\xa0months in median survival with trastuzumab plus anastrozole compared with anastrozole alone. The Committee then considered the overall survival outcomes. The Committee was aware that the manufacturer of trastuzumab had presented an analysis that adjusted for patients who had crossed over from the aromatase inhibitor group to receive trastuzumab plus an aromatase inhibitor, which it considered to be the most appropriate analysis. It noted that this gave a non-statistically significant gain of 6.5\xa0months in overall survival. The Committee concluded that trastuzumab plus an aromatase inhibitor is associated with a statistically significant increase in median progression-free survival but that the trial did not demonstrate a statistically significant increase in overall survival.\n\nThe Committee considered the estimates of progression-free survival in the manufacturer and Assessment Group's models. It noted that the manufacturer's estimate of progression-free survival with trastuzumab treatment was 434\xa0days and the Assessment Group's estimate was 510\xa0days. The Committee accepted the manufacturer's estimate of progression-free survival for trastuzumab because it was based on a complete dataset.\n\nThe Committee considered the modelled estimates of post-progression survival. It noted the large differences in the estimates produced by the manufacturer and the Assessment Group's models. In particular it noted that the Assessment Group's model resulted in a negative value of −60\xa0days in post-progression survival for trastuzumab plus an aromatase inhibitor compared with an aromatase inhibitor. The Committee noted comments from the manufacturer of trastuzumab that it would seem wrong that treatment with trastuzumab causes a shortened life expectancy following disease progression. The Committee heard from clinical specialists that there is no reason why the addition of trastuzumab to an aromatase inhibitor before progression should result in either a shorter or longer duration of post-progression survival. The Committee concluded that it was unable to fully explain this finding. It noted the Assessment Group's opinion that the finding relates to data in the control arm of the trial and the manufacturer's view that other pivotal trials of trastuzumab all showed prolonged post-progression survival. The Committee concluded that there was a considerable lack of clarity around the relationship between progression-free survival and post-progression survival.\n\nThe Committee considered the ICERs for trastuzumab plus anastrozole compared with anastrozole alone. It understood that the manufacturer's revised base-case ICER (£51,000 per QALY) gained was based on the Assessment Group's original estimate (£73,100 per QALY gained), adjusted to correct the number of patients who died at or before progression, minus £6500 (the difference in drug costs between the manufacturer's and the Assessment Group's model) and using the higher utility values used in the Assessment Group's model. The Committee also noted that the Assessment Group's revised estimate of the ICER was £69,500 per QALY gained. The Committee concluded that the most plausible ICER for trastuzumab plus an aromatase inhibitor would be at least £51,000 per QALY gained.\n\nSupplementary advice to the Committee for end-of-life conditions\n\nThe Committee considered the supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that:\n\nthe estimates of the extension to life are robust and can be shown or reasonably inferred from either progression-free survival or overall survival (taking account of trials in which crossover has occurred and has been accounted for in the effectiveness review) and\n\nthe assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nTrastuzumab plus an aromatase inhibitor\n\nThe Committee considered whether trastuzumab met the criterion for a small population. The Committee examined the estimates provided by the manufacturer of the number of patients diagnosed annually with conditions for which trastuzumab is indicated. It noted that the total number (7158) had previously been accepted as fulfilling the criterion for a small population by another Committee. It also noted that on that occasion, the other Committee had accepted that patients in clinical trials could be excluded from the calculation of population size. The Committee was not persuaded that a population of over 7000 was small, or that it was valid to exclude patients in clinical trials from the calculation of population size. The Committee recognised that these different conclusions from those of a previous Committee were matters of judgement. However in the interest of fairness to this patient population, the Committee agreed not to differ from the other Committee's conclusion on this occasion. On this basis the Committee accepted that trastuzumab plus an aromatase inhibitor fulfilled the small population criterion.\n\nThe Committee considered the criterion for short life expectancy. The Committee reviewed all the evidence for life expectancy in this group of patients, including historical published data and estimates of overall survival in the aromatase inhibitor arms of the trials. It considered that the best estimate of expected survival using current standard NHS treatment was demonstrated in the control arms of the trials. The Committee noted that a range of overall survival estimates were presented, from the median survival in the ITT population of 23.9\xa0months, median survival in the centrally confirmed population of 28.6\xa0months and the Assessment Group and manufacturer's estimates of mean survival of 29 and 31\xa0months respectively. The Committee was aware that, in distributions of survival times that are asymmetrical and skewed to the right (that is, most patients are alive in the first few months and then a few patients survive for much longer), the median would always underestimate the mean. The Committee noted that when an attempt was made to remove the effect of crossover (rank preserving structural failure time analysis) the median survival was 22\xa0months, but considered that in clinical practice patients may be offered further treatment on progression. The Committee also noted that additional information on survival with standard NHS treatment was available from the aromatase inhibitor arm of the EGF30008 trial in which median overall survival was 32\xa0months. The Committee concluded that, taken together, the balance of evidence on survival indicated that patients receiving current standard NHS treatment would have an expected survival of greater than 24\xa0months. The Committee therefore concluded that the life expectancy of patients exceeded 24\xa0months and that trastuzumab plus an aromatase inhibitor did not fulfil the criterion for short life expectancy.\n\nThe Committee discussed the extension to life criterion. The Committee discussed whether a 3-month survival gain could be reasonably inferred from the data provided and it decided that as trastuzumab did not meet the end-of-life criterion for life expectancy it was not necessary to make a decision about the extension to life criterion.\n\nOn the basis of these discussions (sections 4.3.15–4.3.17) the Committee concluded that treatment with trastuzumab plus an aromatase inhibitor did not fulfil all of the criteria for special consideration under the supplementary advice from NICE. The Committee also considered that even if all the criteria had been satisfied, the ICERs were too high to consider trastuzumab plus an aromatase inhibitor a cost-effective use of NHS resources.\n\nLapatinib plus an aromatase inhibitor\n\nThe Committee considered whether lapatinib plus an aromatase inhibitor for the treatment of metastatic hormone-receptor-positive and HER2+ metastatic breast cancer fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee discussed the first criterion and noted that the evidence for life expectancy in this group of patients exceeded 24\xa0months (see section 4.3.16). The Committee concluded that lapatinib plus an aromatase inhibitor did not fulfil the criterion for short life expectancy.\n\nThe Committee considered the second criterion. The Committee considered that no robust evidence had been presented to indicate that lapatinib plus an aromatase inhibitor compared with an aromatase inhibitor alone offered a 3-month survival gain and concluded that lapatinib plus an aromatase inhibitor did not meet this criterion.\n\nThe Committee considered that the potential population covered by the marketing authorisation for lapatinib would not be as large as for trastuzumab (see 4.3.15) because lapatinib does not have a marketing authorisation for early breast cancer or for gastric cancer. The Committee concluded that lapatinib did fulfil the small population criterion.\n\nOn the basis of these discussions (sections 4.3.19–4.3.21) the Committee concluded that lapatinib did not fulfil all the criteria for special consideration under the supplementary advice from NICE. The Committee also concluded that even if all the criteria had been satisfied, the ICERs were too high to consider lapatinib plus an aromatase inhibitor a cost-effective use of NHS resources.\n\nThe Committee considered the clinical and cost effectiveness of lapatinib plus an aromatase inhibitor and trastuzumab plus an aromatase inhibitor in light of the submitted evidence and the comments of the clinical specialists, the commissioning expert and the patient experts. The Committee agreed that the cost-effectiveness estimates for both technologies were high and subject to uncertainties which would increase, rather than decrease, the manufacturers' ICERs. The Committee concluded that neither lapatinib nor trastuzumab would be a cost-effective use of NHS resources when combined with an aromatase inhibitor for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2 compared with an aromatase inhibitor alone.\n\nThe Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. The Committee discussed comments from consultees indicating that a small population of older patients who are not fit enough to receive chemotherapy may not have access to an alternative treatment and so may be disadvantaged. The Committee agreed that this was not an issue of age discrimination because other factors can also affect whether people are fit enough to receive chemotherapy, such as comorbidities. The Committee also noted that the cost-effectiveness estimates had been based on the comparison with an aromatase inhibitor alone and not with chemotherapy, and that neither lapatinib nor trastuzumab plus an aromatase inhibitor were cost effective relative to an aromatase inhibitor alone. The Committee concluded that there was no need to change or add to its recommendations.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA257\n\nAppraisal title: Lapatinib or trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2\n\nSection\n\nKey conclusion\n\nLapatinib in combination with an aromatase inhibitor is not recommended for first-line treatment in postmenopausal women with metastatic hormone-receptor-positive breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2).\n\n\n\nTrastuzumab in combination with an aromatase inhibitor is not recommended for first-line treatment in postmenopausal women with metastatic hormone-receptor-positive breast cancer that overexpresses HER2.\n\n\n\nThe end-of-life supplementary advice was not accepted for either technology.\n\n–4.3.22\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard from clinical specialists that in current UK clinical practice, women with metastatic HER2+ breast cancer are more likely to receive trastuzumab plus chemotherapy than an aromatase inhibitor. The Committee concluded that lapatinib or trastuzumab plus an aromatase inhibitor would be most likely to be used in women who, in consultation with their clinicians, consider that chemotherapy is not the best option for first-line treatment of metastatic disease.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nClinical specialists stated that lapatinib or trastuzumab plus an aromatase inhibitor might be preferred for some women in whom chemotherapy would currently be offered because the combination has a better adverse reaction profile than chemotherapy.\n\nThe Committee heard from patient experts that for some women, chemotherapy was particularly difficult to cope with and treatment with lapatinib or trastuzumab in combination with an aromatase inhibitor may make carrying on with their lives easier.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee concluded that lapatinib or trastuzumab plus an aromatase inhibitor are likely to be used in women who, in consultation with their clinicians, consider that chemotherapy is not the best option for first-line treatment of metastatic disease.\n\n\n\nAdverse reactions\n\nClinical specialists stated that that lapatinib or trastuzumab plus an aromatase inhibitor might be preferred for some women in whom chemotherapy would currently be offered because the combination has a better adverse reaction profile than chemotherapy.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee heard from the Assessment Group that it was not possible to combine the EGF30008 and TAnDEM trials in a meta-analysis because of the different populations included in the trials, and that the results of the manufacturer's meta-analyses should be interpreted with caution. The Committee accepted that it would need to consider the clinical effectiveness of lapatinib plus an aromatase inhibitor and trastuzumab plus an aromatase inhibitor independently, at least in the first instance.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee understood from the clinical specialists that no difference in the clinical effectiveness of lapatinib and trastuzumab plus an aromatase inhibitor would be expected in clinical practice. It also heard that the trials did not provide robust evidence for or against a real difference between the two agents.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee concluded that lapatinib plus an aromatase inhibitor offered a benefit in progression-free survival but only a small and uncertain overall survival gain.\n\n\n\nThe Committee concluded that trastuzumab plus an aromatase inhibitor is associated with a statistically significant increase in median progression-free survival but that the evidence did not demonstrate a statistically significant increase in overall survival.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo subgroups were identified in this appraisal.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee noted that the trial results suggested a greater difference between treatment and comparators in median progression-free survival in the lapatinib and trastuzumab trials (that is, a difference of 5.2\xa0months in EGF30008, compared with 2.4\xa0months in the TAnDEM trial).\n\n\n\n\n\nEvidence of an overall survival gain was not demonstrated conclusively for either drug.\n\n, 4.3.10\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Assessment Group did not identify any published economic analyses that were considered relevant to the appraisal. The manufacturer of trastuzumab identified one study that it considered to be relevant. This was a poster by Hastings et al. presented in June 2010 at the annual meeting of the American Society of Clinical Oncology.\n\n\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nIn the Assessment Group's models, the estimates of additional post-progression survival with treatment with either lapatinib or trastuzumab plus an aromatase inhibitor were negative. Conversely, in both the manufacturer's models, the gain was a positive number. The Committee heard from clinical specialists that there is no reason why the addition of lapatinib or trastuzumab to an aromatase inhibitor before progression should result in either a shorter or longer duration of post-progression survival.\n\n, 4.3.12\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee did not discuss the incorporation of health-related quality of life benefits or utility values.\n\n–\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo subgroups were identified in this appraisal.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee considered that the differences in the ICERs were mainly because of different incremental QALYs that resulted from the different progression-free and post-progression survival estimates.\n\nand 4.3.13\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee concluded that the most plausible ICER for lapatinib plus an aromatase inhibitor would be near to £74,000 per QALY gained.\n\n\n\n\n\nThe Committee concluded that the most plausible ICER for trastuzumab plus an aromatase inhibitor would be at least £51,000 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable to this appraisal.\n\n–\n\nEnd-of-life considerations\n\nTrastuzumab\n\n\n\nThe Committee noted that the total number (7158) of patients diagnosed annually with conditions for which trastuzumab is indicated had been accepted by another Committee. The Committee was not persuaded that a population of over 7000 was small, or that it was valid to exclude patients in clinical trials from the calculation of population size. The Committee recognised that these different conclusions from that of a previous Committee were matters of judgement. However in the interest of fairness to this patient population, the Committee agreed not to differ from the other Committee's conclusion on this occasion. It therefore concluded that trastuzumab plus an aromatase inhibitor fulfilled the small population criterion.\n\n\n\nThe Committee noted that a range of survival estimates were presented and that all the evidence indicated that patients receiving current standard NHS treatment would have an expected survival greater than 24\xa0months. The Committee concluded that trastuzumab did not fulfil the criterion for short life expectancy.\n\n\n\n\n\nThe Committee discussed whether a 3-month survival gain could be reasonably inferred from the data provided and it decided that as trastuzumab did not meet the end-of-life criteria for life expectancy it was not required to make a decision for the extension to life criterion. The Committee concluded that treatment with trastuzumab plus an aromatase inhibitor did not fulfil all of the criteria for special consideration under the supplementary advice from NICE.\n\n, 4.3.18\n\n\n\nLapatinib\n\n\n\nThe Committee noted that the mean overall survival in the aromatase inhibitor monotherapy arm of the EGF30008 trial and in the ITT population of the TAnDEM trial exceeded 24\xa0months. The Committee concluded that lapatinib plus an aromatase inhibitor did not fulfil the criterion for short life expectancy.\n\n\n\n\n\nThe Committee considered that no robust evidence had been presented to indicate that lapatinib plus an aromatase inhibitor compared with an aromatase inhibitor alone offered a 3-month survival gain and concluded that lapatinib plus an aromatase inhibitor did not meet this criterion.\n\n\n\n\n\nThe Committee concluded that lapatinib did fulfil the small population criterion. However, because lapatinib had failed to meet the first and second criteria for consideration as a life-extending end-of-life treatment, the Committee concluded that lapatinib did not fulfil all the criteria for special consideration under the supplementary advice from NICE.\n\n, 4.3.22\n\n\n\nEqualities considerations and social value judgements\n\nComments from consultees indicated that a small population of older patients who are not fit enough to receive chemotherapy may not have access to an alternative treatment and so may be disadvantaged. The Committee agreed that this was not an issue of age discrimination because other factors can also affect whether people are fit enough to receive chemotherapy, such as comorbidities. The Committee concluded that there was no need to change or add to its recommendations.\n\n", 'Related NICE guidance': 'Advanced breast cancer: diagnosis and treatment. NICE clinical guideline 81 (2009).\n\nFamilial breast cancer: the classification and care of women at risk of familial breast cancer in primary, secondary and tertiary care. NICE clinical guideline 41 (2006).\n\nGuidance on the use of trastuzumab for the treatment of advanced breast cancer. NICE technology appraisal guidance 34 (2002).\n\nGuidance on the use of eribulin for the treatment of locally advanced or metastatic breast cancer. NICE technology appraisal guidance 250 (2012).', 'Review of guidance': 'The guidance on this technology will be considered for review by the Guidance Executive in June 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveJune 2012', 'Changes after publication': 'February 2014:\n minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta257
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Evidence-based recommendations on lapatinib (Tyverb) and trastuzumab (Herceptin) for treating metastatic hormone receptor-positive breast cancer that overexpresses HER2 in adults.
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3068d7273ca71025e82c4c13d3d9b1aa5acafd47
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nice
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Erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer
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Erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer
Evidence-based recommendations on erlotinib (Tarceva) for treating EGFR-TK-positive non-small-cell lung cancer in adults.
# Guidance
Erlotinib is recommended as an option for the first-line treatment of people with locally advanced or metastatic non-small-cell lung cancer (NSCLC) if:
they test positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and
the manufacturer provides erlotinib at the discounted price agreed under the patient access scheme (as revised in 2012).# The technology
Erlotinib (Tarceva, Roche Products) is an active inhibitor of the epidermal growth factor receptor tyrosine kinase (EGFR-TK). It blocks the signal pathways involved in cell proliferation and slows the growth and spread of the tumour. It has a UK marketing authorisation 'for the first-line treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with EGFR activating mutations'.
The summary of product characteristics lists the following adverse reactions to erlotinib: diarrhoea, rash, anorexia, gastrointestinal perforation, keratitis and rare cases of hepatic failure. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Erlotinib is given orally at a recommended dosage of 150 mg/day. The cost of a pack of 30 (150-mg) tablets is £1631.53 (excluding VAT; 'British national formulary' edition 63). Dosage reductions (typically to 100 or 50 mg/day) are possible if the clinician considers it appropriate, and erlotinib is also available in tablet strengths of 100 mg and 25 mg. The manufacturer of erlotinib has agreed a patient access scheme (revised in 2012) with the Department of Health in which a confidential discount from the list price is applied to original invoices. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of erlotinib (Roche Products) and a review of this submission by the Evidence Review Group (ERG; appendix B).
# Decision problem
The manufacturer's approach to the decision problem was in line with the NICE scope for the population, intervention, outcomes and the economic evaluation. The manufacturer's submission focussed on a comparison of erlotinib with gefitinib for first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC. The manufacturer's submission did not include pemetrexed plus cisplatin or carboplatin as a comparator because of the declining use in clinical practice of this combination for first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC and the absence of suitable data for comparison in this population.
# Clinical effectiveness
The manufacturer identified two randomised controlled trials (EURTAC and OPTIMAL) that compared erlotinib with platinum doublet chemotherapy as first-line treatment for patients with locally advanced or metastatic EGFR-TK mutation-positive NSCLC. The manufacturer based its evidence submission on the EURTAC trial with the OPTIMAL trial as supporting evidence. No studies were identified that compared erlotinib directly with gefitinib in this patient population, and so the manufacturer presented an indirect treatment comparison to assess the relative effectiveness of erlotinib and gefitinib.
The EURTAC trial was a European-based, open-label, phase III, randomised trial of first-line erlotinib treatment compared with platinum doublet chemotherapy for patients with stage IIIb or stage IV NSCLC and EGFR-TK mutation-positive tumours. The trial included 173 randomised patients and was conducted in 42 centres in Spain, France and Italy. Patients were screened for EGFR-TK mutations and those with EGFR-TK mutation-positive tumours were randomised to receive either 150 mg of erlotinib orally once a day or one of the following standard platinum-based chemotherapy regimens: cisplatin or carboplatin plus docetaxel; cisplatin or carboplatin plus gemcitabine. In the randomisation, patients were stratified according to Eastern Cooperative Oncology Group (ECOG) status (either ECOG=0, or ECOG=1 or 2) and the mutation type (deletion in exon 19 or mutation in exon 21 L858R). Treatment continued until disease progression, unacceptable adverse reactions, death, or until four chemotherapy cycles were completed. Following disease progression, patients were allowed to cross over in either direction, if clinically appropriate.
The primary outcome examined in the EURTAC trial was the length of progression-free survival. This was assessed as the time from randomisation to the first occurrence of progressive disease or death from any cause. Secondary outcomes included overall survival, best overall response, disease control, health-related quality of life and safety. Best overall response was defined in terms of the number of patients with either a complete or partial response (as defined by the Response Evaluation Criteria in Solid Tumours version 1 criteria) and disease control included patients with either a complete or partial response and those with stable disease for at least 6 weeks.
The manufacturer's submission described the results of the intention-to-treat analysis for all randomised patients. The median and 95% confidence limits of progression-free and overall survival between the erlotinib and the platinum doublet chemotherapy arms were obtained from the Kaplan–Meier estimate of the survival function. A two-sided log-rank test was used to assess the difference in outcomes between the two treatment arms. A Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence intervals.
The EURTAC trial included 153 patients at the time of the interim analysis and 173 at the updated analysis. For the updated analysis there were 86 patients in the erlotinib arm and 87 in the platinum doublet chemotherapy arm. Data for progression-free survival and overall survival from the EURTAC trial are still being collected. Both the interim and updated analyses showed that progression-free survival was statistically significantly longer for patients treated with erlotinib than for patients treated with platinum doublet chemotherapy. In the updated analysis the median progression-free survival in the platinum doublet chemotherapy arm was 5.2 months compared with 9.7 months in the erlotinib arm. The risk of disease progression or death was statistically significantly reduced (by 63%, HR 0.37, 95% CI 0.25 to 0.54, p<0.0001) for patients in the erlotinib arm. In the updated analysis the manufacturer reported overall survival results for 69 (40%) events. The median overall survival was 19.5 months in the platinum doublet chemotherapy arm and 19.3 months in the erlotinib arm (hazard ratio 1.04 , p=0.8702). More patients in the platinum doublet chemotherapy arm received second and further-line treatments than patients in the erlotinib arm (77% compared with 45% ). In the platinum doublet chemotherapy arm, 66 of the 67 patients received at least one treatment with either erlotinib or gefitinib. In the updated analysis, the best overall response (as defined in section 3.4) was statistically significantly greater in the erlotinib arm than the platinum doublet chemotherapy arm (58.1% compared with 14.9% , p<0.0001).
The manufacturer submitted the results of the OPTIMAL trial, which was carried out in 22 centres in China, as additional evidence. The OPTIMAL trial was a multicentre, open-label, phase III, randomised trial of first-line erlotinib treatment compared with platinum doublet chemotherapy for chemotherapy-naive patients with stage IIIb or stage IV NSCLC whose tumours were EGFR-TK mutation-positive. Patients were randomised (n=165) to receive either 150 mg of erlotinib orally once daily or gemcitabine plus cisplatin chemotherapy. Treatment continued until disease progression, unacceptable adverse reactions or death, or until four chemotherapy cycles were completed. Following disease progression, patients were allowed to cross over in either direction, if clinically appropriate.
In the most recent analysis from the OPTIMAL trial, progression-free survival was statistically significantly longer in patients treated with erlotinib than in patients treated with platinum doublet chemotherapy. The median progression-free survival in the platinum doublet chemotherapy arm was 4.6 months (95% CI 4.21 to 5.42) compared with 13.7 months (95% CI 10.58 to 15.28) in the erlotinib arm. The risk of progression or death was statistically significantly reduced (by 84%, HR 0.16; 95% CI 0.10 to 0.26, p<0.0001) for patients in the erlotinib arm. The overall survival data from the OPTIMAL trial were not presented because too few deaths had been recorded at the time of the analysis.
The manufacturer did not perform a meta-analysis of progression-free survival from the EURTAC and OPTIMAL trials because heterogeneity between the treatment effects was identified using an assessment of heterogeneity recommended by the Cochrane Collaboration. The manufacturer noted that factors possibly contributing to the heterogeneity included: the different ethnicity of the patients in the trials; better adherence in the OPTIMAL trial and poorer efficacy of the comparator in the OPTIMAL trial.
A systematic review identified four randomised controlled trials comparing gefitinib with various doublet chemotherapy regimens in East Asian populations (IPASS, First-SIGNAL, WJTOG3405 and NEJGSG002). The data from the gefitinib trials were pooled by assuming that the doublet chemotherapy was of equal efficacy in each of the four trials (Ku et al. 2011). Across the four studies, the estimated hazard ratio for median progression-free survival was 0.45 (95% CI 0.38 to 0.55, p<0.001).
For the indirect comparison of erlotinib with gefitinib the manufacturer assumed that the platinum doublet chemotherapy arms of the EURTAC and OPTIMAL trials could be linked to the gefitinib meta-analysis using platinum doublet chemotherapy as the anchor point. From an assessment of the similarities and differences between the studies, the manufacturer concluded that ethnicity is the key factor for the differences and so a robust indirect comparison should involve studies based in an East Asian population. The manufacturer presented results from four possible indirect comparisons of the two erlotinib trials and combinations of them against the gefitinib meta-analysis. In the indirect comparisons the hazard ratio for median progression-free survival varied between 0.36 (95% CI 0.22 to 0.59) and 0.82 (95% CI 0.54 to 1.26) depending on the combination of studies chosen. In the manufacturer's view the hazard ratio for progression-free survival from the indirect comparison of EURTAC with the gefitinib meta-analysis (hazard ratio 0.82 ) was the most appropriate estimate of the clinical effectiveness of erlotinib compared with gefitinib in patients with EGFR-TK mutation-positive NSCLC in England and Wales.
The manufacturer stated that there were insufficient data on health-related quality of life collected in the EURTAC trial for any analysis to be done. In the OPTIMAL trial quality of life was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire and the Trial Outcome Index. Results were presented from 128 (83.2%) patients and demonstrated that approximately 70% of patients receiving first-line erlotinib experienced significant, clinically relevant improvements in quality of life compared with 30% of patients receiving platinum doublet chemotherapy across all FACT-L scales measured.
The incidence and nature of adverse reactions to erlotinib in the EURTAC and OPTIMAL trials were consistent with previously collected data on the use of erlotinib for first-line maintenance treatment and relapsed NSCLC. The manufacturer noted the longer duration of active treatment with erlotinib compared with chemotherapy and that the extended treatment period may also have increased the number of adverse reactions reported. In the EURTAC trial, patients in the erlotinib arm had a typical treatment duration of 9–10 months before progression or unacceptable adverse reactions, whereas patients in the chemotherapy arm received a maximum of four cycles over approximately 3 months. Most of the reported adverse reactions in both arms were grade 1 or grade 2 (432/527 events in the chemotherapy arm and 621/681 events in the erlotinib arm). Fewer patients experienced grade 3 or 4 events in the erlotinib arm (31 patients ) than in the chemotherapy arm (49 patients ).
In the EURTAC trial low grade skin reactions and diarrhoea were the most commonly reported adverse reactions in patients who received erlotinib. Skin reactions were mainly mild or moderate, with 5% of patients experiencing grade 3 rash and 1% experiencing dry skin. No grade 4 skin reactions were reported. Diarrhoea was also mainly mild or moderate, with 4% of patients experiencing grade 3 diarrhoea.
# Cost effectiveness
The manufacturer presented a de novo economic analysis that assessed the cost effectiveness of erlotinib compared with gefitinib for the first-line treatment of EGFR mutation-positive NSCLC. In line with the NICE reference case, outcomes were expressed in terms of quality-adjusted life years (QALYs), an NHS and personal social services perspective was adopted, and costs and benefits were discounted at 3.5%. The treatments compared in the model were first-line erlotinib (one 150-mg tablet daily until disease progression) or gefitinib (one 250-mg tablet daily until disease progression). No second-line treatments were included because the second-line treatment options were considered identical for both erlotinib and gefitinib. The manufacturer presented a semi-Markov economic model with three health states: progression-free survival, progressed disease and death. The model had a 10-year time horizon and a cycle length of 1 month.
The manufacturer considered that the EURTAC study was more representative of the outcomes expected in UK clinical practice than the OPTIMAL study and so the clinical data in the model were derived from the EURTAC trial and the indirect comparison of erlotinib (EURTAC trial) and gefitinib (Ku et al. 2011). An area under the curve approach was used to calculate the proportion of patients in the progression-free survival health state each month. For erlotinib, the estimated survival curve for the progression-free state was based on the observed EURTAC data up to month 16 and was then extrapolated assuming an exponential distribution. For gefitinib, the progression-free survival curve was derived by transforming the erlotinib survival curve using the hazard ratio for progression-free survival (HR 0.82) from the indirect comparison of erlotinib (EURTAC trial) and gefitinib (Ku et al. 2011). The same transition probabilities, derived from the EURTAC data, were used for both erlotinib and gefitinib for the transition between the progression-free survival health state and death and between the progressed disease health state and death.
Utilities in the model were based on values from the study of Nafees et al. (2008). These utility values were estimated using the standard gamble approach with 105 members of the UK general public who were asked to value health-state descriptions of patients receiving second-line chemotherapy for NSCLC. These values have been used in four previous NICE appraisals of drugs for NSCLC (Pemexetred for the first-line treatment of non-small-cell lung cancer , Pemexetred for the maintenance treatment of non-small-cell lung cancer , Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer , Erlotinib monotherapy for the maintenance treatment of non-small-cell lung cancer, ). The utility values for the progression-free survival health state were treatment dependent and were calculated from the response rate and the incidence of adverse reactions (grade 3 or 4 rash; grade 3 or 4 diarrhoea). The utility value for the progression-free health state for patients receiving erlotinib (0.661) was based on the response rate in the EURTAC trial (58.10%). The value for patients receiving gefitinib (0.656) was based on a gefitinib response rate (28.23%) which was estimated indirectly by applying the relative response from the gefitinib meta-analysis to the chemotherapy response rate observed in the EURTAC trial (14.9%). The utility decrement value for progressed disease (−0.1798 relative to the progression-free survival stable disease baseline value of 0.6532) was taken from the study of Nafees et al. (2008) and assumed that the choice of first-line treatment had no influence on the utility patients experienced post progression.
The manufacturer included costs associated with drug acquisition and administration, best supportive care, terminal care, monitoring and adverse reactions in the economic model. These were estimated from a range of secondary sources such as reference costs, BNF and submissions for previous NICE technology appraisals. The monthly cost of erlotinib with the list price (see section 2.3) was £1631.53 based on a daily dose of 150 mg. The manufacturer also presented analyses based on the erlotinib drug cost with the earlier 14.5% discount and with the revised patient access scheme. Under the terms of the gefitinib patient access scheme approved by the Department of Health, there is a single fixed cost of £12,200 per patient when the third monthly pack of gefitinib is supplied. In the base-case analysis, the proportion of patients for whom the £12,200 payment was made was derived by applying the hazard ratio for progression-free survival from the indirect comparison of erlotinib and gefitinib (HR 0.82) to the 'time to last dose' curve generated from the EURTAC data. This results in approximately 76% patients incurring the fixed cost for gefitinib. No administration cost for the erlotinib patient access scheme was included in the economic model because it is a simple discount. For the gefitinib patient access scheme, the manufacturer assumed that the administration cost includes a one-off £70 cost (patient registration, invoicing and query management) and an ongoing monthly cost of £35 (completion of request pack and payment reconciliation).
Results from the manufacturer's base-case analyses (including the discount under the patient access scheme as revised in 2012) for erlotinib compared with gefitinib show an incremental cost-effectiveness ratio (ICER) of £21,874 per QALY gained. From deterministic sensitivity analyses for a range of parameters, the manufacturer identified the main factors affecting the cost effectiveness as the hazard ratio for progression-free survival for gefitinib and the proportion of patients for whom the gefitinib patient access scheme payment was needed. Varying the hazard ratio for progression-free survival from the indirect comparison from 0.36 to 0.58 resulted in an ICER between £15,712 and £16,552 per QALY gained. When the proportion of patients incurring the fixed charge for gefitinib was varied from 85% to 100%, the ICER was always less than £10,066 per QALY gained. The manufacturer also presented a probabilistic sensitivity analysis which resulted in an ICER of £25,791 per QALY gained for erlotinib compared with gefitinib. There was a 36% probability of erlotinib being cost effective if the maximum acceptable ICER was £20,000 per QALY gained; the probability was 63% if the maximum acceptable ICER was £30,000 per QALY gained.
# Evidence Review Group comments
The ERG stated that without consideration of pemetrexed in combination with another drug (doublet chemotherapy) as a comparator, the evidence presented in the manufacturer's submission was incomplete and did not allow a full evaluation of erlotinib as set out in the decision problem. The ERG considered pemetrexed-based doublet chemotherapy a valid comparator because almost all patients whose tumours are EGFR-TK mutation-positive have non-squamous lung cancer. In addition some of these will be treated with pemetrexed-based doublet chemotherapy in hospitals that do not routinely test for EGFR and also in situations when delaying treatment to await EGFR-TK status would be detrimental to the patient's health. The ERG stated that the difference in efficacy between pemetrexed and gefitinib has become clearer since the publication of Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (NICE technology appraisal guidance 192). The ERG stated that pemetrexed is the only first-line treatment for patients with non-squamous cell lung cancer which has demonstrated a statistically significant gain in overall survival when compared with third-generation chemotherapy. Recently published updates to a randomised controlled trial of gefitinib have reported no overall survival gain for gefitinib compared with third-generation chemotherapy.
In the ERG's view the EURTAC trial was well-designed and suitably powered to demonstrate its primary objective. It considered the inclusion and exclusion criteria to be reasonable and the baseline characteristics of patients in EURTAC trial to reflect patients in UK clinical practice who would be considered eligible for treatment with an EGFR-TK inhibitor. The ERG was unable to comment definitively on the quality of the supporting evidence from the OPTIMAL trial because the clinical study report was not made available.
The ERG considered that the use of conventional proportional hazards methods to estimate hazard ratios in either the gefitinib or erlotinib trials compared with any other drug is problematic. The assumption of proportional hazards was not tested by the manufacturer. The ERG presented plots of the hazard rates for gefitinib and erlotinib and comparators, which suggested an assumption of proportional hazards was not valid. A comparison of the cumulative hazards for each of the six trials of a tyrosine kinase inhibitor (either gefitinib or erlotinib) compared with platinum doublet chemotherapy showed two separate phases. During the first 4 months of treatment (corresponding approximately to the period of standard chemotherapy), there is very little difference in hazards between intervention and comparator arms. However, in the following 2–3 months the slopes of the lines in all trial arms increase, but with the comparator arms diverging rapidly from the erlotinib or gefitinib arms. A more appropriate method of estimating the relative efficacy involves treating these two time periods as separate phases (equivalent to active therapy followed by observation/maintenance therapy) and deriving separate hazard ratios for each phase (using a landmark analysis for the second phase). In the ERG's view, relative efficacy should be estimated using this approach and the estimates obtained explored in a revised economic model.
The ERG highlighted that the manufacturer identified heterogeneity between the EURTAC and OPTIMAL trials by comparing the median progression-free survival. In the ERG's view the heterogeneity identified by the manufacturer is simply a consequence of using this outcome measure. A comparison of the Kaplan–Meier curves for progression-free survival from the two trials shows close correspondence in the comparator arms. The two erlotinib arms follow very similar trends although they are slightly separated. Crucially, across successive time periods the gradients of the cumulative hazard curves are very similar. The ERG concluded that the balance of evidence favours including results from both EURTAC and OPTIMAL trials in any indirect comparison.
The ERG was not convinced that any of the four options for the indirect comparison described by the manufacturer are appropriate. It believed that data from the EURTAC and OPTIMAL trials should be pooled and that revised relative efficacy measures be used (see section 3.22). From an analysis of the progression-free survival and the cumulative hazard curves, the ERG showed that after 12 months the results for patients in the IPASS trial (gefitinib compared with doublet chemotherapy) diverge from the other gefitinib trials. The ERG recommended that a sensitivity analysis that excludes the IPASS data should be undertaken as part of the indirect comparison.
The ERG was only able to offer a limited critique of the cost-effectiveness results submitted by the manufacturer because of its concerns about the structure of the model. In the ERG's view pemetrexed plus cisplatin should be included as a comparator and there was also an argument for including the four third-generation platinum doublets (docetaxel, gemcitabine, paclitaxel and vinorelbine) in a full evaluation as in Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (NICE technology appraisal guidance 192). In the ERG's view the omission of all comparators other than gefitinib has resulted in a simple model structure without a robust, multi-way economic comparison that would most likely have reduced the probability of erlotinib appearing as the most cost-effective option.
The ERG highlighted that the current model yielded an overall survival benefit for patients with EGFR-TK mutation-positive NSCLC receiving first-line erlotinib compared with those receiving gefitinib, which has not been demonstrated by the published evidence from randomised controlled trials. The submitted model does not include any data on overall survival and after disease progression all surviving patients are assumed to follow the same post-progression course and incur the same costs. The direct consequence of the simple model structure is that most of the estimated difference in progression-free survival between patients receiving gefitinib and those receiving erlotinib is preserved by a common post-progression phase, which translates into a similar difference in overall survival.
# Revised economic analyses following consultation
Additional evidence was provided by the manufacturer in response to NICE's request in the appraisal consultation document for an updated economic model and analyses. The updated model included, as requested, an assumption of equal progression-free survival and equal utilities for the progression-free survival health state for the two treatments (erlotinib and gefitinib). The manufacturer provided analyses exploring the sensitivity of the cost-effectiveness results to varying the proportion of patients (equally for erlotinib and gefitinib) in the progression-free survival health state at day 60 (for whom the fixed charge for gefitinib is incurred under the patient access scheme). The proportion in the base case was 80%, which was the proportion of patients still receiving erlotinib at the start of the third month of the EURTAC trial. In the sensitivity analyses, the proportion was varied, equally for erlotinib and gefitinib, from the base case to 100%. The costs in the model were not modified. Results from the updated model showed that erlotinib becomes more cost effective than gefitinib when at least 91% of patients incur the gefitinib fixed charge. In the manufacturer's view the proportion of patients incurring the gefitinib fixed charge at day 60 is likely to be more than 90%, as demonstrated in each of the four gefitinib trials. Also data from recent market surveys in Europe and the UK indicate that at least 95% of patients receiving gefitinib have 60 or more days of treatment (and thus incur the fixed charge).
The ERG explored the analyses using the manufacturer's updated model and confirmed that the Committee's requests specified in the appraisal consultation document had been implemented. However, the ERG noted that the manufacturer assumed the same rates of adverse reactions for the two treatments (erlotinib and gefitinib) when calculating the utility value. The ERG showed that when the same utility value is used for both treatments and the different rates of adverse reactions are retained in the updated model, there is a small additional cost of £5.24 per patient for erlotinib treatment. The ERG was concerned that the cost of administering the gefitinib patient access scheme (a mean cost of £438 per patient over the treatment period) was overstated in the manufacturer's model. The ERG assumed that pack ordering and reconciliation would be needed only once a year and estimated a mean cost for administering the gefitinib patient access scheme of between £111 and £118 per patient. The ERG explored the impact of updating the manufacturer's model with these costs and included the adverse reaction rates for each treatment. The ERG's results demonstrated that erlotinib is cost effective compared with gefitinib when 95% or more of patients receiving gefitinib incur the fixed charge for gefitinib.
Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA258# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of erlotinib, having considered evidence on the nature of locally advanced or metastatic EGFR-TK mutation-positive NSCLC and the value placed on the benefits of erlotinib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
# Clinical practice
The Committee discussed the clinical need of patients with locally advanced or metastatic EGFR-TK mutation-positive NSCLC. It heard from the clinical specialists that the main aim of treatment is to extend progression-free and overall survival with the fewest adverse reactions and with the best quality of life possible for the remaining months of life. The clinical specialists also highlighted that for this patient population an oral treatment with a tyrosine kinase inhibitor, such as gefitinib or erlotinib, is usually associated with an improved quality of life compared with platinum doublet chemotherapy.
The Committee heard from the clinical specialists that current UK clinical practice for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC is to use gefitinib as recommended in NICE technology appraisal guidance 192. The Committee also heard that chemotherapy with pemetrexed plus carboplatin or cisplatin may be used as a second-line treatment and is rarely used as first-line treatment for this patient population. The Committee accepted that gefitinib is current standard practice in England and Wales for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC.
The Committee discussed the availability of EGFR testing to inform the first-line treatment of locally advanced or metastatic NSCLC. It heard from the clinical specialists that EGFR testing is standard practice for this patient population across almost all the NHS. The Committee accepted that EGFR testing is standard practice in England and Wales when making decisions about the first-line treatment of locally advanced or metastatic NSCLC.
The Committee discussed the use of tyrosine kinase inhibitors in clinical practice for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC. It heard from clinical specialists that in their opinion erlotinib and gefitinib are very similar treatments with similar efficacy and levels of adverse reactions. The clinical specialists highlighted that having the choice of two similar treatments enables better management of adverse reactions. The Committee also heard from the clinical specialists that the adverse reactions associated with both these treatments are much less common than those associated with chemotherapy but may vary (for example, rash may be more common with erlotinib and interstitial lung disease may be more common with gefitinib). Erlotinib offers the advantage of being able to vary the dosage by using tablets of different dose strength. The Committee also heard that the patient access scheme for gefitinib is not straightforward and that hospitals may find the patient access scheme for erlotinib easier to administer. The Committee concluded that further first-line treatment options for patients with locally advanced or metastatic EGFR-TK mutation-positive NSCLC would be valuable for clinical practice.
# Clinical effectiveness
The Committee considered the evidence submitted by the manufacturer on the clinical effectiveness of erlotinib. The Committee agreed with the manufacturer that although pemetrexed plus cisplatin or carboplatin was listed as a comparator in the scope, recent changes in the clinical pathway since the publication of NICE technology appraisal guidance 192 in 2011 have resulted in the use of gefitinib for first-line treatment for most patients with EGFR-TK mutation-positive NSCLC, as confirmed by the clinical specialists (see section 4.3). The Committee concluded that gefitinib is the appropriate comparator for this appraisal.
The Committee noted that the evidence of clinical effectiveness of erlotinib in locally advanced or metastatic EGFR-TK mutation-positive NSCLC was based on the EURTAC trial with supporting evidence from the OPTIMAL trial. The Committee noted that both trials provided evidence of increased progression-free survival compared with doublet chemotherapy. The Committee agreed that the EURTAC trial provided evidence relevant to clinical practice in the NHS in England and Wales. The Committee concluded that the evidence from the EURTAC trial demonstrated that erlotinib increased progression-free survival compared with doublet chemotherapy.
The Committee considered the indirect comparison presented by the manufacturer. The hazard ratio for progression-free survival used in the model (0.82, 95% CI 0.54 to 1.26) was obtained by comparing the EURTAC trial with the gefitinib meta-analysis. The Committee noted the wide confidence intervals around the estimated hazard ratio for progression-free survival, but recognised the difficulties in constructing a robust indirect comparison given the limited number of studies in this patient population and the heterogeneity between the studies. The Committee discussed the heterogeneity between the trials and the possible prognostic factors that may have influenced heterogeneity, such as ethnic group and class of mutation (exon 19 deletion compared with mutation in exon 21 L858R). It heard from the clinical specialists that the difference in the response rate in the chemotherapy arms between the EURTAC and OPTIMAL trials was within the acceptable range for this group of patients. The Committee noted that the ERG had pointed out the similarities in the curves for progression-free survival from the EURTAC and OPTIMAL trials and the difference between the results from the IPASS trial and the other gefitinib trials after 12 months of treatment. The Committee heard from the ERG that the gefitinib trials had not been uniformly reported so it was not possible to be certain whether the differences were caused by factors such as differing variables in multivariate analyses or small patient numbers. The Committee also discussed the ERG's comments about the difficulties associated with using the proportional hazards assumption for these data and the possibility of using revised efficacy outcomes. The Committee was not convinced that an indirect comparison could be used with the existing data, to support the assumption that erlotinib was more effective than gefitinib, given the heterogeneity of the populations included and the variations in prognostic factors within the populations. In addition, the Committee noted the clinical specialists' view that erlotinib and gefitinib are very similar treatments with similar efficacy for locally advanced or metastatic EGFR-TK mutation-positive NSCLC (see section 4.5). The Committee concluded that there was insufficient evidence to suggest a difference in clinical effectiveness between erlotinib and gefitinib in the model and therefore the most appropriate value for the hazard ratio for progression-free survival between the treatments is 1.
The Committee discussed the overall survival data from the trials. It noted that the data for overall survival were incomplete (either not available for all patients or not known) for the EURTAC and OPTIMAL trials and therefore no comparison of overall survival benefit for erlotinib and gefitinib was available. It also noted the ERG's concerns about whether there was an overall survival benefit for treatment with a tyrosine kinase inhibitor compared with doublet chemotherapy in light of the recently published final results from the IPASS trial (gefitinib compared with doublet chemotherapy). Because of the similarities in the treatments and the lack of data on overall survival, the Committee was not convinced of a survival benefit for erlotinib compared with gefitinib for patients with locally advanced or metastatic EGFR-TK mutation-positive NSCLC.
The Committee considered the adverse reactions experienced by patients receiving treatment for locally advanced or metastatic NSCLC. It noted that data from the EURTAC trial demonstrated that fewer patients in the erlotinib arm experienced grade 3 or 4 events compared with the chemotherapy arm. Low grade skin reactions (rash grade 3, 5%) and diarrhoea (grade 3, 4%) were the most commonly reported adverse reactions associated with erlotinib. The clinical specialists confirmed that the adverse reactions associated with erlotinib and gefitinib were generally modest but slightly different. The Committee concluded that the adverse reactions associated with erlotinib were relatively mild in most patients and that from a clinical perspective there may be some advantage to having a choice of tyrosine kinase inhibitors for this patient group.
The Committee noted the lack of quality of life data from the EURTAC trial and heard from the clinical specialists that a common problem with studies in this patient population is the failure to complete questionnaires. The Committee was disappointed that there were insufficient quality of life data from the EURTAC trial for analysis. Because erlotinib and gefitinib are both oral tyrosine kinase inhibitors with similar efficacy and comparable adverse reactions, the Committee concluded that the health-related quality of life of patients would be similar for the two treatments.
# Cost effectiveness
The Committee considered the manufacturer's original cost-effectiveness analysis and the ERG's critique. It noted that the manufacturer used a semi-Markov model to evaluate the cost effectiveness of erlotinib compared with gefitinib. The clinical data used in the model were derived mainly from the EURTAC trial and the indirect comparison of data from the EURTAC trial with the gefitinib meta-analysis described by Ku et al. (2011). The Committee was aware of the ERG's concerns that the structure of the model allowed the benefit in progression-free survival to be translated into an overall survival benefit in the economic model. Given the uncertainties associated with the hazard ratio for progression-free survival obtained from the indirect comparison (described in sections 3.22 to 3.25 and 4.8), as well as the lack of evidence demonstrating an overall survival benefit for erlotinib compared with gefitinib (see section 4.9), the Committee concluded that the cost effectiveness of erlotinib compared with gefitinib could be best assessed from an analysis which assumes equal clinical benefit between the treatments and focuses on their differential costs.
The Committee discussed the utility values used within the original model and noted that the utility value for the progression-free survival health state was 0.661 for erlotinib and 0.656 for gefitinib. It noted that the difference was mainly a result of difference in the response rates (58% for erlotinib compared with 28% for gefitinib) used in the calculation. The Committee heard from the ERG that the response rate from the gefitinib meta-analysis was 71.5% (Ku et al. 2011). The Committee heard from the manufacturer that the difference in utility values (0.005, <1%) used for the two treatments made little difference to the results from the model. However, the Committee saw little clinical justification for the difference in the utilities in the manufacturer's original model, and concluded that an analysis incorporating identical utility values for patients receiving erlotinib and patients receiving gefitinib in the progression-free survival health state should be used as a basis for its decision making.
The Committee acknowledged that, following its request for further clarification in the appraisal consultation document, the manufacturer had provided an updated economic model which incorporated equal progression-free survival and utilities for erlotinib and gefitinib. The results from the model depended on the costs of the drugs, the cost of administering the gefitinib patient access scheme and the proportion of patients on gefitinib who incurred the fixed charge on day 60. The Committee discussed the uncertainties in the clinical evidence which led to this request for an economic model based on there being no difference in the clinical benefit between the treatments. The Committee acknowledged the limitations of this type of economic model which incorporates no uncertainties about survival. The Committee concluded that, although the assumption of equal clinical benefit could be a conservative estimate of the clinical effectiveness of erlotinib, the updated economic model was in line with clinical opinion (see section 4.5), reflected the absence of any clinical data from direct comparisons, and allowed a direct comparison of the costs of the two treatments.
The Committee considered the impact of the cost of administering the gefitinib patient access scheme on the results from the updated economic model. When the mean administration cost changed from £438 per patient in the manufacturer's updated model to £111–118 in the ERG's exploratory analysis, erlotinib was cost effective when the proportion of patients incurring the fixed charge for gefitinib increased from 91% to 95%. The Committee acknowledged that the time taken to complete the online forms for the gefitinib patient access scheme was much shorter than that estimated by the manufacturer and that the typical administration costs for patient access schemes of this type were likely to be nearer to the ERG's estimate rather than the manufacturer's. This remained despite the possibility of additional reporting costs associated with the gefitinib patient access scheme which were not included in the ERG's analyses. The Committee understood that there may not be complete uptake of the gefitinib patient access scheme across the NHS, that some trusts may pay the list price for gefitinib and that this has not been considered in the updated model, which assumed all patients on gefitinib for more than 60 days would incur the fixed charge. The Committee concluded that the administration costs of the gefitinib patient access scheme were likely to be nearer the ERG's estimates rather than the manufacturer's, and that there may be some additional savings not included in the updated model because of the incomplete uptake of the gefitinib patient access scheme across the NHS.
The Committee considered the impact of the proportion of patients who receive gefitinib for more than 60 days (and would therefore incur the fixed charge) on the results from the updated economic model. Both the manufacturer and the ERG presented sensitivity analyses incorporating different costs for administering the gefitinib patient access scheme (see section 4.15). The Committee discussed the evidence on the proportion of patients who receive gefitinib for more than 60 days (and incur the fixed charge). The Committee was disappointed that there was not more reliable evidence available from the NHS. The Committee heard from clinical specialists that nearly all patients on gefitinib survive until day 60 when the third pack is issued. The Committee noted that the base-case analysis presented by the manufacturer used a proportion of 80%, which was the proportion of patients in the EURTAC trial who had completed 60 days of erlotinib treatment. There were about 88% of erlotinib patients in the EURTAC trial who were in the progression-free survival health state on day 60 but this included some patients who had not completed 60 days of treatment. The sensitivity analysis presented by the manufacturer identified that erlotinib became cost effective compared with gefitinib when 91% of patients incurred the fixed charge for gefitinib. The ERG's exploratory analysis estimated this proportion to be 95%. The Committee discussed the results from the updated analyses and on balance agreed that the sums of money either saved or spent are small given the uncertainties associated with the analysis. The Committee concluded that at the price agreed under the patient access scheme (as revised in 2012) erlotinib should be recommended as an option for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC.
# Other considerations
The Committee discussed whether it needed to consider the supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. It noted that the manufacturer did not make a case for erlotinib to be considered as an end-of life treatment in the submission. The Committee also heard from the manufacturer that in its view erlotinib does not meet the criteria for an end-of-life treatment. The Committee noted that in Erlotinib monotherapy for the maintenance treatment of non-small-cell lung cancer (NICE technology appraisal guidance 227) erlotinib did not meet the end-of-life criteria because the cumulative population for erlotinib was not considered small. The Committee therefore concluded that erlotinib did not need to be considered as a life-extending, end-of-life treatment.
The Committee discussed whether erlotinib should be considered an innovative technology, or if there were any significant and substantial health benefits which were not included in the economic model. It noted that the manufacturer did not make a case for erlotinib to be considered innovative, and did not identify any additional health benefits not included in the economic model. The Committee heard from the manufacturer that erlotinib is not considered a major change in treatment for locally advanced or metastatic EGFR-TK mutation-positive NSCLC, but is an incremental advance. The manufacturer stated that the oral administration and the straightforward patient access scheme gave value to erlotinib. The Committee concluded that erlotinib could not be considered to show significant innovation and that no additional health benefits had been identified which had not been adequately captured by the economic model.
The Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. The Committee noted that no equality issues were included in the manufacturer's submission. It also noted that the reduced adverse reactions associated with tyrosine kinase inhibitors compared with those associated with chemotherapy raised during the scope consultation was not an equalities issue for this appraisal. No equalities issues were identified by the Committee. Given that the recommendations did not differentiate between any groups of people, the Committee concluded that its recommendations did not limit access to the technology for any specific group compared with other groups and that there was no need to alter or add to its recommendations.
# Summary of Appraisal Committee's key conclusions
TA258
Appraisal title: Erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer
Section
Key conclusion
Erlotinib is recommended as an option for the first-line treatment of people with locally advanced or metastatic non-small-cell lung cancer (NSCLC) if:
they test positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and
the manufacturer provides erlotinib at the discounted price agreed under the patient access scheme (as revised in 2012).
The Committee concluded that gefitinib was the comparator for this appraisal.
The Committee concluded there was insufficient evidence to suggest a difference in clinical effectiveness between erlotinib and gefitinib and it heard from clinical specialists that erlotinib and gefitinib are very similar treatments with similar efficacy. The Committee concluded that the cost effectiveness of erlotinib compared with gefitinib could be best assessed from the updated economic model which assumes equal clinical benefit for the treatments and focuses on their differential costs.
The Committee agreed that the results from the economic model showed that on balance the sums of money lost or saved are small given the uncertainties in the analysis, and so it recommended erlotinib as a treatment option.
Current practice
Clinical need of patients, including the availability of alternative treatments
The main aim of treatment is to extend progression-free and overall survival with the fewest adverse reactions and with the best quality of life possible for the remaining months of life.
Current standard practice in England and Wales for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC is gefitinib.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The oral method of administration and less common adverse reactions with either erlotinib or gefitinib offers an advantage for patients compared with chemotherapy. Erlotinib offers the advantage of being able to vary the dosage by using tablets of different dose strength.
The manufacturer confirmed that erlotinib is not considered a major change in treatment, but is an incremental advance. The Committee concluded that erlotinib could not be considered to show significant innovation.
What is the position of the treatment in the pathway of care for the condition?
Erlotinib has a UK marketing authorisation 'for the first-line treatment of patients with locally advanced or metastatic non-small-cell lung cancer with EGFR activating mutations'.
The Committee heard from clinical specialists the current UK clinical practice for this indication is to use gefitinib as recommended by NICE technology appraisal guidance 192.
Adverse reactions
The adverse reactions associated with erlotinib and gefitinib were modest but slightly different. The Committee concluded that the adverse reactions associated with erlotinib were relatively mild in most patients and that from a clinical perspective there may be some advantage to having a choice of tyrosine kinase inhibitors for this patient group.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The evidence of clinical effectiveness was derived from the EURTAC trial (a European-based, open-label, randomised trial of first-line erlotinib treatment compared with platinum doublet chemotherapy for patients with stage IIIb or stage IV NSCLC and EGFR-TK mutation-positive tumours). Additional evidence was provided by the OPTIMAL trial (a Chinese-based open-label randomised trial of first-line erlotinib treatment compared with platinum doublet chemotherapy for chemotherapy-naive patients with stage IIIb or stage IV NSCLC whose tumours were EGFR-TK mutation-positive.
There was no evidence from a direct comparison of erlotinib and gefitinib.
Relevance to general clinical practice in the NHS
The Committee agreed that the EURTAC trial provided evidence relevant to clinical practice in the NHS in England and Wales.
Uncertainties generated by the evidence
The Committee was not convinced that an indirect comparison could be used with the existing data, to support the assumption that erlotinib was more effective than gefitinib, given the heterogeneity of the populations included and the variations in prognostic factors within the populations.
The Committee noted that the overall survival data from the trials were incomplete. The Committee was not convinced of a survival benefit for erlotinib compared with gefitinib.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee did not consider any subgroups.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee was not convinced that an indirect comparison could be used with the existing data to support the assumption that erlotinib was more effective than gefitinib. The Committee noted the clinical specialists' view that erlotinib and gefitinib are very similar treatments with similar efficacy for locally advanced or metastatic EGFR-TK mutation-positive NSCLC. The Committee concluded that there was insufficient evidence to suggest a difference in clinical effectiveness between erlotinib and gefitinib in the model and therefore the most appropriate value for the hazard ratio for progression-free survival between the treatments is 1.
Evidence for cost effectiveness
Availability and nature of evidence
The manufacturer originally submitted a semi-Markov model to evaluate the cost effectiveness of erlotinib compared with gefitinib. The clinical data for this model were derived from the EURTAC trial and the indirect comparison.
In response to NICE's request in the appraisal consultation document, the manufacturer submitted an updated model. This model assumed equal progression-free survival and equal utilities for the progression-free survival health state for the two treatments (erlotinib and gefitinib).
Uncertainties around and plausibility of assumptions and inputs in the economic model
In the Committee's view, the survival benefit for erlotinib compared with gefitinib was uncertain.
The Committee concluded that the cost effectiveness of erlotinib compared with gefitinib could be best assessed from the updated economic model which assumes equal clinical benefit for the treatments and focuses on their differential costs.
The Committee acknowledged the limitations of this type of economic model which incorporates no uncertainties about survival. The Committee concluded that, although the assumption of equal clinical benefit could be a conservative estimate of the clinical effectiveness of erlotinib, the updated economic model was in line with clinical opinion (see section 4.5), reflected the absence of any clinical data from direct comparisons, and allowed a direct comparison of the costs of the two treatments.
The Committee concluded that the administration costs of the gefitinib patient access scheme were likely to be nearer the ERG's estimates than the manufacturer's, and that there may be some additional savings not included in the updated model because of the incomplete uptake of the gefitinib patient access scheme across the NHS.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee saw little clinical justification for the difference in the utilities for the progression-free survival health state for erlotinib and gefitinib in the original economic model and requested that they be made identical in the updated model.
No significant and substantial health-related benefits that have not been captured by the QALY calculation were identified either in the submission or at the Committee meeting. The Committee concluded that no additional health benefits had been identified which had not been adequately captured by the economic model.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee did not consider any subgroups.
What are the key drivers of cost effectiveness?
In the Committee's view the main factors affecting cost effectiveness were the difference in efficacy between erlotinib and gefitinib and the proportion of patients incurring the fixed charge for gefitinib under the patient access scheme.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee discussed the results from the updated analyses and on balance agreed that the sums of money either saved or spent are small given the uncertainties associated with the analysis. The Committee concluded that at the price agreed under the patient access scheme (as revised in 2012) erlotinib should be recommended as an option for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC.
Additional factors taken into account
Patient access schemes (PPRS)
The Committee noted the patient access scheme (as revised in 2012) for erlotinib based on a confidential discount on the list price. It noted that hospitals may find the patient access scheme for erlotinib easier to administer than the scheme for gefitinib.
The Committee acknowledged that the time taken to complete the online forms for the gefitinib patient access scheme was much shorter than that estimated by the manufacturer and that the typical administration costs for patient access schemes of this type were likely to be nearer to the ERG's estimate rather than the manufacturer's.
End-of-life considerations
The Committee noted that the manufacturer did not make a case for erlotinib to be considered as an end-of-life treatment. The Committee also noted that in Erlotinib monotherapy for the maintenance treatment of non-small-cell lung cancer (NICE technology appraisal guidance 227) erlotinib did not meet the end-of-life criteria because the cumulative population was not considered small. The Committee therefore concluded that erlotinib did not need to be considered as a life-extending, end-of-life treatment.
Equalities considerations and social value judgements
The Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. The Committee noted that no equalities issues were raised in the submission or at the meeting. Given that the recommendations did not differentiate between any groups of people, the Committee concluded that its recommendations did not limit access to the technology for any specific group compared with other groups and that there was no need to alter or add to its recommendations.
# Related NICE guidance
Published
Lung cancer: The diagnosis and treatment of lung cancer. NICE clinical guideline 121 (2011).
Erlotinib monotherapy for the maintenance treatment of non-small-cell lung cancer. NICE technology appraisal guidance 227 (2011).
Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer. NICE technology appraisal guidance 192 (2010).
Pemetrexed for the maintenance treatment of non-small-cell lung cancer. NICE technology appraisal guidance 190 (2010).
Pemetrexed for the first-line treatment of non-small-cell lung cancer. NICE technology appraisal guidance 181 (2009).
Erlotinib for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 162 (2008).
Bevacizumab for the treatment of non-small-cell lung cancer (terminated appraisal). NICE technology appraisal 148 (2008).# Review of guidance
The guidance on this technology will be considered for review in April 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveJune 2012# Changes after publication
February 2014:
minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Erlotinib is recommended as an option for the first-line treatment of people with locally advanced or metastatic non-small-cell lung cancer (NSCLC) if:\n\nthey test positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and\n\nthe manufacturer provides erlotinib at the discounted price agreed under the patient access scheme (as revised in 2012).', 'The technology ': "Erlotinib (Tarceva, Roche Products) is an active inhibitor of the epidermal growth factor receptor tyrosine kinase (EGFR-TK). It blocks the signal pathways involved in cell proliferation and slows the growth and spread of the tumour. It has a UK marketing authorisation 'for the first-line treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with EGFR activating mutations'.\n\nThe summary of product characteristics lists the following adverse reactions to erlotinib: diarrhoea, rash, anorexia, gastrointestinal perforation, keratitis and rare cases of hepatic failure. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nErlotinib is given orally at a recommended dosage of 150\xa0mg/day. The cost of a pack of 30 (150-mg) tablets is £1631.53 (excluding VAT; 'British national formulary' [BNF] edition 63). Dosage reductions (typically to 100 or 50\xa0mg/day) are possible if the clinician considers it appropriate, and erlotinib is also available in tablet strengths of 100\xa0mg and 25\xa0mg. The manufacturer of erlotinib has agreed a patient access scheme (revised in 2012) with the Department of Health in which a confidential discount from the list price is applied to original invoices. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of erlotinib (Roche Products) and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\n# Decision problem\n\nThe manufacturer's approach to the decision problem was in line with the NICE scope for the population, intervention, outcomes and the economic evaluation. The manufacturer's submission focussed on a comparison of erlotinib with gefitinib for first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC. The manufacturer's submission did not include pemetrexed plus cisplatin or carboplatin as a comparator because of the declining use in clinical practice of this combination for first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC and the absence of suitable data for comparison in this population.\n\n# Clinical effectiveness\n\nThe manufacturer identified two randomised controlled trials (EURTAC and OPTIMAL) that compared erlotinib with platinum doublet chemotherapy as first-line treatment for patients with locally advanced or metastatic EGFR-TK mutation-positive NSCLC. The manufacturer based its evidence submission on the EURTAC trial with the OPTIMAL trial as supporting evidence. No studies were identified that compared erlotinib directly with gefitinib in this patient population, and so the manufacturer presented an indirect treatment comparison to assess the relative effectiveness of erlotinib and gefitinib.\n\nThe EURTAC trial was a European-based, open-label, phase III, randomised trial of first-line erlotinib treatment compared with platinum doublet chemotherapy for patients with stage IIIb or stage IV NSCLC and EGFR-TK mutation-positive tumours. The trial included 173\xa0randomised patients and was conducted in 42\xa0centres in Spain, France and Italy. Patients were screened for EGFR-TK mutations and those with EGFR-TK mutation-positive tumours were randomised to receive either 150\xa0mg of erlotinib orally once a day or one of the following standard platinum-based chemotherapy regimens: cisplatin or carboplatin plus docetaxel; cisplatin or carboplatin plus gemcitabine. In the randomisation, patients were stratified according to Eastern Cooperative Oncology Group (ECOG) status (either ECOG=0, or ECOG=1 or 2) and the mutation type (deletion in exon\xa019 or mutation in exon\xa021\xa0L858R). Treatment continued until disease progression, unacceptable adverse reactions, death, or until four chemotherapy cycles were completed. Following disease progression, patients were allowed to cross over in either direction, if clinically appropriate.\n\nThe primary outcome examined in the EURTAC trial was the length of progression-free survival. This was assessed as the time from randomisation to the first occurrence of progressive disease or death from any cause. Secondary outcomes included overall survival, best overall response, disease control, health-related quality of life and safety. Best overall response was defined in terms of the number of patients with either a complete or partial response (as defined by the Response Evaluation Criteria in Solid Tumours [RECIST] version 1 criteria) and disease control included patients with either a complete or partial response and those with stable disease for at least 6\xa0weeks.\n\nThe manufacturer's submission described the results of the intention-to-treat analysis for all randomised patients. The median and 95% confidence limits of progression-free and overall survival between the erlotinib and the platinum doublet chemotherapy arms were obtained from the Kaplan–Meier estimate of the survival function. A two-sided log-rank test was used to assess the difference in outcomes between the two treatment arms. A Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence intervals.\n\nThe EURTAC trial included 153\xa0patients at the time of the interim analysis and 173\xa0at the updated analysis. For the updated analysis there were 86\xa0patients in the erlotinib arm and 87 in the platinum doublet chemotherapy arm. Data for progression-free survival and overall survival from the EURTAC trial are still being collected. Both the interim and updated analyses showed that progression-free survival was statistically significantly longer for patients treated with erlotinib than for patients treated with platinum doublet chemotherapy. In the updated analysis the median progression-free survival in the platinum doublet chemotherapy arm was 5.2\xa0months compared with 9.7\xa0months in the erlotinib arm. The risk of disease progression or death was statistically significantly reduced (by 63%, HR 0.37, 95% CI 0.25 to 0.54, p<0.0001) for patients in the erlotinib arm. In the updated analysis the manufacturer reported overall survival results for 69 (40%) events. The median overall survival was 19.5\xa0months in the platinum doublet chemotherapy arm and 19.3\xa0months in the erlotinib arm (hazard ratio 1.04 [95%\xa0CI 0.65 to 1.68], p=0.8702). More patients in the platinum doublet chemotherapy arm received second and further-line treatments than patients in the erlotinib arm (77% [n=67] compared with 45% [n=39]). In the platinum doublet chemotherapy arm, 66 of the 67 patients received at least one treatment with either erlotinib or gefitinib. In the updated analysis, the best overall response (as defined in section 3.4) was statistically significantly greater in the erlotinib arm than the platinum doublet chemotherapy arm (58.1% [95%\xa0CI 47.0% to 68.7%] compared with 14.9% [95% CI 8.2% to 24.2%], p<0.0001).\n\nThe manufacturer submitted the results of the OPTIMAL trial, which was carried out in 22\xa0centres in China, as additional evidence. The OPTIMAL trial was a multicentre, open-label, phase III, randomised trial of first-line erlotinib treatment compared with platinum doublet chemotherapy for chemotherapy-naive patients with stage IIIb or stage IV NSCLC whose tumours were EGFR-TK mutation-positive. Patients were randomised (n=165) to receive either 150\xa0mg of erlotinib orally once daily or gemcitabine plus cisplatin chemotherapy. Treatment continued until disease progression, unacceptable adverse reactions or death, or until four chemotherapy cycles were completed. Following disease progression, patients were allowed to cross over in either direction, if clinically appropriate.\n\nIn the most recent analysis from the OPTIMAL trial, progression-free survival was statistically significantly longer in patients treated with erlotinib than in patients treated with platinum doublet chemotherapy. The median progression-free survival in the platinum doublet chemotherapy arm was 4.6\xa0months (95% CI 4.21 to 5.42) compared with 13.7\xa0months (95% CI 10.58 to 15.28) in the erlotinib arm. The risk of progression or death was statistically significantly reduced (by 84%, HR 0.16; 95% CI 0.10 to 0.26, p<0.0001) for patients in the erlotinib arm. The overall survival data from the OPTIMAL trial were not presented because too few deaths had been recorded at the time of the analysis.\n\nThe manufacturer did not perform a meta-analysis of progression-free survival from the EURTAC and OPTIMAL trials because heterogeneity between the treatment effects was identified using an assessment of heterogeneity recommended by the Cochrane Collaboration. The manufacturer noted that factors possibly contributing to the heterogeneity included: the different ethnicity of the patients in the trials; better adherence in the OPTIMAL trial and poorer efficacy of the comparator in the OPTIMAL trial.\n\nA systematic review identified four randomised controlled trials comparing gefitinib with various doublet chemotherapy regimens in East Asian populations (IPASS, First-SIGNAL, WJTOG3405 and NEJGSG002). The data from the gefitinib trials were pooled by assuming that the doublet chemotherapy was of equal efficacy in each of the four trials (Ku et al. 2011). Across the four studies, the estimated hazard ratio for median progression-free survival was 0.45 (95% CI 0.38 to 0.55, p<0.001).\n\nFor the indirect comparison of erlotinib with gefitinib the manufacturer assumed that the platinum doublet chemotherapy arms of the EURTAC and OPTIMAL trials could be linked to the gefitinib meta-analysis using platinum doublet chemotherapy as the anchor point. From an assessment of the similarities and differences between the studies, the manufacturer concluded that ethnicity is the key factor for the differences and so a robust indirect comparison should involve studies based in an East Asian population. The manufacturer presented results from four possible indirect comparisons of the two erlotinib trials and combinations of them against the gefitinib meta-analysis. In the indirect comparisons the hazard ratio for median progression-free survival varied between 0.36 (95% CI 0.22 to 0.59) and 0.82 (95% CI 0.54 to 1.26) depending on the combination of studies chosen. In the manufacturer's view the hazard ratio for progression-free survival from the indirect comparison of EURTAC with the gefitinib meta-analysis (hazard ratio 0.82 [95% CI 0.54 to 1.26]) was the most appropriate estimate of the clinical effectiveness of erlotinib compared with gefitinib in patients with EGFR-TK mutation-positive NSCLC in England and Wales.\n\nThe manufacturer stated that there were insufficient data on health-related quality of life collected in the EURTAC trial for any analysis to be done. In the OPTIMAL trial quality of life was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire and the Trial Outcome Index. Results were presented from 128 (83.2%) patients and demonstrated that approximately 70% of patients receiving first-line erlotinib experienced significant, clinically relevant improvements in quality of life compared with 30% of patients receiving platinum doublet chemotherapy across all FACT-L scales measured.\n\nThe incidence and nature of adverse reactions to erlotinib in the EURTAC and OPTIMAL trials were consistent with previously collected data on the use of erlotinib for first-line maintenance treatment and relapsed NSCLC. The manufacturer noted the longer duration of active treatment with erlotinib compared with chemotherapy and that the extended treatment period may also have increased the number of adverse reactions reported. In the EURTAC trial, patients in the erlotinib arm had a typical treatment duration of 9–10\xa0months before progression or unacceptable adverse reactions, whereas patients in the chemotherapy arm received a maximum of four cycles over approximately 3\xa0months. Most of the reported adverse reactions in both arms were grade 1 or grade 2 (432/527 events [82.0%] in the chemotherapy arm and 621/681 events [91.2%] in the erlotinib arm). Fewer patients experienced grade 3 or 4 events in the erlotinib arm (31\xa0patients [41.3%]) than in the chemotherapy arm (49 patients [66.2%]).\n\nIn the EURTAC trial low grade skin reactions and diarrhoea were the most commonly reported adverse reactions in patients who received erlotinib. Skin reactions were mainly mild or moderate, with 5% of patients experiencing grade 3 rash and 1% experiencing dry skin. No grade 4 skin reactions were reported. Diarrhoea was also mainly mild or moderate, with 4% of patients experiencing grade 3 diarrhoea.\n\n# Cost effectiveness\n\nThe manufacturer presented a de novo economic analysis that assessed the cost effectiveness of erlotinib compared with gefitinib for the first-line treatment of EGFR mutation-positive NSCLC. In line with the NICE reference case, outcomes were expressed in terms of quality-adjusted life years (QALYs), an NHS and personal social services perspective was adopted, and costs and benefits were discounted at 3.5%. The treatments compared in the model were first-line erlotinib (one 150-mg tablet daily until disease progression) or gefitinib (one 250-mg tablet daily until disease progression). No second-line treatments were included because the second-line treatment options were considered identical for both erlotinib and gefitinib. The manufacturer presented a semi-Markov economic model with three health states: progression-free survival, progressed disease and death. The model had a 10-year time horizon and a cycle length of 1\xa0month.\n\nThe manufacturer considered that the EURTAC study was more representative of the outcomes expected in UK clinical practice than the OPTIMAL study and so the clinical data in the model were derived from the EURTAC trial and the indirect comparison of erlotinib (EURTAC trial) and gefitinib (Ku et al. 2011). An area under the curve approach was used to calculate the proportion of patients in the progression-free survival health state each month. For erlotinib, the estimated survival curve for the progression-free state was based on the observed EURTAC data up to month 16 and was then extrapolated assuming an exponential distribution. For gefitinib, the progression-free survival curve was derived by transforming the erlotinib survival curve using the hazard ratio for progression-free survival (HR 0.82) from the indirect comparison of erlotinib (EURTAC trial) and gefitinib (Ku et al. 2011). The same transition probabilities, derived from the EURTAC data, were used for both erlotinib and gefitinib for the transition between the progression-free survival health state and death and between the progressed disease health state and death.\n\nUtilities in the model were based on values from the study of Nafees et al. (2008). These utility values were estimated using the standard gamble approach with 105 members of the UK general public who were asked to value health-state descriptions of patients receiving second-line chemotherapy for NSCLC. These values have been used in four previous NICE appraisals of drugs for NSCLC (Pemexetred for the first-line treatment of non-small-cell lung cancer [NICE technology appraisal guidance 181], Pemexetred for the maintenance treatment of non-small-cell lung cancer [NICE technology appraisal guidance 190], Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer [NICE technology appraisal guidance 192], Erlotinib monotherapy for the maintenance treatment of non-small-cell lung cancer, [NICE technology appraisal guidance 227]). The utility values for the progression-free survival health state were treatment dependent and were calculated from the response rate and the incidence of adverse reactions (grade 3 or 4 rash; grade 3 or 4 diarrhoea). The utility value for the progression-free health state for patients receiving erlotinib (0.661) was based on the response rate in the EURTAC trial (58.10%). The value for patients receiving gefitinib (0.656) was based on a gefitinib response rate (28.23%) which was estimated indirectly by applying the relative response from the gefitinib meta-analysis to the chemotherapy response rate observed in the EURTAC trial (14.9%). The utility decrement value for progressed disease (−0.1798 relative to the progression-free survival stable disease baseline value of 0.6532) was taken from the study of Nafees et al. (2008) and assumed that the choice of first-line treatment had no influence on the utility patients experienced post progression.\n\nThe manufacturer included costs associated with drug acquisition and administration, best supportive care, terminal care, monitoring and adverse reactions in the economic model. These were estimated from a range of secondary sources such as reference costs, BNF and submissions for previous NICE technology appraisals. The monthly cost of erlotinib with the list price (see section 2.3) was £1631.53 based on a daily dose of 150 mg. The manufacturer also presented analyses based on the erlotinib drug cost with the earlier 14.5% discount and with the revised patient access scheme. Under the terms of the gefitinib patient access scheme approved by the Department of Health, there is a single fixed cost of £12,200 per patient when the third monthly pack of gefitinib is supplied. In the base-case analysis, the proportion of patients for whom the £12,200 payment was made was derived by applying the hazard ratio for progression-free survival from the indirect comparison of erlotinib and gefitinib (HR 0.82) to the 'time to last dose' curve generated from the EURTAC data. This results in approximately 76% patients incurring the fixed cost for gefitinib. No administration cost for the erlotinib patient access scheme was included in the economic model because it is a simple discount. For the gefitinib patient access scheme, the manufacturer assumed that the administration cost includes a one-off £70 cost (patient registration, invoicing and query management) and an ongoing monthly cost of £35 (completion of request pack and payment reconciliation).\n\nResults from the manufacturer's base-case analyses (including the discount under the patient access scheme as revised in 2012) for erlotinib compared with gefitinib show an incremental cost-effectiveness ratio (ICER) of £21,874 per QALY gained. From deterministic sensitivity analyses for a range of parameters, the manufacturer identified the main factors affecting the cost effectiveness as the hazard ratio for progression-free survival for gefitinib and the proportion of patients for whom the gefitinib patient access scheme payment was needed. Varying the hazard ratio for progression-free survival from the indirect comparison from 0.36 to 0.58 resulted in an ICER between £15,712 and £16,552 per QALY gained. When the proportion of patients incurring the fixed charge for gefitinib was varied from 85% to 100%, the ICER was always less than £10,066 per QALY gained. The manufacturer also presented a probabilistic sensitivity analysis which resulted in an ICER of £25,791 per QALY gained for erlotinib compared with gefitinib. There was a 36% probability of erlotinib being cost effective if the maximum acceptable ICER was £20,000 per QALY gained; the probability was 63% if the maximum acceptable ICER was £30,000 per QALY gained.\n\n# Evidence Review Group comments\n\nThe ERG stated that without consideration of pemetrexed in combination with another drug (doublet chemotherapy) as a comparator, the evidence presented in the manufacturer's submission was incomplete and did not allow a full evaluation of erlotinib as set out in the decision problem. The ERG considered pemetrexed-based doublet chemotherapy a valid comparator because almost all patients whose tumours are EGFR-TK mutation-positive have non-squamous lung cancer. In addition some of these will be treated with pemetrexed-based doublet chemotherapy in hospitals that do not routinely test for EGFR and also in situations when delaying treatment to await EGFR-TK status would be detrimental to the patient's health. The ERG stated that the difference in efficacy between pemetrexed and gefitinib has become clearer since the publication of Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (NICE technology appraisal guidance 192). The ERG stated that pemetrexed is the only first-line treatment for patients with non-squamous cell lung cancer which has demonstrated a statistically significant gain in overall survival when compared with third-generation chemotherapy. Recently published updates to a randomised controlled trial of gefitinib have reported no overall survival gain for gefitinib compared with third-generation chemotherapy.\n\nIn the ERG's view the EURTAC trial was well-designed and suitably powered to demonstrate its primary objective. It considered the inclusion and exclusion criteria to be reasonable and the baseline characteristics of patients in EURTAC trial to reflect patients in UK clinical practice who would be considered eligible for treatment with an EGFR-TK inhibitor. The ERG was unable to comment definitively on the quality of the supporting evidence from the OPTIMAL trial because the clinical study report was not made available.\n\nThe ERG considered that the use of conventional proportional hazards methods to estimate hazard ratios in either the gefitinib or erlotinib trials compared with any other drug is problematic. The assumption of proportional hazards was not tested by the manufacturer. The ERG presented plots of the hazard rates for gefitinib and erlotinib and comparators, which suggested an assumption of proportional hazards was not valid. A comparison of the cumulative hazards for each of the six trials of a tyrosine kinase inhibitor (either gefitinib or erlotinib) compared with platinum doublet chemotherapy showed two separate phases. During the first 4\xa0months of treatment (corresponding approximately to the period of standard chemotherapy), there is very little difference in hazards between intervention and comparator arms. However, in the following 2–3\xa0months the slopes of the lines in all trial arms increase, but with the comparator arms diverging rapidly from the erlotinib or gefitinib arms. A more appropriate method of estimating the relative efficacy involves treating these two time periods as separate phases (equivalent to active therapy followed by observation/maintenance therapy) and deriving separate hazard ratios for each phase (using a landmark analysis for the second phase). In the ERG's view, relative efficacy should be estimated using this approach and the estimates obtained explored in a revised economic model.\n\nThe ERG highlighted that the manufacturer identified heterogeneity between the EURTAC and OPTIMAL trials by comparing the median progression-free survival. In the ERG's view the heterogeneity identified by the manufacturer is simply a consequence of using this outcome measure. A comparison of the Kaplan–Meier curves for progression-free survival from the two trials shows close correspondence in the comparator arms. The two erlotinib arms follow very similar trends although they are slightly separated. Crucially, across successive time periods the gradients of the cumulative hazard curves are very similar. The ERG concluded that the balance of evidence favours including results from both EURTAC and OPTIMAL trials in any indirect comparison.\n\nThe ERG was not convinced that any of the four options for the indirect comparison described by the manufacturer are appropriate. It believed that data from the EURTAC and OPTIMAL trials should be pooled and that revised relative efficacy measures be used (see section 3.22). From an analysis of the progression-free survival and the cumulative hazard curves, the ERG showed that after 12\xa0months the results for patients in the IPASS trial (gefitinib compared with doublet chemotherapy) diverge from the other gefitinib trials. The ERG recommended that a sensitivity analysis that excludes the IPASS data should be undertaken as part of the indirect comparison.\n\nThe ERG was only able to offer a limited critique of the cost-effectiveness results submitted by the manufacturer because of its concerns about the structure of the model. In the ERG's view pemetrexed plus cisplatin should be included as a comparator and there was also an argument for including the four third-generation platinum doublets (docetaxel, gemcitabine, paclitaxel and vinorelbine) in a full evaluation as in Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (NICE technology appraisal guidance 192). In the ERG's view the omission of all comparators other than gefitinib has resulted in a simple model structure without a robust, multi-way economic comparison that would most likely have reduced the probability of erlotinib appearing as the most cost-effective option.\n\nThe ERG highlighted that the current model yielded an overall survival benefit for patients with EGFR-TK mutation-positive NSCLC receiving first-line erlotinib compared with those receiving gefitinib, which has not been demonstrated by the published evidence from randomised controlled trials. The submitted model does not include any data on overall survival and after disease progression all surviving patients are assumed to follow the same post-progression course and incur the same costs. The direct consequence of the simple model structure is that most of the estimated difference in progression-free survival between patients receiving gefitinib and those receiving erlotinib is preserved by a common post-progression phase, which translates into a similar difference in overall survival.\n\n# Revised economic analyses following consultation\n\nAdditional evidence was provided by the manufacturer in response to NICE's request in the appraisal consultation document for an updated economic model and analyses. The updated model included, as requested, an assumption of equal progression-free survival and equal utilities for the progression-free survival health state for the two treatments (erlotinib and gefitinib). The manufacturer provided analyses exploring the sensitivity of the cost-effectiveness results to varying the proportion of patients (equally for erlotinib and gefitinib) in the progression-free survival health state at day 60 (for whom the fixed charge for gefitinib is incurred under the patient access scheme). The proportion in the base case was 80%, which was the proportion of patients still receiving erlotinib at the start of the third month of the EURTAC trial. In the sensitivity analyses, the proportion was varied, equally for erlotinib and gefitinib, from the base case to 100%. The costs in the model were not modified. Results from the updated model showed that erlotinib becomes more cost effective than gefitinib when at least 91% of patients incur the gefitinib fixed charge. In the manufacturer's view the proportion of patients incurring the gefitinib fixed charge at day 60 is likely to be more than 90%, as demonstrated in each of the four gefitinib trials. Also data from recent market surveys in Europe and the UK indicate that at least 95% of patients receiving gefitinib have 60 or more days of treatment (and thus incur the fixed charge).\n\nThe ERG explored the analyses using the manufacturer's updated model and confirmed that the Committee's requests specified in the appraisal consultation document had been implemented. However, the ERG noted that the manufacturer assumed the same rates of adverse reactions for the two treatments (erlotinib and gefitinib) when calculating the utility value. The ERG showed that when the same utility value is used for both treatments and the different rates of adverse reactions are retained in the updated model, there is a small additional cost of £5.24 per patient for erlotinib treatment. The ERG was concerned that the cost of administering the gefitinib patient access scheme (a mean cost of £438 per patient over the treatment period) was overstated in the manufacturer's model. The ERG assumed that pack ordering and reconciliation would be needed only once a year and estimated a mean cost for administering the gefitinib patient access scheme of between £111 and £118 per patient. The ERG explored the impact of updating the manufacturer's model with these costs and included the adverse reaction rates for each treatment. The ERG's results demonstrated that erlotinib is cost effective compared with gefitinib when 95% or more of patients receiving gefitinib incur the fixed charge for gefitinib.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA258", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of erlotinib, having considered evidence on the nature of locally advanced or metastatic EGFR-TK mutation-positive NSCLC and the value placed on the benefits of erlotinib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical practice\n\nThe Committee discussed the clinical need of patients with locally advanced or metastatic EGFR-TK mutation-positive NSCLC. It heard from the clinical specialists that the main aim of treatment is to extend progression-free and overall survival with the fewest adverse reactions and with the best quality of life possible for the remaining months of life. The clinical specialists also highlighted that for this patient population an oral treatment with a tyrosine kinase inhibitor, such as gefitinib or erlotinib, is usually associated with an improved quality of life compared with platinum doublet chemotherapy.\n\nThe Committee heard from the clinical specialists that current UK clinical practice for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC is to use gefitinib as recommended in NICE technology appraisal guidance 192. The Committee also heard that chemotherapy with pemetrexed plus carboplatin or cisplatin may be used as a second-line treatment and is rarely used as first-line treatment for this patient population. The Committee accepted that gefitinib is current standard practice in England and Wales for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC.\n\nThe Committee discussed the availability of EGFR testing to inform the first-line treatment of locally advanced or metastatic NSCLC. It heard from the clinical specialists that EGFR testing is standard practice for this patient population across almost all the NHS. The Committee accepted that EGFR testing is standard practice in England and Wales when making decisions about the first-line treatment of locally advanced or metastatic NSCLC.\n\nThe Committee discussed the use of tyrosine kinase inhibitors in clinical practice for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC. It heard from clinical specialists that in their opinion erlotinib and gefitinib are very similar treatments with similar efficacy and levels of adverse reactions. The clinical specialists highlighted that having the choice of two similar treatments enables better management of adverse reactions. The Committee also heard from the clinical specialists that the adverse reactions associated with both these treatments are much less common than those associated with chemotherapy but may vary (for example, rash may be more common with erlotinib and interstitial lung disease may be more common with gefitinib). Erlotinib offers the advantage of being able to vary the dosage by using tablets of different dose strength. The Committee also heard that the patient access scheme for gefitinib is not straightforward and that hospitals may find the patient access scheme for erlotinib easier to administer. The Committee concluded that further first-line treatment options for patients with locally advanced or metastatic EGFR-TK mutation-positive NSCLC would be valuable for clinical practice.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence submitted by the manufacturer on the clinical effectiveness of erlotinib. The Committee agreed with the manufacturer that although pemetrexed plus cisplatin or carboplatin was listed as a comparator in the scope, recent changes in the clinical pathway since the publication of NICE technology appraisal guidance 192 in 2011 have resulted in the use of gefitinib for first-line treatment for most patients with EGFR-TK mutation-positive NSCLC, as confirmed by the clinical specialists (see section 4.3). The Committee concluded that gefitinib is the appropriate comparator for this appraisal.\n\nThe Committee noted that the evidence of clinical effectiveness of erlotinib in locally advanced or metastatic EGFR-TK mutation-positive NSCLC was based on the EURTAC trial with supporting evidence from the OPTIMAL trial. The Committee noted that both trials provided evidence of increased progression-free survival compared with doublet chemotherapy. The Committee agreed that the EURTAC trial provided evidence relevant to clinical practice in the NHS in England and Wales. The Committee concluded that the evidence from the EURTAC trial demonstrated that erlotinib increased progression-free survival compared with doublet chemotherapy.\n\nThe Committee considered the indirect comparison presented by the manufacturer. The hazard ratio for progression-free survival used in the model (0.82, 95% CI 0.54 to 1.26) was obtained by comparing the EURTAC trial with the gefitinib meta-analysis. The Committee noted the wide confidence intervals around the estimated hazard ratio for progression-free survival, but recognised the difficulties in constructing a robust indirect comparison given the limited number of studies in this patient population and the heterogeneity between the studies. The Committee discussed the heterogeneity between the trials and the possible prognostic factors that may have influenced heterogeneity, such as ethnic group and class of mutation (exon 19 deletion compared with mutation in exon 21 L858R). It heard from the clinical specialists that the difference in the response rate in the chemotherapy arms between the EURTAC and OPTIMAL trials was within the acceptable range for this group of patients. The Committee noted that the ERG had pointed out the similarities in the curves for progression-free survival from the EURTAC and OPTIMAL trials and the difference between the results from the IPASS trial and the other gefitinib trials after 12\xa0months of treatment. The Committee heard from the ERG that the gefitinib trials had not been uniformly reported so it was not possible to be certain whether the differences were caused by factors such as differing variables in multivariate analyses or small patient numbers. The Committee also discussed the ERG's comments about the difficulties associated with using the proportional hazards assumption for these data and the possibility of using revised efficacy outcomes. The Committee was not convinced that an indirect comparison could be used with the existing data, to support the assumption that erlotinib was more effective than gefitinib, given the heterogeneity of the populations included and the variations in prognostic factors within the populations. In addition, the Committee noted the clinical specialists' view that erlotinib and gefitinib are very similar treatments with similar efficacy for locally advanced or metastatic EGFR-TK mutation-positive NSCLC (see section 4.5). The Committee concluded that there was insufficient evidence to suggest a difference in clinical effectiveness between erlotinib and gefitinib in the model and therefore the most appropriate value for the hazard ratio for progression-free survival between the treatments is 1.\n\nThe Committee discussed the overall survival data from the trials. It noted that the data for overall survival were incomplete (either not available for all patients or not known) for the EURTAC and OPTIMAL trials and therefore no comparison of overall survival benefit for erlotinib and gefitinib was available. It also noted the ERG's concerns about whether there was an overall survival benefit for treatment with a tyrosine kinase inhibitor compared with doublet chemotherapy in light of the recently published final results from the IPASS trial (gefitinib compared with doublet chemotherapy). Because of the similarities in the treatments and the lack of data on overall survival, the Committee was not convinced of a survival benefit for erlotinib compared with gefitinib for patients with locally advanced or metastatic EGFR-TK mutation-positive NSCLC.\n\nThe Committee considered the adverse reactions experienced by patients receiving treatment for locally advanced or metastatic NSCLC. It noted that data from the EURTAC trial demonstrated that fewer patients in the erlotinib arm experienced grade 3 or 4 events compared with the chemotherapy arm. Low grade skin reactions (rash grade 3, 5%) and diarrhoea (grade 3, 4%) were the most commonly reported adverse reactions associated with erlotinib. The clinical specialists confirmed that the adverse reactions associated with erlotinib and gefitinib were generally modest but slightly different. The Committee concluded that the adverse reactions associated with erlotinib were relatively mild in most patients and that from a clinical perspective there may be some advantage to having a choice of tyrosine kinase inhibitors for this patient group.\n\nThe Committee noted the lack of quality of life data from the EURTAC trial and heard from the clinical specialists that a common problem with studies in this patient population is the failure to complete questionnaires. The Committee was disappointed that there were insufficient quality of life data from the EURTAC trial for analysis. Because erlotinib and gefitinib are both oral tyrosine kinase inhibitors with similar efficacy and comparable adverse reactions, the Committee concluded that the health-related quality of life of patients would be similar for the two treatments.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's original cost-effectiveness analysis and the ERG's critique. It noted that the manufacturer used a semi-Markov model to evaluate the cost effectiveness of erlotinib compared with gefitinib. The clinical data used in the model were derived mainly from the EURTAC trial and the indirect comparison of data from the EURTAC trial with the gefitinib meta-analysis described by Ku et al. (2011). The Committee was aware of the ERG's concerns that the structure of the model allowed the benefit in progression-free survival to be translated into an overall survival benefit in the economic model. Given the uncertainties associated with the hazard ratio for progression-free survival obtained from the indirect comparison (described in sections 3.22 to 3.25 and 4.8), as well as the lack of evidence demonstrating an overall survival benefit for erlotinib compared with gefitinib (see section 4.9), the Committee concluded that the cost effectiveness of erlotinib compared with gefitinib could be best assessed from an analysis which assumes equal clinical benefit between the treatments and focuses on their differential costs.\n\nThe Committee discussed the utility values used within the original model and noted that the utility value for the progression-free survival health state was 0.661 for erlotinib and 0.656 for gefitinib. It noted that the difference was mainly a result of difference in the response rates (58% for erlotinib compared with 28% for gefitinib) used in the calculation. The Committee heard from the ERG that the response rate from the gefitinib meta-analysis was 71.5% (Ku et al. 2011). The Committee heard from the manufacturer that the difference in utility values (0.005, <1%) used for the two treatments made little difference to the results from the model. However, the Committee saw little clinical justification for the difference in the utilities in the manufacturer's original model, and concluded that an analysis incorporating identical utility values for patients receiving erlotinib and patients receiving gefitinib in the progression-free survival health state should be used as a basis for its decision making.\n\nThe Committee acknowledged that, following its request for further clarification in the appraisal consultation document, the manufacturer had provided an updated economic model which incorporated equal progression-free survival and utilities for erlotinib and gefitinib. The results from the model depended on the costs of the drugs, the cost of administering the gefitinib patient access scheme and the proportion of patients on gefitinib who incurred the fixed charge on day 60. The Committee discussed the uncertainties in the clinical evidence which led to this request for an economic model based on there being no difference in the clinical benefit between the treatments. The Committee acknowledged the limitations of this type of economic model which incorporates no uncertainties about survival. The Committee concluded that, although the assumption of equal clinical benefit could be a conservative estimate of the clinical effectiveness of erlotinib, the updated economic model was in line with clinical opinion (see section 4.5), reflected the absence of any clinical data from direct comparisons, and allowed a direct comparison of the costs of the two treatments.\n\nThe Committee considered the impact of the cost of administering the gefitinib patient access scheme on the results from the updated economic model. When the mean administration cost changed from £438 per patient in the manufacturer's updated model to £111–118 in the ERG's exploratory analysis, erlotinib was cost effective when the proportion of patients incurring the fixed charge for gefitinib increased from 91% to 95%. The Committee acknowledged that the time taken to complete the online forms for the gefitinib patient access scheme was much shorter than that estimated by the manufacturer and that the typical administration costs for patient access schemes of this type were likely to be nearer to the ERG's estimate rather than the manufacturer's. This remained despite the possibility of additional reporting costs associated with the gefitinib patient access scheme which were not included in the ERG's analyses. The Committee understood that there may not be complete uptake of the gefitinib patient access scheme across the NHS, that some trusts may pay the list price for gefitinib and that this has not been considered in the updated model, which assumed all patients on gefitinib for more than 60\xa0days would incur the fixed charge. The Committee concluded that the administration costs of the gefitinib patient access scheme were likely to be nearer the ERG's estimates rather than the manufacturer's, and that there may be some additional savings not included in the updated model because of the incomplete uptake of the gefitinib patient access scheme across the NHS.\n\nThe Committee considered the impact of the proportion of patients who receive gefitinib for more than 60\xa0days (and would therefore incur the fixed charge) on the results from the updated economic model. Both the manufacturer and the ERG presented sensitivity analyses incorporating different costs for administering the gefitinib patient access scheme (see section 4.15). The Committee discussed the evidence on the proportion of patients who receive gefitinib for more than 60\xa0days (and incur the fixed charge). The Committee was disappointed that there was not more reliable evidence available from the NHS. The Committee heard from clinical specialists that nearly all patients on gefitinib survive until day\xa060 when the third pack is issued. The Committee noted that the base-case analysis presented by the manufacturer used a proportion of 80%, which was the proportion of patients in the EURTAC trial who had completed 60\xa0days of erlotinib treatment. There were about 88% of erlotinib patients in the EURTAC trial who were in the progression-free survival health state on day\xa060 but this included some patients who had not completed 60\xa0days of treatment. The sensitivity analysis presented by the manufacturer identified that erlotinib became cost effective compared with gefitinib when 91% of patients incurred the fixed charge for gefitinib. The ERG's exploratory analysis estimated this proportion to be 95%. The Committee discussed the results from the updated analyses and on balance agreed that the sums of money either saved or spent are small given the uncertainties associated with the analysis. The Committee concluded that at the price agreed under the patient access scheme (as revised in 2012) erlotinib should be recommended as an option for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC.\n\n# Other considerations\n\nThe Committee discussed whether it needed to consider the supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. It noted that the manufacturer did not make a case for erlotinib to be considered as an end-of life treatment in the submission. The Committee also heard from the manufacturer that in its view erlotinib does not meet the criteria for an end-of-life treatment. The Committee noted that in Erlotinib monotherapy for the maintenance treatment of non-small-cell lung cancer (NICE technology appraisal guidance 227) erlotinib did not meet the end-of-life criteria because the cumulative population for erlotinib was not considered small. The Committee therefore concluded that erlotinib did not need to be considered as a life-extending, end-of-life treatment.\n\nThe Committee discussed whether erlotinib should be considered an innovative technology, or if there were any significant and substantial health benefits which were not included in the economic model. It noted that the manufacturer did not make a case for erlotinib to be considered innovative, and did not identify any additional health benefits not included in the economic model. The Committee heard from the manufacturer that erlotinib is not considered a major change in treatment for locally advanced or metastatic EGFR-TK mutation-positive NSCLC, but is an incremental advance. The manufacturer stated that the oral administration and the straightforward patient access scheme gave value to erlotinib. The Committee concluded that erlotinib could not be considered to show significant innovation and that no additional health benefits had been identified which had not been adequately captured by the economic model.\n\nThe Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. The Committee noted that no equality issues were included in the manufacturer's submission. It also noted that the reduced adverse reactions associated with tyrosine kinase inhibitors compared with those associated with chemotherapy raised during the scope consultation was not an equalities issue for this appraisal. No equalities issues were identified by the Committee. Given that the recommendations did not differentiate between any groups of people, the Committee concluded that its recommendations did not limit access to the technology for any specific group compared with other groups and that there was no need to alter or add to its recommendations.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA258\n\nAppraisal title: Erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer\n\nSection\n\nKey conclusion\n\nErlotinib is recommended as an option for the first-line treatment of people with locally advanced or metastatic non-small-cell lung cancer (NSCLC) if:\n\nthey test positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and\n\nthe manufacturer provides erlotinib at the discounted price agreed under the patient access scheme (as revised in 2012).\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee concluded that gefitinib was the comparator for this appraisal.\n\n\n\nThe Committee concluded there was insufficient evidence to suggest a difference in clinical effectiveness between erlotinib and gefitinib and it heard from clinical specialists that erlotinib and gefitinib are very similar treatments with similar efficacy. The Committee concluded that the cost effectiveness of erlotinib compared with gefitinib could be best assessed from the updated economic model which assumes equal clinical benefit for the treatments and focuses on their differential costs.\n\n\n\n, 4.8,\n\n\n\n\n\nThe Committee agreed that the results from the economic model showed that on balance the sums of money lost or saved are small given the uncertainties in the analysis, and so it recommended erlotinib as a treatment option.\n\n\n\nCurrent practice\n\n\n\nClinical need of patients, including the availability of alternative treatments\n\nThe main aim of treatment is to extend progression-free and overall survival with the fewest adverse reactions and with the best quality of life possible for the remaining months of life.\n\n\n\n\n\n\n\n\n\n\n\nCurrent standard practice in England and Wales for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC is gefitinib.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe oral method of administration and less common adverse reactions with either erlotinib or gefitinib offers an advantage for patients compared with chemotherapy. Erlotinib offers the advantage of being able to vary the dosage by using tablets of different dose strength.\n\n\n\n, 4.5\n\n\n\n\n\n\n\n\n\nThe manufacturer confirmed that erlotinib is not considered a major change in treatment, but is an incremental advance. The Committee concluded that erlotinib could not be considered to show significant innovation.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nErlotinib has a UK marketing authorisation 'for the first-line treatment of patients with locally advanced or metastatic non-small-cell lung cancer with EGFR activating mutations'.\n\n\n\n\n\n\n\n\n\nThe Committee heard from clinical specialists the current UK clinical practice for this indication is to use gefitinib as recommended by NICE technology appraisal guidance 192.\n\n\n\nAdverse reactions\n\nThe adverse reactions associated with erlotinib and gefitinib were modest but slightly different. The Committee concluded that the adverse reactions associated with erlotinib were relatively mild in most patients and that from a clinical perspective there may be some advantage to having a choice of tyrosine kinase inhibitors for this patient group.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe evidence of clinical effectiveness was derived from the EURTAC trial (a European-based, open-label, randomised trial of first-line erlotinib treatment compared with platinum doublet chemotherapy for patients with stage IIIb or stage IV NSCLC and EGFR-TK mutation-positive tumours). Additional evidence was provided by the OPTIMAL trial (a Chinese-based open-label randomised trial of first-line erlotinib treatment compared with platinum doublet chemotherapy for chemotherapy-naive patients with stage IIIb or stage IV NSCLC whose tumours were EGFR-TK mutation-positive.\n\n\n\n, 3.3, 3.7\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThere was no evidence from a direct comparison of erlotinib and gefitinib.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee agreed that the EURTAC trial provided evidence relevant to clinical practice in the NHS in England and Wales.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee was not convinced that an indirect comparison could be used with the existing data, to support the assumption that erlotinib was more effective than gefitinib, given the heterogeneity of the populations included and the variations in prognostic factors within the populations.\n\n\n\n\n\n\n\n\n\n\n\nThe Committee noted that the overall survival data from the trials were incomplete. The Committee was not convinced of a survival benefit for erlotinib compared with gefitinib.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee did not consider any subgroups.\n\n-\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee was not convinced that an indirect comparison could be used with the existing data to support the assumption that erlotinib was more effective than gefitinib. The Committee noted the clinical specialists' view that erlotinib and gefitinib are very similar treatments with similar efficacy for locally advanced or metastatic EGFR-TK mutation-positive NSCLC. The Committee concluded that there was insufficient evidence to suggest a difference in clinical effectiveness between erlotinib and gefitinib in the model and therefore the most appropriate value for the hazard ratio for progression-free survival between the treatments is 1.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer originally submitted a semi-Markov model to evaluate the cost effectiveness of erlotinib compared with gefitinib. The clinical data for this model were derived from the EURTAC trial and the indirect comparison.\n\n, 3.16\n\n\n\n\n\n\n\nIn response to NICE's request in the appraisal consultation document, the manufacturer submitted an updated model. This model assumed equal progression-free survival and equal utilities for the progression-free survival health state for the two treatments (erlotinib and gefitinib).\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nIn the Committee's view, the survival benefit for erlotinib compared with gefitinib was uncertain.\n\n, 4.9\n\n\n\nThe Committee concluded that the cost effectiveness of erlotinib compared with gefitinib could be best assessed from the updated economic model which assumes equal clinical benefit for the treatments and focuses on their differential costs.\n\n\n\n\n\n\n\nThe Committee acknowledged the limitations of this type of economic model which incorporates no uncertainties about survival. The Committee concluded that, although the assumption of equal clinical benefit could be a conservative estimate of the clinical effectiveness of erlotinib, the updated economic model was in line with clinical opinion (see section 4.5), reflected the absence of any clinical data from direct comparisons, and allowed a direct comparison of the costs of the two treatments.\n\n\n\n\n\n\n\nThe Committee concluded that the administration costs of the gefitinib patient access scheme were likely to be nearer the ERG's estimates than the manufacturer's, and that there may be some additional savings not included in the updated model because of the incomplete uptake of the gefitinib patient access scheme across the NHS.\n\n\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee saw little clinical justification for the difference in the utilities for the progression-free survival health state for erlotinib and gefitinib in the original economic model and requested that they be made identical in the updated model.\n\nNo significant and substantial health-related benefits that have not been captured by the QALY calculation were identified either in the submission or at the Committee meeting. The Committee concluded that no additional health benefits had been identified which had not been adequately captured by the economic model.\n\n\n\n\n\n\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee did not consider any subgroups.\n\n-\n\nWhat are the key drivers of cost effectiveness?\n\nIn the Committee's view the main factors affecting cost effectiveness were the difference in efficacy between erlotinib and gefitinib and the proportion of patients incurring the fixed charge for gefitinib under the patient access scheme.\n\n, 4.16\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee discussed the results from the updated analyses and on balance agreed that the sums of money either saved or spent are small given the uncertainties associated with the analysis. The Committee concluded that at the price agreed under the patient access scheme (as revised in 2012) erlotinib should be recommended as an option for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive NSCLC.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe Committee noted the patient access scheme (as revised in 2012) for erlotinib based on a confidential discount on the list price. It noted that hospitals may find the patient access scheme for erlotinib easier to administer than the scheme for gefitinib.\n\n\n\n, 4.5,\n\n\n\n\n\n\n\n\n\nThe Committee acknowledged that the time taken to complete the online forms for the gefitinib patient access scheme was much shorter than that estimated by the manufacturer and that the typical administration costs for patient access schemes of this type were likely to be nearer to the ERG's estimate rather than the manufacturer's.\n\n\n\nEnd-of-life considerations\n\nThe Committee noted that the manufacturer did not make a case for erlotinib to be considered as an end-of-life treatment. The Committee also noted that in Erlotinib monotherapy for the maintenance treatment of non-small-cell lung cancer (NICE technology appraisal guidance 227) erlotinib did not meet the end-of-life criteria because the cumulative population was not considered small. The Committee therefore concluded that erlotinib did not need to be considered as a life-extending, end-of-life treatment.\n\n\n\nEqualities considerations and social value judgements\n\nThe Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. The Committee noted that no equalities issues were raised in the submission or at the meeting. Given that the recommendations did not differentiate between any groups of people, the Committee concluded that its recommendations did not limit access to the technology for any specific group compared with other groups and that there was no need to alter or add to its recommendations.\n\n", 'Related NICE guidance': 'Published\n\nLung cancer: The diagnosis and treatment of lung cancer. NICE clinical guideline 121 (2011).\n\nErlotinib monotherapy for the maintenance treatment of non-small-cell lung cancer. NICE technology appraisal guidance 227 (2011).\n\nGefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer. NICE technology appraisal guidance 192 (2010).\n\nPemetrexed for the maintenance treatment of non-small-cell lung cancer. NICE technology appraisal guidance 190 (2010).\n\nPemetrexed for the first-line treatment of non-small-cell lung cancer. NICE technology appraisal guidance 181 (2009).\n\nErlotinib for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 162 (2008).\n\nBevacizumab for the treatment of non-small-cell lung cancer (terminated appraisal). NICE technology appraisal 148 (2008).', 'Review of guidance': 'The guidance on this technology will be considered for review in April 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveJune 2012', 'Changes after publication': 'February 2014:\n minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta258
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Evidence-based recommendations on erlotinib (Tarceva) for treating EGFR-TK-positive non-small-cell lung cancer in adults.
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0c195c69615a2aa53a5b957abc67e1f8d1e92054
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nice
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Sickle cell disease: managing acute painful episodes in hospital
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Sickle cell disease: managing acute painful episodes in hospital
This guideline covers managing acute painful sickle cell episodes in children, young people and adults who present at hospital, from presentation until when they are discharged. It aims to reduce variation in how acute episodes are managed in hospital, focusing on effective, prompt and safe pain relief.
# Introduction
Sickle cell disease is the name given to a group of lifelong inherited conditions of haemoglobin formation. Most people affected are of African or African-Caribbean origin, although the sickle gene is found in all ethnic groups. Sickle cell disease can have a significant impact on morbidity and mortality.
It is estimated that there are between 12,500 and 15,000 people with sickle cell disease in the UK. The prevalence of the disease is increasing because of immigration into the UK and new births. The NHS Sickle Cell and Thalassaemia Screening Programme also means that more cases are being diagnosed.
Acute painful sickle cell episodes (also known as painful crises) are caused by blockage of the small blood vessels. The red blood cells in people with sickle cell disease behave differently under a variety of conditions, including dehydration, low oxygen levels and elevated temperature. Changes in any of these conditions may cause the cells to block small blood vessels and cause tissue infarction. Repeated episodes may result in organ damage.
Acute painful sickle cell episodes occur unpredictably, often without clear precipitating factors. Their frequency may vary from less than 1 episode a year to severe pain at least once a week. Pain can fluctuate in both intensity and duration, and may be excruciating. Most of the painful episodes are managed at home, with patients usually seeking hospital care only if the pain is uncontrolled or they have no access to analgesia. Patients who require admission may remain in hospital for several days. The primary goal in the management of an acute painful sickle cell episode is to achieve effective pain control both promptly and safely.
The management of acute painful sickle cell episodes for patients presenting at hospital is variable throughout the UK, and this is a frequent source of complaints from patients. Common problems include unacceptable delays in receiving analgesia, insufficient or excessive doses, inappropriate analgesia, and stigmatising the patient as drug seeking.
This guideline addresses the management of an acute painful sickle cell episode in patients presenting to hospital until discharge. This includes the use of pharmacological and non-pharmacological interventions, identifying the signs and symptoms of acute complications, skills and settings for managing an acute painful episode, and the information and support needs of patients.
This is an overarching guideline covering the principles of how to manage an acute painful sickle cell episode in hospital. Local protocols should be referred to for specific management plans, including drug choice and dosages. This guideline includes the management of acute painful sickle cell episodes in children and young people and in pregnant women. The guideline recommendations apply to all patients presenting with an acute painful sickle episode unless there are differences in management for these groups, in which case these are clearly outlined.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Individualised assessment at presentation
NICE has produced a guideline on babies, children and young people's experience of healthcare.
Treat an acute painful sickle cell episode as an acute medical emergency. Follow locally agreed protocols for managing acute painful sickle cell episodes and/or acute medical emergencies that are consistent with this guideline.
Throughout an acute painful sickle cell episode, regard the patient (and/or their carer) as an expert in their condition, listen to their views and discuss with them:
the planned treatment regimen for the episode
treatment received during previous episodes
any concerns they may have about the current episode
any psychological and/or social support they may need.
Assess pain and use an age-appropriate pain scoring tool for all patients presenting at hospital with an acute painful sickle cell episode.
Offer analgesia within 30 minutes of presentation to all patients presenting at hospital with an acute painful sickle cell episode (see also the recommendations on primary analgesia).
Clinically assess all patients presenting at hospital with an acute painful sickle cell episode, including monitoring of:
blood pressure
-xygen saturation on air (if oxygen saturation is 95% or below, offer oxygen therapy)
pulse rate
respiratory rate
temperature.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
Assess all patients with sickle cell disease who present with acute pain to determine whether their pain is being caused by an acute painful sickle cell episode or whether an alternative diagnosis is possible, particularly if pain is reported as atypical by the patient.
# Primary analgesia
When offering analgesia for an acute painful sickle cell episode:
ask about and take into account any analgesia taken by the patient for the current episode before presentation
ensure that the drug, dose and administration route are suitable for the severity of the pain and the age of the patient
refer to the patient's individual care plan if available.
Offer a bolus dose of a strong opioid by a suitable administration route, in accordance with locally agreed protocols for managing acute painful sickle cell episodes, to:
all patients presenting with severe pain
all patients presenting with moderate pain who have already had some analgesia before presentation.
Consider a weak opioid as an alternative to a strong opioid for patients presenting with moderate pain who have not yet had any analgesia.
Offer all patients regular paracetamol and NSAIDs (non-steroidal anti-inflammatory drugs) by a suitable administration route, in addition to an opioid, unless contraindicated.The use of NSAIDs should be avoided during pregnancy, unless the potential benefits outweigh the risks. NSAIDs should be avoided for treating an acute painful sickle cell episode in women in the third trimester. See the BNF for details of contraindications.
Do not offer pethidine for treating pain in an acute painful sickle cell episode.
# Reassessment and ongoing management
Assess the effectiveness of pain relief:
every 30 minutes until satisfactory pain relief has been achieved, and at least every 4 hours thereafter
using an age-appropriate pain scoring tool
by asking questions, such as:
How well did that last painkiller work?
Do you feel that you need more pain relief?
If the patient has severe pain on reassessment, offer a second bolus dose of a strong opioid (or a first bolus dose if they have not yet received a strong opioid).
Consider patient-controlled analgesia if repeated bolus doses of a strong opioid are needed within 2 hours. Ensure that patient-controlled analgesia is used in accordance with locally agreed protocols for managing acute painful sickle cell episodes and/or acute medical emergencies.
Offer all patients who are taking an opioid:
laxatives on a regular basis
anti-emetics as needed
antipruritics as needed.
Monitor patients taking strong opioids for adverse events, and perform a clinical assessment (including sedation score):
every 1 hour for the first 6 hours
at least every 4 hours thereafter.
If the patient does not respond to standard treatment for an acute painful sickle cell episode, reassess them for the possibility of an alternative diagnosis.
As the acute painful sickle cell episode resolves, follow locally agreed protocols for managing acute painful sickle cell episodes to step down pharmacological treatment, in consultation with the patient.
# Possible acute complications
Be aware of the possibility of acute chest syndrome in patients with an acute painful sickle cell episode if any of the following are present at any time from presentation to discharge:
abnormal respiratory signs and/or symptoms
chest pain
fever
signs and symptoms of hypoxia:
-xygen saturation of 95% or below or
an escalating oxygen requirement.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
Be aware of other possible complications seen with an acute painful sickle cell episode, at any time from presentation to discharge, including:
acute stroke
aplastic crisis
infections
-steomyelitis
splenic sequestration.
# Management of underlying pathology
Do not use corticosteroids in the management of an uncomplicated acute painful sickle cell episode.
# Non-pharmacological interventions
Encourage the patient to use their own coping mechanisms (for example, relaxation techniques) for dealing with acute pain.
# Settings and training
All healthcare professionals who care for patients with an acute painful sickle cell episode should receive regular training, with topics including:
pain monitoring and relief
the ability to identify potential acute complications
attitudes towards and preconceptions about patients presenting with an acute painful sickle cell episode.
Where available, use day care settings in which staff have specialist knowledge and training for the initial assessment and treatment of patients presenting with an acute painful sickle cell episode.
All healthcare professionals in emergency departments who care for patients with an acute painful sickle cell episode should have access to locally agreed protocols and specialist support from designated centres.
Patients with an acute painful sickle cell episode should be cared for in an age-appropriate setting.
For pregnant women with an acute painful sickle cell episode, seek advice from the obstetrics team and refer when indicated.
# Discharge information
Before discharge, provide the patient (and/or their carer) with information on how to continue to manage the current episode, including:
how to obtain specialist support
how to obtain additional medication
how to manage any potential side effects of the treatment they have received in hospital.
# Terms used in this guideline
## Moderate pain
Pain with a Visual Analogue Scale (VAS; or equivalent) score typically within the range of 4 to 7 (this description should not be interpreted as a strict definition and will not apply to all patients, as pain is subjective).
## Patient-controlled analgesia (PCA)
A method of safely administering strong opioids which is controlled by the patient (or a nurse for nurse-controlled analgesia).
## Severe pain
Pain with a VAS (or equivalent) score typically above 7 (this description should not be interpreted as a strict definition and will not apply to all patients, as pain is subjective).# Recommendations for research
The guideline development group has made the following recommendations for research.
# Pain management for patients with an acute painful sickle cell episode
For patients with an acute painful sickle cell episode, what are the effects of different opioid formulations, adjunct pain therapies and routes of administration on pain relief and acute sickle cell complications?
## Why this is important
Limited evidence is available on the effectiveness of different opioid formulations, routes of administration and adjunct therapies in the treatment of an acute painful sickle cell episode. A series of randomised controlled trials (RCTs) should be conducted that compare the effects of different opioid formulations, adjunct pain therapies and routes of administration. These RCTs should be conducted separately in adults and children, and cover the duration of the acute painful episode. Outcomes should include pain and adverse events such as acute chest syndrome.
# Use of low-molecular-weight heparin to treat patients with an acute painful sickle cell episode
Are therapeutic doses of low-molecular-weight heparin (LMWH) effective, compared with prophylactic doses of LMWH, in reducing the length of stay in hospital of patients with an acute painful sickle cell episode?
## Why this is important
Moderate-quality evidence from one RCT suggested a significant benefit of treating patients with an acute painful sickle cell episode with LMWH. This was supported by exploratory health economic analyses suggesting a large reduction in length of stay and associated costs. An RCT should be conducted that examines the effect of therapeutic doses of LMWH, compared with prophylactic doses, on the length of stay in hospital of patients with an acute painful sickle cell episode. The RCT should be conducted separately in adults and children, and cover the duration of the painful episode.
# Non-pharmacological interventions for patients with an acute painful sickle cell episode
For patients with an acute painful sickle cell episode, are non-pharmacological interventions, such as massage, effective in improving their recovery from the episode?
## Why this is important
There was a lack of evidence on the potential benefits of supportive interventions for patients with an acute painful sickle cell episode. An RCT should be conducted that examines the effect of providing rehabilitation interventions that are aimed at improving a patient's recovery after an acute painful sickle cell episode. Such interventions could include massage and physical therapy. The intervention should be provided within the hospital setting, and patients should be followed up 7 days after the episode. Data should be collected to inform outcomes such as length of stay, health-related quality of life and coping strategies.
# Cost effectiveness of daycare units for treating patients with an acute painful sickle cell episode
Are day care units cost effective compared with emergency settings for treating patients with an acute painful sickle cell episode?
## Why this is important
There was a lack of evidence on the cost effectiveness of day care units for treating patients with an acute painful sickle cell episode in the UK. A trial should be carried out that compares treating patients with an acute painful sickle cell episode in an emergency department setting and in a specialist sickle cell day care unit. Outcomes should include health-related quality of life (HRQoL). Data should be collected using validated measure(s) of HRQoL, including EQ-5D.
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{'Introduction': 'Sickle cell disease is the name given to a group of lifelong inherited conditions of haemoglobin formation. Most people affected are of African or African-Caribbean origin, although the sickle gene is found in all ethnic groups. Sickle cell disease can have a significant impact on morbidity and mortality.\n\nIt is estimated that there are between 12,500 and 15,000 people with sickle cell disease in the UK. The prevalence of the disease is increasing because of immigration into the UK and new births. The NHS Sickle Cell and Thalassaemia Screening Programme also means that more cases are being diagnosed.\n\nAcute painful sickle cell episodes (also known as painful crises) are caused by blockage of the small blood vessels. The red blood cells in people with sickle cell disease behave differently under a variety of conditions, including dehydration, low oxygen levels and elevated temperature. Changes in any of these conditions may cause the cells to block small blood vessels and cause tissue infarction. Repeated episodes may result in organ damage.\n\nAcute painful sickle cell episodes occur unpredictably, often without clear precipitating factors. Their frequency may vary from less than 1\xa0episode a year to severe pain at least once a week. Pain can fluctuate in both intensity and duration, and may be excruciating. Most of the painful episodes are managed at home, with patients usually seeking hospital care only if the pain is uncontrolled or they have no access to analgesia. Patients who require admission may remain in hospital for several days. The primary goal in the management of an acute painful sickle cell episode is to achieve effective pain control both promptly and safely.\n\nThe management of acute painful sickle cell episodes for patients presenting at hospital is variable throughout the UK, and this is a frequent source of complaints from patients. Common problems include unacceptable delays in receiving analgesia, insufficient or excessive doses, inappropriate analgesia, and stigmatising the patient as drug seeking.\n\nThis guideline addresses the management of an acute painful sickle cell episode in patients presenting to hospital until discharge. This includes the use of pharmacological and non-pharmacological interventions, identifying the signs and symptoms of acute complications, skills and settings for managing an acute painful episode, and the information and support needs of patients.\n\nThis is an overarching guideline covering the principles of how to manage an acute painful sickle cell episode in hospital. Local protocols should be referred to for specific management plans, including drug choice and dosages. This guideline includes the management of acute painful sickle cell episodes in children and young people and in pregnant women. The guideline recommendations apply to all patients presenting with an acute painful sickle episode unless there are differences in management for these groups, in which case these are clearly outlined.', 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Individualised assessment at presentation\n\nNICE has produced a guideline on babies, children and young people's experience of healthcare.\n\nTreat an acute painful sickle cell episode as an acute medical emergency. Follow locally agreed protocols for managing acute painful sickle cell episodes and/or acute medical emergencies that are consistent with this guideline.\n\nThroughout an acute painful sickle cell episode, regard the patient (and/or their carer) as an expert in their condition, listen to their views and discuss with them:\n\nthe planned treatment regimen for the episode\n\ntreatment received during previous episodes\n\nany concerns they may have about the current episode\n\nany psychological and/or social support they may need.\n\nAssess pain and use an age-appropriate pain scoring tool for all patients presenting at hospital with an acute painful sickle cell episode.\n\nOffer analgesia within 30\xa0minutes of presentation to all patients presenting at hospital with an acute painful sickle cell episode (see also the recommendations on primary analgesia).\n\nClinically assess all patients presenting at hospital with an acute painful sickle cell episode, including monitoring of:\n\nblood pressure\n\noxygen saturation on air (if oxygen saturation is 95% or below, offer oxygen therapy)\n\npulse rate\n\nrespiratory rate\n\ntemperature.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nAssess all patients with sickle cell disease who present with acute pain to determine whether their pain is being caused by an acute painful sickle cell episode or whether an alternative diagnosis is possible, particularly if pain is reported as atypical by the patient.\n\n# Primary analgesia\n\nWhen offering analgesia for an acute painful sickle cell episode:\n\nask about and take into account any analgesia taken by the patient for the current episode before presentation\n\nensure that the drug, dose and administration route are suitable for the severity of the pain and the age of the patient\n\nrefer to the patient's individual care plan if available.\n\nOffer a bolus dose of a strong opioid by a suitable administration route, in accordance with locally agreed protocols for managing acute painful sickle cell episodes, to:\n\nall patients presenting with severe pain\n\nall patients presenting with moderate pain who have already had some analgesia before presentation.\n\nConsider a weak opioid as an alternative to a strong opioid for patients presenting with moderate pain who have not yet had any analgesia.\n\nOffer all patients regular paracetamol and NSAIDs (non-steroidal anti-inflammatory drugs) by a suitable administration route, in addition to an opioid, unless contraindicated.The use of NSAIDs should be avoided during pregnancy, unless the potential benefits outweigh the risks. NSAIDs should be avoided for treating an acute painful sickle cell episode in women in the third trimester. See the BNF for details of contraindications.\n\nDo not offer pethidine for treating pain in an acute painful sickle cell episode.\n\n# Reassessment and ongoing management\n\nAssess the effectiveness of pain relief:\n\nevery 30\xa0minutes until satisfactory pain relief has been achieved, and at least every 4\xa0hours thereafter\n\nusing an age-appropriate pain scoring tool\n\nby asking questions, such as:\n\n\n\nHow well did that last painkiller work?\n\nDo you feel that you need more pain relief?\n\n\n\nIf the patient has severe pain on reassessment, offer a second bolus dose of a strong opioid (or a first bolus dose if they have not yet received a strong opioid).\n\nConsider patient-controlled analgesia if repeated bolus doses of a strong opioid are needed within 2\xa0hours. Ensure that patient-controlled analgesia is used in accordance with locally agreed protocols for managing acute painful sickle cell episodes and/or acute medical emergencies.\n\nOffer all patients who are taking an opioid:\n\nlaxatives on a regular basis\n\nanti-emetics as needed\n\nantipruritics as needed.\n\nMonitor patients taking strong opioids for adverse events, and perform a clinical assessment (including sedation score):\n\nevery 1\xa0hour for the first 6\xa0hours\n\nat least every 4\xa0hours thereafter.\n\nIf the patient does not respond to standard treatment for an acute painful sickle cell episode, reassess them for the possibility of an alternative diagnosis.\n\nAs the acute painful sickle cell episode resolves, follow locally agreed protocols for managing acute painful sickle cell episodes to step down pharmacological treatment, in consultation with the patient.\n\n# Possible acute complications\n\nBe aware of the possibility of acute chest syndrome in patients with an acute painful sickle cell episode if any of the following are present at any time from presentation to discharge:\n\nabnormal respiratory signs and/or symptoms\n\nchest pain\n\nfever\n\nsigns and symptoms of hypoxia:\n\n\n\noxygen saturation of 95% or below or\n\nan escalating oxygen requirement.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\n\n\nBe aware of other possible complications seen with an acute painful sickle cell episode, at any time from presentation to discharge, including:\n\nacute stroke\n\naplastic crisis\n\ninfections\n\nosteomyelitis\n\nsplenic sequestration.\n\n# Management of underlying pathology\n\nDo not use corticosteroids in the management of an uncomplicated acute painful sickle cell episode.\n\n# Non-pharmacological interventions\n\nEncourage the patient to use their own coping mechanisms (for example, relaxation techniques) for dealing with acute pain.\n\n# Settings and training\n\nAll healthcare professionals who care for patients with an acute painful sickle cell episode should receive regular training, with topics including:\n\npain monitoring and relief\n\nthe ability to identify potential acute complications\n\nattitudes towards and preconceptions about patients presenting with an acute painful sickle cell episode.\n\nWhere available, use day care settings in which staff have specialist knowledge and training for the initial assessment and treatment of patients presenting with an acute painful sickle cell episode.\n\nAll healthcare professionals in emergency departments who care for patients with an acute painful sickle cell episode should have access to locally agreed protocols and specialist support from designated centres.\n\nPatients with an acute painful sickle cell episode should be cared for in an age-appropriate setting.\n\nFor pregnant women with an acute painful sickle cell episode, seek advice from the obstetrics team and refer when indicated.\n\n# Discharge information\n\nBefore discharge, provide the patient (and/or their carer) with information on how to continue to manage the current episode, including:\n\nhow to obtain specialist support\n\nhow to obtain additional medication\n\nhow to manage any potential side effects of the treatment they have received in hospital.\n\n# Terms used in this guideline\n\n## Moderate pain\n\nPain with a Visual Analogue Scale (VAS; or equivalent) score typically within the range of 4\xa0to\xa07 (this description should not be interpreted as a strict definition and will not apply to all patients, as pain is subjective).\n\n## Patient-controlled analgesia (PCA)\n\nA method of safely administering strong opioids which is controlled by the patient (or a nurse for nurse-controlled analgesia).\n\n## Severe pain\n\nPain with a VAS (or equivalent) score typically above\xa07 (this description should not be interpreted as a strict definition and will not apply to all patients, as pain is subjective).", 'Recommendations for research': "The guideline development group has made the following recommendations for research.\n\n# Pain management for patients with an acute painful sickle cell episode\n\nFor patients with an acute painful sickle cell episode, what are the effects of different opioid formulations, adjunct pain therapies and routes of administration on pain relief and acute sickle cell complications?\n\n## Why this is important\n\nLimited evidence is available on the effectiveness of different opioid formulations, routes of administration and adjunct therapies in the treatment of an acute painful sickle cell episode. A series of randomised controlled trials (RCTs) should be conducted that compare the effects of different opioid formulations, adjunct pain therapies and routes of administration. These RCTs should be conducted separately in adults and children, and cover the duration of the acute painful episode. Outcomes should include pain and adverse events such as acute chest syndrome.\n\n# Use of low-molecular-weight heparin to treat patients with an acute painful sickle cell episode\n\nAre therapeutic doses of low-molecular-weight heparin (LMWH) effective, compared with prophylactic doses of LMWH, in reducing the length of stay in hospital of patients with an acute painful sickle cell episode?\n\n## Why this is important\n\nModerate-quality evidence from one RCT suggested a significant benefit of treating patients with an acute painful sickle cell episode with LMWH. This was supported by exploratory health economic analyses suggesting a large reduction in length of stay and associated costs. An RCT should be conducted that examines the effect of therapeutic doses of LMWH, compared with prophylactic doses, on the length of stay in hospital of patients with an acute painful sickle cell episode. The RCT should be conducted separately in adults and children, and cover the duration of the painful episode.\n\n# Non-pharmacological interventions for patients with an acute painful sickle cell episode\n\nFor patients with an acute painful sickle cell episode, are non-pharmacological interventions, such as massage, effective in improving their recovery from the episode?\n\n## Why this is important\n\nThere was a lack of evidence on the potential benefits of supportive interventions for patients with an acute painful sickle cell episode. An RCT should be conducted that examines the effect of providing rehabilitation interventions that are aimed at improving a patient's recovery after an acute painful sickle cell episode. Such interventions could include massage and physical therapy. The intervention should be provided within the hospital setting, and patients should be followed up 7 days after the episode. Data should be collected to inform outcomes such as length of stay, health-related quality of life and coping strategies.\n\n# Cost effectiveness of daycare units for treating patients with an acute painful sickle cell episode\n\nAre day care units cost effective compared with emergency settings for treating patients with an acute painful sickle cell episode?\n\n## Why this is important\n\nThere was a lack of evidence on the cost effectiveness of day care units for treating patients with an acute painful sickle cell episode in the UK. A trial should be carried out that compares treating patients with an acute painful sickle cell episode in an emergency department setting and in a specialist sickle cell day care unit. Outcomes should include health-related quality of life (HRQoL). Data should be collected using validated measure(s) of HRQoL, including EQ-5D."}
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https://www.nice.org.uk/guidance/cg143
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This guideline covers managing acute painful sickle cell episodes in children, young people and adults who present at hospital, from presentation until when they are discharged. It aims to reduce variation in how acute episodes are managed in hospital, focusing on effective, prompt and safe pain relief.
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225cde9bef6a7b4899fe29535c790b5797a9590a
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nice
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Percutaneous balloon cryoablation for pulmonary vein isolation in atrial fibrillation
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Percutaneous balloon cryoablation for pulmonary vein isolation in atrial fibrillation
# Guidance
Current evidence on the efficacy and safety of percutaneous balloon cryoablation for pulmonary vein isolation in atrial fibrillation is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.
Patient selection and treatment should only be carried out by interventional cardiologists with expertise in electrophysiology and complex ablation procedures.
This procedure should be carried out only in units with arrangements for emergency cardiac surgical support in case of complications.
Clinicians should enter details about all patients undergoing percutaneous balloon cryoablation for pulmonary vein isolation in atrial fibrillation onto the UK Central Cardiac Audit Database.
NICE encourages clinicians to enter patients into research studies with the particular aims of guiding selection of patients and of defining the place of percutaneous balloon cryoablation in relation to other procedures for treating atrial fibrillation. Further research should define patient selection criteria clearly and should document adverse events and long-term control of atrial fibrillation.# The procedure
# Indications and current treatments
Atrial fibrillation is the irregular and rapid activation of the atria. It is caused by uncoordinated electrical stimulation of the atrial muscle. Atrial fibrillation may be classified as paroxysmal, persistent or permanent. Patients may be asymptomatic or have symptoms such as palpitations, fatigue and chest pain.
Patients considered to be at high risk of embolic stroke from thrombus in the fibrillating left atrium are usually treated with anticoagulation therapy. Medical treatment for atrial fibrillation includes drugs to control heart rate or to help maintain a normal cardiac rhythm after cardioversion. Ablation procedures, designed to disrupt abnormal conduction pathways, may be used when drug therapy is either not tolerated or is ineffective. Several methods are available to deliver cardiac ablation including cryoablation with or without a balloon.
# Outline of the procedure
Percutaneous balloon cryoablation for pulmonary vein isolation in atrial fibrillation helps maintain normal heart rhythm by isolating the electrical impulses originating in the pulmonary veins that are thought to be responsible for 'triggering' atrial fibrillation.
With the patient under general anaesthesia, or using local anaesthesia and sedation, catheters are introduced percutaneously through one or both femoral veins. One or more electrode catheters are placed in the heart to allow pacing. An additional electrode catheter is placed in a vein or the heart to allow stimulation of the phrenic nerve. One or two sheaths are advanced into the left atrium transseptally. A multipolar circular mapping catheter (to record electrical signals from the pulmonary vein ostia) and the balloon cryoablation catheter are passed through the two sheaths. The balloon cryoablation catheter is placed at one of the pulmonary vein ostia and the balloon is inflated to allow continuous contact between the balloon and the atrial myocardium. Good contact is confirmed fluoroscopically by injecting contrast into the pulmonary vein through the lumen of the balloon catheter.
When the balloon catheter has been positioned satisfactorily, it is cooled in bursts of approximately 4 minutes, to achieve circumferential isolation of the cells responsible for the arrhythmia. This is assessed using the mapping catheter. Each of the pulmonary veins is treated in the same way, until all are electrically isolated.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A systematic review with 1308 patients (23 studies) reported acute procedural success (defined as complete isolation of all targeted pulmonary veins) in 99% (95% confidence interval 98 to 99) of patients (19 studies; n = 924; I2 = 0% ) (timing of assessment unclear). A comparative case series of 94 patients treated by balloon cryoablation (n = 30), radiofrequency ablation (n = 29) or robotically assisted radiofrequency ablation (n = 35) reported procedure success (defined as 'no atrial tachyarrhythmias lasting ≥ 30 seconds, identified on surface electrocardiogram , Holter monitoring or 7-day ECG recording') without anti-arrhythmic drugs in 66% (23), 66% (19) and 67% (20) of patients respectively at a mean follow-up of 13 months (p = 0.625) (denominator not reported).
The systematic review reported 1-year freedom from atrial fibrillation in 73% of patients (95% CI 69 to 77) with paroxysmal atrial fibrillation after a 3-month blanking period (time period during which transient episodes of arrhythmia were not considered recurrences) (5 studies; n = 519; I2 = 0% ); in 60% of patients (95% CI 55 to 66) with paroxysmal atrial fibrillation without a 3-month blanking period (3 studies; n = 316; I2 = 0% ); and in 45% of patients (95% CI 32 to 58) with persistent atrial fibrillation after a 3-month blanking period (2 studies; n = 62; I2 = 0% ).
In a case series of 346 patients treated by balloon cryoablation (treatment completed by cryoablation catheter if isolation was not achieved), sinus rhythm was maintained without anti-arrhythmic drugs in 74% (159, denominator not reported) of patients with paroxysmal atrial fibrillation and 42% (13/31) of patients with persistent atrial fibrillation (follow-up not stated).
A case series of 141 patients reported recurrence of atrial fibrillation in 51% (71/139) of patients after 1 procedure (follow-up 457 days).
A non-randomised comparative case series of 177 patients treated by balloon cryoablation or radiofrequency ablation reported that 14% (17) and 23% (12) of patients respectively needed retreatment for recurrent atrial fibrillation (denominators and timing of events not reported; mean follow-up 13 months).
The Specialist Advisers listed key efficacy outcomes as electrical isolation of 'all pulmonary veins' or 'all 4 pulmonary veins', procedure duration, freedom from atrial fibrillation, avoidance of repeat procedures and reduced use of anti-arrhythmic drugs.
# Safety
The case series of 346 patients reported periprocedural pericardial tamponade in 2 patients, both successfully treated by pericardial drainage and without the need for surgery. A comparative case series of 133 patients reported pericardial effusion within 24 hours in 11% (5/46) of patients treated by balloon cryoablation and in 16% (14/87) of patients treated by radiofrequency ablation (drainage was needed in 1 patient in each group; all the other effusions resolved spontaneously).
The case series of 346 patients reported right phrenic nerve injury in 8% (26/346) of patients during balloon cryoablation of the right superior pulmonary vein. Of these, 2 resolved during the procedure and full function recovered in all patients during follow-up of less than 1 year.
A comparative case series of 74 patients treated by balloon cryoablation (n = 67) or cryocatheter (n = 7) reported oesophageal ulceration identified by endoscopy in 17% (6/35) of patients and 0/7 patients respectively within 1 week of the procedure. All were asymptomatic and resolved within 3 months.
Stroke or transient ischaemic attack was reported in less than 1% of patients (4/1241) in the systematic review. Three of the 4 cerebrovascular events were observed in the same study and resolved within 24 hours.
In the case series of 141 patients, 2 patients had haemoptysis during the first month after pulmonary vein isolation. This resolved after temporary cessation of oral anticoagulation therapy.
The Specialist Advisers listed adverse events reported in the literature as pulmonary vein stenosis, groin haematoma at venous entry site and pseudoaneurysm. They reported anecdotal adverse events of air embolus and phrenic nerve injury, and they considered theoretical adverse events to include death, atrio-oesophageal fistula, permanent phrenic nerve palsy, damage to structures anatomically close to pulmonary veins and deep vein thrombosis.
# Other comments
The Committee noted the advances in the understanding of the causes of atrial fibrillation and acknowledged that this procedure is likely to be more effective in paroxysmal than persistent atrial fibrillation.
The Committee noted that asymptomatic cerebral lesions have been shown after percutaneous balloon cryoablation for pulmonary vein isolation in atrial fibrillation but that it is unknown whether these have clinical consequences.# Further information
For related NICE guidance see www.nice.org.uk
Information for patients
NICE has produced information on this procedure for patients and carers (Understanding NICE guidance). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedures guidance process.
We have produced a summary of this guidance for patients and carers. Information about the evidence that the guidance is based on is also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
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{'Guidance': 'Current evidence on the efficacy and safety of percutaneous balloon cryoablation for pulmonary vein isolation in atrial fibrillation is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatient selection and treatment should only be carried out by interventional cardiologists with expertise in electrophysiology and complex ablation procedures.\n\nThis procedure should be carried out only in units with arrangements for emergency cardiac surgical support in case of complications.\n\nClinicians should enter details about all patients undergoing percutaneous balloon cryoablation for pulmonary vein isolation in atrial fibrillation onto the UK Central Cardiac Audit Database.\n\nNICE encourages clinicians to enter patients into research studies with the particular aims of guiding selection of patients and of defining the place of percutaneous balloon cryoablation in relation to other procedures for treating atrial fibrillation. Further research should define patient selection criteria clearly and should document adverse events and long-term control of atrial fibrillation.', 'The procedure': "# Indications and current treatments\n\nAtrial fibrillation is the irregular and rapid activation of the atria. It is caused by uncoordinated electrical stimulation of the atrial muscle. Atrial fibrillation may be classified as paroxysmal, persistent or permanent. Patients may be asymptomatic or have symptoms such as palpitations, fatigue and chest pain.\n\nPatients considered to be at high risk of embolic stroke from thrombus in the fibrillating left atrium are usually treated with anticoagulation therapy. Medical treatment for atrial fibrillation includes drugs to control heart rate or to help maintain a normal cardiac rhythm after cardioversion. Ablation procedures, designed to disrupt abnormal conduction pathways, may be used when drug therapy is either not tolerated or is ineffective. Several methods are available to deliver cardiac ablation including cryoablation with or without a balloon.\n\n# Outline of the procedure\n\nPercutaneous balloon cryoablation for pulmonary vein isolation in atrial fibrillation helps maintain normal heart rhythm by isolating the electrical impulses originating in the pulmonary veins that are thought to be responsible for 'triggering' atrial fibrillation.\n\nWith the patient under general anaesthesia, or using local anaesthesia and sedation, catheters are introduced percutaneously through one or both femoral veins. One or more electrode catheters are placed in the heart to allow pacing. An additional electrode catheter is placed in a vein or the heart to allow stimulation of the phrenic nerve. One or two sheaths are advanced into the left atrium transseptally. A multipolar circular mapping catheter (to record electrical signals from the pulmonary vein ostia) and the balloon cryoablation catheter are passed through the two sheaths. The balloon cryoablation catheter is placed at one of the pulmonary vein ostia and the balloon is inflated to allow continuous contact between the balloon and the atrial myocardium. Good contact is confirmed fluoroscopically by injecting contrast into the pulmonary vein through the lumen of the balloon catheter.\n\nWhen the balloon catheter has been positioned satisfactorily, it is cooled in bursts of approximately 4\xa0minutes, to achieve circumferential isolation of the cells responsible for the arrhythmia. This is assessed using the mapping catheter. Each of the pulmonary veins is treated in the same way, until all are electrically isolated.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA systematic review with 1308 patients (23\xa0studies) reported acute procedural success (defined as complete isolation of all targeted pulmonary veins) in 99% (95% confidence interval [CI] 98 to 99) of patients (19\xa0studies; n\xa0=\xa0924; I2\xa0=\xa00% [no heterogeneity]) (timing of assessment unclear). A comparative case series of 94 patients treated by balloon cryoablation (n\xa0=\xa030), radiofrequency ablation (n\xa0=\xa029) or robotically assisted radiofrequency ablation (n\xa0=\xa035) reported procedure success (defined as 'no atrial tachyarrhythmias [symptomatic or asymptomatic] lasting\xa0≥\xa030\xa0seconds, identified on surface electrocardiogram [ECG], Holter monitoring or 7-day ECG recording') without anti-arrhythmic drugs in 66% (23), 66% (19) and 67% (20) of patients respectively at a mean follow-up of 13\xa0months (p\xa0=\xa00.625) (denominator not reported).\n\nThe systematic review reported 1-year freedom from atrial fibrillation in 73% of patients (95% CI 69 to 77) with paroxysmal atrial fibrillation after a 3-month blanking period (time period during which transient episodes of arrhythmia were not considered recurrences) (5\xa0studies; n\xa0=\xa0519; I2\xa0=\xa00% [no heterogeneity]); in 60% of patients (95% CI 55 to 66) with paroxysmal atrial fibrillation without a 3-month blanking period (3 studies; n\xa0=\xa0316; I2\xa0=\xa00% [no heterogeneity]); and in 45% of patients (95% CI 32 to 58) with persistent atrial fibrillation after a 3-month blanking period (2\xa0studies; n\xa0=\xa062; I2\xa0=\xa00% [no heterogeneity]).\n\nIn a case series of 346\xa0patients treated by balloon cryoablation (treatment completed by cryoablation catheter if isolation was not achieved), sinus rhythm was maintained without anti-arrhythmic drugs in 74% (159, denominator not reported) of patients with paroxysmal atrial fibrillation and 42% (13/31) of patients with persistent atrial fibrillation (follow-up not stated).\n\nA case series of 141\xa0patients reported recurrence of atrial fibrillation in 51% (71/139) of patients after 1 procedure (follow-up 457\xa0days).\n\nA non-randomised comparative case series of 177\xa0patients treated by balloon cryoablation or radiofrequency ablation reported that 14% (17) and 23% (12) of patients respectively needed retreatment for recurrent atrial fibrillation (denominators and timing of events not reported; mean follow-up 13\xa0months).\n\nThe Specialist Advisers listed key efficacy outcomes as electrical isolation of 'all pulmonary veins' or 'all 4 pulmonary veins', procedure duration, freedom from atrial fibrillation, avoidance of repeat procedures and reduced use of anti-arrhythmic drugs.\n\n# Safety\n\nThe case series of 346 patients reported periprocedural pericardial tamponade in 2 patients, both successfully treated by pericardial drainage and without the need for surgery. A comparative case series of 133 patients reported pericardial effusion within 24\xa0hours in 11% (5/46) of patients treated by balloon cryoablation and in 16% (14/87) of patients treated by radiofrequency ablation (drainage was needed in 1\xa0patient in each group; all the other effusions resolved spontaneously).\n\nThe case series of 346\xa0patients reported right phrenic nerve injury in 8% (26/346) of patients during balloon cryoablation of the right superior pulmonary vein. Of these, 2 resolved during the procedure and full function recovered in all patients during follow-up of less than 1\xa0year.\n\nA comparative case series of 74\xa0patients treated by balloon cryoablation (n\xa0=\xa067) or cryocatheter (n\xa0=\xa07) reported oesophageal ulceration identified by endoscopy in 17% (6/35) of patients and 0/7 patients respectively within 1\xa0week of the procedure. All were asymptomatic and resolved within 3\xa0months.\n\nStroke or transient ischaemic attack was reported in less than 1% of patients (4/1241) in the systematic review. Three of the 4 cerebrovascular events were observed in the same study and resolved within 24\xa0hours.\n\nIn the case series of 141\xa0patients, 2\xa0patients had haemoptysis during the first\xa0month after pulmonary vein isolation. This resolved after temporary cessation of oral anticoagulation therapy.\n\nThe Specialist Advisers listed adverse events reported in the literature as pulmonary vein stenosis, groin haematoma at venous entry site and pseudoaneurysm. They reported anecdotal adverse events of air embolus and phrenic nerve injury, and they considered theoretical adverse events to include death, atrio-oesophageal fistula, permanent phrenic nerve palsy, damage to structures anatomically close to pulmonary veins and deep vein thrombosis.\n\n# Other comments\n\nThe Committee noted the advances in the understanding of the causes of atrial fibrillation and acknowledged that this procedure is likely to be more effective in paroxysmal than persistent atrial fibrillation.\n\nThe Committee noted that asymptomatic cerebral lesions have been shown after percutaneous balloon cryoablation for pulmonary vein isolation in atrial fibrillation but that it is unknown whether these have clinical consequences.", 'Further information': 'For related NICE guidance see www.nice.org.uk\n\nInformation for patients\n\nNICE has produced information on this procedure for patients and carers (Understanding NICE guidance). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence that the guidance is based on is also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n\n033 7780'}
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https://www.nice.org.uk/guidance/ipg427
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23a629778122317f2dc101a31cfa69b1afac93e2
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nice
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Ranibizumab and pegaptanib for the treatment of age-related macular degeneration
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Ranibizumab and pegaptanib for the treatment of age-related macular degeneration
Evidence-based recommendations on ranibizumab (Lucentis) and pegaptanib (Macugen) for treating wet age-related macular oedema in adults.
# Guidance
This guidance has been re-issued after a change to the patient access scheme in May 2012. See About this guidance for more information.
Ranibizumab, within its marketing authorisation, is recommended as an option for the treatment of wet age-related macular degeneration if:
all of the following circumstances apply in the eye to be treated:
the best-corrected visual acuity is between 6/12 and 6/96
there is no permanent structural damage to the central fovea
the lesion size is less than or equal to 12 disc areas in greatest linear dimension
there is evidence of recent presumed disease progression (blood vessel growth, as indicated by fluorescein angiography, or recent visual acuity changes)and
the manufacturer provides ranibizumab with the discount agreed in the patient access scheme (as revised in 2012).
It is recommended that treatment with ranibizumab should be continued only in people who maintain adequate response to therapy. Criteria for discontinuation should include persistent deterioration in visual acuity and identification of anatomical changes in the retina that indicate inadequate response to therapy. It is recommended that a national protocol specifying criteria for discontinuation is developed.
Pegaptanib is not recommended for the treatment of wet age-related macular degeneration.
People who are currently receiving pegaptanib for any lesion type should have the option to continue therapy until they and their clinicians consider it appropriate to stop.# Clinical need and practice
Age-related macular degeneration (AMD) is an eye condition that leads to a progressive loss of central vision. People retain some peripheral vision, but the ability to see well enough to recognise faces, drive and read is affected, and vision can deteriorate rapidly.
AMD occurs in two forms, dry and wet AMD. Dry AMD (non-neovascular) is a form of extensive atrophy (wasting) of cells that progresses slowly, whereas the wet form can lead to a rapid worsening of vision. Wet (neovascular) AMD is characterised by the development of immature blood vessels that grow between the retinal pigment epithelial cells and the photoreceptor cells in the centre of the retina, a process known as choroidal neovascularisation (CNV). These vessels easily haemorrhage and cause lesions on the macula, leading to visual impairment. A protein known as vascular endothelial growth factor (VEGF), which induces new blood vessel formation (angiogenesis), vascular permeability and inflammation, has been implicated in the development and progression of CNV. CNV can be subdivided into classic and occult forms according to its appearance on investigation by fluorescein angiography. A mixture of classic and occult CNV can occur in the same lesion. CNV can also be described in terms of its location: the fovea is the central part of the macula, and CNV that develops below the foveal area is termed 'subfoveal CNV'.
There are about 26,000 new cases of wet AMD in the UK each year and the condition affects more women than men. The condition usually affects people who are over 50 years old and the risk increases significantly with age. The most commonly cited risk factor for AMD is cigarette smoking; the risk of developing AMD is 3.6 times greater for current and former smokers than for people who have never smoked.
Patient management consists of social support, visual rehabilitation and the provision of aids to help with low vision. However, in the 20% of patients with classic no occult subfoveal CNV and a best-corrected visual acuity of 6/60 or better, photodynamic therapy (PDT) is an option. Visual acuity of 6/60 means that the patient can only see from a distance of 6 metres or less what someone with normal vision can see from 60 metres away. PDT involves injecting verteporfin, a photosensitive drug that remains in the new blood vessels in the eye. This is followed by treatment with a low-powered laser, which activates the drug causing cell death. The aim is to destroy the CNV lesions without damaging the retina, thereby halting or reducing progressive loss of vision. PDT does not prevent new vessels forming: it only treats established pathological vessels. More recently, drugs that inhibit the action of VEGF have been developed for the treatment of wet AMD.# The technologies
# Ranibizumab
Ranibizumab (Lucentis, Novartis) is a humanised therapeutic antibody fragment that binds to VEGF-A isoforms of VEGF thereby preventing binding of VEGF-A to receptors VEGFR-1 and VEGFR-2.
Ranibizumab has a UK marketing authorisation for the treatment of neovascular (wet) AMD. It is administered through intravitreal injection at a recommended dose of 0.5 mg. Treatment is started with a loading phase of one injection per month for 3 consecutive months, followed by a maintenance phase in which patients are monitored monthly for visual acuity. If the patient experiences a loss of greater than five letters in visual acuity (on the Early Treatment Diabetic Retinopathy Study chart or one Snellen line equivalent) during this maintenance phase, a further dose of ranibizumab should be administered. The interval between two doses should not be shorter than 1 month.
The summary of product characteristics (SPC) states that adverse events commonly associated with ranibizumab include conjunctival haemorrhage, eye pain, vitreous floaters, retinal haemorrhage, increased intraocular pressure, vitreous detachment, intraocular inflammation, eye irritation, cataract, foreign body sensation in the eyes, visual disturbance, blepharitis, subretinal fibrosis, ocular hyperaemia, blurred/decreased visual acuity, dry eye and vitreitis. For full details of side effects and contraindications, see the SPC.
The cost of a ranibizumab injection is £761.20 (excluding VAT; British national formulary 54th edition). The 2-year cost of ranibizumab is about £10,700 assuming 8 injections in the first year and 6 injections in the second year, and about £18,300 assuming 12 injections in the first year and another 12 in the second year as per clinical trial regimen. Costs may vary in different settings because of negotiated procurement discounts.
# Pegaptanib
Pegaptanib (Macugen, Pfizer) is a pegylated modified oligonucleotide that binds to VEGF-165 and inhibits its activity.
Pegaptanib has a UK marketing authorisation for the treatment of neovascular (wet) AMD. It is administered at 0.3 mg once every 6 weeks (9 injections per year) by intravitreal injection into the affected eye.
The SPC states that adverse events commonly associated with pegaptanib are anterior chamber inflammation, eye pain, increased intraocular pressure, punctate keratitis, vitreous floaters and vitreous opacities. For full details of side effects and contraindications, see the SPC.
The cost of pegaptanib is £514.00 per injection (excluding VAT; BNF 52nd edition). The 2-year cost of pegaptanib is about £9,300 (9 injections in the first year and another 9 in the second year). Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
# Clinical effectiveness
The Assessment Group's systematic review identified four randomised controlled trials (RCTs) of ranibizumab and two RCTs of pegaptanib. Outcomes measured in the RCTs included changes in visual acuity (loss, maintenance, gain, mean change and deterioration to visual acuity 3/60 ), anatomical changes in CNV lesions, visual function questionnaire scores, contrast sensitivity and adverse events.
## Ranibizumab
Four RCTs of ranibizumab (MARINA , ANCHOR , PIER and FOCUS ) were included in the assessment report and the manufacturer's submission. The length of follow-up in the trials varied from 12 to 24 months and the doses used were 0.3 mg (unlicensed) and 0.5 mg (licensed). The populations in the trials met inclusion criteria including best-corrected visual acuity between 6/12 and 6/96; no permanent structural damage to the central fovea; lesion size less than or equal to 12 disc areas in greatest linear dimension; and evidence of recent presumed disease progression (blood vessel growth as indicated by fluorescein angiography, or recent visual acuity changes). Outcomes were assessed at different time points, and the number and frequency of injections varied among the trials.
Loss of fewer than 15 letters of visual acuity was the primary endpoint in the studies. From baseline to 12 months, statistically significantly more patients receiving 0.5 mg ranibizumab lost fewer than 15 letters of visual acuity compared with both sham injection (94.6% compared with 62.2%, MARINA study) and PDT (96.4% compared with 64.3%, ANCHOR study). In the PIER study, 90.2% of the 0.5 mg ranibizumab group lost fewer than 15 letters compared with 49.2% in the sham group (p < 0.0001).
Gain in visual acuity was a secondary endpoint in the studies. A third of the 0.5 mg ranibizumab group gained at least 15 letters compared with 4% of the sham injection group at 24 months in the MARINA study. In the ANCHOR trial, 40% of the 0.5 mg ranibizumab group gained at least 15 letters compared with 6% of the PDT plus sham injection group (p < 0.0001). In the FOCUS study, 24% of the 0.5 mg ranibizumab plus PDT group gained at least 15 letters compared with 5% of the sham injection plus PDT group (p = 0.0033).
The MARINA, ANCHOR and FOCUS trials all reported mean increases in visual acuity in the 0.5 mg ranibizumab group compared with baseline. The FOCUS trial reported mean gains in letters of 4.9 (0.5 mg ranibizumab plus PDT group) compared with mean losses of 8.2 letters in the sham plus PDT group. The ANCHOR study (0.5 mg ranibizumab group) reported mean gains of 11.3 letters compared with a loss of 9.5 letters in the sham plus PDT group. In the MARINA trial, mean gains in letters were 7.2 and 6.6 at 12 and 24 months, respectively, and the corresponding mean losses in the sham group were 10.4 and 14.9 letters at 12 and 24 months respectively. These results were statistically significant in all the trials.
Most adverse events were mild to moderate. Conjunctival haemorrhage was the most widely reported eye-related adverse event, but its incidence varied among the ranibizumab RCTs and it was also common in the control groups. More patients in the ranibizumab group experienced increased intraocular pressure and vitreous floaters compared with those in the sham injection group. Endophthalmitis affected about 1% and 0.7% of patients in the MARINA and ANCHOR RCTs respectively. The SPC stated that the overall incidence of arterial thromboembolic events from the MARINA, ANCHOR and PIER trials was higher for patients treated with ranibizumab 0.5 mg (2.5%) compared with the control arm (1.1%). However, in the second year of the MARINA study, the rate of arterial thromboembolic events was similar in patients treated with ranibizumab 0.5 mg (2.6%) compared with patients in the control arm (3.2%).
## Pegaptanib
The combined results of two concurrent RCTs (one carried out in the USA and Canada, the other at centres worldwide) comparing doses of 0.3 mg (licensed), 1.0 mg (unlicensed) and 3.0 mg (unlicensed) pegaptanib with sham injection were published as the VISION study. A total of 1208 patients with all types of CNV lesion were included. Patients were followed for up to 54 weeks, then for a further 48 weeks after re-randomisation.
Loss of fewer than 15 letters of visual acuity was the primary endpoint in the VISION study. Statistically significantly more patients (70%) receiving 0.3 mg (the licensed dose) pegaptanib compared with sham injection (55%) lost fewer than 15 letters of visual acuity from baseline to 54 weeks. More patients in the 0.3 mg group gained at least five letters (22%) compared with the sham injection group (12%; p = 0.004). Gains of at least 10 letters were reported for 11% of the 0.3 mg pegaptanib group compared with 6% of the sham injection group (p = 0.02). In the 0.3 mg group 6% of patients gained more than 15 letters compared with 2% in the sham group.
Mean loss of letters of visual acuity at week 54 was significantly higher in the sham injection group than in the 0.3 mg pegaptanib group. A mean loss of 7.5 letters was observed in the 0.3 mg pegaptanib group, compared with a mean loss of 14.5 letters in the sham injection group.
The VISION study reported that the proportion of people losing at least 15 letters of visual acuity from baseline after 2 years was lower for patients who stopped pegaptanib (at the licensed dose) after 1 year compared with those who had never received pegaptanib (relative risk 0.68, 95% confidence interval 0.51 to 0.90, p = 0.008). The manufacturer interpreted this as demonstrating a disease-modifying effect; if the treatment effect was exclusively symptomatic, the visual acuity of patients who discontinued treatment after 1 year would have quickly returned to that seen in the sham injection group, rather than remaining significantly better a year after stopping treatment, as observed in the study. The Assessment Group considered this to be biologically plausible because anti-VEGF drugs target the underlying pathology in AMD. However the Assessment Group also noted uncertainty in this conclusion because the decline in the proportion of people losing fewer than 15 letters from 54 weeks to 102 weeks in the VISION study was the same for patients who received pegaptanib as for those who had never received the drug (14%).
In the VISION study most adverse events reported were mild to moderate. After 1 year of treatment they were similar among treatment arms except for vitreous floaters, vitreous opacities, and anterior-chamber inflammation. Eye-related adverse events were more common in the study eye in patients in the sham injection group than in those in the 0.3 mg pegaptanib group, suggesting that the preparation procedure itself (which included an ocular antisepsis procedure and an injection of subconjunctival anaesthetic) may be associated with adverse events. Endophthalmitis affected about 1.3% of all patients in the first year. In two thirds of these cases, there had been a protocol violation (for example, failure to use aseptic technique).
# Cost effectiveness
## Published economic evaluations
The Assessment Group identified 421 publications relating to cost effectiveness in AMD. None of these were fully published economic evaluations of either ranibizumab or pegaptanib. No additional publications were identified from the manufacturers' submissions. Three conference abstracts identified and reviewed model-based evaluations of pegaptanib.
## Manufacturers' submissions
Both manufacturers provided cost-utility models. Both models were Markov state transition models, with the states being different levels of visual acuity and death. Both models assumed that only the better-seeing eye is treated. The models were based on 1 or 2 year data from randomised controlled trials, after which there was extrapolation, based on the life expectancy of the cohort, to a 10-year time horizon. Input assumptions were determined from an NHS and personal social services perspective. There was no comparison, direct or indirect, of ranibizumab and pegaptanib with each other.
The manufacturer's submission compared the use of ranibizumab with best supportive care for patients with minimally classic or occult no classic lesions, and with both PDT with verteporfin and best supportive care for patients with predominantly classic lesions. The different types of wet AMD were analysed separately based on results from RCTs (ANCHOR for comparison with PDT in predominantly classic lesions, MARINA for comparison with best supportive care in minimally classic lesions and PIER for reduced- frequency dosage in all lesion types). Because the ANCHOR trial did not include a sham injection arm, comparison between treatment with ranibizumab and best supportive care for patients with predominantly classic lesions was made through indirect comparison using data from a study (TAP) in which PDT was compared with best supportive care.
The model had five health states defined by declining visual acuity ranging from 6/15 or better (least severe) to less than 3/60 (most severe), and an additional absorbing state, death. The manufacturer's model applied a different dosing schedule from that used in the clinical trials. The MARINA and ANCHOR trials involved 24 injections over 2 years and 12 injections over 1 year respectively, but in the base-case analysis for the model, 8 injections in the first year and 6 injections in the second year were used with the assumption that the same clinical efficacy would be achieved with this lower dosing frequency.
The utility values used in the model were based on a study in which outcomes were assessed in members of the general UK population (n = 108) who experienced simulated AMD vision states using custom-made lenses. The study included a preference-based measure (HUI-3), selected questions from a visual function questionnaire and time-trade-off (TTO) by direct elicitation (Brazier study). The utility values derived using TTO by direct elicitation were stated to have a strong relationship with visual acuity and these were the utility values used in the model. The difference in mean values between the lowest and highest visual acuity groups was 0.367 (0.497 in the group with a visual acuity of less than 3/60 and 0.864 in the group with a visual acuity of 6/15 or better). These values were based on impaired vision in both eyes. However, the manufacturer argued that the relative benefits of binocular and monocular vision should be taken into account, citing a study which showed a difference in utility value of approximately 0.1 between people with good visual acuity in both eyes and people with good vision in only one eye. The manufacturer's submission also discussed utility values derived using the HUI-3 instrument (Espallargues). In this study, a utility difference of 0.02 between people with visual acuity ranging from 6/12 to 6/24 (utility value of 0.38) and people with visual acuity ranging from 6/24 to 3/60 (utility value of 0.36) was reported.
The base-case incremental cost-effectiveness ratios (ICERs) for predominantly classic lesions, assuming 1 year of treatment as per the ANCHOR RCT, were £4489 per quality-adjusted life-year (QALY) gained for ranibizumab versus PDT, and £14,781 per QALY gained for ranibizumab versus best supportive care. For occult no classic lesions, assuming 2 years of treatment, the ICER was £26,454 per QALY gained for ranibizumab versus best supportive care. Likewise, for minimally classic lesions, the ICER was £25,796 per QALY gained. For all lesion types (PIER), assuming 1 year of treatment, the ICER was £12,050 per QALY gained.
The manufacturer's model for pegaptanib compared the cost effectiveness of pegaptanib with usual care in the NHS. Usual care was identified as the best supportive care (visual rehabilitation and provision of visual aids) for all patients, with the addition of PDT with verteporfin in patients with predominantly classic lesions. The base-case analysis is based on all lesion types. The analysis was based on patient-level data from the VISION study.
The model had 12 health states, defined by visual acuity ranging from 6/10 or better to less than 3/60, and an additional absorbing state, death. Treatment was assumed to be stopped if visual acuity dropped below 6/96 or by six or more lines from baseline at the end of a year. This is referred to as scenario A. The cost effectiveness of adopting an alternative stopping rule with a higher threshold of visual acuity (6/60) for stopping pegaptanib treatment, labelled scenario B, is also reported in the submission. Cycle length in the model is 6 weeks.
The utility values used in the model were based on a study of health-related quality of life in AMD patients (Brown study, n = 80). The utility values were derived by direct elicitation using both the standard gamble and TTO methods. In multivariate linear regression analysis, the TTO method produced a higher correlation with visual acuity than the standard gamble approach. The difference in mean TTO values between the lowest and highest visual acuity groups was 0.49 (0.40 in the group with a visual acuity of less than 3/60 and 0.89 in the group with a visual acuity of 6/12 or better).
In the base case, the ICER was £15,819 per QALY gained for scenario A and £14,202 per QALY gained for scenario B. Results of sensitivity analyses carried out by the manufacturer showed that the costs and probabilities of receiving visual impairment services and the model time horizon had a significant effect on the ICERs.
## The Assessment Group model
The Assessment Group's model evaluated the cost effectiveness of ranibizumab and pegaptanib compared with current practice (PDT with verteporfin for classic no occult lesions or predominantly classic lesions, and best supportive care for all lesion types). The transitions between states in the model were based on RCT data, noting that the endpoints in the RCTs fell broadly into three clinically accepted endpoints; loss of less than 15 letters, intermediate vision loss (loss of 15–30 letters) and severe vision loss (loss of more than 30 letters). The estimated impact of these changes in visual acuity on the cost effectiveness of ranibizumab and pegaptanib was estimated using a Markov state transition model. The model assumes that only the better-seeing eye is treated.
A six-state Markov model was developed and the rate of disease progression was modelled as the probability of progressing to a different level of visual acuity health state in each model cycle. The model extrapolated the effects of the 2-year trial period (or 1 year for ranibizumab in predominantly classic lesions) to 10 years in both arms of the model. Ranibizumab and pegaptanib treatments are assumed to have stopped at the end of year 2, and thereafter benefits were assumed to decline at the same rate as those for usual care, although from a higher level of visual acuity.
Where possible, the Assessment Group used routinely available unit cost estimates, that is NHS reference costs and unit costs of community care, in its economic analyses. Resources and costs incorporated in the Assessment Group model included those for treatment, administration, monitoring, managing adverse events and blindness. Costs related to blindness included the administrative cost of registering as blind or partially sighted, and the cost of low vision aids, low vision rehabilitation, community care, residential care, treatment of depression and hip replacement. In the base case it was assumed that all injections would be carried out as outpatient procedures at a unit cost of £90.20. In sensitivity analyses, it was assumed that all injections would be carried out as day-case procedures at a unit cost of £395, or that the cost of administering the injection would be a mix of day case (75%) and outpatient (25%) costs.
Health state utility values derived using TTO by direct elicitation from patients with AMD (Brown study, n = 80, see section 4.2.2.8) were used because the Assessment Group considered these to be the most credible published utility values for visual loss associated with AMD.
The Assessment Group's base-case ICERs over a 10-year time horizon for predominantly classic lesions assuming 1 year of treatment were £15,638 per QALY gained compared with PDT, and £11,412 per QALY gained compared with best supportive care. For minimally classic lesions and occult no classic lesions, assuming 2 years of treatment, they were £25,098 per QALY gained compared with best supportive care.
The Assessment Group carried out sensitivity analyses of different assumptions used in their model. The results for ranibizumab showed that as the time horizon decreased the ICERs increased.
In one-way sensitivity analyses, for predominantly classic lesions, reducing the number of injections from 12 to 9 in the first year of treatment reduced the ICER from £15,638 to £6,897 per QALY gained compared with PDT and from £11,412 to £6,087 per QALY gained compared with best supportive care. For patients with minimally classic and occult no classic lesions, with a treatment duration of 2 years (as per the MARINA trial protocol), reducing the number of injections in the first year of treatment from 12 to 9 (with a further reduction from 12 to 6 injections in year 2) reduced the ICER considerably from £25,098 to £12,649 per QALY gained compared with best supportive care. In these analyses, it was assumed that the QALY gain would not differ with changes in the number of injections.
In one-way sensitivity analyses in which the injections were costed as day-case rather than outpatient procedures, the ICERs increased. The ICER increased from £15,638 to £26,102 per QALY gained compared with PDT and from £11,412 to £17,787 per QALY gained compared with best supportive care. For patients with minimally classic and occult no classic lesions, the ICER increased from £25,098 to £35,157 per QALY gained compared with best supportive care.
The cost-effectiveness estimates were sensitive to assumptions over uptake of visual support services (estimated as the proportion of patients with visual acuity of less than 6/60 receiving services). Using high uptake and high unit-cost estimates resulted in ranibizumab being economically dominant (with a lower cost and better outcome) compared with either PDT or best supportive care for patients with predominantly classic lesions. However, when low costs and medium uptake assumptions were used in one-way sensitivity analyses, the ICERs increased from £15,638 to £19,967 per QALY gained for predominantly classic lesions compared with PDT, and from £11,412 to £16,281 per QALY gained for predominantly classic lesions compared with best supportive care. For minimally classic lesions, the ICER increased from £25,098 to £29,446 per QALY gained.
In sensitivity analyses, varying the distribution of initial visual acuity had very little effect on the ICERs for ranibizumab. For example, for minimally classic lesions compared with best supportive care, a cohort equally split between the 6/12–6/24 and 6/24–6/60 states produced an ICER of £25,179 per QALY gained, whilst a cohort with initial visual acuity of 6/24–6/60 produced an ICER of £25,268 per QALY gained.
In probabilistic sensitivity analyses using the base-case assumptions, for patients with predominantly classic lesions compared with PDT, ranibizumab had a probability of being cost effective of 72% at a willingness to pay of £20,000 per QALY gained and 97% at a willingness to pay of £30,000 per QALY gained. For patients with predominantly classic lesions compared with best supportive care, ranibizumab had a probability of being cost effective of 95% at a willingness to pay of £20,000 per QALY gained and 99% at a willingness to pay of £30,000 per QALY gained. For patients with minimally classic and occult no classic lesions, for the base-case analysis ranibizumab had a probability of being cost effective (compared with best supportive care) of 15% at a willingness to pay threshold of £20,000 per QALY gained and 81% at a willingness to pay threshold of £30,000 per QALY gained.
The Assessment Group estimated the base-case ICER for pegaptanib (all lesion types) compared with usual care to be £30,986 per QALY gained over a 10-year time horizon.
The Assessment Group carried out sensitivity analyses of different assumptions used in their model. As with ranibizumab, the results for pegaptanib showed that decreasing the time horizon increased the ICERs. The ICER was also sensitive to the costs of blindness, in particular the uptake of services, estimated as the proportion of patients with visual acuity of less than 6/60 receiving services. Using high uptake and high unit-cost estimates resulted in pegaptanib being economically dominant (with a lower cost and better outcome) compared with usual care. However, when low costs and medium uptake assumptions were used, the ICER increased from the base case of £30,986 to £37,154 per QALY gained.
In another sensitivity analysis, a higher cost was assumed for providing all injections as a day-case procedure and the ICER for pegaptanib increased from the base case of £30,986 to £47,845 per QALY gained compared with best supportive care.
The Assessment Group also performed a sensitivity analysis to explore the assumption of a potential disease-modifying effect of pegaptanib. This relative risk reduction (see section 4.1.10) was applied to the estimated transition probabilities for losing three to six lines and losing more than six lines of visual acuity in the sensitivity analyses. When this relative risk reduction was applied to the Assessment Group model in year 3 (that is, for one year following cessation of treatment), the ICER decreased from £47,845 (using the day-case injection cost assumption, see 4.2.3.14) to £42,198 per QALY gained compared with best supportive care.
When the distribution of initial visual acuity was varied in sensitivity analyses, a cohort equally split between the 6/12–6/24 and 6/24–6/60 states produced an ICER of £35,913 per QALY gained, while a cohort with initial visual acuity of 6/24–6/60 produced an ICER of £46,285 per QALY gained compared with best supportive care.
In probabilistic sensitivity analyses using the base-case assumptions, pegaptanib had a probability of being cost effective (compared with usual care) of 17% at a willingness to pay of £20,000 per QALY gained and 58% at a willingness to pay of £30,000 per QALY gained using the base-case assumptions.
## Further analysis by the Assessment Group and the Decision Support Unit
After considering the responses from consultation, the Committee requested additional analysis from the Assessment Group and the Decision Support Unit. The Assessment Group explored alternative assumptions for the main drivers of the economic model: namely the costs of blindness, the costs of administering the injections, the number of injections of ranibizumab, and the utility values used in the analysis. The Decision Support Unit provided similar analyses using the manufacturer's model for pegaptanib; this was requested because the manufacturer's model enabled consideration of differential treatment effects by subgroup of baseline visual acuity, based on patient-level data to which the Assessment Group did not have access.
The Assessment Group explored the cost of treating the first eye to come to clinical attention rather than treating only the better-seeing eye. The analysis assumed an annual incidence of AMD in the second eye of 10% and explored a number of different scenarios. It found that for ranibizumab the additional cost of treating two eyes ranged from about £9,900 to about £28,600, depending on the number of injections (9 to 24) over 2 years. For pegaptanib, the additional cost of treating two eyes ranged from about £9,100 to about £15,700.
In one-way sensitivity analyses on the costs of blindness, the Assessment Group found that the alternative assumptions derived from consultation responses were very similar to those used in the original Assessment Group report. The Assessment Group noted that the level of uptake of community services (that is, the proportion of people who are blind and receiving community care services) had a much greater effect on the ICERs than other components of the costs of blindness. Therefore sensitivity analyses focused on varying this proportion from 6% to 17% or 25%.
In a one-way sensitivity analysis the Assessment Group used alternative utility values to its base case. This was a set of utility values estimated to be equivalent to those derived in the Brazier study, but adapted for the visual acuity states in the Assessment Group model (which were slightly different from those in the Brazier study). The difference in mean values between the lowest and highest visual acuity groups was 0.382 (0.518 in the group with a visual acuity of less than 3/60 and 0.900 in the group with a visual acuity of 6/12 or better).
The Assessment Group also explored the cumulative impact on the ICER of the following assumptions, which were preferred by the Committee to the original base case: alternative utility values (Brazier study), splitting the cost of administering the injection between day-case (75%) and outpatient (25%) costs and higher uptake of community care services (from 6% to 17% or 25%). When the Brazier utilities were used, the ICER for ranibizumab for predominantly classic lesions increased from the base case of £15,638 to £19,491 per QALY gained compared with PDT, and from the base case of £11,412 to £14,388 per QALY gained compared with best supportive care; for minimally classic and occult no classic lesions the ICER increased from the base case of £25,098 to £31,966 per QALY gained compared with best supportive care. When the costs of administering the injection were split between day-case (75%) and outpatient (25%) costs, the ICER for ranibizumab for predominantly classic lesions was £29,272 per QALY gained compared with PDT and £20,416 per QALY gained compared with best supportive care; for minimally classic lesions the ICER was £41,575 per QALY gained compared with best supportive care. In addition, when the uptake of community care was assumed to increase from 6% (base case) to 25%, the ICER for ranibizumab for predominantly classic lesions decreased to £26,425 per QALY gained compared with PDT, and to £17,175 per QALY gained compared with best supportive care; for minimally classic lesions the ICER was £38,659 per QALY gained compared with best supportive care.
The Assessment Group also explored the cost effectiveness of ranibizumab in predominantly classic lesions assuming two years of treatment, whereas previously one year of treatment was assumed. Assuming 12 injections in each year, this increased the ICERs from the cumulative scenario described in section 4.2.4.5 from £26,425 to £37,489 per QALY gained for ranibizumab compared with PDT, and from £17,175 to £23,887 per QALY gained for ranibizumab compared with best supportive care.
Finally, in addition to the cumulative assumptions described in sections 4.2.4.5 and 4.2.4.6, but instead assuming that only 14 injections would be required over two years to attain the same clinical benefit without reducing the frequency of monitoring costs, the ICER for ranibizumab for predominantly classic lesions further decreased from £37,489 to £13,671 per QALY gained compared with PDT, and from £23,887 to £9,900 per QALY gained compared with best supportive care. For minimally classic or classic no occult lesions the ICER decreased from £38,659 to £19,904 per QALY gained compared with best supportive care.
For pegaptanib, the Decision Support Unit used the manufacturer's model to reproduce the manufacturer's finding that the cost per QALY gained for pegaptanib treatment is lower in subgroups with better baseline visual acuity using all the Committee's preferred assumptions. The lowest cost per QALY gained was obtained in a subgroup of people with visual acuity between 6/12 and 6/24. When the inputs outlined in section 4.2.4.4 were cumulatively considered in the manufacturer's model, the ICER was £23,124 per QALY gained in the 6/12 to 6/24 subgroup compared with best supportive care, £40,627 per QALY gained for the 6/24 to >6/60 subgroup, £115,244 per QALY gained for the 6/60 to >3/60 subgroup, and £34,602 per QALY gained for the whole cohort. Using the same set of assumptions, the ICER from the Assessment Group model was £44,259 per QALY gained for the whole group irrespective of visual acuity levels.
# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ranibizumab and pegaptanib for the treatment of wet AMD, having considered evidence on the nature of the condition and the value placed on the benefits of these drugs by people with wet AMD, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.
The Committee considered the clinical effectiveness evidence. It discussed the results for loss of fewer than 15 letters of visual acuity, which was the primary outcome of all the RCTs. It noted that the effect size was greater for all lesion types in the ranibizumab studies than in the pegaptanib studies. The Committee concluded that both pegaptanib and ranibizumab reduce loss of visual acuity compared with sham injection, and ranibizumab reduces loss of visual acuity compared with PDT in patients with predominantly classic lesions.
The Committee discussed the RCT results for gain in visual acuity, recognising the importance of this to patients with AMD. It noted that there were differences between ranibizumab and pegaptanib in the RCT data for this endpoint. In the ranibizumab trials, there was a substantial increase in the proportion of patients gaining 15 or more letters of visual acuity, whereas for pegaptanib relatively few patients gained 15 letters or more compared with control. The Committee also discussed the RCT results on mean change in visual acuity, reported as the mean number of letters lost or gained in the treatment groups compared with the control arms. Results showed that there were statistically significant mean gains of letters for ranibizumab whereas pegaptanib reduced only the mean loss of letters. The Committee concluded on the basis of the RCT evidence that ranibizumab is more clinically effective than pegaptanib in improving visual acuity.
The Committee considered the licensed dosing regimen for ranibizumab compared with that used in the main RCTs. It understood that the rationale for the regimen in the marketing authorisation was based on evidence from a drug and disease model submitted by the manufacturer indicating that the beneficial effects of ranibizumab peak after three injections at 3 months, after which a plateau of effect is reached, and that continued monthly injections may not be necessary in all patients to maintain this benefit. It was concerned that the results of the PIER trial, in which injections were given less frequently (3-monthly) to all patients after the third month, showed ranibizumab to be less effective than in the MARINA and ANCHOR trials in which monthly injections (24) were given. The Committee noted the results of a further study, PrONTO, which suggested that clinical benefit may be maintained with a lower average number of injections per patient, if injections are given more or less frequently depending on visual acuity and on a measure of response on optical coherence tomography (a regimen similar to that in the marketing authorisation). However, it noted that PrONTO was a small, uncontrolled study investigating only a subset of patients with wet AMD. The Committee concluded that there was some uncertainty about the number and frequency of injections required to achieve the results seen in the MARINA and ANCHOR trials.
The Committee discussed the adverse events associated with the use of the anti-VEGF agents. The Committee heard from clinical specialists that ranibizumab and pegaptanib have broadly similar adverse-event profiles, that most adverse events are manageable and that serious ones are rare. The Committee considered the data listed under 'undesirable effects' in the SPC showed that the overall incidence of arterial thromboembolic events from the MARINA, ANCHOR and PIER trials was higher for patients treated with ranibizumab compared with the control group, but that in the second year of the MARINA study the rate of arterial thromboembolic events was similar in patients treated with ranibizumab and patients in the control arm. The Committee concluded that ranibizumab and pegaptanib have broadly similar adverse-event profiles; most adverse events are manageable and serious ones are rare. It noted that the costs of adverse events were included in the Assessment Group model.
The Committee considered whether the clinical effectiveness of the two anti-VEGFs (ranibizumab and pegaptanib) varied by lesion type. It noted that, in the ranibizumab RCTs, the effects in patients who had predominantly classic lesion types were similar to those in patients with minimally classic and occult no classic lesion types. The Committee heard that in clinical practice anti-VEGF treatment results in similar effects across all lesion types. It heard from clinical specialists that although the classification by lesion type is relevant to laser-based treatments where there is a need to delineate the margins of CNV, such classification is not relevant to the use of anti-VEGFs. The Committee concluded that anti-VEGF treatments were clinically effective across lesion types.
The Committee considered whether the clinical effectiveness of the anti-VEGFs varied between subgroups defined according to baseline visual acuity. It noted that in the Assessment Group's model, treatment effect and rate of deterioration of vision were assumed to be independent of baseline visual acuity, but the model submitted by the manufacturer of pegaptanib assumed greater clinical benefits to be associated with better baseline vision. The Committee considered it to be plausible that people with better pre-treatment visual acuity are likely to benefit more from treatment than those with lower pre-treatment visual acuity. This could be, for example, because wet AMD lesions that have caused greater deterioration in visual acuity are also more likely to have caused permanent structural damage, which reduces response to anti-VEGF treatment.
The Committee discussed key assumptions affecting the cost-effectiveness analysis of the treatments. These were the:
duration of treatment
frequency of injections of ranibizumab that would be required to maintain response in clinical practice
extrapolation of treatment benefit associated with anti-VEGF treatment beyond the duration of the RCTs, including consideration of any disease-modifying effect
utility values used in the economic model
costs related to blindness (defined as visual acuity less than 6/60 for those registered as partially sighted and 3/60 for those registered as blind), including low-vision aids, visual rehabilitation and community care
costs of adequate facilities and staffing for intravitreal injection
cost effectiveness of anti-VEGF treatment in the first-affected eye.
The Committee discussed the assumption of treatment duration being limited to 2 years. It understood that CNV may recur after cessation of treatment, and heard from some consultees that rapid deterioration of vision after treatment cessation was sometimes observed. It heard from clinical specialists that it was unclear how long treatment would be continued in practice, that there was an evolving evidence base, and that for some patients it would be appropriate to continue treatment beyond 2 years into the third or even fourth year. This would result in additional drug, administration and monitoring costs, which were not included in any of the economic models.
The Committee also noted that for economic modelling of predominantly classic lesion types with ranibizumab, the Assessment Group model was based on only 1 year of treatment (in keeping with the ANCHOR study), while for ranibizumab in minimally classic and occult no classic lesions, and for pegaptanib for all lesion types, 2 years of treatment had been modelled (in keeping with the MARINA and VISION studies). The Committee believed that the scenario in which the Assessment Group had estimated the ICER for 2 years of treatment in predominantly classic lesions would be more appropriate, noting that the duration of treatment was not expected to vary by lesion type in clinical practice and could extend beyond 2 years (see sections 4.3.6 and 4.3.9).
The Committee discussed assumptions for the frequency of ranibizumab injection, bearing in mind the issues discussed in section 4.3.4. It noted that the drug dosing model presented by the manufacturer had been accepted by the European Medicines Agency (EMEA) as a basis for the regimen in the marketing authorisation. It noted that the model assumed that the individualised dosing would result in stable visual acuity for the majority of the patients, with a mean of 8 injections required in the first year followed by a mean of 6 injections in the second year. It noted, based on comments from clinical specialists and from consultees including the Royal College of Ophthalmologists, that such a dosing model was likely to be frequently borne out in practice. However, the Committee remained concerned about the assumption that the benefit achieved in the pivotal trials could be matched if injections were less frequent.
Taking into account its considerations over the required frequency of ranibizumab injections (as in section 4.3.10) and that treatment may continue beyond 2 years for some patients (as in section 4.3.9), the Committee concluded that on balance it would be reasonable to consider an assumption of a total of 24 injections of ranibizumab. In other words the Committee considered that although 24 injections over 2 years may be an overestimate, the assumption that no one would receive further injections after 2 years was not probable.
The Committee further noted that there was no evidence to ascertain how benefits would accrue in the long term if treatment is stopped after 2 years, as assumed in all three economic models. There is therefore great uncertainty in appraising the validity of extrapolations made in the models. The approach used in the Assessment Group model was to assume that benefits of treatment would gradually decline at the same rate as for the usual care cohort, although starting at a higher visual acuity – that is, retaining higher visual acuity levels over the control arm throughout the 10-year time horizon. The Committee concluded that this approach would be reasonable to accept as a basis for decision-making.
The Committee also noted that a disease-modifying effect had been suggested for pegaptanib. It accepted that such an effect was plausible, but not for a lifetime duration after treatment had stopped. It was persuaded that it was reasonable to infer that there was some effect for a year after stopping treatment. It therefore concluded that pegaptanib could be assumed to slow disease progression for a year after stopping treatment with the drug, but that thereafter progression was at the same rate as in the control arm.
The Committee discussed the utility values used in the models. It noted that the Assessment Group and the manufacturer for pegaptanib used utilities derived from AMD patients (Brown study), whilst the manufacturer for ranibizumab used utilities derived from the general population (Brazier study). Both sets of utility values had been derived using TTO direct elicitation. The Committee considered that in principle it is more appropriate to use utility values derived using a standardised and validated generic (non-disease-specific) instrument, such as the EQ-5D or HUI-3. It noted the utility values derived using HUI-3 (Espallargues) which reported a utility difference of 0.02 between two health states with markedly different visual acuities. The Committee agreed that this measure may therefore not fully capture the impact of AMD on patients' quality of life. The Committee concluded that on balance, the Brazier utility values provided the most plausible set of utility values for use in the economic models.
The Committee discussed the assumptions about costs related to blindness (such as registration, low-vision aids and rehabilitation). It heard from consultees that the assumptions in the Assessment Group base case were low, if not for standard practice, then for best practice. The Committee considered sensitivity analyses in the assessment report using high uptake and high costs of blindness and noted that these resulted in significant reductions in the ICERs for both drugs. The Committee decided that it was unrealistic to accept the extreme high or low uptake rates and costs of blindness presented in the sensitivity analysis in the assessment report. In addition, the Committee considered that for those patients who retained good to normal visual acuity in one eye, the absolute cost of 'blindness' would be proportionately lower than in those patients in whom both eyes were affected. Taking these factors into account, the Committee concluded that an appropriate assumption about the costs of blindness would lie between the Assessment Group base case and the combined high-uptake, high-cost scenario.
The Committee discussed the assumptions in the models for the costs of administering intravitreal injections. The Committee heard from clinical specialists that the costs of appropriate facilities and staffing for intravitreal injection were higher than had been assumed in the base case (NHS reference cost of £90.20 for an outpatient procedure) because provision had to be made for sterile conditions. It noted an analysis based on the NHS reference cost of £395 for a day-case procedure. The Committee also considered an additional analysis in which the Assessment Group estimated costs based on the Royal College of Ophthalmologists' commissioning guidelines for provision and treatment of AMD with anti-VEGFs. This analysis showed that the costs based on the Royal College of Ophthalmologists' guidelines were higher than for day-case procedures. The Committee considered the conflicting information available on the cost of administering intravitreal injections, and was persuaded by comments received during consultation that in practice, for the foreseeable future, a mixture of day-case and outpatient procedures would occur. It concluded that a reasonable approach would be to assume that the costs of administering intravitreal injections were equivalent to a mix of 75% of the cost of a day case procedure and 25% of the cost of an outpatient procedure.
The Committee discussed whether it would be appropriate to consider recommending treatment in the better-seeing eye only: that is, not to treat where patients present with only one eye affected. It noted the concerns raised by consultees and understood that most consultees felt that it would be unacceptable, and clinically inappropriate, not to treat the first eye that comes to clinical attention. It was persuaded that any other scenario could result in losing the opportunity to preserve vision because the untreated better-seeing eye could subsequently be affected by an untreatable cause of vision loss, or might not respond to treatment with anti VEGFs. With all these issues in mind the Committee concluded that its considerations of cost effectiveness should relate to starting treatment with the first eye to present clinically.
The Committee discussed the cost effectiveness of treating the first eye affected by AMD even while good (albeit) monocular vision was available from an unaffected eye. Firstly it noted that patients' quality of life was strongly correlated with, and mainly driven by, vision in the better-seeing eye. The Committee noted, however, that loss of normal binocular vision can result in a reduction in quality of life. It understood, for example, that there would be considerable anxiety and depression associated with allowing an eye known to be affected with AMD to deteriorate without treatment. It noted one study cited by the manufacturer of ranibizumab, in which the difference in utility between having 6/6 vision in both eyes, and having 6/6 vision in one eye but 6/12 or worse in the other eye, was approximately 0.1. The Committee noted that this utility difference was substantially smaller than that between very good and very poor vision in the better-seeing eye (approximately 0.4 or 0.5 if Brazier or Brown utility values are used, respectively). Secondly, the Committee considered that for those patients who retained good to normal visual acuity in one eye, the savings in costs of 'blindness' would be considerably lower than in those patients with poor vision in both eyes.
The Committee discussed the proportion of patients who presented with AMD when only one eye was affected with the condition. It noted estimates from clinical specialists and consultees that about 70% of patients present with both eyes affected by AMD and that the standard approach is to treat the better-seeing eye if there is wet AMD in both. Of the 30% presenting with one eye affected, it noted estimates that about 10% per year (and 40% after 5 years) develop the disease in the second eye.
The Committee noted that the economic modelling was carried out assuming that the better-seeing eye was treated. A policy of treating the first eye to come to clinical attention would result in substantially higher costs, but fewer savings and lower utility gains, than a policy of only treating the better-seeing affected eye. The Committee estimated that treatment for the first eye yields an 80% lower QALY gain than for treating the better-seeing eye. In addition there would be reduced savings on costs of blindness. Based on this the Committee agreed that an expected cost per QALY for a first-eye strategy would be about 50% higher than that for treating the better-seeing affected eye. It concluded that the ICERs for pegaptanib or ranibizumab would not fall within a range considered to be a cost-effective use of NHS resources using the assumptions outlined in 4.2.4.5 and 4.2.4.6 and assuming a strategy of treating the first-affected eye.
The Committee discussed the number of injections of ranibizumab assumed in the model. It noted that if 8 injections were required in the first year and 6 in the second, as suggested by consultees (see section 4.3.10), the ICERs for the different lesion types would be £13,671, £9,900 and £19,904 per QALY gained depending on lesion type and comparator, as detailed in section 4.2.4.7. These figures assume that only the better-seeing eye is treated. Applying a 50% increase in these ICERs to include the treatment of the first eye, these ICERs would become approximately £20,500 and £14,800 per QALY gained in predominantly classic lesions compared with best supportive care and PDT respectively, and £29,900 in minimally classic or classic no occult lesions compared with best supportive care. However, the Committee considered that many patients would be likely to require more injections than this to maintain benefit. It discussed a proposal by the manufacturer in their response to consultation that the number of ranibizumab injections for which drug costs are paid by the NHS could be capped, with any remaining ranibizumab drug costs paid for by the manufacturer. It noted that the feasibility and administrative burden on the NHS of such a scheme would need to be considered in appraising the cost effectiveness of ranibizumab within such a scheme. Additionally, continued administration and monitoring costs would also need to be considered as patients would require regular re-assessment on a monthly basis to monitor the progress of their disease. The Committee noted that these costs were not included in the modelling, but estimated that ranibizumab was likely to be cost effective if the cost to the NHS was limited such that the manufacturer pays for the drug cost of ranibizumab beyond 14 injections in the treated eye.
The Committee then reconsidered the economic modelling undertaken for pegaptanib compared with best supportive care after taking into account the following assumptions: disease-modifying effect up to 1 year after cessation of treatment ('year 3'), higher costs of blindness, costs of administering the injection as 75% day case and 25% outpatient, use of Brazier utility values, and 25% uptake of community care. In the Assessment Group model, this resulted in an ICER of £44,259 per QALY gained using a better-seeing eye strategy. Applying a 50% increase in these ICERs to include the treatment of the first eye, this ICER would become approximately £66,400 per QALY gained. The Committee also noted that the manufacturer's model produced a lower ICER of £34,602 per QALY gained based on the same assumptions using a better-seeing eye strategy, corresponding to approximately £51,900 per QALY gained when there is a policy of treating the first eye to come to clinical attention.
The Committee further considered that there could be differential gains from pegaptinib for different subgroups of patients according to their starting visual acuity. The Committee considered the position of the different subgroups with reference to cost effectiveness and to whether there were any steps which the Committee should take to fulfil NICE's duties under the equalities legislation. It considered whether it would be appropriate to recommend pegaptanib for a specific subgroup. It noted that focusing on the most responsive subgroup resulted in lower ICERs. The Committee noted that, after considering all its preferred assumptions, the ICERs were: £23,124 per QALY gained for the 6/12 to 6/24 visual acuity subgroup; £40,627 per QALY gained for the 6/24 to >6/60 subgroup; and £115,244 for the 6/60 to >3/60 visual acuity subgroup. Applying a 50% increase in these ICERs to include the treatment of the first eye, these ICERs would become approximately £34,700, £60,900 and £172,900 per QALY gained respectively. The Committee thus concluded that for all visual acuity subgroups, pegaptanib was not a cost-effective use of NHS resources. It concluded that there was no impact on any particular group of patients that required particular action in order to comply with the Institute's obligations under the equalities legislation. The Committee noted that ranibizumab would be recommended as a treatment option for the whole of the patient group.
The Committee discussed criteria for starting therapy with anti-VEGF treatments. It was in agreement in general with the criteria set out in the clinical trials for both drugs in terms of best-corrected visual acuity, no permanent structural damage to the central fovea, the lesion size being less than or equal to 12 disc areas in greatest linear dimension and that there is evidence of recent presumed disease progression as shown by blood vessel growth or visual acuity changes. The Committee was aware that to ensure the presence of wet AMD, it was essential that these criteria were met. The Committee also considered when treatment should be recommended as an option in terms of baseline visual acuity. It noted that the population in the clinical evidence base had a corrected visual acuity between 6/12 and 6/96, and that there was no evidence from ranibizumab studies that would allow consideration of differences in clinical and cost effectiveness between subgroups with different baseline visual acuity. The Committee therefore concluded that it would be appropriate for treatment with ranibizumab to be recommended at a visual acuity range between 6/12 and 6/96.
The Committee discussed the issue of discontinuing therapy. It noted the lack of a formal clinical guideline in this area, but thought it was important that continuation of treatment be carefully considered by patients and their clinicians. It discussed suggestions from clinical specialists for criteria for defining a loss of adequate response and concluded that a clear protocol for discontinuation in people who have a loss of adequate response to therapy should be developed. It thought that such a protocol should specify criteria for discontinuation, which are likely to include persistent deterioration in visual acuity and identification of anatomical changes in the retina that indicate inadequate response to therapy. The Committee thought that the most appropriate body to develop this protocol would be the Royal College of Ophthalmologists. Until such a protocol is developed it is recommended that locally agreed protocols be used. The Committee also noted that there could be a long gap between one dose and the need for the next dose. It concluded that in this situation treatment should be considered as continuous regardless of whether a patient had been discharged from a clinic in between doses.
In summary, the Committee concluded that both pegaptanib and ranibizumab are clinically effective in the treatment of wet AMD, but that ranibizumab is associated with greater clinical benefit. It concluded that treatment with ranibizumab of the eye to be treated would be cost effective if the manufacturer pays for the drug cost of ranibizumab beyond 14 injections in the treated eye. The Committee further concluded that treatment with pegaptanib for wet AMD is not a cost-effective use of NHS resources.# Recommendations for further research
The Appraisal Committee considered that further research into the effectiveness of anti-VEGFs in wet AMD could include studies:
about the cost effectiveness of ranibizumab compared with bevacizumab
to investigate the long-term effects of anti-VEGFs in patients with AMD, including effects on visual acuity, anatomical damage to the macula, quality of life and adverse events
to establish the appropriate duration and optimal treatment regimen in terms of frequency of injections.# Related NICE guidance
Guidance on the use of photodynamic therapy for age-related macular degeneration. NICE technology appraisal 68 (2003).# Review of guidance
The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.
The guidance on this technology will be considered for review in February 2014.
Andrew DillonChief ExecutiveAugust 2008# Changes after publication
February 2014: implementation section updated to clarify that ranibizumab and pegaptanib are recommended as options for treating age-related macular degeneration. Additional minor maintenance update also carried out.
March 2012: minor maintenance
May 2012: re-issued after a change to the patient access scheme# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE multiple technology appraisal process. It has been re-issued after a change to the patient access scheme in May 2012. Recommendation 1.1 and section 5.3 have been updated.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'This guidance has been re-issued after a change to the patient access scheme in May 2012. See About this guidance for more information.\n\nRanibizumab, within its marketing authorisation, is recommended as an option for the treatment of wet age-related macular degeneration if:\n\nall of the following circumstances apply in the eye to be treated:\n\n\n\nthe best-corrected visual acuity is between 6/12 and 6/96\n\nthere is no permanent structural damage to the central fovea\n\nthe lesion size is less than or equal to 12 disc areas in greatest linear dimension\n\nthere is evidence of recent presumed disease progression (blood vessel growth, as indicated by fluorescein angiography, or recent visual acuity changes)and\n\n\n\nthe manufacturer provides ranibizumab with the discount agreed in the patient access scheme (as revised in 2012).\n\nIt is recommended that treatment with ranibizumab should be continued only in people who maintain adequate response to therapy. Criteria for discontinuation should include persistent deterioration in visual acuity and identification of anatomical changes in the retina that indicate inadequate response to therapy. It is recommended that a national protocol specifying criteria for discontinuation is developed.\n\nPegaptanib is not recommended for the treatment of wet age-related macular degeneration.\n\nPeople who are currently receiving pegaptanib for any lesion type should have the option to continue therapy until they and their clinicians consider it appropriate to stop.', 'Clinical need and practice': "Age-related macular degeneration (AMD) is an eye condition that leads to a progressive loss of central vision. People retain some peripheral vision, but the ability to see well enough to recognise faces, drive and read is affected, and vision can deteriorate rapidly.\n\nAMD occurs in two forms, dry and wet AMD. Dry AMD (non-neovascular) is a form of extensive atrophy (wasting) of cells that progresses slowly, whereas the wet form can lead to a rapid worsening of vision. Wet (neovascular) AMD is characterised by the development of immature blood vessels that grow between the retinal pigment epithelial cells and the photoreceptor cells in the centre of the retina, a process known as choroidal neovascularisation (CNV). These vessels easily haemorrhage and cause lesions on the macula, leading to visual impairment. A protein known as vascular endothelial growth factor (VEGF), which induces new blood vessel formation (angiogenesis), vascular permeability and inflammation, has been implicated in the development and progression of CNV. CNV can be subdivided into classic and occult forms according to its appearance on investigation by fluorescein angiography. A mixture of classic and occult CNV can occur in the same lesion. CNV can also be described in terms of its location: the fovea is the central part of the macula, and CNV that develops below the foveal area is termed 'subfoveal CNV'.\n\nThere are about 26,000 new cases of wet AMD in the UK each year and the condition affects more women than men. The condition usually affects people who are over 50\xa0years old and the risk increases significantly with age. The most commonly cited risk factor for AMD is cigarette smoking; the risk of developing AMD is 3.6 times greater for current and former smokers than for people who have never smoked.\n\nPatient management consists of social support, visual rehabilitation and the provision of aids to help with low vision. However, in the 20% of patients with classic no occult subfoveal CNV and a best-corrected visual acuity of 6/60 or better, photodynamic therapy (PDT) is an option. Visual acuity of 6/60 means that the patient can only see from a distance of 6\xa0metres or less what someone with normal vision can see from 60\xa0metres away. PDT involves injecting verteporfin, a photosensitive drug that remains in the new blood vessels in the eye. This is followed by treatment with a low-powered laser, which activates the drug causing cell death. The aim is to destroy the CNV lesions without damaging the retina, thereby halting or reducing progressive loss of vision. PDT does not prevent new vessels forming: it only treats established pathological vessels. More recently, drugs that inhibit the action of VEGF have been developed for the treatment of wet AMD.", 'The technologies': '# Ranibizumab\n\nRanibizumab (Lucentis, Novartis) is a humanised therapeutic antibody fragment that binds to VEGF-A isoforms of VEGF thereby preventing binding of VEGF-A to receptors VEGFR-1 and VEGFR-2.\n\nRanibizumab has a UK marketing authorisation for the treatment of neovascular (wet) AMD. It is administered through intravitreal injection at a recommended dose of 0.5\xa0mg. Treatment is started with a loading phase of one injection per month for 3 consecutive months, followed by a maintenance phase in which patients are monitored monthly for visual acuity. If the patient experiences a loss of greater than five letters in visual acuity (on the Early Treatment Diabetic Retinopathy Study [ETDRS] chart or one Snellen line equivalent) during this maintenance phase, a further dose of ranibizumab should be administered. The interval between two doses should not be shorter than 1\xa0month.\n\nThe summary of product characteristics (SPC) states that adverse events commonly associated with ranibizumab include conjunctival haemorrhage, eye pain, vitreous floaters, retinal haemorrhage, increased intraocular pressure, vitreous detachment, intraocular inflammation, eye irritation, cataract, foreign body sensation in the eyes, visual disturbance, blepharitis, subretinal fibrosis, ocular hyperaemia, blurred/decreased visual acuity, dry eye and vitreitis. For full details of side effects and contraindications, see the SPC.\n\nThe cost of a ranibizumab injection is £761.20 (excluding VAT; British national formulary [BNF] 54th edition). The 2-year cost of ranibizumab is about £10,700 assuming 8\xa0injections in the first year and 6\xa0injections in the second year, and about £18,300 assuming 12\xa0injections in the first year and another 12 in the second year as per clinical trial regimen. Costs may vary in different settings because of negotiated procurement discounts.\n\n# Pegaptanib\n\nPegaptanib (Macugen, Pfizer) is a pegylated modified oligonucleotide that binds to VEGF-165 and inhibits its activity.\n\nPegaptanib has a UK marketing authorisation for the treatment of neovascular (wet) AMD. It is administered at 0.3\xa0mg once every 6\xa0weeks (9 injections per year) by intravitreal injection into the affected eye.\n\nThe SPC states that adverse events commonly associated with pegaptanib are anterior chamber inflammation, eye pain, increased intraocular pressure, punctate keratitis, vitreous floaters and vitreous opacities. For full details of side effects and contraindications, see the SPC.\n\nThe cost of pegaptanib is £514.00 per injection (excluding VAT; BNF 52nd edition). The 2-year cost of pegaptanib is about £9,300 (9\xa0injections in the first year and another 9 in the second year). Costs may vary in different settings because of negotiated procurement discounts.', 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nThe Assessment Group's systematic review identified four randomised controlled trials (RCTs) of ranibizumab and two RCTs of pegaptanib. Outcomes measured in the RCTs included changes in visual acuity (loss, maintenance, gain, mean change and deterioration to visual acuity 3/60 [in the UK, 3/60 is the level of visual acuity at which patients are registered blind]), anatomical changes in CNV lesions, visual function questionnaire scores, contrast sensitivity and adverse events.\n\n## Ranibizumab\n\nFour RCTs of ranibizumab (MARINA [minimally classic lesions; ranibizumab versus sham injection], ANCHOR [predominantly classic lesions; ranibizumab versus sham plus PDT], PIER [all lesions; ranibizumab versus sham injection] and FOCUS [predominantly and minimally classic lesions; ranibizumab plus PDT versus sham plus PDT]) were included in the assessment report and the manufacturer's submission. The length of follow-up in the trials varied from 12 to 24\xa0months and the doses used were 0.3\xa0mg (unlicensed) and 0.5\xa0mg (licensed). The populations in the trials met inclusion criteria including best-corrected visual acuity between 6/12 and 6/96; no permanent structural damage to the central fovea; lesion size less than or equal to 12 disc areas in greatest linear dimension; and evidence of recent presumed disease progression (blood vessel growth as indicated by fluorescein angiography, or recent visual acuity changes). Outcomes were assessed at different time points, and the number and frequency of injections varied among the trials.\n\nLoss of fewer than 15 letters of visual acuity was the primary endpoint in the studies. From baseline to 12\xa0months, statistically significantly more patients receiving 0.5\xa0mg ranibizumab lost fewer than 15 letters of visual acuity compared with both sham injection (94.6% compared with 62.2%, MARINA study) and PDT (96.4% compared with 64.3%, ANCHOR study). In the PIER study, 90.2% of the 0.5\xa0mg ranibizumab group lost fewer than 15 letters compared with 49.2% in the sham group (p\xa0<\xa00.0001).\n\nGain in visual acuity was a secondary endpoint in the studies. A third of the 0.5\xa0mg ranibizumab group gained at least 15 letters compared with 4% of the sham injection group at 24\xa0months in the MARINA study. In the ANCHOR trial, 40% of the 0.5\xa0mg ranibizumab group gained at least 15 letters compared with 6% of the PDT plus sham injection group (p\xa0<\xa00.0001). In the FOCUS study, 24% of the 0.5\xa0mg ranibizumab plus PDT group gained at least 15 letters compared with 5% of the sham injection plus PDT group (p\xa0=\xa00.0033).\n\nThe MARINA, ANCHOR and FOCUS trials all reported mean increases in visual acuity in the 0.5\xa0mg ranibizumab group compared with baseline. The FOCUS trial reported mean gains in letters of 4.9 (0.5\xa0mg ranibizumab plus PDT group) compared with mean losses of 8.2 letters in the sham plus PDT group. The ANCHOR study (0.5\xa0mg ranibizumab group) reported mean gains of 11.3 letters compared with a loss of 9.5 letters in the sham plus PDT group. In the MARINA trial, mean gains in letters were 7.2 and 6.6 at 12 and 24\xa0months, respectively, and the corresponding mean losses in the sham group were 10.4 and 14.9 letters at 12 and 24\xa0months respectively. These results were statistically significant in all the trials.\n\nMost adverse events were mild to moderate. Conjunctival haemorrhage was the most widely reported eye-related adverse event, but its incidence varied among the ranibizumab RCTs and it was also common in the control groups. More patients in the ranibizumab group experienced increased intraocular pressure and vitreous floaters compared with those in the sham injection group. Endophthalmitis affected about 1% and 0.7% of patients in the MARINA and ANCHOR RCTs respectively. The SPC stated that the overall incidence of arterial thromboembolic events from the MARINA, ANCHOR and PIER trials was higher for patients treated with ranibizumab 0.5\xa0mg (2.5%) compared with the control arm (1.1%). However, in the second year of the MARINA study, the rate of arterial thromboembolic events was similar in patients treated with ranibizumab 0.5\xa0mg (2.6%) compared with patients in the control arm (3.2%).\n\n## Pegaptanib\n\nThe combined results of two concurrent RCTs (one carried out in the USA and Canada, the other at centres worldwide) comparing doses of 0.3\xa0mg (licensed), 1.0\xa0mg (unlicensed) and 3.0\xa0mg (unlicensed) pegaptanib with sham injection were published as the VISION study. A total of 1208 patients with all types of CNV lesion were included. Patients were followed for up to 54\xa0weeks, then for a further 48\xa0weeks after re-randomisation.\n\nLoss of fewer than 15 letters of visual acuity was the primary endpoint in the VISION study. Statistically significantly more patients (70%) receiving 0.3\xa0mg (the licensed dose) pegaptanib compared with sham injection (55%) lost fewer than 15 letters of visual acuity from baseline to 54\xa0weeks. More patients in the 0.3\xa0mg group gained at least five letters (22%) compared with the sham injection group (12%; p\xa0=\xa00.004). Gains of at least 10 letters were reported for 11% of the 0.3\xa0mg pegaptanib group compared with 6% of the sham injection group (p\xa0=\xa00.02). In the 0.3\xa0mg group 6% of patients gained more than 15 letters compared with 2% in the sham group.\n\nMean loss of letters of visual acuity at week 54 was significantly higher in the sham injection group than in the 0.3\xa0mg pegaptanib group. A mean loss of 7.5 letters was observed in the 0.3\xa0mg pegaptanib group, compared with a mean loss of 14.5\xa0letters in the sham injection group.\n\nThe VISION study reported that the proportion of people losing at least 15 letters of visual acuity from baseline after 2\xa0years was lower for patients who stopped pegaptanib (at the licensed dose) after 1\xa0year compared with those who had never received pegaptanib (relative risk 0.68, 95% confidence interval [CI] 0.51 to 0.90, p\xa0=\xa00.008). The manufacturer interpreted this as demonstrating a disease-modifying effect; if the treatment effect was exclusively symptomatic, the visual acuity of patients who discontinued treatment after 1\xa0year would have quickly returned to that seen in the sham injection group, rather than remaining significantly better a year after stopping treatment, as observed in the study. The Assessment Group considered this to be biologically plausible because anti-VEGF drugs target the underlying pathology in AMD. However the Assessment Group also noted uncertainty in this conclusion because the decline in the proportion of people losing fewer than 15 letters from 54\xa0weeks to 102\xa0weeks in the VISION study was the same for patients who received pegaptanib as for those who had never received the drug (14%).\n\nIn the VISION study most adverse events reported were mild to moderate. After 1\xa0year of treatment they were similar among treatment arms except for vitreous floaters, vitreous opacities, and anterior-chamber inflammation. Eye-related adverse events were more common in the study eye in patients in the sham injection group than in those in the 0.3\xa0mg pegaptanib group, suggesting that the preparation procedure itself (which included an ocular antisepsis procedure and an injection of subconjunctival anaesthetic) may be associated with adverse events. Endophthalmitis affected about 1.3% of all patients in the first year. In two thirds of these cases, there had been a protocol violation (for example, failure to use aseptic technique).\n\n# Cost effectiveness\n\n## Published economic evaluations\n\nThe Assessment Group identified 421 publications relating to cost effectiveness in AMD. None of these were fully published economic evaluations of either ranibizumab or pegaptanib. No additional publications were identified from the manufacturers' submissions. Three conference abstracts identified and reviewed model-based evaluations of pegaptanib.\n\n## Manufacturers' submissions\n\nBoth manufacturers provided cost-utility models. Both models were Markov state transition models, with the states being different levels of visual acuity and death. Both models assumed that only the better-seeing eye is treated. The models were based on 1 or 2\xa0year data from randomised controlled trials, after which there was extrapolation, based on the life expectancy of the cohort, to a 10-year time horizon. Input assumptions were determined from an NHS and personal social services perspective. There was no comparison, direct or indirect, of ranibizumab and pegaptanib with each other.\n\nThe manufacturer's submission compared the use of ranibizumab with best supportive care for patients with minimally classic or occult no classic lesions, and with both PDT with verteporfin and best supportive care for patients with predominantly classic lesions. The different types of wet AMD were analysed separately based on results from RCTs (ANCHOR for comparison with PDT in predominantly classic lesions, MARINA for comparison with best supportive care in minimally classic lesions and PIER for reduced- frequency dosage in all lesion types). Because the ANCHOR trial did not include a sham injection arm, comparison between treatment with ranibizumab and best supportive care for patients with predominantly classic lesions was made through indirect comparison using data from a study (TAP) in which PDT was compared with best supportive care.\n\nThe model had five health states defined by declining visual acuity ranging from 6/15 or better (least severe) to less than 3/60 (most severe), and an additional absorbing state, death. The manufacturer's model applied a different dosing schedule from that used in the clinical trials. The MARINA and ANCHOR trials involved 24\xa0injections over 2\xa0years and 12\xa0injections over 1\xa0year respectively, but in the base-case analysis for the model, 8\xa0injections in the first year and 6\xa0injections in the second year were used with the assumption that the same clinical efficacy would be achieved with this lower dosing frequency.\n\nThe utility values used in the model were based on a study in which outcomes were assessed in members of the general UK population (n\xa0=\xa0108) who experienced simulated AMD vision states using custom-made lenses. The study included a preference-based measure (HUI-3), selected questions from a visual function questionnaire and time-trade-off (TTO) by direct elicitation (Brazier study). The utility values derived using TTO by direct elicitation were stated to have a strong relationship with visual acuity and these were the utility values used in the model. The difference in mean values between the lowest and highest visual acuity groups was 0.367 (0.497 in the group with a visual acuity of less than 3/60 and 0.864 in the group with a visual acuity of 6/15 or better). These values were based on impaired vision in both eyes. However, the manufacturer argued that the relative benefits of binocular and monocular vision should be taken into account, citing a study which showed a difference in utility value of approximately 0.1 between people with good visual acuity in both eyes and people with good vision in only one eye. The manufacturer's submission also discussed utility values derived using the HUI-3 instrument (Espallargues). In this study, a utility difference of 0.02 between people with visual acuity ranging from 6/12 to 6/24 (utility value of 0.38) and people with visual acuity ranging from 6/24 to 3/60 (utility value of 0.36) was reported.\n\nThe base-case incremental cost-effectiveness ratios (ICERs) for predominantly classic lesions, assuming 1\xa0year of treatment as per the ANCHOR RCT, were £4489 per quality-adjusted life-year (QALY) gained for ranibizumab versus PDT, and £14,781 per QALY gained for ranibizumab versus best supportive care. For occult no classic lesions, assuming 2\xa0years of treatment, the ICER was £26,454 per QALY gained for ranibizumab versus best supportive care. Likewise, for minimally classic lesions, the ICER was £25,796 per QALY gained. For all lesion types (PIER), assuming 1 year of treatment, the ICER was £12,050 per QALY gained.\n\nThe manufacturer's model for pegaptanib compared the cost effectiveness of pegaptanib with usual care in the NHS. Usual care was identified as the best supportive care (visual rehabilitation and provision of visual aids) for all patients, with the addition of PDT with verteporfin in patients with predominantly classic lesions. The base-case analysis is based on all lesion types. The analysis was based on patient-level data from the VISION study.\n\nThe model had 12 health states, defined by visual acuity ranging from 6/10 or better to less than 3/60, and an additional absorbing state, death. Treatment was assumed to be stopped if visual acuity dropped below 6/96 or by six or more lines from baseline at the end of a year. This is referred to as scenario A. The cost effectiveness of adopting an alternative stopping rule with a higher threshold of visual acuity (6/60) for stopping pegaptanib treatment, labelled scenario B, is also reported in the submission. Cycle length in the model is 6\xa0weeks.\n\nThe utility values used in the model were based on a study of health-related quality of life in AMD patients (Brown study, n\xa0=\xa080). The utility values were derived by direct elicitation using both the standard gamble and TTO methods. In multivariate linear regression analysis, the TTO method produced a higher correlation with visual acuity than the standard gamble approach. The difference in mean TTO values between the lowest and highest visual acuity groups was 0.49 (0.40 in the group with a visual acuity of less than 3/60 and 0.89 in the group with a visual acuity of 6/12 or better).\n\nIn the base case, the ICER was £15,819 per QALY gained for scenario A and £14,202 per QALY gained for scenario B. Results of sensitivity analyses carried out by the manufacturer showed that the costs and probabilities of receiving visual impairment services and the model time horizon had a significant effect on the ICERs.\n\n## The Assessment Group model\n\nThe Assessment Group's model evaluated the cost effectiveness of ranibizumab and pegaptanib compared with current practice (PDT with verteporfin for classic no occult lesions or predominantly classic lesions, and best supportive care for all lesion types). The transitions between states in the model were based on RCT data, noting that the endpoints in the RCTs fell broadly into three clinically accepted endpoints; loss of less than 15 letters, intermediate vision loss (loss of 15–30 letters) and severe vision loss (loss of more than 30 letters). The estimated impact of these changes in visual acuity on the cost effectiveness of ranibizumab and pegaptanib was estimated using a Markov state transition model. The model assumes that only the better-seeing eye is treated.\n\nA six-state Markov model was developed and the rate of disease progression was modelled as the probability of progressing to a different level of visual acuity health state in each model cycle. The model extrapolated the effects of the 2-year trial period (or 1\xa0year for ranibizumab in predominantly classic lesions) to 10\xa0years in both arms of the model. Ranibizumab and pegaptanib treatments are assumed to have stopped at the end of year 2, and thereafter benefits were assumed to decline at the same rate as those for usual care, although from a higher level of visual acuity.\n\nWhere possible, the Assessment Group used routinely available unit cost estimates, that is NHS reference costs and unit costs of community care, in its economic analyses. Resources and costs incorporated in the Assessment Group model included those for treatment, administration, monitoring, managing adverse events and blindness. Costs related to blindness included the administrative cost of registering as blind or partially sighted, and the cost of low vision aids, low vision rehabilitation, community care, residential care, treatment of depression and hip replacement. In the base case it was assumed that all injections would be carried out as outpatient procedures at a unit cost of £90.20. In sensitivity analyses, it was assumed that all injections would be carried out as day-case procedures at a unit cost of £395, or that the cost of administering the injection would be a mix of day case (75%) and outpatient (25%) costs.\n\nHealth state utility values derived using TTO by direct elicitation from patients with AMD (Brown study, n\xa0=\xa080, see section 4.2.2.8) were used because the Assessment Group considered these to be the most credible published utility values for visual loss associated with AMD.\n\nThe Assessment Group's base-case ICERs over a 10-year time horizon for predominantly classic lesions assuming 1\xa0year of treatment were £15,638 per QALY gained compared with PDT, and £11,412 per QALY gained compared with best supportive care. For minimally classic lesions and occult no classic lesions, assuming 2\xa0years of treatment, they were £25,098 per QALY gained compared with best supportive care.\n\nThe Assessment Group carried out sensitivity analyses of different assumptions used in their model. The results for ranibizumab showed that as the time horizon decreased the ICERs increased.\n\nIn one-way sensitivity analyses, for predominantly classic lesions, reducing the number of injections from 12 to 9 in the first year of treatment reduced the ICER from £15,638 to £6,897 per QALY gained compared with PDT and from £11,412 to £6,087 per QALY gained compared with best supportive care. For patients with minimally classic and occult no classic lesions, with a treatment duration of 2\xa0years (as per the MARINA trial protocol), reducing the number of injections in the first year of treatment from 12 to 9 (with a further reduction from 12 to 6 injections in year 2) reduced the ICER considerably from £25,098 to £12,649 per QALY gained compared with best supportive care. In these analyses, it was assumed that the QALY gain would not differ with changes in the number of injections.\n\nIn one-way sensitivity analyses in which the injections were costed as day-case rather than outpatient procedures, the ICERs increased. The ICER increased from £15,638 to £26,102 per QALY gained compared with PDT and from £11,412 to £17,787 per QALY gained compared with best supportive care. For patients with minimally classic and occult no classic lesions, the ICER increased from £25,098 to £35,157 per QALY gained compared with best supportive care.\n\nThe cost-effectiveness estimates were sensitive to assumptions over uptake of visual support services (estimated as the proportion of patients with visual acuity of less than 6/60 receiving services). Using high uptake and high unit-cost estimates resulted in ranibizumab being economically dominant (with a lower cost and better outcome) compared with either PDT or best supportive care for patients with predominantly classic lesions. However, when low costs and medium uptake assumptions were used in one-way sensitivity analyses, the ICERs increased from £15,638 to £19,967 per QALY gained for predominantly classic lesions compared with PDT, and from £11,412 to £16,281 per QALY gained for predominantly classic lesions compared with best supportive care. For minimally classic lesions, the ICER increased from £25,098 to £29,446 per QALY gained.\n\nIn sensitivity analyses, varying the distribution of initial visual acuity had very little effect on the ICERs for ranibizumab. For example, for minimally classic lesions compared with best supportive care, a cohort equally split between the 6/12–6/24 and 6/24–6/60 states produced an ICER of £25,179 per QALY gained, whilst a cohort with initial visual acuity of 6/24–6/60 produced an ICER of £25,268 per QALY gained.\n\nIn probabilistic sensitivity analyses using the base-case assumptions, for patients with predominantly classic lesions compared with PDT, ranibizumab had a probability of being cost effective of 72% at a willingness to pay of £20,000 per QALY gained and 97% at a willingness to pay of £30,000 per QALY gained. For patients with predominantly classic lesions compared with best supportive care, ranibizumab had a probability of being cost effective of 95% at a willingness to pay of £20,000 per QALY gained and 99% at a willingness to pay of £30,000 per QALY gained. For patients with minimally classic and occult no classic lesions, for the base-case analysis ranibizumab had a probability of being cost effective (compared with best supportive care) of 15% at a willingness to pay threshold of £20,000 per QALY gained and 81% at a willingness to pay threshold of £30,000 per QALY gained.\n\nThe Assessment Group estimated the base-case ICER for pegaptanib (all lesion types) compared with usual care to be £30,986 per QALY gained over a 10-year time horizon.\n\nThe Assessment Group carried out sensitivity analyses of different assumptions used in their model. As with ranibizumab, the results for pegaptanib showed that decreasing the time horizon increased the ICERs. The ICER was also sensitive to the costs of blindness, in particular the uptake of services, estimated as the proportion of patients with visual acuity of less than 6/60 receiving services. Using high uptake and high unit-cost estimates resulted in pegaptanib being economically dominant (with a lower cost and better outcome) compared with usual care. However, when low costs and medium uptake assumptions were used, the ICER increased from the base case of £30,986 to £37,154 per QALY gained.\n\nIn another sensitivity analysis, a higher cost was assumed for providing all injections as a day-case procedure and the ICER for pegaptanib increased from the base case of £30,986 to £47,845 per QALY gained compared with best supportive care.\n\nThe Assessment Group also performed a sensitivity analysis to explore the assumption of a potential disease-modifying effect of pegaptanib. This relative risk reduction (see section 4.1.10) was applied to the estimated transition probabilities for losing three to six lines and losing more than six lines of visual acuity in the sensitivity analyses. When this relative risk reduction was applied to the Assessment Group model in year 3 (that is, for one year following cessation of treatment), the ICER decreased from £47,845 (using the day-case injection cost assumption, see 4.2.3.14) to £42,198 per QALY gained compared with best supportive care.\n\nWhen the distribution of initial visual acuity was varied in sensitivity analyses, a cohort equally split between the 6/12–6/24 and 6/24–6/60 states produced an ICER of £35,913 per QALY gained, while a cohort with initial visual acuity of 6/24–6/60 produced an ICER of £46,285 per QALY gained compared with best supportive care.\n\nIn probabilistic sensitivity analyses using the base-case assumptions, pegaptanib had a probability of being cost effective (compared with usual care) of 17% at a willingness to pay of £20,000 per QALY gained and 58% at a willingness to pay of £30,000 per QALY gained using the base-case assumptions.\n\n## Further analysis by the Assessment Group and the Decision Support Unit\n\nAfter considering the responses from consultation, the Committee requested additional analysis from the Assessment Group and the Decision Support Unit. The Assessment Group explored alternative assumptions for the main drivers of the economic model: namely the costs of blindness, the costs of administering the injections, the number of injections of ranibizumab, and the utility values used in the analysis. The Decision Support Unit provided similar analyses using the manufacturer's model for pegaptanib; this was requested because the manufacturer's model enabled consideration of differential treatment effects by subgroup of baseline visual acuity, based on patient-level data to which the Assessment Group did not have access.\n\nThe Assessment Group explored the cost of treating the first eye to come to clinical attention rather than treating only the better-seeing eye. The analysis assumed an annual incidence of AMD in the second eye of 10% and explored a number of different scenarios. It found that for ranibizumab the additional cost of treating two eyes ranged from about £9,900 to about £28,600, depending on the number of injections (9 to 24) over 2\xa0years. For pegaptanib, the additional cost of treating two eyes ranged from about £9,100 to about £15,700.\n\nIn one-way sensitivity analyses on the costs of blindness, the Assessment Group found that the alternative assumptions derived from consultation responses were very similar to those used in the original Assessment Group report. The Assessment Group noted that the level of uptake of community services (that is, the proportion of people who are blind and receiving community care services) had a much greater effect on the ICERs than other components of the costs of blindness. Therefore sensitivity analyses focused on varying this proportion from 6% to 17% or 25%.\n\nIn a one-way sensitivity analysis the Assessment Group used alternative utility values to its base case. This was a set of utility values estimated to be equivalent to those derived in the Brazier study, but adapted for the visual acuity states in the Assessment Group model (which were slightly different from those in the Brazier study). The difference in mean values between the lowest and highest visual acuity groups was 0.382 (0.518 in the group with a visual acuity of less than 3/60 and 0.900 in the group with a visual acuity of 6/12 or better).\n\nThe Assessment Group also explored the cumulative impact on the ICER of the following assumptions, which were preferred by the Committee to the original base case: alternative utility values (Brazier study), splitting the cost of administering the injection between day-case (75%) and outpatient (25%) costs and higher uptake of community care services (from 6% to 17% or 25%). When the Brazier utilities were used, the ICER for ranibizumab for predominantly classic lesions increased from the base case of £15,638 to £19,491 per QALY gained compared with PDT, and from the base case of £11,412 to £14,388 per QALY gained compared with best supportive care; for minimally classic and occult no classic lesions the ICER increased from the base case of £25,098 to £31,966 per QALY gained compared with best supportive care. When the costs of administering the injection were split between day-case (75%) and outpatient (25%) costs, the ICER for ranibizumab for predominantly classic lesions was £29,272 per QALY gained compared with PDT and £20,416 per QALY gained compared with best supportive care; for minimally classic lesions the ICER was £41,575 per QALY gained compared with best supportive care. In addition, when the uptake of community care was assumed to increase from 6% (base case) to 25%, the ICER for ranibizumab for predominantly classic lesions decreased to £26,425 per QALY gained compared with PDT, and to £17,175 per QALY gained compared with best supportive care; for minimally classic lesions the ICER was £38,659 per QALY gained compared with best supportive care.\n\nThe Assessment Group also explored the cost effectiveness of ranibizumab in predominantly classic lesions assuming two years of treatment, whereas previously one year of treatment was assumed. Assuming 12 injections in each year, this increased the ICERs from the cumulative scenario described in section 4.2.4.5 from £26,425 to £37,489 per QALY gained for ranibizumab compared with PDT, and from £17,175 to £23,887 per QALY gained for ranibizumab compared with best supportive care.\n\nFinally, in addition to the cumulative assumptions described in sections 4.2.4.5 and 4.2.4.6, but instead assuming that only 14\xa0injections would be required over two years to attain the same clinical benefit without reducing the frequency of monitoring costs, the ICER for ranibizumab for predominantly classic lesions further decreased from £37,489 to £13,671 per QALY gained compared with PDT, and from £23,887 to £9,900 per QALY gained compared with best supportive care. For minimally classic or classic no occult lesions the ICER decreased from £38,659 to £19,904 per QALY gained compared with best supportive care.\n\nFor pegaptanib, the Decision Support Unit used the manufacturer's model to reproduce the manufacturer's finding that the cost per QALY gained for pegaptanib treatment is lower in subgroups with better baseline visual acuity using all the Committee's preferred assumptions. The lowest cost per QALY gained was obtained in a subgroup of people with visual acuity between 6/12 and 6/24. When the inputs outlined in section 4.2.4.4 were cumulatively considered in the manufacturer's model, the ICER was £23,124 per QALY gained in the 6/12 to 6/24 subgroup compared with best supportive care, £40,627 per QALY gained for the 6/24 to >6/60 subgroup, £115,244 per QALY gained for the 6/60 to >3/60 subgroup, and £34,602 per QALY gained for the whole cohort. Using the same set of assumptions, the ICER from the Assessment Group model was £44,259 per QALY gained for the whole group irrespective of visual acuity levels.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ranibizumab and pegaptanib for the treatment of wet AMD, having considered evidence on the nature of the condition and the value placed on the benefits of these drugs by people with wet AMD, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee considered the clinical effectiveness evidence. It discussed the results for loss of fewer than 15\xa0letters of visual acuity, which was the primary outcome of all the RCTs. It noted that the effect size was greater for all lesion types in the ranibizumab studies than in the pegaptanib studies. The Committee concluded that both pegaptanib and ranibizumab reduce loss of visual acuity compared with sham injection, and ranibizumab reduces loss of visual acuity compared with PDT in patients with predominantly classic lesions.\n\nThe Committee discussed the RCT results for gain in visual acuity, recognising the importance of this to patients with AMD. It noted that there were differences between ranibizumab and pegaptanib in the RCT data for this endpoint. In the ranibizumab trials, there was a substantial increase in the proportion of patients gaining 15 or more letters of visual acuity, whereas for pegaptanib relatively few patients gained 15 letters or more compared with control. The Committee also discussed the RCT results on mean change in visual acuity, reported as the mean number of letters lost or gained in the treatment groups compared with the control arms. Results showed that there were statistically significant mean gains of letters for ranibizumab whereas pegaptanib reduced only the mean loss of letters. The Committee concluded on the basis of the RCT evidence that ranibizumab is more clinically effective than pegaptanib in improving visual acuity.\n\nThe Committee considered the licensed dosing regimen for ranibizumab compared with that used in the main RCTs. It understood that the rationale for the regimen in the marketing authorisation was based on evidence from a drug and disease model submitted by the manufacturer indicating that the beneficial effects of ranibizumab peak after three injections at 3\xa0months, after which a plateau of effect is reached, and that continued monthly injections may not be necessary in all patients to maintain this benefit. It was concerned that the results of the PIER trial, in which injections were given less frequently (3-monthly) to all patients after the third month, showed ranibizumab to be less effective than in the MARINA and ANCHOR trials in which monthly injections (24) were given. The Committee noted the results of a further study, PrONTO, which suggested that clinical benefit may be maintained with a lower average number of injections per patient, if injections are given more or less frequently depending on visual acuity and on a measure of response on optical coherence tomography (a regimen similar to that in the marketing authorisation). However, it noted that PrONTO was a small, uncontrolled study investigating only a subset of patients with wet AMD. The Committee concluded that there was some uncertainty about the number and frequency of injections required to achieve the results seen in the MARINA and ANCHOR trials.\n\nThe Committee discussed the adverse events associated with the use of the anti-VEGF agents. The Committee heard from clinical specialists that ranibizumab and pegaptanib have broadly similar adverse-event profiles, that most adverse events are manageable and that serious ones are rare. The Committee considered the data listed under 'undesirable effects' in the SPC showed that the overall incidence of arterial thromboembolic events from the MARINA, ANCHOR and PIER trials was higher for patients treated with ranibizumab compared with the control group, but that in the second year of the MARINA study the rate of arterial thromboembolic events was similar in patients treated with ranibizumab and patients in the control arm. The Committee concluded that ranibizumab and pegaptanib have broadly similar adverse-event profiles; most adverse events are manageable and serious ones are rare. It noted that the costs of adverse events were included in the Assessment Group model.\n\nThe Committee considered whether the clinical effectiveness of the two anti-VEGFs (ranibizumab and pegaptanib) varied by lesion type. It noted that, in the ranibizumab RCTs, the effects in patients who had predominantly classic lesion types were similar to those in patients with minimally classic and occult no classic lesion types. The Committee heard that in clinical practice anti-VEGF treatment results in similar effects across all lesion types. It heard from clinical specialists that although the classification by lesion type is relevant to laser-based treatments where there is a need to delineate the margins of CNV, such classification is not relevant to the use of anti-VEGFs. The Committee concluded that anti-VEGF treatments were clinically effective across lesion types.\n\nThe Committee considered whether the clinical effectiveness of the anti-VEGFs varied between subgroups defined according to baseline visual acuity. It noted that in the Assessment Group's model, treatment effect and rate of deterioration of vision were assumed to be independent of baseline visual acuity, but the model submitted by the manufacturer of pegaptanib assumed greater clinical benefits to be associated with better baseline vision. The Committee considered it to be plausible that people with better pre-treatment visual acuity are likely to benefit more from treatment than those with lower pre-treatment visual acuity. This could be, for example, because wet AMD lesions that have caused greater deterioration in visual acuity are also more likely to have caused permanent structural damage, which reduces response to anti-VEGF treatment.\n\nThe Committee discussed key assumptions affecting the cost-effectiveness analysis of the treatments. These were the:\n\nduration of treatment\n\nfrequency of injections of ranibizumab that would be required to maintain response in clinical practice\n\nextrapolation of treatment benefit associated with anti-VEGF treatment beyond the duration of the RCTs, including consideration of any disease-modifying effect\n\nutility values used in the economic model\n\ncosts related to blindness (defined as visual acuity less than 6/60 for those registered as partially sighted and 3/60 for those registered as blind), including low-vision aids, visual rehabilitation and community care\n\ncosts of adequate facilities and staffing for intravitreal injection\n\ncost effectiveness of anti-VEGF treatment in the first-affected eye.\n\nThe Committee discussed the assumption of treatment duration being limited to 2\xa0years. It understood that CNV may recur after cessation of treatment, and heard from some consultees that rapid deterioration of vision after treatment cessation was sometimes observed. It heard from clinical specialists that it was unclear how long treatment would be continued in practice, that there was an evolving evidence base, and that for some patients it would be appropriate to continue treatment beyond 2\xa0years into the third or even fourth year. This would result in additional drug, administration and monitoring costs, which were not included in any of the economic models.\n\nThe Committee also noted that for economic modelling of predominantly classic lesion types with ranibizumab, the Assessment Group model was based on only 1\xa0year of treatment (in keeping with the ANCHOR study), while for ranibizumab in minimally classic and occult no classic lesions, and for pegaptanib for all lesion types, 2\xa0years of treatment had been modelled (in keeping with the MARINA and VISION studies). The Committee believed that the scenario in which the Assessment Group had estimated the ICER for 2\xa0years of treatment in predominantly classic lesions would be more appropriate, noting that the duration of treatment was not expected to vary by lesion type in clinical practice and could extend beyond 2\xa0years (see sections 4.3.6 and 4.3.9).\n\nThe Committee discussed assumptions for the frequency of ranibizumab injection, bearing in mind the issues discussed in section 4.3.4. It noted that the drug dosing model presented by the manufacturer had been accepted by the European Medicines Agency (EMEA) as a basis for the regimen in the marketing authorisation. It noted that the model assumed that the individualised dosing would result in stable visual acuity for the majority of the patients, with a mean of 8\xa0injections required in the first year followed by a mean of 6\xa0injections in the second year. It noted, based on comments from clinical specialists and from consultees including the Royal College of Ophthalmologists, that such a dosing model was likely to be frequently borne out in practice. However, the Committee remained concerned about the assumption that the benefit achieved in the pivotal trials could be matched if injections were less frequent.\n\nTaking into account its considerations over the required frequency of ranibizumab injections (as in section 4.3.10) and that treatment may continue beyond 2\xa0years for some patients (as in section\xa04.3.9), the Committee concluded that on balance it would be reasonable to consider an assumption of a total of 24 injections of ranibizumab. In other words the Committee considered that although 24 injections over 2\xa0years may be an overestimate, the assumption that no one would receive further injections after 2\xa0years was not probable.\n\nThe Committee further noted that there was no evidence to ascertain how benefits would accrue in the long term if treatment is stopped after 2\xa0years, as assumed in all three economic models. There is therefore great uncertainty in appraising the validity of extrapolations made in the models. The approach used in the Assessment Group model was to assume that benefits of treatment would gradually decline at the same rate as for the usual care cohort, although starting at a higher visual acuity – that is, retaining higher visual acuity levels over the control arm throughout the 10-year time horizon. The Committee concluded that this approach would be reasonable to accept as a basis for decision-making.\n\nThe Committee also noted that a disease-modifying effect had been suggested for pegaptanib. It accepted that such an effect was plausible, but not for a lifetime duration after treatment had stopped. It was persuaded that it was reasonable to infer that there was some effect for a year after stopping treatment. It therefore concluded that pegaptanib could be assumed to slow disease progression for a year after stopping treatment with the drug, but that thereafter progression was at the same rate as in the control arm.\n\nThe Committee discussed the utility values used in the models. It noted that the Assessment Group and the manufacturer for pegaptanib used utilities derived from AMD patients (Brown study), whilst the manufacturer for ranibizumab used utilities derived from the general population (Brazier study). Both sets of utility values had been derived using TTO direct elicitation. The Committee considered that in principle it is more appropriate to use utility values derived using a standardised and validated generic (non-disease-specific) instrument, such as the EQ-5D or HUI-3. It noted the utility values derived using HUI-3 (Espallargues) which reported a utility difference of 0.02 between two health states with markedly different visual acuities. The Committee agreed that this measure may therefore not fully capture the impact of AMD on patients' quality of life. The Committee concluded that on balance, the Brazier utility values provided the most plausible set of utility values for use in the economic models.\n\nThe Committee discussed the assumptions about costs related to blindness (such as registration, low-vision aids and rehabilitation). It heard from consultees that the assumptions in the Assessment Group base case were low, if not for standard practice, then for best practice. The Committee considered sensitivity analyses in the assessment report using high uptake and high costs of blindness and noted that these resulted in significant reductions in the ICERs for both drugs. The Committee decided that it was unrealistic to accept the extreme high or low uptake rates and costs of blindness presented in the sensitivity analysis in the assessment report. In addition, the Committee considered that for those patients who retained good to normal visual acuity in one eye, the absolute cost of 'blindness' would be proportionately lower than in those patients in whom both eyes were affected. Taking these factors into account, the Committee concluded that an appropriate assumption about the costs of blindness would lie between the Assessment Group base case and the combined high-uptake, high-cost scenario.\n\nThe Committee discussed the assumptions in the models for the costs of administering intravitreal injections. The Committee heard from clinical specialists that the costs of appropriate facilities and staffing for intravitreal injection were higher than had been assumed in the base case (NHS reference cost of £90.20 for an outpatient procedure) because provision had to be made for sterile conditions. It noted an analysis based on the NHS reference cost of £395 for a day-case procedure. The Committee also considered an additional analysis in which the Assessment Group estimated costs based on the Royal College of Ophthalmologists' commissioning guidelines for provision and treatment of AMD with anti-VEGFs. This analysis showed that the costs based on the Royal College of Ophthalmologists' guidelines were higher than for day-case procedures. The Committee considered the conflicting information available on the cost of administering intravitreal injections, and was persuaded by comments received during consultation that in practice, for the foreseeable future, a mixture of day-case and outpatient procedures would occur. It concluded that a reasonable approach would be to assume that the costs of administering intravitreal injections were equivalent to a mix of 75% of the cost of a day case procedure and 25% of the cost of an outpatient procedure.\n\nThe Committee discussed whether it would be appropriate to consider recommending treatment in the better-seeing eye only: that is, not to treat where patients present with only one eye affected. It noted the concerns raised by consultees and understood that most consultees felt that it would be unacceptable, and clinically inappropriate, not to treat the first eye that comes to clinical attention. It was persuaded that any other scenario could result in losing the opportunity to preserve vision because the untreated better-seeing eye could subsequently be affected by an untreatable cause of vision loss, or might not respond to treatment with anti VEGFs. With all these issues in mind the Committee concluded that its considerations of cost effectiveness should relate to starting treatment with the first eye to present clinically.\n\nThe Committee discussed the cost effectiveness of treating the first eye affected by AMD even while good (albeit) monocular vision was available from an unaffected eye. Firstly it noted that patients' quality of life was strongly correlated with, and mainly driven by, vision in the better-seeing eye. The Committee noted, however, that loss of normal binocular vision can result in a reduction in quality of life. It understood, for example, that there would be considerable anxiety and depression associated with allowing an eye known to be affected with AMD to deteriorate without treatment. It noted one study cited by the manufacturer of ranibizumab, in which the difference in utility between having 6/6 vision in both eyes, and having 6/6 vision in one eye but 6/12 or worse in the other eye, was approximately 0.1. The Committee noted that this utility difference was substantially smaller than that between very good and very poor vision in the better-seeing eye (approximately 0.4 or 0.5 if Brazier or Brown utility values are used, respectively). Secondly, the Committee considered that for those patients who retained good to normal visual acuity in one eye, the savings in costs of 'blindness' would be considerably lower than in those patients with poor vision in both eyes.\n\nThe Committee discussed the proportion of patients who presented with AMD when only one eye was affected with the condition. It noted estimates from clinical specialists and consultees that about 70% of patients present with both eyes affected by AMD and that the standard approach is to treat the better-seeing eye if there is wet AMD in both. Of the 30% presenting with one eye affected, it noted estimates that about 10% per year (and 40% after 5\xa0years) develop the disease in the second eye.\n\nThe Committee noted that the economic modelling was carried out assuming that the better-seeing eye was treated. A policy of treating the first eye to come to clinical attention would result in substantially higher costs, but fewer savings and lower utility gains, than a policy of only treating the better-seeing affected eye. The Committee estimated that treatment for the first eye yields an 80% lower QALY gain than for treating the better-seeing eye. In addition there would be reduced savings on costs of blindness. Based on this the Committee agreed that an expected cost per QALY for a first-eye strategy would be about 50% higher than that for treating the better-seeing affected eye. It concluded that the ICERs for pegaptanib or ranibizumab would not fall within a range considered to be a cost-effective use of NHS resources using the assumptions outlined in 4.2.4.5 and 4.2.4.6 and assuming a strategy of treating the first-affected eye.\n\nThe Committee discussed the number of injections of ranibizumab assumed in the model. It noted that if 8\xa0injections were required in the first year and 6 in the second, as suggested by consultees (see section 4.3.10), the ICERs for the different lesion types would be £13,671, £9,900 and £19,904 per QALY gained depending on lesion type and comparator, as detailed in section 4.2.4.7. These figures assume that only the better-seeing eye is treated. Applying a 50% increase in these ICERs to include the treatment of the first eye, these ICERs would become approximately £20,500 and £14,800 per QALY gained in predominantly classic lesions compared with best supportive care and PDT respectively, and £29,900 in minimally classic or classic no occult lesions compared with best supportive care. However, the Committee considered that many patients would be likely to require more injections than this to maintain benefit. It discussed a proposal by the manufacturer in their response to consultation that the number of ranibizumab injections for which drug costs are paid by the NHS could be capped, with any remaining ranibizumab drug costs paid for by the manufacturer. It noted that the feasibility and administrative burden on the NHS of such a scheme would need to be considered in appraising the cost effectiveness of ranibizumab within such a scheme. Additionally, continued administration and monitoring costs would also need to be considered as patients would require regular re-assessment on a monthly basis to monitor the progress of their disease. The Committee noted that these costs were not included in the modelling, but estimated that ranibizumab was likely to be cost effective if the cost to the NHS was limited such that the manufacturer pays for the drug cost of ranibizumab beyond 14\xa0injections in the treated eye.\n\nThe Committee then reconsidered the economic modelling undertaken for pegaptanib compared with best supportive care after taking into account the following assumptions: disease-modifying effect up to 1\xa0year after cessation of treatment ('year 3'), higher costs of blindness, costs of administering the injection as 75% day case and 25% outpatient, use of Brazier utility values, and 25% uptake of community care. In the Assessment Group model, this resulted in an ICER of £44,259 per QALY gained using a better-seeing eye strategy. Applying a 50% increase in these ICERs to include the treatment of the first eye, this ICER would become approximately £66,400 per QALY gained. The Committee also noted that the manufacturer's model produced a lower ICER of £34,602 per QALY gained based on the same assumptions using a better-seeing eye strategy, corresponding to approximately £51,900 per QALY gained when there is a policy of treating the first eye to come to clinical attention.\n\nThe Committee further considered that there could be differential gains from pegaptinib for different subgroups of patients according to their starting visual acuity. The Committee considered the position of the different subgroups with reference to cost effectiveness and to whether there were any steps which the Committee should take to fulfil NICE's duties under the equalities legislation. It considered whether it would be appropriate to recommend pegaptanib for a specific subgroup. It noted that focusing on the most responsive subgroup resulted in lower ICERs. The Committee noted that, after considering all its preferred assumptions, the ICERs were: £23,124 per QALY gained for the 6/12 to 6/24 visual acuity subgroup; £40,627 per QALY gained for the 6/24 to >6/60 subgroup; and £115,244 for the 6/60 to >3/60 visual acuity subgroup. Applying a 50% increase in these ICERs to include the treatment of the first eye, these ICERs would become approximately £34,700, £60,900 and £172,900 per QALY gained respectively. The Committee thus concluded that for all visual acuity subgroups, pegaptanib was not a cost-effective use of NHS resources. It concluded that there was no impact on any particular group of patients that required particular action in order to comply with the Institute's obligations under the equalities legislation. The Committee noted that ranibizumab would be recommended as a treatment option for the whole of the patient group.\n\nThe Committee discussed criteria for starting therapy with anti-VEGF treatments. It was in agreement in general with the criteria set out in the clinical trials for both drugs in terms of best-corrected visual acuity, no permanent structural damage to the central fovea, the lesion size being less than or equal to 12 disc areas in greatest linear dimension and that there is evidence of recent presumed disease progression as shown by blood vessel growth or visual acuity changes. The Committee was aware that to ensure the presence of wet AMD, it was essential that these criteria were met. The Committee also considered when treatment should be recommended as an option in terms of baseline visual acuity. It noted that the population in the clinical evidence base had a corrected visual acuity between 6/12 and 6/96, and that there was no evidence from ranibizumab studies that would allow consideration of differences in clinical and cost effectiveness between subgroups with different baseline visual acuity. The Committee therefore concluded that it would be appropriate for treatment with ranibizumab to be recommended at a visual acuity range between 6/12 and 6/96.\n\nThe Committee discussed the issue of discontinuing therapy. It noted the lack of a formal clinical guideline in this area, but thought it was important that continuation of treatment be carefully considered by patients and their clinicians. It discussed suggestions from clinical specialists for criteria for defining a loss of adequate response and concluded that a clear protocol for discontinuation in people who have a loss of adequate response to therapy should be developed. It thought that such a protocol should specify criteria for discontinuation, which are likely to include persistent deterioration in visual acuity and identification of anatomical changes in the retina that indicate inadequate response to therapy. The Committee thought that the most appropriate body to develop this protocol would be the Royal College of Ophthalmologists. Until such a protocol is developed it is recommended that locally agreed protocols be used. The Committee also noted that there could be a long gap between one dose and the need for the next dose. It concluded that in this situation treatment should be considered as continuous regardless of whether a patient had been discharged from a clinic in between doses.\n\nIn summary, the Committee concluded that both pegaptanib and ranibizumab are clinically effective in the treatment of wet AMD, but that ranibizumab is associated with greater clinical benefit. It concluded that treatment with ranibizumab of the eye to be treated would be cost effective if the manufacturer pays for the drug cost of ranibizumab beyond 14 injections in the treated eye. The Committee further concluded that treatment with pegaptanib for wet AMD is not a cost-effective use of NHS resources.", 'Recommendations for further research ': 'The Appraisal Committee considered that further research into the effectiveness of anti-VEGFs in wet AMD could include studies:\n\nabout the cost effectiveness of ranibizumab compared with bevacizumab\n\nto investigate the long-term effects of anti-VEGFs in patients with AMD, including effects on visual acuity, anatomical damage to the macula, quality of life and adverse events\n\nto establish the appropriate duration and optimal treatment regimen in terms of frequency of injections.', 'Related NICE guidance': 'Guidance on the use of photodynamic therapy for age-related macular degeneration. NICE technology appraisal 68 (2003).', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.\n\nThe guidance on this technology will be considered for review in February 2014.\n\nAndrew DillonChief ExecutiveAugust 2008', 'Changes after publication': 'February 2014: implementation section updated to clarify that ranibizumab and pegaptanib are recommended as options for treating age-related macular degeneration. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance\n\nMay 2012: re-issued after a change to the patient access scheme', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process. It has been re-issued after a change to the patient access scheme in May 2012. Recommendation 1.1 and section 5.3 have been updated.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta155
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Evidence-based recommendations on ranibizumab (Lucentis) and pegaptanib (Macugen) for treating wet age-related macular oedema in adults.
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595ff6d74ab5cfa42972b1b0d3b001d9917cd866
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nice
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Focal therapy using cryoablation for localised prostate cancer
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Focal therapy using cryoablation for localised prostate cancer
# Guidance
Current evidence on focal therapy using cryoablation for localised prostate cancer raises no major safety concerns. However, evidence on efficacy is limited in quantity and there is a concern that prostate cancer is commonly multifocal. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake focal therapy using cryoablation for localised prostate cancer should take the following actions.
Inform the clinical governance leads in their Trusts.
Ensure that patients and their carers understand the uncertainty about the procedure's efficacy and the risks (specifically the risk of sexual dysfunction), and provide them with clear written information. In addition, the use of NICE's information for patients (Understanding NICE guidance) is recommended.
Patient selection and treatment should be carried out by a multidisciplinary urological cancer team.
NICE encourages further research into focal cryoablation for localised prostate cancer. This should take the form of controlled studies comparing the procedure against other forms of management. Studies should clearly define patient selection criteria and should report outcomes including local recurrence in the long term.
Clinicians should collect data on all patients undergoing focal cryoablation (including details of case selection, methods of follow-up and outcomes) for local audit. Clinicians should enter details about all patients undergoing focal therapy using cryoablation for localised prostate cancer onto the European Registry for Cryosurgical Ablation of the Prostate (EuCAP) register and review clinical outcomes locally.# The procedure
# Indications and current treatments
Symptoms of localised prostate cancer include difficulty in passing urine, although the condition is often diagnosed at an asymptomatic stage.
Treatment options for patients with localised prostate cancer include active surveillance, radical prostatectomy, external beam radiotherapy, brachytherapy, and ablation of the whole gland using cryotherapy or high-intensity focused ultrasound (HIFU). All radical treatment options are associated with substantial risks of sexual, urinary or bowel dysfunction. Focal therapy using cryoablation is intended to be used in patients with localised prostate cancer – specifically patients with tumours that are confined to 1 prostatic lobe.
# Outline of the procedure
Imaging and biopsy mapping studies are used to confirm that the tumour is suitable for focal therapy and to show its precise location. Using local or general anaesthesia, the bladder is catheterised. Using transrectal ultrasound and a template placed on the perineum, fine needles are inserted transperineally into the prostate. Pressurised argon is passed through the needles to freeze the targeted area of the prostate, destroying the tissue. Implantable temperature probes and transrectal ultrasound guidance are used to monitor the treatment, and steps are taken to protect surrounding tissue from the effects of freezing.
After treatment patients are usually followed up regularly with prostate-specific antigen (PSA) measurements, imaging, and repeated biopsies to detect recurrence.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A case series of 54 patients reported overall and disease-specific survival of 100% of 48 patients at mean 4.5-year follow-up. In a register report of 1160 patients treated by focal cryoablation (total 5853 patients), the biochemical recurrence-free rate (as defined by the American Society for Therapeutic Radiation and Oncology ) was 76% (absolute numbers not given) at 3-year follow-up. Two case series of 54 and 60 patients reported biochemical recurrence-free survival of 94% (45/48) and 80% (41/51) of patients at mean 2-year and 15-month follow-up respectively. In a case series of 25 patients 36% (9/25) were considered to be biochemically disease-free (defined as a PSA nadir of 1.0 ng/ml or less) at median 28-month follow-up.
In the register report of 1160 patients, 164 patients underwent biopsy because of increased post-treatment serum PSA levels. Of these, 26% (43/164) had a positive biopsy at median 21-month follow-up. The case series of 60 patients reported positive findings in 40% (14/35) of patients who had a follow-up biopsy (tumours were in the untreated lobe except for 1 patient who had a positive biopsy result from the lobe that was treated by the procedure; this patient was treated with whole gland cryoablation). Eleven of these patients were treated with a second focal cryoablation procedure, after which 73% (8/11) were biochemically disease-free at mean 15-month follow-up. In the case series of 25 patients, 28% (7/25) had repeat biopsies and residual or recurrent cancer was found in 3 of these patients. All of these patients underwent repeat focal cryoablation and were biochemically disease-free at median 28-month follow-up.
The Specialist Advisers listed key efficacy outcomes for this procedure as biochemical disease-free survival and biopsy-proven absence of cancer.
# Safety
Sixty-seven per cent (40/60) of patients who were sexually potent before treatment became impotent immediately after treatment in the case series of 60 patients. Seventy-one per cent (24/34) of patients for whom data were available at 12-month follow-up had regained potency. In the case series of 54 patients 90% (36/40) of the patients who were potent before treatment remained potent after treatment.
With regard to urinary continence, the case series of 54 and 25 patients reported that all patients were continent after treatment. The case series of 60 patients reported incontinence in 4% (2/55) of the patients followed up for more than 6 months (neither patient required incontinence pads). The register report of 1160 patients reported urinary incontinence in 2% (8/507) of patients at 12-month follow-up.
Rectourethral fistula was reported in less than 1% (1/1160) of patients in the register report of 1160 patients at 12-month follow-up. In all 4 case series, there were no reports of fistulae developing after the procedure.
Prolonged urinary retention (> 30 days) was reported in 1.2% (6/518) of patients at 12-month follow-up in the register report of 1160 patients.
The case series of 54 patients reported that 1 patient required a transurethral prostatectomy for the removal of sloughed tissue.
The Specialist Advisers listed adverse events reported in the literature as erectile dysfunction and incontinence. They considered theoretical adverse events as urinary tract infection and pain.
# Other comments
The Committee was mindful of the variable natural history of prostate cancer: this underpinned the recommendation for controlled studies and the need for details of long-term outcomes.
The Committee noted the potential for this procedure to avoid many of the complications of more radical treatments for localised prostate cancer in properly selected patients, if further evidence supports its efficacy.
The Committee noted a number of patient commentaries that described benefits from the procedure, but which reported instances of sexual dysfunction.
The Committee noted variation in the methods used to deliver focal therapy using cryoablation for localised prostate cancer and that techniques are continuing to evolve.# Further information
For related NICE guidance see the NICE website.
Information for patients
NICE has produced information on this procedure for patients and carers (Understanding NICE guidance). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedures guidance process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical Excellence
Level 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': "Current evidence on focal therapy using cryoablation for localised prostate cancer raises no major safety concerns. However, evidence on efficacy is limited in quantity and there is a concern that prostate cancer is commonly multifocal. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake focal therapy using cryoablation for localised prostate cancer should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's efficacy and the risks (specifically the risk of sexual dysfunction), and provide them with clear written information. In addition, the use of NICE's information for patients (Understanding NICE guidance) is recommended.\n\nPatient selection and treatment should be carried out by a multidisciplinary urological cancer team.\n\nNICE encourages further research into focal cryoablation for localised prostate cancer. This should take the form of controlled studies comparing the procedure against other forms of management. Studies should clearly define patient selection criteria and should report outcomes including local recurrence in the long term.\n\nClinicians should collect data on all patients undergoing focal cryoablation (including details of case selection, methods of follow-up and outcomes) for local audit. Clinicians should enter details about all patients undergoing focal therapy using cryoablation for localised prostate cancer onto the European Registry for Cryosurgical Ablation of the Prostate (EuCAP) register and review clinical outcomes locally.", 'The procedure': '# Indications and current treatments\n\nSymptoms of localised prostate cancer include difficulty in passing urine, although the condition is often diagnosed at an asymptomatic stage.\n\nTreatment options for patients with localised prostate cancer include active surveillance, radical prostatectomy, external beam radiotherapy, brachytherapy, and ablation of the whole gland using cryotherapy or high-intensity focused ultrasound (HIFU). All radical treatment options are associated with substantial risks of sexual, urinary or bowel dysfunction. Focal therapy using cryoablation is intended to be used in patients with localised prostate cancer – specifically patients with tumours that are confined to 1\xa0prostatic lobe.\n\n# Outline of the procedure\n\nImaging and biopsy mapping studies are used to confirm that the tumour is suitable for focal therapy and to show its precise location. Using local or general anaesthesia, the bladder is catheterised. Using transrectal ultrasound and a template placed on the perineum, fine needles are inserted transperineally into the prostate. Pressurised argon is passed through the needles to freeze the targeted area of the prostate, destroying the tissue. Implantable temperature probes and transrectal ultrasound guidance are used to monitor the treatment, and steps are taken to protect surrounding tissue from the effects of freezing.\n\nAfter treatment patients are usually followed up regularly with prostate-specific antigen (PSA) measurements, imaging, and repeated biopsies to detect recurrence.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 54\xa0patients reported overall and disease-specific survival of 100% of 48\xa0patients at mean 4.5-year follow-up. In a register report of 1160\xa0patients treated by focal cryoablation (total 5853\xa0patients), the biochemical recurrence-free rate (as defined by the American Society for Therapeutic Radiation and Oncology [ASTRO]) was 76% (absolute numbers not given) at 3-year follow-up. Two case series of 54 and 60\xa0patients reported biochemical recurrence-free survival of 94% (45/48) and 80% (41/51) of patients at mean 2-year and 15-month follow-up respectively. In a case series of 25\xa0patients 36% (9/25) were considered to be biochemically disease-free (defined as a PSA nadir of 1.0\xa0ng/ml or less) at median 28-month follow-up.\n\nIn the register report of 1160\xa0patients, 164\xa0patients underwent biopsy because of increased post-treatment serum PSA levels. Of these, 26% (43/164) had a positive biopsy at median 21-month follow-up. The case series of 60 patients reported positive findings in 40% (14/35) of patients who had a follow-up biopsy (tumours were in the untreated lobe except for 1\xa0patient who had a positive biopsy result from the lobe that was treated by the procedure; this patient was treated with whole gland cryoablation). Eleven of these patients were treated with a second focal cryoablation procedure, after which 73% (8/11) were biochemically disease-free at mean 15-month follow-up. In the case series of 25\xa0patients, 28% (7/25) had repeat biopsies and residual or recurrent cancer was found in 3 of these patients. All of these patients underwent repeat focal cryoablation and were biochemically disease-free at median 28-month follow-up.\n\nThe Specialist Advisers listed key efficacy outcomes for this procedure as biochemical disease-free survival and biopsy-proven absence of cancer.\n\n# Safety\n\nSixty-seven per cent (40/60) of patients who were sexually potent before treatment became impotent immediately after treatment in the case series of 60\xa0patients. Seventy-one per cent (24/34) of patients for whom data were available at 12-month follow-up had regained potency. In the case series of 54\xa0patients 90% (36/40) of the patients who were potent before treatment remained potent after treatment.\n\nWith regard to urinary continence, the case series of 54 and 25\xa0patients reported that all patients were continent after treatment. The case series of 60\xa0patients reported incontinence in 4% (2/55) of the patients followed up for more than 6\xa0months (neither patient required incontinence pads). The register report of 1160\xa0patients reported urinary incontinence in 2% (8/507) of patients at 12-month follow-up.\n\nRectourethral fistula was reported in less than 1% (1/1160) of patients in the register report of 1160\xa0patients at 12-month follow-up. In all 4\xa0case series, there were no reports of fistulae developing after the procedure.\n\nProlonged urinary retention (>\xa030\xa0days) was reported in 1.2% (6/518) of patients at 12-month follow-up in the register report of 1160\xa0patients.\n\nThe case series of 54\xa0patients reported that 1\xa0patient required a transurethral prostatectomy for the removal of sloughed tissue.\n\nThe Specialist Advisers listed adverse events reported in the literature as erectile dysfunction and incontinence. They considered theoretical adverse events as urinary tract infection and pain.\n\n# Other comments\n\nThe Committee was mindful of the variable natural history of prostate cancer: this underpinned the recommendation for controlled studies and the need for details of long-term outcomes.\n\nThe Committee noted the potential for this procedure to avoid many of the complications of more radical treatments for localised prostate cancer in properly selected patients, if further evidence supports its efficacy.\n\nThe Committee noted a number of patient commentaries that described benefits from the procedure, but which reported instances of sexual dysfunction.\n\nThe Committee noted variation in the methods used to deliver focal therapy using cryoablation for localised prostate cancer and that techniques are continuing to evolve.', 'Further information': 'For related NICE guidance see the NICE website.\n\nInformation for patients\n\nNICE has produced information on this procedure for patients and carers (Understanding NICE guidance). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical Excellence\n\nLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}
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https://www.nice.org.uk/guidance/ipg423
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5a8450eac26e1566b46509e69ed0d27d1a5590b4
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nice
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Micropressure therapy for refractory Ménière's disease
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Micropressure therapy for refractory Ménière's disease
# Guidance
Current evidence on the safety of micropressure therapy for refractory Ménière's disease is inadequate in quantity. There is some evidence of efficacy, but it is based on limited numbers of patients. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake micropressure therapy for refractory Ménière's disease should take the following actions.
Inform the clinical governance leads in their Trusts.
Ensure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.
Audit and review clinical outcomes of all patients having micropressure therapy for refractory Ménière's disease (see section 3.1).
NICE encourages further research into micropressure therapy for refractory Ménière's disease. Research studies should report long-term outcomes, in particular the need for subsequent surgical treatment.# The procedure
# Indications and current treatments
Ménière's disease is characterised by symptoms of tinnitus, vertigo and deafness. Diagnosis of the disease is based on the American Academy of Otolaryngology–Head and Neck Surgery (AAO–HNS) Foundation's guidelines, based on the presence of recurrent, spontaneous episodic vertigo, hearing loss, aural fullness and tinnitus. It is thought to be caused by raised endolymph pressure in the inner ear (endolymphatic hydrops).
Surgery may be indicated for patients who are refractory to medical management and/or a low-salt diet. Surgical treatments include gentamicin vestibular ablation, labyrinthectomy, endolymphatic sac decompression and vestibular neurectomy.
# Outline of the procedure
Micropressure therapy for refractory Ménière's disease aims to reduce endolymph pressure in the inner ear by administering low-pressure air pulses through the tympanic membrane onto the round window membrane, with the aim of stimulating the flow of endolymphatic fluid.
With the patient under local or general anaesthesia, a grommet (ventilation tube) is inserted into the tympanic membrane of the affected ear. A few weeks later, after checking for patency of the grommet by the Valsalva manoeuvre, a hand-held air pressure generator forms an airtight seal in the outer ear. The device administers computer-controlled micropressure pulses across the tympanic membrane.
Three 60-second pulses are administered per treatment, with rest periods (usually less than 1 minute) between each pulse. Micropressure therapy is administered by the patient at home, usually 3 times per day. Treatment is normally continued for 4–6 weeks, but it can be used for longer.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A randomised controlled trial of 40 patients (20 treated by micropressure therapy and 20 treated by a sham procedure) reported a mean number of vertigo attacks of 1.9 and 4 respectively during the last 4 weeks of treatment (p = 0.09) (maximum follow-up 8 weeks). The same study reported a significantly improved functional level (measured using AAO–HNS criteria on a scale of 1 to 6, lower score indicates better functional level) in the micropressure therapy group compared with the sham group (2.4 compared with 3.5, p = 0.0014) during the last 4 weeks of treatment.
A case series of 36 patients reported a positive response (defined as a shift from Class D to Class A; AAO–HNS criteria) at 2-year follow-up after treatment in 69% (25/36) of patients (that is, patients went from having 81 to 120 vertigo spells over 6 months to no vertigo after treatment). A study of 22 patients reported a significant reduction in the mean number of vertigo attacks after 20 days: from 9.22 to 1.28 (p = 0.001) when the patients had grommet insertion only (n = 20), and from 9.22 to 1.67 (p < 0.001) when micropressure therapy was started (n = 18). There was no significant difference in the number of vertigo attacks between the two groups at 40 days.
In a case series of 37 patients, 79% (27/34) reported that the treatment had been helpful and had substantially improved their ability to perform daily tasks and work at 2-year follow-up.
The Specialist Advisers listed key efficacy outcomes as reduced frequency and severity of vertigo, improved hearing threshold, reduced tinnitus and reduced need for further therapy.
# Safety
Middle ear infection was reported in 5 patients in the case series of 37 patients; micropressure treatment was resumed after local antibiotics and grommet replacement.
Immediate postoperative ear discharge was reported in 6% (2/36) of patients in the case series of 36 patients.
The Specialist Advisers listed adverse events reported in the literature or anecdotally as post-tympanostomy otorrhoea, repeated need for short-stay ventilation tube insertion and permanent ear drum perforation if a long-stay ventilation tube is used. The Specialist Advisers considered theoretical adverse events to include infection of the grommet, loss of the ventilation tube in the middle ear, scarring of the ear drum and hearing loss.
# Other comments
The Committee noted that vertigo causes significant disability for some patients and that there is a lack of predictably efficacious conservative treatments for chronic vertigo in Ménière's disease. Therefore, if micropressure therapy were shown to be efficacious it could offer a useful option to improve quality of life in selected patients.
The Committee recognised the fluctuating course of Ménière's disease, which complicates the interpretation of evidence on its treatment.# Further information
This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedures guidance process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence, 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical Excellence
Level 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
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{'Guidance': "Current evidence on the safety of micropressure therapy for refractory Ménière's disease is inadequate in quantity. There is some evidence of efficacy, but it is based on limited numbers of patients. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake micropressure therapy for refractory Ménière's disease should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having micropressure therapy for refractory Ménière's disease (see section 3.1).\n\nNICE encourages further research into micropressure therapy for refractory Ménière's disease. Research studies should report long-term outcomes, in particular the need for subsequent surgical treatment.", 'The procedure': "# Indications and current treatments\n\nMénière's disease is characterised by symptoms of tinnitus, vertigo and deafness. Diagnosis of the disease is based on the American Academy of Otolaryngology–Head and Neck Surgery (AAO–HNS) Foundation's guidelines, based on the presence of recurrent, spontaneous episodic vertigo, hearing loss, aural fullness and tinnitus. It is thought to be caused by raised endolymph pressure in the inner ear (endolymphatic hydrops).\n\nSurgery may be indicated for patients who are refractory to medical management and/or a low-salt diet. Surgical treatments include gentamicin vestibular ablation, labyrinthectomy, endolymphatic sac decompression and vestibular neurectomy.\n\n# Outline of the procedure\n\nMicropressure therapy for refractory Ménière's disease aims to reduce endolymph pressure in the inner ear by administering low-pressure air pulses through the tympanic membrane onto the round window membrane, with the aim of stimulating the flow of endolymphatic fluid.\n\nWith the patient under local or general anaesthesia, a grommet (ventilation tube) is inserted into the tympanic membrane of the affected ear. A few weeks later, after checking for patency of the grommet by the Valsalva manoeuvre, a hand-held air pressure generator forms an airtight seal in the outer ear. The device administers computer-controlled micropressure pulses across the tympanic membrane.\n\nThree 60-second pulses are administered per treatment, with rest periods (usually less than 1\xa0minute) between each pulse. Micropressure therapy is administered by the patient at home, usually 3\xa0times per day. Treatment is normally continued for 4–6\xa0weeks, but it can be used for longer.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial of 40\xa0patients (20 treated by micropressure therapy and 20 treated by a sham procedure) reported a mean number of vertigo attacks of 1.9 and 4 respectively during the last 4\xa0weeks of treatment (p\xa0=\xa00.09) (maximum follow-up 8\xa0weeks). The same study reported a significantly improved functional level (measured using AAO–HNS criteria on a scale of 1 to 6, lower score indicates better functional level) in the micropressure therapy group compared with the sham group (2.4 compared with 3.5, p\xa0=\xa00.0014) during the last 4\xa0weeks of treatment.\n\nA case series of 36\xa0patients reported a positive response (defined as a shift from Class D to Class A; AAO–HNS criteria) at 2-year follow-up after treatment in 69% (25/36) of patients (that is, patients went from having 81 to 120 vertigo spells over 6\xa0months to no vertigo after treatment). A study of 22\xa0patients reported a significant reduction in the mean number of vertigo attacks after 20\xa0days: from 9.22 to 1.28 (p\xa0=\xa00.001) when the patients had grommet insertion only (n\xa0=\xa020), and from 9.22 to 1.67 (p\xa0<\xa00.001) when micropressure therapy was started (n\xa0=\xa018). There was no significant difference in the number of vertigo attacks between the two groups at 40\xa0days.\n\nIn a case series of 37\xa0patients, 79% (27/34) reported that the treatment had been helpful and had substantially improved their ability to perform daily tasks and work at 2-year follow-up.\n\nThe Specialist Advisers listed key efficacy outcomes as reduced frequency and severity of vertigo, improved hearing threshold, reduced tinnitus and reduced need for further therapy.\n\n# Safety\n\nMiddle ear infection was reported in 5\xa0patients in the case series of 37\xa0patients; micropressure treatment was resumed after local antibiotics and grommet replacement.\n\nImmediate postoperative ear discharge was reported in 6% (2/36) of patients in the case series of 36\xa0patients.\n\nThe Specialist Advisers listed adverse events reported in the literature or anecdotally as post-tympanostomy otorrhoea, repeated need for short-stay ventilation tube insertion and permanent ear drum perforation if a long-stay ventilation tube is used. The Specialist Advisers considered theoretical adverse events to include infection of the grommet, loss of the ventilation tube in the middle ear, scarring of the ear drum and hearing loss.\n\n# Other comments\n\nThe Committee noted that vertigo causes significant disability for some patients and that there is a lack of predictably efficacious conservative treatments for chronic vertigo in Ménière's disease. Therefore, if micropressure therapy were shown to be efficacious it could offer a useful option to improve quality of life in selected patients.\n\nThe Committee recognised the fluctuating course of Ménière's disease, which complicates the interpretation of evidence on its treatment.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nInformation for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence, 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical Excellence\n\nLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}
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Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis
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Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis
Evidence-based recommendations on fingolimod (Gilenya) for highly active relapsing-remitting multiple sclerosis.
# Guidance
Fingolimod is recommended as an option for the treatment of highly active relapsing–remitting multiple sclerosis in adults, only if:
they have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon, and
the manufacturer provides fingolimod with the discount agreed as part of the patient access scheme.
People currently receiving fingolimod whose disease does not meet the criteria in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.# The technology
Fingolimod (Gilenya, Novartis Pharmaceuticals UK) is a sphingosine-1-phosphate receptor modulator that prevents lymphocytes from crossing the blood–brain barrier and causing damage to nerve cells in the brain and spinal cord. Fingolimod has a marketing authorisation as a single disease-modifying therapy in highly active relapsing–remitting multiple sclerosis for the following groups:
Adults with high disease activity despite treatment with a beta interferon. These patients may be defined as 'those who have failed to respond to a full and adequate course (normally at least one year of treatment) of beta-interferon. Patients should have had at least one relapse in the previous year while on therapy, and have at least nine T2-hyperintense lesions in cranial magnetic resonance imaging (MRI) or at least one gadolinium-enhancing lesion. A "non-responder" could also be defined as a patient with an unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous year'.
Adults with rapidly evolving severe relapsing–remitting multiple sclerosis defined by two or more disabling relapses in 1 year, and with one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.
The most common adverse reactions to treatment with fingolimod include influenza virus infections, headaches, diarrhoea and elevated liver enzyme activity. The summary of product characteristics (SPC) states that 'macular oedema with or without visual symptoms has been reported in 0.4% of patients treated with fingolimod 0.5 mg, occurring predominantly in the first 3–4 months of therapy. An ophthalmological evaluation is therefore recommended at 3–4 months after treatment initiation'. For full details of adverse reactions and contraindications, see the SPC.
Fingolimod is given as a 0.5 mg oral dose once daily. The SPC states that 'patients can switch directly from beta interferon or glatiramer acetate to fingolimod provided there are no signs of relevant treatment-related abnormalities'. The list price of fingolimod is £1470 for 28 capsules (excluding VAT; MIMS July 2011), which is equivalent to an annual cost of approximately £19,169 per person. The manufacturer of fingolimod has agreed a patient access scheme with the Department of Health, in which a discount on the list price of fingolimod is offered. The size of the discount is commercial-in-confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of fingolimod and a review of this submission by the Evidence Review Group (ERG; appendix B).
The manufacturer presented three populations in its submission:
population 1a, consisting of people with highly active relapsing–remitting multiple sclerosis with at least one relapse in the previous year while on treatment with beta interferon and at least nine T2-hyperintense lesions on a brain MRI or at least one gadolinium-enhancing lesion
population 1b, consisting of people with highly active relapsing–remitting multiple sclerosis who have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon
population 2, consisting of people with rapidly evolving severe relapsing–remitting multiple sclerosis defined by two or more disabling relapses in 1 year, and with one or more gadolinium-enhancing lesions on a brain MRI or a significant increase in T2 lesion load compared with a previous recent MRI. The manufacturer's original submission focused on population 1b, but demographic data were also provided for populations 1a and 2. The manufacturer's base-case analysis considered the effect of fingolimod in population 1b relative to beta interferon-1a (Avonex). The outcomes defining effectiveness included the number of confirmed relapses during a 12-month period (annualised relapse rate), confirmed disability progression at 3 months, mortality, adverse reactions to treatment and health-related quality of life.
The manufacturer undertook a systematic literature review and identified two randomised controlled trials, the FREEDOMS trial and the TRANSFORMS trial, which both assessed the efficacy and safety of fingolimod in adults with relapsing–remitting multiple sclerosis. The FREEDOMS trial was a phase III, multicentre, double-blind trial in which 1272 adults with relapsing–remitting multiple sclerosis were randomised to receive daily doses of oral fingolimod 0.5 mg (425 patients), oral fingolimod 1.25 mg (429 patients) or placebo (418 patients) for 24 months. In the FREEDOMS trial, 90 patients treated with fingolimod 0.5 mg and 79 patients treated with placebo were considered by the manufacturer to meet the criteria for population 1b. The TRANSFORMS trial was a phase III, multicentre, double-blind trial in which 1292 adults with relapsing–remitting multiple sclerosis were randomised to receive oral fingolimod 0.5 mg (431 patients) or oral fingolimod 1.25 mg (426 patients) once a day, or intramuscular Avonex 30 micrograms (435 patients) once a week for 12 months. In the TRANSFORMS trial, 191 patients who were treated with fingolimod 0.5 mg and 183 patients who received Avonex met the criteria for population 1b in the decision problem. Only data relating to fingolimod 0.5 mg are presented in the remaining sections of this document.
Patients were eligible for inclusion in the FREEDOMS and TRANSFORMS trials if they had an Expanded Disability Status Scale (EDSS) score between 0 and 5.5 (the EDSS ranges from 0 to 10 with 0.5-unit increments representing higher levels of disability), and at least one documented relapse during the previous year or at least two documented relapses during the 2 years preceding study enrolment. The primary outcome of the trials was annualised relapse rate. Secondary outcomes included disability progression confirmed after 3 months, time to first relapse and radiological outcomes, such as the number of new or enlarged lesions. In the FREEDOMS trial, patient-reported outcomes were assessed using the EuroQoL 5-dimension survey (EQ-5D). Quality-of-life data were collected in the TRANSFORMS trial using the Patient-Reported Indices for Multiple Sclerosis – Quality of life (PRIMUS–QoL), the Patient-Reported Indices for Multiple Sclerosis – Activities (PRIMUS–Activities) and the Unidimensional Fatigue Impact Scale (UFIS).
Results from the FREEDOMS and TRANSFORMS trials showed that the annualised relapse rates were statistically significantly reduced for all patients treated with fingolimod compared with placebo (0.18 compared with 0.40; p < 0.001) and those treated with fingolimod compared with Avonex (0.16 compared with 0.33; p < 0.001). Treatment with fingolimod also reduced the annualised relapse rates (primary outcome) for patients in population 1b in the manufacturer's submission (see section 3.1), compared with placebo (0.21 compared with 0.54; p < 0.001) and for those who received fingolimod compared with Avonex (0.25 compared with 0.51; p < 0.001). In the TRANSFORMS trial, 94.1% of all patients treated with fingolimod had no disability progression after 3 months (95% confidence interval 91.8 to 96.3) compared with 92.1% of all patients treated with Avonex (95% CI 89.4 to 94.7); however, this difference was not statistically significant (p = 0.25). Among the whole population of the FREEDOMS trial, 82.3% of patients treated with fingolimod had no disability progression after 3 months compared with 75.9% of all patients treated with placebo (p = 0.03). No statistically significant difference in disability progression between the treatment groups was reported for population 1b. The manufacturer pointed to the European Public Assessment Report of the European Medicines Agency which stated that the results in the subgroups with highly active disease were consistent with those obtained in the overall trial population.
Fingolimod was well tolerated by patients in the clinical trials. It was considered to have a comparable safety profile to placebo and to be associated with fewer adverse reactions than Avonex. The incidence of serious adverse reactions after treatment with fingolimod was low across both studies, with the most common being infections, macular oedema and transient atrioventricular block at treatment initiation. In the TRANSFORMS trial, adverse reactions leading to treatment discontinuation in population 1b were reported in 3.1% of patients treated with fingolimod compared with 1.6% of patients treated with Avonex. In the FREEDOMS trial, the rate of treatment discontinuation because of adverse reactions in population 1b was lower in patients receiving fingolimod (2.2%) compared with placebo (7.6%). There were no treatment-related deaths reported with fingolimod or Avonex treatment in the TRANSFORMS trial. In the FREEDOMS trial, no treatment-related deaths were reported among patients receiving fingolimod or placebo.
In the TRANSFORMS trial, patients who received fingolimod showed significantly less deterioration in their ability to perform daily activities according to the PRIMUS–Activities scale compared with patients receiving Avonex (change from baseline 0.08 in patients treated with fingolimod compared with 0.43 in patients treated with Avonex; p < 0.05). In addition, a slight, non-significant improvement in health-related quality of life, as measured on the PRIMUS–QoL scale, was observed in patients treated with either fingolimod or Avonex. After 6 months of treatment with fingolimod, patients showed a statistically significant improvement in UFIS score compared with patients treated with Avonex; however, at 12 months this difference between the groups was no longer statistically significant. In the FREEDOMS trial, no statistically significant changes from baseline for EQ-5D measures were observed in patients with relapsing–remitting multiple sclerosis treated with fingolimod or placebo.
To estimate the relative effectiveness of all of the comparators in the absence of direct evidence, the manufacturer conducted a mixed treatment comparison of 18 trials that assessed annualised relapse rates, disability progression and treatment discontinuation because of adverse reactions, for the following interventions: fingolimod, natalizumab, beta interferon-1a (Avonex, Rebif-22 and Rebif-44), beta interferon-1b (Betaferon), glatiramer acetate and placebo. The manufacturer acknowledged that although the populations in the included trials had a clinical diagnosis of relapsing–remitting multiple sclerosis, they did not fully meet the criteria for highly active disease described in the marketing authorisation for fingolimod. There was also considerable clinical heterogeneity between the trials with respect to permitted and actual prior use of disease-modifying treatments, treatment duration and the criteria used to define the trial end points. As a consequence, the manufacturer did not use the results of the mixed treatment comparison to inform the economic model. Instead, an indirect comparison using the TRANSFORMS and FREEDOMS trials provided an estimate of the relative efficacy of Avonex and placebo for population 1b in the model.
The manufacturer undertook a systematic search but did not identify any economic evaluations of fingolimod for the treatment of relapsing–remitting multiple sclerosis. The manufacturer submitted a de novo economic model that is structurally similar to models used in previous NICE technology appraisal guidance on treatments for multiple sclerosis (Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis and Beta interferon and glatiramer acetate for the treatment of multiple sclerosis ). The model is based on a Markov cohort approach and estimates disease progression through 21 disability states that are defined by EDSS score (ranging from 0 to 10) and account for disability for patients with relapsing–remitting multiple sclerosis (10 states), patients with secondary progressive multiple sclerosis (10 states) and death. In each cycle of the model, a patient with relapsing–remitting multiple sclerosis can progress to a worse EDSS state or remain in the same state. Patients can also convert from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis; however, once a patient reaches this point in the disease course they cannot convert back to relapsing–remitting disease. Only people with relapsing–remitting multiple sclerosis and an EDSS score of 6 or less are assumed to receive disease-modifying treatment in the model. People with an EDSS score greater than 6, or with secondary progressive multiple sclerosis, are assumed to receive best supportive care.
Disability progression rates in the model were defined in a natural history transition matrix and derived from a longitudinal data set from patients with multiple sclerosis in Ontario, Canada. The manufacturer excluded patients with less progressive forms of relapsing–remitting multiple sclerosis from the data set and adjusted the natural history transition matrices to represent patients for whom treatment with disease-modifying therapies would be suitable. The probability of relapse in each model cycle was determined using published sources to estimate the natural history of relapses by disease type and EDSS stage.
All patients were individually followed through the model from treatment initiation for a maximum of 50 years. Probabilities for all-cause mortality for the general population were derived using current statistics for England and Wales, and were then adjusted for patients with multiple sclerosis using mortality ratios from published sources. A published equation was also used to predict the excess mortality for individual EDSS states.
The relative risks of annual relapse rate and of disability progression for fingolimod treatment compared with best supportive care were calculated from the FREEDOMS trial. The corresponding relative risk value for Avonex was calculated indirectly from the TRANSFORMS trial. The relative risks associated with disease progression and relapse were constant over the entire on-treatment period. Discontinuations because of adverse reactions were included in the model based on trial data. The relative risks for disease progression were not applied to patients with secondary progressive multiple sclerosis (who receive best supportive care in the model); instead, patients entering this disease state followed the natural history of the disease (as predicted by data from Ontario, Canada).
Although quality-of-life data were collected in the TRANSFORMS and FREEDOMS trials, the manufacturer did not use these to estimate utilities for the model. Instead, published EDSS-based EQ-5D scores were used, in line with those from NICE technology appraisal guidance 127 and 32. Health-related quality of life was assumed to remain constant over time for each EDSS score, but a single adjustment (0.01 utility gain for each 5-year period) was made to reflect the time since diagnosis. Utility decrements attributable to adverse reactions were applied for the whole duration of the treatment period. The model also incorporated caregiver's disutility for each EDSS score in the base case, in line with estimates from NICE technology appraisal guidance 127. The maximum disutility for a caregiver of a person with multiple sclerosis was assumed to be 0.14 (EDSS 9).
The resource costs included in the model were drug acquisition costs, administration and monitoring costs, and the cost of the disease, which included the cost of each EDSS state, the cost of relapse and the costs associated with serious adverse reactions. Costs associated with non-serious adverse reactions were not considered in the model. The model assumes that when patients discontinue treatment with disease-modifying therapy and receive best supportive care, the only costs incurred are the disease costs by EDSS states.
The original base-case incremental cost-effectiveness ratio (ICER) for fingolimod compared with Avonex was £55,634 per QALY gained for population 1b (patient access scheme not included). Cost-effectiveness analyses for population 1a and population 2 (defined in section 3.1) were not provided by the manufacturer. One-way sensitivity analyses suggested that the ICER for fingolimod compared with Avonex was most sensitive to the relative risks of disease progression assumed for fingolimod and Avonex, and the relative risk of relapse for Avonex. Uncertainty in all other parameter values led to only small changes in the ICER. Results of a probabilistic sensitivity analysis showed that there was a 12% probability that the base-case ICER was less than £20,000 per QALY gained, and a 26% probability that it was less than £30,000 per QALY gained.
The manufacturer explored uncertainty in the model caused by structural assumptions, including possible waning of treatment effect and the assumed time horizon. When treatment efficacy was assumed to be reduced by 50% or 75% after the first 2 years of treatment, the ICER increased to £73,191 and £85,266 per QALY gained respectively. When the time horizon was shortened to 10 years and 20 years, the ICER increased to £97,159 and £64,280 per QALY gained respectively.
The manufacturer acknowledged that there was considerable overlap between the populations defined in the marketing authorisation for fingolimod, and provided an analysis for a subgroup of population 1b that excluded patients who also met the criteria for population 2 (that is, it excluded those with rapidly evolving severe multiple sclerosis). The relative treatment effects estimated from the trials for this subgroup were significantly different from those estimated for the whole of population 1b. In particular, the risk of disease progression with Avonex was estimated (by indirect comparison) to be higher than with placebo. The manufacturer's ICER for fingolimod compared with Avonex in this subgroup was £18,741 per QALY gained (patient access scheme not included). No sensitivity analyses were conducted for this subgroup.
In its response to the first appraisal consultation document, the manufacturer included a patient access scheme, which was agreed with the Department of Health, to apply a simple confidential discount to the list price of fingolimod. The manufacturer's deterministic base-case ICER for fingolimod in population 1b reduced to £10,839 per QALY gained compared with Avonex when the discounted price of fingolimod was included in the model. The probabilistic ICER determined by the manufacturer, including the patient access scheme, was £15,825 per QALY gained. Probabilistic sensitivity analyses suggested that there was a 58% chance that the ICER for fingolimod would be less than £30,000 per QALY gained when the discounted price was included.
Sensitivity analyses provided by the manufacturer in response to the first appraisal consultation document suggested that the ICER for fingolimod compared with Rebif-44 was £27,774 per QALY gained (patient access scheme included). The manufacturer noted that the data to inform this analysis were from patients with relapsing–remitting multiple sclerosis, rather than from those who had a suboptimal response to disease-modifying therapy (that is, population 1b), and therefore the true ICER for population 1b was likely to be lower. The manufacturer also compared fingolimod with Rebif-22 and Betaferon using adjusted data from the mixed treatment comparison. Efficacy rates for each treatment were scaled down by 13.25% to account for the fact that the clinical effects seen in the trials for people with relapsing–remitting multiple sclerosis were likely to be reduced in population 1b. The ICERs from this analysis for fingolimod were £23,587 per QALY gained compared with Rebif-22, and £27,660 per QALY gained compared with Betaferon (patient access scheme included).
In its response to the second appraisal consultation document, the manufacturer provided an updated economic model incorporating the following assumptions which the Committee had concluded to be more plausible:
using utility data from the trials where available, and then published data from Orme et al. (2007) for the remaining EDSS states
a 50% waning of treatment effect at 5 years.The manufacturer presented probabilistic rather than deterministic results from the updated model. After incorporating these changes, the probabilistic ICERs in population 1b were £17,275 per QALY gained for fingolimod compared with Avonex, and £30,936 per QALY gained for fingolimod compared with Rebif-44. Using the updated model, the manufacturer also provided an analysis of fingolimod compared with a weighted average of best supportive care and a mixture of beta interferon treatments (Avonex, Rebif-22, Rebif-44, Betaferon and Extavia). Proportions of each beta interferon treatment were determined according to market share data from the Prescription Pricing Authority, to reflect the current formulations most commonly used in UK clinical practice. The manufacturer assumed that best supportive care represented 5% of the weighted average, in line with clinical opinion and audits from UK multiple sclerosis centres. Results from this analysis showed that the probabilistic ICER for fingolimod compared with the weighted average of the comparators was £27,820 per QALY gained (incremental costs £20,122; incremental QALYs 0.723). Sensitivity analyses provided by the manufacturer showed that the ICER for fingolimod compared with the weighted average of the comparators ranged from £25,000 to approximately £30,000 when the contribution of best supportive care to the comparator was varied between 0% and 10%.
In response to the second appraisal consultation document, the manufacturer also explored the directional effect on the ICER of changing the natural history transition matrix to slow disability progression. The manufacturer noted that in the FREEDOMS and TRANSFORMS trials, the greatest disability progression was three EDSS states within a 12-month period. In a scenario analysis which assumed that people could not progress more than one EDSS state each year in the relapsing–remitting multiple sclerosis natural history matrix, the manufacturer's probabilistic ICER for fingolimod compared with Avonex increased to £21,244 per QALY gained. When it was assumed that people could not progress more than one EDSS state each year in the secondary progressive multiple sclerosis natural history matrix, the probabilistic ICER increased to £19,774 per QALY gained. In the manufacturer's view, these scenario analyses were based on extreme assumptions that did not reflect the available clinical data for patients with relapsing–remitting multiple sclerosis.
The ERG considered that the TRANSFORMS and FREEDOMS trials were well designed to assess the efficacy of fingolimod in patients with relapsing–remitting multiple sclerosis. The ERG noted that the populations in the clinical trials were broader than those defined in the marketing authorisation for fingolimod, but considered that the manufacturer's post-hoc subgroup analyses provided a reasonable approximation to the populations in the marketing authorisation. The ERG noted that population 1b comprised only 43.6% of patients in the TRANSFORMS trial and 19.7% of patients in the FREEDOMS trial. The ERG was concerned that because of the smaller number of patients, the power of the trials to assess fingolimod relative to the comparators in the populations covered by the marketing authorisation was reduced. However, the ERG noted that the SPC for fingolimod states that 'further analyses of clinical trial data demonstrate consistent treatment effects in the highly active subgroups of relapsing–remitting multiple sclerosis'. The ERG was also concerned that there was considerable overlap between the populations and requested separate analyses from the manufacturer for population 1a, population 2, and populations 1a and 1b with patients who also met the criteria for population 2 excluded. The manufacturer provided analyses only for population 1b excluding patients who also met the criteria for population 2.
The ERG was concerned by the manufacturer's approach of using only Avonex as the comparator treatment for population 1b. The ERG noted that population 1b constitutes patients with highly active disease that has remained unchanged or worsened despite treatment with beta interferon. In the ERG's view, a comparison with Avonex may represent continued use of a treatment that is suboptimal in this group of patients, and may also cause adverse reactions. The ERG also noted that the results from the manufacturer's mixed treatment comparisons did not yield clear differences between the beta interferons in patients with relapsing–remitting multiple sclerosis in terms of disease progression and annualised relapse rates. It cautioned that a comparison solely with Avonex could underestimate the ICER of fingolimod and therefore reasoned that a comparison including best supportive care would have been more appropriate.
The ERG considered the additional cost-effectiveness analysis from the manufacturer for the subgroup consisting of population 1b without those who also met the criteria for population 2 (section 3.16). The ERG noted that the ICER for fingolimod compared with Avonex was more favourable for this subgroup than for the whole of population 1b. The ERG considered that this difference was largely attributable to the revised relative efficacy estimates for Avonex from the manufacturer's indirect comparison for this subgroup. This suggested that Avonex provides less benefit than placebo (that is, that Avonex was associated with an increased risk of disease progression compared with placebo).
The ERG was concerned about the resources and costs assumed in the manufacturer's original model. The ERG was unclear why the costs associated with only some severe adverse reactions were included in the model, and why the costs associated with non-serious adverse reactions were not included. The ERG was also unclear whether costs associated with relapsing–remitting multiple sclerosis were different from those associated with secondary progressive multiple sclerosis. In addition, the ERG noted that the cost of relapse used in the model was significantly different from the cost from other data sources and in NICE technology appraisal guidance 127. In the ERG's view, the manufacturer had not adequately justified the administrative and monitoring costs for fingolimod and Avonex. In particular, it was unclear why the manufacturer assumed that patients treated with Avonex would need two more neurology visits in the first year of treatment than patients who received fingolimod. The ERG noted that in response to consultation on the first appraisal consultation document the manufacturer provided additional justification for the resource use and cost assumptions included in the model, and showed that alternative assumptions only slightly increased the ICER.
The ERG noted that although the manufacturer had included a probabilistic model in its original submission, the cost-effectiveness results presented in the original submission were deterministic. The ERG provided a probabilistic analysis for the manufacturer's original base case that gave an ICER of £69,787 per QALY gained for fingolimod compared with Avonex (patient access scheme not included). This ICER was noted to be substantively higher than the manufacturer's original deterministic estimate of £55,634 per QALY gained.
The ERG noted that the manufacturer had presented adjusted hazard ratios in its original submission to describe the relative effect on disease progression of treatment with fingolimod compared with Avonex. However, these estimates were not employed in the model, and instead relative risks from unadjusted trial data were used. The ERG analysed the manufacturer's original base case (population 1b) using hazard ratios instead of relative risks (patient access scheme not included) and noted that, in an incremental analysis, the probabilistic ICER for fingolimod compared with best supportive care was £94,094 per QALY gained. In an incremental analysis, Avonex was extendedly dominated (that is, the ICER for Avonex was higher than the ICER for the next more effective alternative ). For population 1b, excluding those who also met the criteria for population 2, the ICER for fingolimod compared with best supportive care was £81,369 per QALY gained and Avonex was dominated by best supportive care (Avonex was less effective and more expensive). The ERG concluded that the incremental analysis shows that in both populations Avonex is either dominated or extendedly dominated. The ERG therefore advised that the cost effectiveness of fingolimod should be derived from this incremental analysis. The ERG acknowledged that the manufacturer had provided an additional analysis in response to the first appraisal consultation document. In this analysis, hazard ratio values were applied as relative risks in the model, and this reduced the deterministic base-case ICER from £55,634 (section 3.14) to £52,906 per QALY gained for population 1b. In the ERG's view the manufacturer's additional analyses did not address its initial concerns, because it considered that the hazard ratio values used should have been applied as hazard ratios, rather than relative risks, in the probabilistic (not the deterministic) model.
The ERG was concerned that the manufacturer provided insufficient justification in its original submission for choosing published EDSS-based EQ-5D scores rather than the trial outcomes to derive utility data. The ERG cautioned that although the published utility data had been used in previous NICE technology appraisal guidance on treatments for multiple sclerosis, these data had been criticised for coming from studies with low response rates, possible selection bias and unrepresentative populations. The ERG suggested that because the manufacturer's base case targeted a very specific patient population (population 1b), it would have been more appropriate to use utility data for these patients, which were available directly from the FREEDOMS and TRANSFORMS trials. The ERG conducted an exploratory analysis to assess the impact of using the average utilities for each EDSS score in the trial (up to EDSS 6) and then using published sources to impute the missing utility data for EDSS scores of 7 and above. In this analysis, the probabilistic ICER for fingolimod compared with best supportive care in population 1b increased to £106,824 per QALY gained (patient access scheme not included) when the missing utility estimates for EDSS scores 7 to 10 were imputed using values from NICE technology appraisal guidance 127. Based on these results, the ERG cautioned that changing the utility values of only three EDSS scores has a significant impact on the ICER for fingolimod. The ERG acknowledged that in the manufacturer's response to the first appraisal consultation document an additional analysis was provided in which utility data from the trials were used for EDSS states up to 6, and then data from a study by Orme et al. (2007) were used for the remaining 13 states. Using data from the FREEDOMS and TRANSFORMS trials reduced the manufacturer's original deterministic base-case ICER for fingolimod compared with Avonex to £52,982 per QALY gained and £52,866 per QALY gained respectively. In its critique of the manufacturer's original submission, the ERG had previously explored a number of alternative scenarios for incorporating trial utility data into the model, which were shown to both increase and decrease the ICERs. The ERG cautioned that the model predictions are highly sensitive to the utility estimates and therefore it is important to fully justify the data sources and imputation methods used.
The ERG was concerned about the representativeness of the initial EDSS score distribution used in the manufacturer's original model. The ERG examined a number of scenarios and showed that the cost effectiveness of fingolimod varies depending on the initial distribution of patients across EDSS states. The ICER for fingolimod compared with best supportive care in population 1b was £78,338 per QALY gained when it was assumed that all people enter the model with an EDSS score of 4, and £102,718 per QALY gained when all people enter the model with an EDSS score of 2 (patient access scheme not included). The ERG considered that its analyses highlighted that the model was highly sensitive to the initial population EDSS distribution assumed.
The ERG noted from market share data provided by the manufacturer that Rebif-44 is commonly prescribed in the NHS for the treatment of multiple sclerosis. The ERG conducted two exploratory analyses that included Rebif-44 as an additional comparator. The first analysis used direct evidence on the effectiveness of Rebif-44 and Avonex, and the second used the results from the mixed treatment comparison provided by the manufacturer (patient access scheme not included). Deterministic results were calculated using relative risks from the direct evidence and showed that Rebif-44 dominated Avonex in population 1b and in the subgroup of population 1b that excluded patients who also met the criteria for population 2. However, for population 1b, Rebif-44 was extendedly dominated (that is, the ICER for Rebif-44 was higher than the ICER for the next more effective alternative ) in an incremental analysis. The ICER for fingolimod compared with best supportive care was £91,059 per QALY gained for population 1b, and £79,315 per QALY gained for population 1b without those who also met the criteria for population 2. When data from the manufacturer's mixed treatment comparison were used instead, Avonex was dominated by Rebiff-44 for both populations. The ICER for fingolimod compared with best supportive care was £119,213 per QALY gained for population 1b and £119,746 per QALY gained for population 1b without those who also met the criteria for population 2.
The ERG noted that the baseline relapse rates in the manufacturer's original model were dependent on EDSS state but were then adjusted by the relative risk of relapse with a particular disease-modifying therapy compared with best supportive care. The ERG was concerned that these estimates for relative effect were taken from different data sets and therefore had no implicit correlation. In addition, the ERG cautioned that the impact of disease-modifying therapy could be double-counted in the model. To explore this, the ERG re-ran the original model (patient access scheme not included) and excluded all direct treatment effects on relapse rates. For population 1b, the ICER for fingolimod compared with best supportive care increased to £112,294 per QALY gained compared with the ERG's base-case estimate of £94,094 per QALY gained. Avonex was extendedly dominated by best supportive care and fingolimod. For population 1b without those who also met the criteria for population 2, the ICER for fingolimod compared with best supportive care was £98,019 per QALY gained compared with £81,369 per QALY gained in the ERG's base case, and Avonex was dominated by best supportive care.
The ERG was concerned that the underlying progression rates predicted in the manufacturer's original model were higher than the rates seen in the TRANSFORMS and FREEDOMS trials, but the manufacturer did not explain the differences between the model predictions and the trial observations. The ERG conducted four scenario analyses to examine the sensitivity of the manufacturer's model to natural history progression rates. These included reducing natural history progression transitions by 50%, 25% and 10%, and increasing them by 10%. Reducing the natural history progression rates substantially increased the ICER for fingolimod compared with best supportive care. Assuming a 50% decrease in natural history progression rate increased the ICER to £252,147 per QALY gained for population 1b, and to £191,027 per QALY gained for population 1b without those who also met the criteria for population 2 (patient access scheme not included). The ERG considered that the model predictions were highly sensitive to the natural history progression data used in the model.
The ERG noted that the manufacturer's original model assumed a constant and continued treatment effect in patients who receive disease-modifying therapy, as long as they remain on treatment, over the time horizon of the model. In the ERG's view this assumption, which was informed by trials of only 12 months' and 24 months' duration, was optimistic. The ERG conducted an exploratory analysis (expanding on the manufacturer's sensitivity analysis; patient access scheme not included) to evaluate the possible waning of treatment effect over time. Treatment efficacy was modelled to wane by 50%, 75% or 100% of the original level after 2 years and 5 years. In all scenarios, the more the efficacy was reduced, the higher the ICER. This is because the costs of treatment are still incurred but less health benefit is obtained. When the treatment effect was assumed to wane after 2 years, the ICERs for fingolimod compared with best supportive care were £140,282 per QALY gained (50% efficacy reduction), £177,674 per QALY gained (75% efficacy reduction) and £249,735 per QALY gained (100% efficacy reduction). When it was assumed that the treatment effect does not wane until after 5 years, the ICERs for fingolimod compared with best supportive care were £114,532 per QALY gained for a 50% efficacy reduction, £131,135 per QALY gained for a 75% efficacy reduction and £143,869 per QALY gained for a 100% efficacy reduction.
The ERG reviewed the revised model provided by the manufacturer in response to the first appraisal consultation document. It noted that the manufacturer only adjusted the drug acquisition cost in the model in line with the patient access scheme. The ERG noted that the manufacturer had not updated the model to reflect the assumptions that the Committee had considered to be most plausible during the first Committee meeting. The ERG ran the manufacturer's updated model including the patient access scheme and produced a probabilistic base-case ICER for fingolimod compared with Avonex of £14,997 per QALY gained. The ERG also produced an incremental analysis using the manufacturer's updated model which showed that the probabilistic ICER for fingolimod was £58,024 per QALY gained compared with best supportive care, and Avonex was extendedly dominated by fingolimod and best supportive care with an ICER of £176,357 per QALY gained. The ERG cautioned that despite the discounted drug acquisition cost, the remaining uncertainties around the model and its inputs still remained.
The ERG reviewed the revised model provided by the manufacturer in response to the second appraisal consultation document. The ERG confirmed that the manufacturer had correctly revised its model to incorporate the assumptions that the Committee had considered important for exploring the uncertainty surrounding the base-case ICER during its second meeting. The ERG confirmed that it was able to approximate the manufacturer's probabilistic cost-effectiveness results for fingolimod compared with Avonex and for fingolimod compared with Rebif-44. However, it was unable to fully verify the manufacturer's ICER for fingolimod compared with the weighted average of the comparators, because results for some of the comparators (best supportive care and Betaferon) could not be reproduced from the manufacturer's model. The ERG urged caution in using a weighted average for the comparators and considered that a fully incremental analysis was a more appropriate way to explore the cost effectiveness of fingolimod relative to multiple comparators.
Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available on the NICE website.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of fingolimod, having considered evidence on the nature of highly active relapsing–remitting multiple sclerosis and the value placed on the benefits of fingolimod by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee understood from the patient experts that multiple sclerosis is a chronic, disabling, neurological condition that is life altering and has a substantial negative impact on quality of life and activities of daily living. The patient experts placed particular emphasis on loss of independence and implications for employment. They also described a significant impact on emotional wellbeing, which can lead to depression. The Committee understood that any delay or relief from these problems would have a positive impact on the lives of people with multiple sclerosis and their families. The Committee also heard from the patient experts that fingolimod would allow greater flexibility and decrease discomfort because it is given orally whereas other currently available treatments are administered by injection.
The Committee heard from the clinical specialists that treatment of relapsing–remitting multiple sclerosis is determined by the severity of the disease. This, in turn, is determined by the number and severity of relapses and by disability caused by the persistent effects of relapse or by the development of secondary progressive multiple sclerosis. For people with rapidly evolving severe relapsing–remitting multiple sclerosis (whose condition is described in section 2.1), natalizumab is often considered as a first-line treatment in line with NICE technology appraisal guidance 127. A beta interferon or glatiramer acetate is routinely offered to most patients without rapidly evolving severe disease. The Committee also noted comments from consultees that approximately one-third of people may choose not to have a disease-modifying treatment (watchful waiting). The Committee heard from the clinical specialists that after a suboptimal response to the first disease-modifying treatment used, clinicians are likely either to offer a different beta interferon or glatiramer acetate, or offer the patient a higher dose of beta interferon (such as Rebif-44). The Committee also heard that clinicians are generally reluctant to stop treatment altogether after a suboptimal response. The Committee acknowledged market research data from the manufacturer and survey results from 116 consultant neurologists and specialist multiple sclerosis nurses which collectively showed that no more than 5–10% of patients are likely to receive best supportive care (no active treatment) after a suboptimal response to previous disease-modifying treatments. The Committee noted that beta interferons and glatiramer acetate were not recommended in NICE technology appraisal guidance 32. However, it acknowledged that after this guidance was issued, the Department of Health agreed a risk-sharing scheme with manufacturers through which disease-modifying treatments for multiple sclerosis can be provided to patients in the NHS, albeit at a level of cost effectiveness above what is considered an appropriate use of NHS resources as defined in the NICE Guide to the methods of technology appraisal (2008).
The Committee considered the likely place of fingolimod in the treatment of relapsing–remitting multiple sclerosis. The Committee understood that although clinical practice varies among neurologists, many clinical specialists would consider fingolimod as a second or subsequent line of treatment for people with high disease activity despite treatment with beta interferon or glatiramer acetate. It heard from the clinical specialists that fingolimod would provide the greatest benefit to people with rapidly evolving severe relapsing–remitting multiple sclerosis, because they currently have very few treatment options. The Committee acknowledged the clinical specialists' disappointment that a recommendation for the use of fingolimod in this population could not be made because the manufacturer had not submitted an analysis of fingolimod compared with natalizumab in this population.
The Committee understood from the clinical specialists and patient experts that fingolimod is generally well tolerated and that the adverse reactions expected during treatment could be satisfactorily managed in routine clinical practice.
# Clinical effectiveness
The Committee noted that only part of the population covered by the marketing authorisation for fingolimod was considered in the manufacturer's submission, that is, people with highly active relapsing–remitting multiple sclerosis who have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon (population 1b). The Committee noted that the manufacturer's reason for this was that this population represented the largest subgroup in the clinical trials of fingolimod. The Committee concluded that it could only make a recommendation on the use of fingolimod for the population presented in the manufacturer's submission (that is population 1b). It would be unable to make any recommendations for the use of fingolimod in any other populations covered by the marketing authorisation without evidence on the cost effectiveness of fingolimod for these populations from the manufacturer. The Committee also noted that the manufacturer compared fingolimod with only one formulation of beta interferon (Avonex) in its original base-case analysis, and that it included no other comparators from the decision problem. The Committee heard from the manufacturer that Avonex and Rebif are the most commonly prescribed forms of beta interferon in the NHS. The Committee acknowledged the concerns of the ERG that a beta interferon should not be the only comparator in an analysis for a patient group who have had a suboptimal response to prior beta interferon therapy, and that best supportive care should also be considered. The Committee concluded that limiting the analyses to comparisons with Avonex only was not appropriate, and instead comparisons with other beta interferons and best supportive care need to be included as a basis for any recommendations in this appraisal.
The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of fingolimod. It noted that the manufacturer derived data from two clinical trials that assessed the efficacy and safety of fingolimod compared with placebo over 24 months (FREEDOMS trial), and with beta interferon-1a (Avonex) over 12 months (TRANSFORMS trial) in adults with relapsing–remitting multiple sclerosis. The Committee noted that the populations in the FREEDOMS and TRANSFORMS trials were broader than those in the marketing authorisation for fingolimod and therefore after the trials finished the manufacturer had to identify subgroups that approximated the populations in the marketing authorisation. The Committee heard from the ERG that the subgroups identified by the manufacturer were reasonable approximations to the populations in the marketing authorisation but that the subgroups were not mutually exclusive. The Committee noted that in response to clarification the manufacturer provided some revised analyses for people in population 1b who did not have rapidly evolving severe relapsing–remitting multiple sclerosis (that is population 1b, with people who also met the criteria for population 2 excluded). The Committee noted that these analyses generated lower ICERs than those for the whole of population 1b, but it was aware of reservations expressed by the manufacturer and the ERG about the small samples on which the subgroup analysis was based. Separate analyses were not provided for populations 1a or 2. The Committee also considered the manufacturer's mixed treatment comparison, which assessed treatment effects between comparators in the absence of direct evidence. It heard from the manufacturer and the ERG that there was considerable heterogeneity between the studies and that none of the studies in the analysis included populations that closely and consistently match those described in the marketing authorisation for fingolimod. It also heard that the TRANSFORMS and FREEDOMS trials were not powered to assess the efficacy of fingolimod in the subgroups defined by the marketing authorisation. The Committee concluded that the available evidence shows that people with relapsing–remitting multiple sclerosis who are treated with fingolimod have lower relapse rates than people treated with Avonex or placebo. The Committee also agreed that fingolimod was shown to reduce disability progression in people with relapsing–remitting multiple sclerosis compared with placebo in the whole population of the FREEDOMS trial; however, there was no significant impact on disability progression compared with Avonex in the TRANSFORMS trial. The Committee heard from the manufacturer that the European Medicines Agency had judged that the clinical trial data demonstrated consistent treatment effects with fingolimod in all of the subgroups with highly active disease covered by the marketing authorisation. The Committee concluded that the available evidence shows that fingolimod improves outcomes for the whole population in the clinical trials, and in those with highly active disease defined by the marketing authorisation.
The Committee discussed the health-related quality-of-life data from the FREEDOMS and TRANSFORMS trials. It noted that there were no statistically significant changes from baseline for EQ-5D measures observed for people with relapsing–remitting multiple sclerosis treated with fingolimod or placebo in the FREEDOMS trial, and that only a slight non-significant improvement in health-related quality of life according to the PRIMUS-QoL scale was observed for people treated with fingolimod or Avonex in the TRANSFORMS trial. The Committee heard from the clinical specialists that a patient's quality of life may not be affected by treatment because multiple sclerosis is a chronic disease with fluctuating symptoms, particularly in the relatively early stages of the condition. The Committee noted that the populations in the FREEDOMS and TRANSFORMS trials did not experience significant progression of disease and this may also have reduced the apparent impact of treatment on quality of life measures. The Committee concluded that it was therefore clinically plausible to see non-statistically significant changes in health-related quality-of-life measures in the FREEDOMS and TRANSFORMS trials, and that the impact of fingolimod on health-related quality of life remained uncertain.
# Cost effectiveness
The Committee discussed the cost-effectiveness estimates from the manufacturer's original economic model, the assumptions on which these were based, the revised analyses from the manufacturer in response to the first and second appraisal consultation documents and the ERG's critiques and exploratory analyses. The Committee noted that the manufacturer provided a probabilistic Markov model that was structurally similar to other models used in previous NICE technology appraisal guidance on treatments for multiple sclerosis. The Committee noted that the manufacturer's original base-case analysis presented deterministic results for fingolimod compared with Avonex, which were substantially lower than the probabilistic results estimated by the ERG. The Committee acknowledged the concerns of the ERG that deterministic results should not be presented from a probabilistic model, and concluded that it would base its decision on the probabilistic results.
The Committee noted the concerns of the clinical specialists that the manufacturer's model may not reflect the natural history of multiple sclerosis because it does not allow for improvement in EDSS scores. The Committee heard from the manufacturer that the ability to include improvements in EDSS scores had been intentionally removed from the model to produce a conservative estimate of the cost effectiveness of fingolimod. The Committee heard from the clinical specialists that few people experience an improvement in EDSS score and therefore it concluded that the manufacturer's approach was reasonable.
The Committee heard from the manufacturer that disability progression rates in the model were derived from a longitudinal data set from a population with multiple sclerosis in Ontario, Canada. This data source was chosen because it has been considered previously in other NICE technology appraisal guidance on treatments for multiple sclerosis. The Committee heard from the clinical specialists and the ERG that this may have given more rapid disability progression rates than those seen in the clinical trials and in the current UK patient population. However, the Committee noted that no alternative data sources had been made available. The Committee was concerned that the manufacturer did not explain the divergence between model predictions and the trial observations for disease progression in its original submission, because the ERG's exploratory analyses showed that the model predictions were highly sensitive to the natural history progression data used. The Committee noted from subsequent sensitivity analyses carried out by the manufacturer that the ICERs increased only slightly with changes in the assumptions on natural history of disease progression (section 3.20). The Committee was persuaded that disease progression in people initially treated with disease-modifying treatments may be less rapid in current clinical practice than in the Ontario data set and concluded that data on the natural history of disability progression were a source of uncertainty in the model.
The Committee heard from the manufacturer that the utility data from the FREEDOMS or TRANSFORMS trials were not used in the original model because the study populations included only people with an EDSS score up to 6, and therefore utility data for higher EDSS scores were not available. The Committee heard from the ERG that the manufacturer used EDSS-based EQ-5D scores from a published source instead, despite this study being criticised in technology appraisal guidance 127 for having low response rates, not representing the appropriate population and being prone to selection bias. The Committee agreed that because the manufacturer's base case targeted a very specific group (population 1b), it would have been more appropriate to use utility data for that group from the trials where possible, and to use data from other sources only for EDSS scores above 6. The Committee considered additional analyses from the manufacturer in response to the appraisal consultation documents, which indicated that the base-case ICER for population 1b slightly decreased when utility data from the FREEDOMS and TRANSFORMS trials were used for EDSS states up to 6 and published data from Orme et al. (2007) were only used for EDSS scores above 6. The Committee concluded that the manufacturer's revised approach to incorporating utility estimates in the model was reasonable.
The Committee was concerned about the assumption in the manufacturer's original model that the treatment effect observed for the duration of the trials (1 or 2 years) was maintained at the same level during the on-treatment periods. It noted that sensitivity analyses carried out by the manufacturer and the ERG showed that a reduction in the assumed duration of treatment effect increased the ICERs substantively (see sections 3.15 and 3.32). The Committee heard from the manufacturer that there is currently no evidence to support the hypothesis that the efficacy of fingolimod will reduce over time and preliminary results from the FREEDOMS extension study show that there is no loss of efficacy over 4 years. In the absence of data beyond 4 years, the Committee decided to be cautious and considered it appropriate to include a 50% waning of treatment effect after 5 years in the base-case analysis. However, it acknowledged that if the treatment effect did not wane over time then this would overestimate the base-case ICER.
The Committee noted potential inaccuracies in some of the administration costs included in the manufacturer's original model. In particular, it heard from the manufacturer that it was assumed that people treated with Avonex had more visits to a neurologist than people treated with fingolimod. The Committee heard from the clinical specialists that this assumption was probably not correct and that it is more plausible that people receiving fingolimod would have three visits during the first year of treatment, compared with two visits for people receiving Avonex. The Committee noted that the manufacturer had corrected this assumption in the revised analyses submitted in response to the appraisal consultation documents and was persuaded that revising the costs in the model had a minimal impact on the ICER.
The Committee acknowledged that based on current practice in the NHS it would be inappropriate to use Avonex alone as a comparator for fingolimod. The Committee considered exploratory analyses conducted by the ERG on the manufacturer's original model, which incrementally compared fingolimod with best supportive care and Rebif-44. The Committee noted that these analyses were based on indirect comparisons of limited data and that in population 1b Avonex was dominated by Rebif-44. The Committee noted comments from the manufacturer in response to the appraisal consultation documents, which suggested that the Rebif-44 data used in the comparison with fingolimod were from patients with relapsing–remitting multiple sclerosis regardless of previous treatment, rather than from those whose disease had a suboptimal response to disease-modifying therapy (that is, population 1b). The Committee was persuaded that this may have resulted in an overestimation of the ICER for fingolimod compared with Rebif-44.
The Committee acknowledged that although the manufacturer had tried to address some of the concerns raised during the first and second Committee meetings, the manufacturer and the ERG still had divided opinions on the most appropriate methodological approaches to evaluate the cost effectiveness of fingolimod in population 1b. The Committee considered the manufacturer's revised probabilistic base-case ICER of £17,300 per QALY gained for fingolimod compared with Avonex. The Committee noted that in the ERG's incremental analysis, Avonex was extendedly dominated and the probabilistic ICER for fingolimod compared with best supportive care was £58,000 per QALY gained. The Committee acknowledged that the ERG's analyses demonstrated that beta-interferon treatment may not be cost effective compared with what is considered an appropriate use of NHS resources as defined in the NICE Guide to the methods of technology appraisal (2008). However it was mindful of the need to take account of current NHS practice, including the risk-sharing scheme (which currently funds beta-interferon treatments for people with multiple sclerosis), when defining the appropriate comparator(s) for assessment.
The Committee acknowledged that the choice of comparator in the manufacturer's model was a key driver of cost effectiveness. It also acknowledged that there was variation in current practice and therefore concluded that fingolimod should be compared with a weighted average of the comparators currently used in UK clinical practice to manage relapsing–remitting multiple sclerosis. This includes best supportive care together with a mix of beta interferons (with the proportions for the beta interferons based on market share data from the Prescription Pricing Authority). The Committee noted that the manufacturer's probabilistic ICER for fingolimod compared with the weighted average of the comparators was £27,800 per QALY gained. The Committee acknowledged that the manufacturer had assumed that best supportive care contributes only 5% to the weighted average in the base case, and that sensitivity analyses showed that if a higher proportion was assumed, such as 10%, the ICER would increase to approximately £30,000 per QALY gained (see section 3.19). The Committee noted from the manufacturer's and the ERG's sensitivity analyses that the ICER for fingolimod compared with the weighted average of the comparators depends on the proportions assumed for the comparator treatments, and the assumptions about the natural history of disability progression and the waning of treatment effect after 5 years. The Committee concluded that the most plausible ICER for fingolimod compared with the weighted average of the comparators was likely to be in the range of £25,000 to £35,000 per QALY gained.
The Committee noted that the most plausible ICER for fingolimod could be higher than what is normally considered an effective use of NHS resources. It was mindful that the NICE Guide to the methods of technology appraisal (2008) states that a strong case should be identified for an ICER that is higher than £30,000 per QALY gained. The Committee noted that in these circumstances the NICE Guide to methods of technology appraisal states that judgements about the acceptability of the technology as an effective use of NHS resources will specifically take account of:
the degree of certainty around the ICER
any strong reasons to indicate that the assessment of the change in health-related quality of life has been inadequately captured
whether the innovative nature of the technology adds demonstrable and distinctive benefits of a substantial nature which may not have been adequately captured in the QALY measure.
The Committee discussed whether the assessment of the change in health-related quality of life had been inadequately captured in the economic analysis. It heard from the patient experts that people who receive fingolimod have fewer adverse reactions than those who receive beta-interferon therapy. In addition, treatment with fingolimod significantly reduces relapses and could allow people to lead an active and fulfilling life and contribute more fully to society. The Committee also heard from the manufacturer that any impact of treatment with fingolimod on the severity of relapses had not been captured in the model. In addition, the benefits from a decreased need for informal care provided by family and friends of people with multiple sclerosis had not been considered (because it is not in line with NICE's reference case). In the manufacturer's view, inclusion of these factors would decrease the ICER. The Committee accepted that fingolimod is a valuable new therapy and that its oral formulation represents innovation in the treatment of multiple sclerosis. The Committee recognised that including all of the benefits suggested by the manufacturer and patient experts in the manufacturer's model could decrease the ICER to a level that would be considered a cost-effective use of NHS resources.
The Committee noted that the current risk-sharing scheme allows beta interferons to be purchased at a price which the Department of Health considers to be a cost-effective use of NHS resources. However, it regretted that published outcome data from the scheme to justify the negotiated procurement price for these treatments are lacking. Taking these difficulties into consideration, the Committee made an exceptional case and recommended fingolimod as an option for the treatment of highly active relapsing–remitting multiple sclerosis in adults who have an unchanged or increased relapse rate, or ongoing severe relapses, compared with the previous year despite previous treatment with beta interferon (population 1b). The Committee also emphasised that it is important that a new model for multiple sclerosis is developed for any future appraisals of treatments for multiple sclerosis. The new model should ideally be based on UK patient cohorts, should use the best available evidence (including experience to date from the risk-sharing scheme) and should include all currently available treatments, so that future appraisals of treatments for multiple sclerosis are directly relevant to UK clinical practice.
# Summary of Appraisal Committee's key conclusions
TA254
Appraisal title: Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis
Section
Key conclusion
The Committee made an exceptional case and recommended fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis in adults, only if:
they have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon, and
the manufacturer provides fingolimod with the discount agreed as part of the patient access scheme.
The Committee accepted that fingolimod is a valuable new therapy and that its oral formulation represents innovation in the treatment of multiple sclerosis. The Committee recognised that including all of the benefits of fingolimod suggested by the manufacturer and patient experts in the manufacturer's model could decrease the ICER to a level that would be considered a cost-effective use of NHS resources.
The Committee emphasised that it is important that a new model for multiple sclerosis is developed for any future appraisals of treatments for multiple sclerosis. The new model should ideally be based on UK patient cohorts, should use the best available evidence (including experience to date from the risk-sharing scheme) and should include all currently available treatments for multiple sclerosis, so that future appraisals of treatments for multiple sclerosis are directly relevant to UK clinical practice.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee understood from the patient experts that multiple sclerosis is a chronic, disabling, neurological condition that is life altering and has a substantial negative impact on quality of life and activities of daily living. The Committee understood that any delay or relief from these problems would have a positive impact on the lives of people with multiple sclerosis and their families.
The technology
Proposed benefits of the technology
The Committee heard from the patient experts that fingolimod would allow greater flexibility and decrease discomfort because it is given orally whereas other currently available treatments are administered by injection.
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee accepted that fingolimod is a valuable new therapy and that its oral formulation represents innovation in the treatment of multiple sclerosis.
What is the position of the treatment in the pathway of care for the condition?
The Committee understood that although clinical practice varies among neurologists, many clinical specialists would consider fingolimod as a second or subsequent line of treatment for people with high disease activity despite treatment with beta interferon or glatiramer acetate. It heard from the clinical specialists that fingolimod would provide the greatest benefit to people with rapidly evolving severe relapsing–remitting multiple sclerosis, because they currently have very few treatment options. The Committee acknowledged the clinical specialists' disappointment that a specific recommendation for the use of fingolimod in this population could not be made because the manufacturer had not submitted an analysis of fingolimod compared with natalizumab in this population.
Adverse reactions
The Committee understood from the clinical specialists and patient experts that fingolimod is generally well tolerated and that the adverse reactions expected during treatment could be managed in routine clinical practice.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee noted that only part of the population covered by the marketing authorisation for fingolimod was considered in the manufacturer's submission (population 1b). The Committee also noted that the manufacturer compared fingolimod with only one formulation of beta interferon (Avonex) in its original base-case analysis, and that it included no other comparators from the decision problem. The Committee concluded that limiting the analyses to comparisons with Avonex only was not appropriate, and instead comparisons with other beta interferons and best supportive care need to be included as a basis for any recommendations in this appraisal.
The manufacturer derived data from two clinical trials that assessed the efficacy and safety of fingolimod compared with placebo over 24 months (FREEDOMS trial), and with beta interferon-1a (Avonex) over 12 months (TRANSFORMS trial) in adults with relapsing–remitting multiple sclerosis.
In response to clarification the manufacturer provided revised analyses for people in population 1b who did not have rapidly evolving severe relapsing–remitting multiple sclerosis (that is population 1b, with people who also met the criteria for population 2 excluded). However, separate analyses were not provided for populations 1a or 2. The manufacturer also conducted a mixed treatment comparison, which assessed treatment effects between comparators in the absence of direct evidence.
Relevance to general clinical practice in the NHS
The populations in the clinical trials were broader than those in the marketing authorisation for fingolimod. The manufacturer identified subgroups after the trials had finished which approximated the populations in the marketing authorisation. The ERG noted that the populations were not mutually exclusive. The Committee heard from the manufacturer that the European Medicines Agency had judged that the clinical trial data demonstrated consistent treatment effects with fingolimod in all of the subgroups with highly active disease covered by the marketing authorisation. The Committee concluded that the available evidence shows that fingolimod improves outcomes for the whole population in the clinical trials, and in those with highly active disease defined by the marketing authorisation.
Uncertainties generated by the evidence
The Committee concluded that limiting the analyses to comparisons with Avonex only was not appropriate, and instead comparisons with other beta interferons and best supportive care need to be included as a basis for any recommendations in this appraisal.
The Committee concluded that it was clinically plausible to see non-significant changes in health-related quality-of-life measures in the FREEDOMS and TRANSFORMS trials, and that the impact of fingolimod on health-related quality of life remained uncertain.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
An analysis of population 1b that excluded people who also met the criteria for population 2 (that is, a population in which people with rapidly evolving severe disease were excluded) was provided by the manufacturer in response to a request for clarification. The Committee noted that this analysis generated lower ICERs than those for the whole of population 1b, but was aware of reservations expressed by the manufacturer and the ERG about the small samples on which the subgroup analysis was based.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that the available evidence shows that people who are treated with fingolimod have lower relapse rates than people treated with Avonex or placebo. The Committee also agreed that fingolimod was shown to reduce disability progression compared with placebo in the whole population of the FREEDOMS trial; however, there was no significant impact on disability progression compared with Avonex in the TRANSFORMS trial. There were no statistically significant changes from baseline for EQ-5D measures observed for people with relapsing–remitting multiple sclerosis treated with fingolimod or placebo in the FREEDOMS trial. Only a slight non-statistically significant improvement in health-related quality of life according to the PRIMUS-QoL scale was observed for people treated with fingolimod or Avonex in the TRANSFORMS trial.
Evidence for cost effectiveness
Availability and nature of evidence
The manufacturer provided a probabilistic Markov model that was structurally similar to other models used in previous NICE technology appraisal guidance on treatments for multiple sclerosis.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted the concerns of the clinical specialists that the model may not reflect the natural history of multiple sclerosis, because it does not allow for improvement in EDSS scores. The Committee concluded that the manufacturer's approach was reasonable because few people experience an improvement in EDSS score in clinical practice.
The Committee was concerned that the data set used by the manufacturer to estimate disability progression rates in the model may have given more rapid disability progression rates than those seen in the clinical trials and in the current UK patient population. The Committee noted from sensitivity analyses carried out by the manufacturer that the ICERs increased only slightly with changes in the assumptions on natural history of disease progression. The Committee was persuaded that disease progression in people initially treated with disease-modifying treatments may be less rapid in current clinical practice than in the Ontario data set and concluded that the data on the natural history of disability progression were a source of uncertainty in the model.
The Committee was concerned about the assumption in the manufacturer's original model that the treatment effect observed for the duration of the trials (1 or 2 years) was maintained at the same level during the on-treatment periods. The Committee heard from the manufacturer that there is currently no evidence to support the hypothesis that the efficacy of fingolimod will reduce over time and preliminary results from the FREEDOMS extension study show that there is no loss of efficacy over 4 years. In the absence of data beyond 4 years, the Committee decided to be cautious and include a 50% waning of treatment effect after 5 years in the base-case analysis. However, it acknowledged that if the treatment effect did not wane over time then this would overestimate the base-case ICER.
The Committee noted potential inaccuracies in some of the administration costs included in the manufacturer's original model. The Committee noted that the manufacturer had corrected these inaccuracies in the revised analyses submitted in response to the appraisal consultation documents and was persuaded that revising the costs in the model had a minimal impact on the ICER.
The Committee considered exploratory analyses from the ERG, which incrementally compared fingolimod with best supportive care and Rebif-44. The Committee noted comments from the manufacturer which suggested that the Rebif-44 data used in the comparison with fingolimod were from patients with relapsing–remitting multiple sclerosis regardless of previous treatment, rather than from those whose disease had a suboptimal response to disease-modifying therapy (that is, population 1b). The Committee was persuaded that this may have resulted in an overestimation of the ICER for fingolimod compared with Rebif-44.
The Committee acknowledged that there was variation in current practice and therefore concluded that fingolimod should be compared with a weighted average of the comparators currently used in UK clinical practice to manage relapsing–remitting multiple sclerosis. This includes best supportive care together with a mix of beta interferons (with the proportions for the beta interferons based on market share data from the Prescription Pricing Authority).
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee noted that the manufacturer did not use utility data from the FREEDOMS or TRANSFORMS trials in the original model. Additional analyses from the manufacturer in response to the appraisal consultation documents indicated the base-case ICER for population 1b slightly decreased when utility data from the FREEDOMS and TRANSFORMS trials were used for EDSS states up to 6 and data from Orme et al. (2007) were used for EDSS scores above 6. The Committee concluded that the manufacturer's revised approach to incorporating utility estimates in the model was reasonable.
The Committee heard from the patient experts that people who receive fingolimod have fewer adverse reactions than those who receive beta-interferon therapy. In addition, treatment with fingolimod significantly reduces relapses and could allow people to lead an active and fulfilling life and contribute more fully to society. The Committee also heard from the manufacturer that any impact of treatment with fingolimod on the severity of relapses had not been captured in the model. In addition, the benefits from a decreased need for informal care provided by family and friends of people with multiple sclerosis had not been considered. In the manufacturer's view, inclusion of these factors would decrease the ICER.
Are there specific groups of people for whom the technology is particularly cost effective?
None
What are the key drivers of cost effectiveness?
One-way sensitivity analyses conducted by the manufacturer suggested that the ICER for fingolimod compared with Avonex was most sensitive to the relative risks of disease progression assumed for fingolimod and Avonex, and the relative risk of relapse for Avonex.
The Committee acknowledged that the choice of comparator in the manufacturer's model was a key driver of cost effectiveness.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee concluded that depending on the proportions assumed for the comparator treatments, and the assumptions included in the model about the natural history of disability progression and the waning of treatment effect after 5 years, the most plausible ICER for fingolimod compared with the weighted average of the comparators from the manufacturer's model was likely to be in the range of £25,000 to £35,000 per QALY gained. The Committee recognised that including all of the benefits of fingolimod which may not be adequately captured in the QALY calculation (as suggested by the manufacturer and the patient experts) could decrease the ICER to a level that would be considered a cost-effective use of NHS resources.
Additional factors taken into account
Patient access schemes (PPRS)
The manufacturer agreed a patient access scheme with the Department of Health in which a simple confidential discount is applied to the list price of fingolimod.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
No equality issues were raised during the scoping exercise or during the course of the appraisal.
# Recommendations for further research
The Committee recommends the development of patient registries for multiple sclerosis to capture long-term treatment-related outcomes.
The Committee recommends that a new model for multiple sclerosis is developed, ideally based on UK patient cohorts, which uses the best available evidence (including experience to date from the risk-sharing scheme) and includes all currently available treatments.# Related NICE guidance
# Published
Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis. NICE technology appraisal guidance 127 (2007).
Multiple sclerosis: management of multiple sclerosis in primary and secondary care. NICE clinical guideline 8 (2003).
Beta interferon and glatiramer acetate for the treatment of multiple sclerosis. NICE technology appraisal guidance 32 (2002).# Review of guidance
The guidance on this technology will be considered for review by the Guidance Executive at the same time as Beta interferon and glatiramer acetate for the treatment of multiple sclerosis (NICE technology appraisal guidance 32) and Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 127). The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveApril 2012# Changes after publication
January 2014: implementation section updated to clarify that fingolimod is recommended as an option for treating highly active relapsing–remitting multiple sclerosis. Additional minor maintenance update also carried out.# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Fingolimod is recommended as an option for the treatment of highly active relapsing–remitting multiple sclerosis in adults, only if:\n\nthey have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon, and\n\nthe manufacturer provides fingolimod with the discount agreed as part of the patient access scheme.\n\nPeople currently receiving fingolimod whose disease does not meet the criteria in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.', 'The technology ': 'Fingolimod (Gilenya, Novartis Pharmaceuticals UK) is a sphingosine-1-phosphate receptor modulator that prevents lymphocytes from crossing the blood–brain barrier and causing damage to nerve cells in the brain and spinal cord. Fingolimod has a marketing authorisation as a single disease-modifying therapy in highly active relapsing–remitting multiple sclerosis for the following groups:\n\nAdults with high disease activity despite treatment with a beta interferon. These patients may be defined as \'those who have failed to respond to a full and adequate course (normally at least one\xa0year of treatment) of beta-interferon. Patients should have had at least one relapse in the previous year while on therapy, and have at least nine T2-hyperintense lesions in cranial magnetic resonance imaging (MRI) or at least one gadolinium-enhancing lesion. A "non-responder" could also be defined as a patient with an unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous year\'.\n\nAdults with rapidly evolving severe relapsing–remitting multiple sclerosis defined by two or more disabling relapses in 1\xa0year, and with one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.\n\nThe most common adverse reactions to treatment with fingolimod include influenza virus infections, headaches, diarrhoea and elevated liver enzyme activity. The summary of product characteristics (SPC) states that \'macular oedema with or without visual symptoms has been reported in 0.4% of patients treated with fingolimod 0.5\xa0mg, occurring predominantly in the first 3–4\xa0months of therapy. An ophthalmological evaluation is therefore recommended at 3–4\xa0months after treatment initiation\'. For full details of adverse reactions and contraindications, see the SPC.\n\nFingolimod is given as a 0.5\xa0mg oral dose once daily. The SPC states that \'patients can switch directly from beta interferon or glatiramer acetate to fingolimod provided there are no signs of relevant treatment-related abnormalities\'. The list price of fingolimod is £1470 for 28\xa0capsules (excluding VAT; MIMS July 2011), which is equivalent to an annual cost of approximately £19,169 per person. The manufacturer of fingolimod has agreed a patient access scheme with the Department of Health, in which a discount on the list price of fingolimod is offered. The size of the discount is commercial-in-confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.', "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of fingolimod and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer presented three populations in its submission:\n\npopulation\xa01a, consisting of people with highly active relapsing–remitting multiple sclerosis with at least one relapse in the previous year while on treatment with beta interferon and at least nine T2-hyperintense lesions on a brain MRI or at least one gadolinium-enhancing lesion\n\npopulation\xa01b, consisting of people with highly active relapsing–remitting multiple sclerosis who have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon\n\npopulation\xa02, consisting of people with rapidly evolving severe relapsing–remitting multiple sclerosis defined by two or more disabling relapses in 1\xa0year, and with one or more gadolinium-enhancing lesions on a brain MRI or a significant increase in T2 lesion load compared with a previous recent MRI. The manufacturer's original submission focused on population\xa01b, but demographic data were also provided for populations 1a and 2. The manufacturer's base-case analysis considered the effect of fingolimod in population\xa01b relative to beta interferon-1a (Avonex). The outcomes defining effectiveness included the number of confirmed relapses during a 12-month period (annualised relapse rate), confirmed disability progression at 3\xa0months, mortality, adverse reactions to treatment and health-related quality of life.\n\nThe manufacturer undertook a systematic literature review and identified two randomised controlled trials, the FREEDOMS trial and the TRANSFORMS trial, which both assessed the efficacy and safety of fingolimod in adults with relapsing–remitting multiple sclerosis. The FREEDOMS trial was a phase III, multicentre, double-blind trial in which 1272 adults with relapsing–remitting multiple sclerosis were randomised to receive daily doses of oral fingolimod 0.5\xa0mg (425 patients), oral fingolimod 1.25\xa0mg (429\xa0patients) or placebo (418\xa0patients) for 24\xa0months. In the FREEDOMS trial, 90\xa0patients treated with fingolimod 0.5\xa0mg and 79\xa0patients treated with placebo were considered by the manufacturer to meet the criteria for population\xa01b. The TRANSFORMS trial was a phase III, multicentre, double-blind trial in which 1292 adults with relapsing–remitting multiple sclerosis were randomised to receive oral fingolimod 0.5\xa0mg (431\xa0patients) or oral fingolimod 1.25\xa0mg (426\xa0patients) once a day, or intramuscular Avonex 30\xa0micrograms (435\xa0patients) once a week for 12\xa0months. In the TRANSFORMS trial, 191\xa0patients who were treated with fingolimod 0.5\xa0mg and 183\xa0patients who received Avonex met the criteria for population\xa01b in the decision problem. Only data relating to fingolimod 0.5\xa0mg are presented in the remaining sections of this document.\n\nPatients were eligible for inclusion in the FREEDOMS and TRANSFORMS trials if they had an Expanded Disability Status Scale (EDSS) score between 0 and 5.5 (the EDSS ranges from 0 to 10 with 0.5-unit increments representing higher levels of disability), and at least one documented relapse during the previous year or at least two documented relapses during the 2\xa0years preceding study enrolment. The primary outcome of the trials was annualised relapse rate. Secondary outcomes included disability progression confirmed after 3\xa0months, time to first relapse and radiological outcomes, such as the number of new or enlarged lesions. In the FREEDOMS trial, patient-reported outcomes were assessed using the EuroQoL 5-dimension survey (EQ-5D). Quality-of-life data were collected in the TRANSFORMS trial using the Patient-Reported Indices for Multiple Sclerosis – Quality of life (PRIMUS–QoL), the Patient-Reported Indices for Multiple Sclerosis – Activities (PRIMUS–Activities) and the Unidimensional Fatigue Impact Scale (UFIS).\n\nResults from the FREEDOMS and TRANSFORMS trials showed that the annualised relapse rates were statistically significantly reduced for all patients treated with fingolimod compared with placebo (0.18 compared with 0.40; p\xa0<\xa00.001) and those treated with fingolimod compared with Avonex (0.16 compared with 0.33; p\xa0<\xa00.001). Treatment with fingolimod also reduced the annualised relapse rates (primary outcome) for patients in population\xa01b in the manufacturer's submission (see section 3.1), compared with placebo (0.21 compared with 0.54; p\xa0<\xa00.001) and for those who received fingolimod compared with Avonex (0.25 compared with 0.51; p\xa0<\xa00.001). In the TRANSFORMS trial, 94.1% of all patients treated with fingolimod had no disability progression after 3\xa0months (95% confidence interval [CI] 91.8 to 96.3) compared with 92.1% of all patients treated with Avonex (95% CI 89.4 to 94.7); however, this difference was not statistically significant (p\xa0=\xa00.25). Among the whole population of the FREEDOMS trial, 82.3% of patients treated with fingolimod had no disability progression after 3\xa0months compared with 75.9% of all patients treated with placebo (p\xa0=\xa00.03). No statistically significant difference in disability progression between the treatment groups was reported for population\xa01b. The manufacturer pointed to the European Public Assessment Report of the European Medicines Agency which stated that the results in the subgroups with highly active disease were consistent with those obtained in the overall trial population.\n\nFingolimod was well tolerated by patients in the clinical trials. It was considered to have a comparable safety profile to placebo and to be associated with fewer adverse reactions than Avonex. The incidence of serious adverse reactions after treatment with fingolimod was low across both studies, with the most common being infections, macular oedema and transient atrioventricular block at treatment initiation. In the TRANSFORMS trial, adverse reactions leading to treatment discontinuation in population\xa01b were reported in 3.1% of patients treated with fingolimod compared with 1.6% of patients treated with Avonex. In the FREEDOMS trial, the rate of treatment discontinuation because of adverse reactions in population\xa01b was lower in patients receiving fingolimod (2.2%) compared with placebo (7.6%). There were no treatment-related deaths reported with fingolimod or Avonex treatment in the TRANSFORMS trial. In the FREEDOMS trial, no treatment-related deaths were reported among patients receiving fingolimod or placebo.\n\nIn the TRANSFORMS trial, patients who received fingolimod showed significantly less deterioration in their ability to perform daily activities according to the PRIMUS–Activities scale compared with patients receiving Avonex (change from baseline 0.08 in patients treated with fingolimod compared with 0.43 in patients treated with Avonex; p\xa0<\xa00.05). In addition, a slight, non-significant improvement in health-related quality of life, as measured on the PRIMUS–QoL scale, was observed in patients treated with either fingolimod or Avonex. After 6\xa0months of treatment with fingolimod, patients showed a statistically significant improvement in UFIS score compared with patients treated with Avonex; however, at 12\xa0months this difference between the groups was no longer statistically significant. In the FREEDOMS trial, no statistically significant changes from baseline for EQ-5D measures were observed in patients with relapsing–remitting multiple sclerosis treated with fingolimod or placebo.\n\nTo estimate the relative effectiveness of all of the comparators in the absence of direct evidence, the manufacturer conducted a mixed treatment comparison of 18\xa0trials that assessed annualised relapse rates, disability progression and treatment discontinuation because of adverse reactions, for the following interventions: fingolimod, natalizumab, beta interferon-1a (Avonex, Rebif-22 and Rebif-44), beta interferon-1b (Betaferon), glatiramer acetate and placebo. The manufacturer acknowledged that although the populations in the included trials had a clinical diagnosis of relapsing–remitting multiple sclerosis, they did not fully meet the criteria for highly active disease described in the marketing authorisation for fingolimod. There was also considerable clinical heterogeneity between the trials with respect to permitted and actual prior use of disease-modifying treatments, treatment duration and the criteria used to define the trial end points. As a consequence, the manufacturer did not use the results of the mixed treatment comparison to inform the economic model. Instead, an indirect comparison using the TRANSFORMS and FREEDOMS trials provided an estimate of the relative efficacy of Avonex and placebo for population\xa01b in the model.\n\nThe manufacturer undertook a systematic search but did not identify any economic evaluations of fingolimod for the treatment of relapsing–remitting multiple sclerosis. The manufacturer submitted a de novo economic model that is structurally similar to models used in previous NICE technology appraisal guidance on treatments for multiple sclerosis (Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis [NICE technology appraisal guidance 127] and Beta interferon and glatiramer acetate for the treatment of multiple sclerosis [NICE technology appraisal guidance 32]). The model is based on a Markov cohort approach and estimates disease progression through 21 disability states that are defined by EDSS score (ranging from 0 to 10) and account for disability for patients with relapsing–remitting multiple sclerosis (10 states), patients with secondary progressive multiple sclerosis (10 states) and death. In each cycle of the model, a patient with relapsing–remitting multiple sclerosis can progress to a worse EDSS state or remain in the same state. Patients can also convert from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis; however, once a patient reaches this point in the disease course they cannot convert back to relapsing–remitting disease. Only people with relapsing–remitting multiple sclerosis and an EDSS score of 6 or less are assumed to receive disease-modifying treatment in the model. People with an EDSS score greater than 6, or with secondary progressive multiple sclerosis, are assumed to receive best supportive care.\n\nDisability progression rates in the model were defined in a natural history transition matrix and derived from a longitudinal data set from patients with multiple sclerosis in Ontario, Canada. The manufacturer excluded patients with less progressive forms of relapsing–remitting multiple sclerosis from the data set and adjusted the natural history transition matrices to represent patients for whom treatment with disease-modifying therapies would be suitable. The probability of relapse in each model cycle was determined using published sources to estimate the natural history of relapses by disease type and EDSS stage.\n\nAll patients were individually followed through the model from treatment initiation for a maximum of 50 years. Probabilities for all-cause mortality for the general population were derived using current statistics for England and Wales, and were then adjusted for patients with multiple sclerosis using mortality ratios from published sources. A published equation was also used to predict the excess mortality for individual EDSS states.\n\nThe relative risks of annual relapse rate and of disability progression for fingolimod treatment compared with best supportive care were calculated from the FREEDOMS trial. The corresponding relative risk value for Avonex was calculated indirectly from the TRANSFORMS trial. The relative risks associated with disease progression and relapse were constant over the entire on-treatment period. Discontinuations because of adverse reactions were included in the model based on trial data. The relative risks for disease progression were not applied to patients with secondary progressive multiple sclerosis (who receive best supportive care in the model); instead, patients entering this disease state followed the natural history of the disease (as predicted by data from Ontario, Canada).\n\nAlthough quality-of-life data were collected in the TRANSFORMS and FREEDOMS trials, the manufacturer did not use these to estimate utilities for the model. Instead, published EDSS-based EQ-5D scores were used, in line with those from NICE technology appraisal guidance 127 and 32. Health-related quality of life was assumed to remain constant over time for each EDSS score, but a single adjustment (0.01 utility gain for each 5-year period) was made to reflect the time since diagnosis. Utility decrements attributable to adverse reactions were applied for the whole duration of the treatment period. The model also incorporated caregiver's disutility for each EDSS score in the base case, in line with estimates from NICE technology appraisal guidance 127. The maximum disutility for a caregiver of a person with multiple sclerosis was assumed to be 0.14 (EDSS 9).\n\nThe resource costs included in the model were drug acquisition costs, administration and monitoring costs, and the cost of the disease, which included the cost of each EDSS state, the cost of relapse and the costs associated with serious adverse reactions. Costs associated with non-serious adverse reactions were not considered in the model. The model assumes that when patients discontinue treatment with disease-modifying therapy and receive best supportive care, the only costs incurred are the disease costs by EDSS states.\n\nThe original base-case incremental cost-effectiveness ratio (ICER) for fingolimod compared with Avonex was £55,634 per QALY gained for population\xa01b (patient access scheme not included). Cost-effectiveness analyses for population\xa01a and population\xa02 (defined in section 3.1) were not provided by the manufacturer. One-way sensitivity analyses suggested that the ICER for fingolimod compared with Avonex was most sensitive to the relative risks of disease progression assumed for fingolimod and Avonex, and the relative risk of relapse for Avonex. Uncertainty in all other parameter values led to only small changes in the ICER. Results of a probabilistic sensitivity analysis showed that there was a 12% probability that the base-case ICER was less than £20,000 per QALY gained, and a 26% probability that it was less than £30,000 per QALY gained.\n\nThe manufacturer explored uncertainty in the model caused by structural assumptions, including possible waning of treatment effect and the assumed time horizon. When treatment efficacy was assumed to be reduced by 50% or 75% after the first 2\xa0years of treatment, the ICER increased to £73,191 and £85,266 per QALY gained respectively. When the time horizon was shortened to 10\xa0years and 20\xa0years, the ICER increased to £97,159 and £64,280 per QALY gained respectively.\n\nThe manufacturer acknowledged that there was considerable overlap between the populations defined in the marketing authorisation for fingolimod, and provided an analysis for a subgroup of population\xa01b that excluded patients who also met the criteria for population\xa02 (that is, it excluded those with rapidly evolving severe multiple sclerosis). The relative treatment effects estimated from the trials for this subgroup were significantly different from those estimated for the whole of population\xa01b. In particular, the risk of disease progression with Avonex was estimated (by indirect comparison) to be higher than with placebo. The manufacturer's ICER for fingolimod compared with Avonex in this subgroup was £18,741 per QALY gained (patient access scheme not included). No sensitivity analyses were conducted for this subgroup.\n\nIn its response to the first appraisal consultation document, the manufacturer included a patient access scheme, which was agreed with the Department of Health, to apply a simple confidential discount to the list price of fingolimod. The manufacturer's deterministic base-case ICER for fingolimod in population\xa01b reduced to £10,839 per QALY gained compared with Avonex when the discounted price of fingolimod was included in the model. The probabilistic ICER determined by the manufacturer, including the patient access scheme, was £15,825 per QALY gained. Probabilistic sensitivity analyses suggested that there was a 58% chance that the ICER for fingolimod would be less than £30,000 per QALY gained when the discounted price was included.\n\nSensitivity analyses provided by the manufacturer in response to the first appraisal consultation document suggested that the ICER for fingolimod compared with Rebif-44 was £27,774 per QALY gained (patient access scheme included). The manufacturer noted that the data to inform this analysis were from patients with relapsing–remitting multiple sclerosis, rather than from those who had a suboptimal response to disease-modifying therapy (that is, population\xa01b), and therefore the true ICER for population\xa01b was likely to be lower. The manufacturer also compared fingolimod with Rebif-22 and Betaferon using adjusted data from the mixed treatment comparison. Efficacy rates for each treatment were scaled down by 13.25% to account for the fact that the clinical effects seen in the trials for people with relapsing–remitting multiple sclerosis were likely to be reduced in population\xa01b. The ICERs from this analysis for fingolimod were £23,587 per QALY gained compared with Rebif-22, and £27,660 per QALY gained compared with Betaferon (patient access scheme included).\n\nIn its response to the second appraisal consultation document, the manufacturer provided an updated economic model incorporating the following assumptions which the Committee had concluded to be more plausible:\n\nusing utility data from the trials where available, and then published data from Orme et al. (2007) for the remaining EDSS states\n\na 50% waning of treatment effect at 5\xa0years.The manufacturer presented probabilistic rather than deterministic results from the updated model. After incorporating these changes, the probabilistic ICERs in population\xa01b were £17,275 per QALY gained for fingolimod compared with Avonex, and £30,936 per QALY gained for fingolimod compared with Rebif-44. Using the updated model, the manufacturer also provided an analysis of fingolimod compared with a weighted average of best supportive care and a mixture of beta interferon treatments (Avonex, Rebif-22, Rebif-44, Betaferon and Extavia). Proportions of each beta interferon treatment were determined according to market share data from the Prescription Pricing Authority, to reflect the current formulations most commonly used in UK clinical practice. The manufacturer assumed that best supportive care represented 5% of the weighted average, in line with clinical opinion and audits from UK multiple sclerosis centres. Results from this analysis showed that the probabilistic ICER for fingolimod compared with the weighted average of the comparators was £27,820 per QALY gained (incremental costs £20,122; incremental QALYs 0.723). Sensitivity analyses provided by the manufacturer showed that the ICER for fingolimod compared with the weighted average of the comparators ranged from £25,000 to approximately £30,000 when the contribution of best supportive care to the comparator was varied between 0% and 10%.\n\nIn response to the second appraisal consultation document, the manufacturer also explored the directional effect on the ICER of changing the natural history transition matrix to slow disability progression. The manufacturer noted that in the FREEDOMS and TRANSFORMS trials, the greatest disability progression was three EDSS states within a 12-month period. In a scenario analysis which assumed that people could not progress more than one EDSS state each year in the relapsing–remitting multiple sclerosis natural history matrix, the manufacturer's probabilistic ICER for fingolimod compared with Avonex increased to £21,244 per QALY gained. When it was assumed that people could not progress more than one EDSS state each year in the secondary progressive multiple sclerosis natural history matrix, the probabilistic ICER increased to £19,774 per QALY gained. In the manufacturer's view, these scenario analyses were based on extreme assumptions that did not reflect the available clinical data for patients with relapsing–remitting multiple sclerosis.\n\nThe ERG considered that the TRANSFORMS and FREEDOMS trials were well designed to assess the efficacy of fingolimod in patients with relapsing–remitting multiple sclerosis. The ERG noted that the populations in the clinical trials were broader than those defined in the marketing authorisation for fingolimod, but considered that the manufacturer's post-hoc subgroup analyses provided a reasonable approximation to the populations in the marketing authorisation. The ERG noted that population\xa01b comprised only 43.6% of patients in the TRANSFORMS trial and 19.7% of patients in the FREEDOMS trial. The ERG was concerned that because of the smaller number of patients, the power of the trials to assess fingolimod relative to the comparators in the populations covered by the marketing authorisation was reduced. However, the ERG noted that the SPC for fingolimod states that 'further analyses of clinical trial data demonstrate consistent treatment effects in the highly active subgroups of relapsing–remitting multiple sclerosis'. The ERG was also concerned that there was considerable overlap between the populations and requested separate analyses from the manufacturer for population\xa01a, population\xa02, and populations 1a and 1b with patients who also met the criteria for population\xa02 excluded. The manufacturer provided analyses only for population\xa01b excluding patients who also met the criteria for population\xa02.\n\nThe ERG was concerned by the manufacturer's approach of using only Avonex as the comparator treatment for population\xa01b. The ERG noted that population\xa01b constitutes patients with highly active disease that has remained unchanged or worsened despite treatment with beta interferon. In the ERG's view, a comparison with Avonex may represent continued use of a treatment that is suboptimal in this group of patients, and may also cause adverse reactions. The ERG also noted that the results from the manufacturer's mixed treatment comparisons did not yield clear differences between the beta interferons in patients with relapsing–remitting multiple sclerosis in terms of disease progression and annualised relapse rates. It cautioned that a comparison solely with Avonex could underestimate the ICER of fingolimod and therefore reasoned that a comparison including best supportive care would have been more appropriate.\n\nThe ERG considered the additional cost-effectiveness analysis from the manufacturer for the subgroup consisting of population\xa01b without those who also met the criteria for population\xa02 (section 3.16). The ERG noted that the ICER for fingolimod compared with Avonex was more favourable for this subgroup than for the whole of population\xa01b. The ERG considered that this difference was largely attributable to the revised relative efficacy estimates for Avonex from the manufacturer's indirect comparison for this subgroup. This suggested that Avonex provides less benefit than placebo (that is, that Avonex was associated with an increased risk of disease progression compared with placebo).\n\nThe ERG was concerned about the resources and costs assumed in the manufacturer's original model. The ERG was unclear why the costs associated with only some severe adverse reactions were included in the model, and why the costs associated with non-serious adverse reactions were not included. The ERG was also unclear whether costs associated with relapsing–remitting multiple sclerosis were different from those associated with secondary progressive multiple sclerosis. In addition, the ERG noted that the cost of relapse used in the model was significantly different from the cost from other data sources and in NICE technology appraisal guidance 127. In the ERG's view, the manufacturer had not adequately justified the administrative and monitoring costs for fingolimod and Avonex. In particular, it was unclear why the manufacturer assumed that patients treated with Avonex would need two more neurology visits in the first year of treatment than patients who received fingolimod. The ERG noted that in response to consultation on the first appraisal consultation document the manufacturer provided additional justification for the resource use and cost assumptions included in the model, and showed that alternative assumptions only slightly increased the ICER.\n\nThe ERG noted that although the manufacturer had included a probabilistic model in its original submission, the cost-effectiveness results presented in the original submission were deterministic. The ERG provided a probabilistic analysis for the manufacturer's original base case that gave an ICER of £69,787 per QALY gained for fingolimod compared with Avonex (patient access scheme not included). This ICER was noted to be substantively higher than the manufacturer's original deterministic estimate of £55,634 per QALY gained.\n\nThe ERG noted that the manufacturer had presented adjusted hazard ratios in its original submission to describe the relative effect on disease progression of treatment with fingolimod compared with Avonex. However, these estimates were not employed in the model, and instead relative risks from unadjusted trial data were used. The ERG analysed the manufacturer's original base case (population\xa01b) using hazard ratios instead of relative risks (patient access scheme not included) and noted that, in an incremental analysis, the probabilistic ICER for fingolimod compared with best supportive care was £94,094 per QALY gained. In an incremental analysis, Avonex was extendedly dominated (that is, the ICER for Avonex was higher than the ICER for the next more effective alternative [fingolimod]). For population\xa01b, excluding those who also met the criteria for population\xa02, the ICER for fingolimod compared with best supportive care was £81,369 per QALY gained and Avonex was dominated by best supportive care (Avonex was less effective and more expensive). The ERG concluded that the incremental analysis shows that in both populations Avonex is either dominated or extendedly dominated. The ERG therefore advised that the cost effectiveness of fingolimod should be derived from this incremental analysis. The ERG acknowledged that the manufacturer had provided an additional analysis in response to the first appraisal consultation document. In this analysis, hazard ratio values were applied as relative risks in the model, and this reduced the deterministic base-case ICER from £55,634 (section 3.14) to £52,906 per QALY gained for population\xa01b. In the ERG's view the manufacturer's additional analyses did not address its initial concerns, because it considered that the hazard ratio values used should have been applied as hazard ratios, rather than relative risks, in the probabilistic (not the deterministic) model.\n\nThe ERG was concerned that the manufacturer provided insufficient justification in its original submission for choosing published EDSS-based EQ-5D scores rather than the trial outcomes to derive utility data. The ERG cautioned that although the published utility data had been used in previous NICE technology appraisal guidance on treatments for multiple sclerosis, these data had been criticised for coming from studies with low response rates, possible selection bias and unrepresentative populations. The ERG suggested that because the manufacturer's base case targeted a very specific patient population (population\xa01b), it would have been more appropriate to use utility data for these patients, which were available directly from the FREEDOMS and TRANSFORMS trials. The ERG conducted an exploratory analysis to assess the impact of using the average utilities for each EDSS score in the trial (up to EDSS\xa06) and then using published sources to impute the missing utility data for EDSS scores of 7 and above. In this analysis, the probabilistic ICER for fingolimod compared with best supportive care in population 1b increased to £106,824 per QALY gained (patient access scheme not included) when the missing utility estimates for EDSS scores 7 to 10 were imputed using values from NICE technology appraisal guidance\xa0127. Based on these results, the ERG cautioned that changing the utility values of only three EDSS scores has a significant impact on the ICER for fingolimod. The ERG acknowledged that in the manufacturer's response to the first appraisal consultation document an additional analysis was provided in which utility data from the trials were used for EDSS states up to 6, and then data from a study by Orme et al. (2007) were used for the remaining 13 states. Using data from the FREEDOMS and TRANSFORMS trials reduced the manufacturer's original deterministic base-case ICER for fingolimod compared with Avonex to £52,982 per QALY gained and £52,866 per QALY gained respectively. In its critique of the manufacturer's original submission, the ERG had previously explored a number of alternative scenarios for incorporating trial utility data into the model, which were shown to both increase and decrease the ICERs. The ERG cautioned that the model predictions are highly sensitive to the utility estimates and therefore it is important to fully justify the data sources and imputation methods used.\n\nThe ERG was concerned about the representativeness of the initial EDSS score distribution used in the manufacturer's original model. The ERG examined a number of scenarios and showed that the cost effectiveness of fingolimod varies depending on the initial distribution of patients across EDSS states. The ICER for fingolimod compared with best supportive care in population\xa01b was £78,338 per QALY gained when it was assumed that all people enter the model with an EDSS score of 4, and £102,718 per QALY gained when all people enter the model with an EDSS score of 2 (patient access scheme not included). The ERG considered that its analyses highlighted that the model was highly sensitive to the initial population EDSS distribution assumed.\n\nThe ERG noted from market share data provided by the manufacturer that Rebif-44 is commonly prescribed in the NHS for the treatment of multiple sclerosis. The ERG conducted two exploratory analyses that included Rebif-44 as an additional comparator. The first analysis used direct evidence on the effectiveness of Rebif-44 and Avonex, and the second used the results from the mixed treatment comparison provided by the manufacturer (patient access scheme not included). Deterministic results were calculated using relative risks from the direct evidence and showed that Rebif-44 dominated Avonex in population\xa01b and in the subgroup of population\xa01b that excluded patients who also met the criteria for population\xa02. However, for population\xa01b, Rebif-44 was extendedly dominated (that is, the ICER for Rebif-44 was higher than the ICER for the next more effective alternative [fingolimod]) in an incremental analysis. The ICER for fingolimod compared with best supportive care was £91,059 per QALY gained for population\xa01b, and £79,315 per QALY gained for population\xa01b without those who also met the criteria for population\xa02. When data from the manufacturer's mixed treatment comparison were used instead, Avonex was dominated by Rebiff-44 for both populations. The ICER for fingolimod compared with best supportive care was £119,213 per QALY gained for population\xa01b and £119,746 per QALY gained for population\xa01b without those who also met the criteria for population\xa02.\n\nThe ERG noted that the baseline relapse rates in the manufacturer's original model were dependent on EDSS state but were then adjusted by the relative risk of relapse with a particular disease-modifying therapy compared with best supportive care. The ERG was concerned that these estimates for relative effect were taken from different data sets and therefore had no implicit correlation. In addition, the ERG cautioned that the impact of disease-modifying therapy could be double-counted in the model. To explore this, the ERG re-ran the original model (patient access scheme not included) and excluded all direct treatment effects on relapse rates. For population\xa01b, the ICER for fingolimod compared with best supportive care increased to £112,294 per QALY gained compared with the ERG's base-case estimate of £94,094 per QALY gained. Avonex was extendedly dominated by best supportive care and fingolimod. For population\xa01b without those who also met the criteria for population\xa02, the ICER for fingolimod compared with best supportive care was £98,019 per QALY gained compared with £81,369 per QALY gained in the ERG's base case, and Avonex was dominated by best supportive care.\n\nThe ERG was concerned that the underlying progression rates predicted in the manufacturer's original model were higher than the rates seen in the TRANSFORMS and FREEDOMS trials, but the manufacturer did not explain the differences between the model predictions and the trial observations. The ERG conducted four scenario analyses to examine the sensitivity of the manufacturer's model to natural history progression rates. These included reducing natural history progression transitions by 50%, 25% and 10%, and increasing them by 10%. Reducing the natural history progression rates substantially increased the ICER for fingolimod compared with best supportive care. Assuming a 50% decrease in natural history progression rate increased the ICER to £252,147 per QALY gained for population\xa01b, and to £191,027 per QALY gained for population\xa01b without those who also met the criteria for population\xa02 (patient access scheme not included). The ERG considered that the model predictions were highly sensitive to the natural history progression data used in the model.\n\nThe ERG noted that the manufacturer's original model assumed a constant and continued treatment effect in patients who receive disease-modifying therapy, as long as they remain on treatment, over the time horizon of the model. In the ERG's view this assumption, which was informed by trials of only 12\xa0months' and 24\xa0months' duration, was optimistic. The ERG conducted an exploratory analysis (expanding on the manufacturer's sensitivity analysis; patient access scheme not included) to evaluate the possible waning of treatment effect over time. Treatment efficacy was modelled to wane by 50%, 75% or 100% of the original level after 2\xa0years and 5\xa0years. In all scenarios, the more the efficacy was reduced, the higher the ICER. This is because the costs of treatment are still incurred but less health benefit is obtained. When the treatment effect was assumed to wane after 2\xa0years, the ICERs for fingolimod compared with best supportive care were £140,282 per QALY gained (50% efficacy reduction), £177,674 per QALY gained (75% efficacy reduction) and £249,735 per QALY gained (100% efficacy reduction). When it was assumed that the treatment effect does not wane until after 5\xa0years, the ICERs for fingolimod compared with best supportive care were £114,532 per QALY gained for a 50% efficacy reduction, £131,135 per QALY gained for a 75% efficacy reduction and £143,869 per QALY gained for a 100% efficacy reduction.\n\nThe ERG reviewed the revised model provided by the manufacturer in response to the first appraisal consultation document. It noted that the manufacturer only adjusted the drug acquisition cost in the model in line with the patient access scheme. The ERG noted that the manufacturer had not updated the model to reflect the assumptions that the Committee had considered to be most plausible during the first Committee meeting. The ERG ran the manufacturer's updated model including the patient access scheme and produced a probabilistic base-case ICER for fingolimod compared with Avonex of £14,997 per QALY gained. The ERG also produced an incremental analysis using the manufacturer's updated model which showed that the probabilistic ICER for fingolimod was £58,024 per QALY gained compared with best supportive care, and Avonex was extendedly dominated by fingolimod and best supportive care with an ICER of £176,357 per QALY gained. The ERG cautioned that despite the discounted drug acquisition cost, the remaining uncertainties around the model and its inputs still remained.\n\nThe ERG reviewed the revised model provided by the manufacturer in response to the second appraisal consultation document. The ERG confirmed that the manufacturer had correctly revised its model to incorporate the assumptions that the Committee had considered important for exploring the uncertainty surrounding the base-case ICER during its second meeting. The ERG confirmed that it was able to approximate the manufacturer's probabilistic cost-effectiveness results for fingolimod compared with Avonex and for fingolimod compared with Rebif-44. However, it was unable to fully verify the manufacturer's ICER for fingolimod compared with the weighted average of the comparators, because results for some of the comparators (best supportive care and Betaferon) could not be reproduced from the manufacturer's model. The ERG urged caution in using a weighted average for the comparators and considered that a fully incremental analysis was a more appropriate way to explore the cost effectiveness of fingolimod relative to multiple comparators.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report, which are available on the NICE website.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of fingolimod, having considered evidence on the nature of highly active relapsing–remitting multiple sclerosis and the value placed on the benefits of fingolimod by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee understood from the patient experts that multiple sclerosis is a chronic, disabling, neurological condition that is life altering and has a substantial negative impact on quality of life and activities of daily living. The patient experts placed particular emphasis on loss of independence and implications for employment. They also described a significant impact on emotional wellbeing, which can lead to depression. The Committee understood that any delay or relief from these problems would have a positive impact on the lives of people with multiple sclerosis and their families. The Committee also heard from the patient experts that fingolimod would allow greater flexibility and decrease discomfort because it is given orally whereas other currently available treatments are administered by injection.\n\nThe Committee heard from the clinical specialists that treatment of relapsing–remitting multiple sclerosis is determined by the severity of the disease. This, in turn, is determined by the number and severity of relapses and by disability caused by the persistent effects of relapse or by the development of secondary progressive multiple sclerosis. For people with rapidly evolving severe relapsing–remitting multiple sclerosis (whose condition is described in section 2.1), natalizumab is often considered as a first-line treatment in line with NICE technology appraisal guidance\xa0127. A beta interferon or glatiramer acetate is routinely offered to most patients without rapidly evolving severe disease. The Committee also noted comments from consultees that approximately one-third of people may choose not to have a disease-modifying treatment (watchful waiting). The Committee heard from the clinical specialists that after a suboptimal response to the first disease-modifying treatment used, clinicians are likely either to offer a different beta interferon or glatiramer acetate, or offer the patient a higher dose of beta interferon (such as Rebif-44). The Committee also heard that clinicians are generally reluctant to stop treatment altogether after a suboptimal response. The Committee acknowledged market research data from the manufacturer and survey results from 116 consultant neurologists and specialist multiple sclerosis nurses which collectively showed that no more than 5–10% of patients are likely to receive best supportive care (no active treatment) after a suboptimal response to previous disease-modifying treatments. The Committee noted that beta interferons and glatiramer acetate were not recommended in NICE technology appraisal guidance\xa032. However, it acknowledged that after this guidance was issued, the Department of Health agreed a risk-sharing scheme with manufacturers through which disease-modifying treatments for multiple sclerosis can be provided to patients in the NHS, albeit at a level of cost effectiveness above what is considered an appropriate use of NHS resources as defined in the NICE Guide to the methods of technology appraisal (2008).\n\nThe Committee considered the likely place of fingolimod in the treatment of relapsing–remitting multiple sclerosis. The Committee understood that although clinical practice varies among neurologists, many clinical specialists would consider fingolimod as a second or subsequent line of treatment for people with high disease activity despite treatment with beta interferon or glatiramer acetate. It heard from the clinical specialists that fingolimod would provide the greatest benefit to people with rapidly evolving severe relapsing–remitting multiple sclerosis, because they currently have very few treatment options. The Committee acknowledged the clinical specialists' disappointment that a recommendation for the use of fingolimod in this population could not be made because the manufacturer had not submitted an analysis of fingolimod compared with natalizumab in this population.\n\nThe Committee understood from the clinical specialists and patient experts that fingolimod is generally well tolerated and that the adverse reactions expected during treatment could be satisfactorily managed in routine clinical practice.\n\n# Clinical effectiveness\n\nThe Committee noted that only part of the population covered by the marketing authorisation for fingolimod was considered in the manufacturer's submission, that is, people with highly active relapsing–remitting multiple sclerosis who have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon (population\xa01b). The Committee noted that the manufacturer's reason for this was that this population represented the largest subgroup in the clinical trials of fingolimod. The Committee concluded that it could only make a recommendation on the use of fingolimod for the population presented in the manufacturer's submission (that is population\xa01b). It would be unable to make any recommendations for the use of fingolimod in any other populations covered by the marketing authorisation without evidence on the cost effectiveness of fingolimod for these populations from the manufacturer. The Committee also noted that the manufacturer compared fingolimod with only one formulation of beta interferon (Avonex) in its original base-case analysis, and that it included no other comparators from the decision problem. The Committee heard from the manufacturer that Avonex and Rebif are the most commonly prescribed forms of beta interferon in the NHS. The Committee acknowledged the concerns of the ERG that a beta interferon should not be the only comparator in an analysis for a patient group who have had a suboptimal response to prior beta interferon therapy, and that best supportive care should also be considered. The Committee concluded that limiting the analyses to comparisons with Avonex only was not appropriate, and instead comparisons with other beta interferons and best supportive care need to be included as a basis for any recommendations in this appraisal.\n\nThe Committee considered the evidence presented by the manufacturer on the clinical effectiveness of fingolimod. It noted that the manufacturer derived data from two clinical trials that assessed the efficacy and safety of fingolimod compared with placebo over 24\xa0months (FREEDOMS trial), and with beta interferon-1a (Avonex) over 12\xa0months (TRANSFORMS trial) in adults with relapsing–remitting multiple sclerosis. The Committee noted that the populations in the FREEDOMS and TRANSFORMS trials were broader than those in the marketing authorisation for fingolimod and therefore after the trials finished the manufacturer had to identify subgroups that approximated the populations in the marketing authorisation. The Committee heard from the ERG that the subgroups identified by the manufacturer were reasonable approximations to the populations in the marketing authorisation but that the subgroups were not mutually exclusive. The Committee noted that in response to clarification the manufacturer provided some revised analyses for people in population\xa01b who did not have rapidly evolving severe relapsing–remitting multiple sclerosis (that is population\xa01b, with people who also met the criteria for population\xa02 excluded). The Committee noted that these analyses generated lower ICERs than those for the whole of population\xa01b, but it was aware of reservations expressed by the manufacturer and the ERG about the small samples on which the subgroup analysis was based. Separate analyses were not provided for populations 1a or 2. The Committee also considered the manufacturer's mixed treatment comparison, which assessed treatment effects between comparators in the absence of direct evidence. It heard from the manufacturer and the ERG that there was considerable heterogeneity between the studies and that none of the studies in the analysis included populations that closely and consistently match those described in the marketing authorisation for fingolimod. It also heard that the TRANSFORMS and FREEDOMS trials were not powered to assess the efficacy of fingolimod in the subgroups defined by the marketing authorisation. The Committee concluded that the available evidence shows that people with relapsing–remitting multiple sclerosis who are treated with fingolimod have lower relapse rates than people treated with Avonex or placebo. The Committee also agreed that fingolimod was shown to reduce disability progression in people with relapsing–remitting multiple sclerosis compared with placebo in the whole population of the FREEDOMS trial; however, there was no significant impact on disability progression compared with Avonex in the TRANSFORMS trial. The Committee heard from the manufacturer that the European Medicines Agency had judged that the clinical trial data demonstrated consistent treatment effects with fingolimod in all of the subgroups with highly active disease covered by the marketing authorisation. The Committee concluded that the available evidence shows that fingolimod improves outcomes for the whole population in the clinical trials, and in those with highly active disease defined by the marketing authorisation.\n\nThe Committee discussed the health-related quality-of-life data from the FREEDOMS and TRANSFORMS trials. It noted that there were no statistically significant changes from baseline for EQ-5D measures observed for people with relapsing–remitting multiple sclerosis treated with fingolimod or placebo in the FREEDOMS trial, and that only a slight non-significant improvement in health-related quality of life according to the PRIMUS-QoL scale was observed for people treated with fingolimod or Avonex in the TRANSFORMS trial. The Committee heard from the clinical specialists that a patient's quality of life may not be affected by treatment because multiple sclerosis is a chronic disease with fluctuating symptoms, particularly in the relatively early stages of the condition. The Committee noted that the populations in the FREEDOMS and TRANSFORMS trials did not experience significant progression of disease and this may also have reduced the apparent impact of treatment on quality of life measures. The Committee concluded that it was therefore clinically plausible to see non-statistically significant changes in health-related quality-of-life measures in the FREEDOMS and TRANSFORMS trials, and that the impact of fingolimod on health-related quality of life remained uncertain.\n\n# Cost effectiveness\n\nThe Committee discussed the cost-effectiveness estimates from the manufacturer's original economic model, the assumptions on which these were based, the revised analyses from the manufacturer in response to the first and second appraisal consultation documents and the ERG's critiques and exploratory analyses. The Committee noted that the manufacturer provided a probabilistic Markov model that was structurally similar to other models used in previous NICE technology appraisal guidance on treatments for multiple sclerosis. The Committee noted that the manufacturer's original base-case analysis presented deterministic results for fingolimod compared with Avonex, which were substantially lower than the probabilistic results estimated by the ERG. The Committee acknowledged the concerns of the ERG that deterministic results should not be presented from a probabilistic model, and concluded that it would base its decision on the probabilistic results.\n\nThe Committee noted the concerns of the clinical specialists that the manufacturer's model may not reflect the natural history of multiple sclerosis because it does not allow for improvement in EDSS scores. The Committee heard from the manufacturer that the ability to include improvements in EDSS scores had been intentionally removed from the model to produce a conservative estimate of the cost effectiveness of fingolimod. The Committee heard from the clinical specialists that few people experience an improvement in EDSS score and therefore it concluded that the manufacturer's approach was reasonable.\n\nThe Committee heard from the manufacturer that disability progression rates in the model were derived from a longitudinal data set from a population with multiple sclerosis in Ontario, Canada. This data source was chosen because it has been considered previously in other NICE technology appraisal guidance on treatments for multiple sclerosis. The Committee heard from the clinical specialists and the ERG that this may have given more rapid disability progression rates than those seen in the clinical trials and in the current UK patient population. However, the Committee noted that no alternative data sources had been made available. The Committee was concerned that the manufacturer did not explain the divergence between model predictions and the trial observations for disease progression in its original submission, because the ERG's exploratory analyses showed that the model predictions were highly sensitive to the natural history progression data used. The Committee noted from subsequent sensitivity analyses carried out by the manufacturer that the ICERs increased only slightly with changes in the assumptions on natural history of disease progression (section 3.20). The Committee was persuaded that disease progression in people initially treated with disease-modifying treatments may be less rapid in current clinical practice than in the Ontario data set and concluded that data on the natural history of disability progression were a source of uncertainty in the model.\n\nThe Committee heard from the manufacturer that the utility data from the FREEDOMS or TRANSFORMS trials were not used in the original model because the study populations included only people with an EDSS score up to 6, and therefore utility data for higher EDSS scores were not available. The Committee heard from the ERG that the manufacturer used EDSS-based EQ-5D scores from a published source instead, despite this study being criticised in technology appraisal guidance\xa0127 for having low response rates, not representing the appropriate population and being prone to selection bias. The Committee agreed that because the manufacturer's base case targeted a very specific group (population\xa01b), it would have been more appropriate to use utility data for that group from the trials where possible, and to use data from other sources only for EDSS scores above 6. The Committee considered additional analyses from the manufacturer in response to the appraisal consultation documents, which indicated that the base-case ICER for population\xa01b slightly decreased when utility data from the FREEDOMS and TRANSFORMS trials were used for EDSS states up to 6 and published data from Orme et al. (2007) were only used for EDSS scores above 6. The Committee concluded that the manufacturer's revised approach to incorporating utility estimates in the model was reasonable.\n\nThe Committee was concerned about the assumption in the manufacturer's original model that the treatment effect observed for the duration of the trials (1 or 2\xa0years) was maintained at the same level during the on-treatment periods. It noted that sensitivity analyses carried out by the manufacturer and the ERG showed that a reduction in the assumed duration of treatment effect increased the ICERs substantively (see sections 3.15 and 3.32). The Committee heard from the manufacturer that there is currently no evidence to support the hypothesis that the efficacy of fingolimod will reduce over time and preliminary results from the FREEDOMS extension study show that there is no loss of efficacy over 4\xa0years. In the absence of data beyond 4\xa0years, the Committee decided to be cautious and considered it appropriate to include a 50% waning of treatment effect after 5\xa0years in the base-case analysis. However, it acknowledged that if the treatment effect did not wane over time then this would overestimate the base-case ICER.\n\nThe Committee noted potential inaccuracies in some of the administration costs included in the manufacturer's original model. In particular, it heard from the manufacturer that it was assumed that people treated with Avonex had more visits to a neurologist than people treated with fingolimod. The Committee heard from the clinical specialists that this assumption was probably not correct and that it is more plausible that people receiving fingolimod would have three visits during the first year of treatment, compared with two visits for people receiving Avonex. The Committee noted that the manufacturer had corrected this assumption in the revised analyses submitted in response to the appraisal consultation documents and was persuaded that revising the costs in the model had a minimal impact on the ICER.\n\nThe Committee acknowledged that based on current practice in the NHS it would be inappropriate to use Avonex alone as a comparator for fingolimod. The Committee considered exploratory analyses conducted by the ERG on the manufacturer's original model, which incrementally compared fingolimod with best supportive care and Rebif-44. The Committee noted that these analyses were based on indirect comparisons of limited data and that in population\xa01b Avonex was dominated by Rebif-44. The Committee noted comments from the manufacturer in response to the appraisal consultation documents, which suggested that the Rebif-44 data used in the comparison with fingolimod were from patients with relapsing–remitting multiple sclerosis regardless of previous treatment, rather than from those whose disease had a suboptimal response to disease-modifying therapy (that is, population\xa01b). The Committee was persuaded that this may have resulted in an overestimation of the ICER for fingolimod compared with Rebif-44.\n\nThe Committee acknowledged that although the manufacturer had tried to address some of the concerns raised during the first and second Committee meetings, the manufacturer and the ERG still had divided opinions on the most appropriate methodological approaches to evaluate the cost effectiveness of fingolimod in population\xa01b. The Committee considered the manufacturer's revised probabilistic base-case ICER of £17,300 per QALY gained for fingolimod compared with Avonex. The Committee noted that in the ERG's incremental analysis, Avonex was extendedly dominated and the probabilistic ICER for fingolimod compared with best supportive care was £58,000 per QALY gained. The Committee acknowledged that the ERG's analyses demonstrated that beta-interferon treatment may not be cost effective compared with what is considered an appropriate use of NHS resources as defined in the NICE Guide to the methods of technology appraisal (2008). However it was mindful of the need to take account of current NHS practice, including the risk-sharing scheme (which currently funds beta-interferon treatments for people with multiple sclerosis), when defining the appropriate comparator(s) for assessment.\n\nThe Committee acknowledged that the choice of comparator in the manufacturer's model was a key driver of cost effectiveness. It also acknowledged that there was variation in current practice and therefore concluded that fingolimod should be compared with a weighted average of the comparators currently used in UK clinical practice to manage relapsing–remitting multiple sclerosis. This includes best supportive care together with a mix of beta interferons (with the proportions for the beta interferons based on market share data from the Prescription Pricing Authority). The Committee noted that the manufacturer's probabilistic ICER for fingolimod compared with the weighted average of the comparators was £27,800 per QALY gained. The Committee acknowledged that the manufacturer had assumed that best supportive care contributes only 5% to the weighted average in the base case, and that sensitivity analyses showed that if a higher proportion was assumed, such as 10%, the ICER would increase to approximately £30,000 per QALY gained (see section 3.19). The Committee noted from the manufacturer's and the ERG's sensitivity analyses that the ICER for fingolimod compared with the weighted average of the comparators depends on the proportions assumed for the comparator treatments, and the assumptions about the natural history of disability progression and the waning of treatment effect after 5\xa0years. The Committee concluded that the most plausible ICER for fingolimod compared with the weighted average of the comparators was likely to be in the range of £25,000 to £35,000 per QALY gained.\n\nThe Committee noted that the most plausible ICER for fingolimod could be higher than what is normally considered an effective use of NHS resources. It was mindful that the NICE Guide to the methods of technology appraisal (2008) states that a strong case should be identified for an ICER that is higher than £30,000 per QALY gained. The Committee noted that in these circumstances the NICE Guide to methods of technology appraisal states that judgements about the acceptability of the technology as an effective use of NHS resources will specifically take account of:\n\nthe degree of certainty around the ICER\n\nany strong reasons to indicate that the assessment of the change in health-related quality of life has been inadequately captured\n\nwhether the innovative nature of the technology adds demonstrable and distinctive benefits of a substantial nature which may not have been adequately captured in the QALY measure.\n\nThe Committee discussed whether the assessment of the change in health-related quality of life had been inadequately captured in the economic analysis. It heard from the patient experts that people who receive fingolimod have fewer adverse reactions than those who receive beta-interferon therapy. In addition, treatment with fingolimod significantly reduces relapses and could allow people to lead an active and fulfilling life and contribute more fully to society. The Committee also heard from the manufacturer that any impact of treatment with fingolimod on the severity of relapses had not been captured in the model. In addition, the benefits from a decreased need for informal care provided by family and friends of people with multiple sclerosis had not been considered (because it is not in line with NICE's reference case). In the manufacturer's view, inclusion of these factors would decrease the ICER. The Committee accepted that fingolimod is a valuable new therapy and that its oral formulation represents innovation in the treatment of multiple sclerosis. The Committee recognised that including all of the benefits suggested by the manufacturer and patient experts in the manufacturer's model could decrease the ICER to a level that would be considered a cost-effective use of NHS resources.\n\nThe Committee noted that the current risk-sharing scheme allows beta interferons to be purchased at a price which the Department of Health considers to be a cost-effective use of NHS resources. However, it regretted that published outcome data from the scheme to justify the negotiated procurement price for these treatments are lacking. Taking these difficulties into consideration, the Committee made an exceptional case and recommended fingolimod as an option for the treatment of highly active relapsing–remitting multiple sclerosis in adults who have an unchanged or increased relapse rate, or ongoing severe relapses, compared with the previous year despite previous treatment with beta interferon (population\xa01b). The Committee also emphasised that it is important that a new model for multiple sclerosis is developed for any future appraisals of treatments for multiple sclerosis. The new model should ideally be based on UK patient cohorts, should use the best available evidence (including experience to date from the risk-sharing scheme) and should include all currently available treatments, so that future appraisals of treatments for multiple sclerosis are directly relevant to UK clinical practice.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA254\n\nAppraisal title: Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis\n\nSection\n\nKey conclusion\n\nThe Committee made an exceptional case and recommended fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis in adults, only if:\n\nthey have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon, and\n\nthe manufacturer provides fingolimod with the discount agreed as part of the patient access scheme.\n\n\n\nThe Committee accepted that fingolimod is a valuable new therapy and that its oral formulation represents innovation in the treatment of multiple sclerosis. The Committee recognised that including all of the benefits of fingolimod suggested by the manufacturer and patient experts in the manufacturer's model could decrease the ICER to a level that would be considered a cost-effective use of NHS resources.\n\n\n\nThe Committee emphasised that it is important that a new model for multiple sclerosis is developed for any future appraisals of treatments for multiple sclerosis. The new model should ideally be based on UK patient cohorts, should use the best available evidence (including experience to date from the risk-sharing scheme) and should include all currently available treatments for multiple sclerosis, so that future appraisals of treatments for multiple sclerosis are directly relevant to UK clinical practice.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee understood from the patient experts that multiple sclerosis is a chronic, disabling, neurological condition that is life altering and has a substantial negative impact on quality of life and activities of daily living. The Committee understood that any delay or relief from these problems would have a positive impact on the lives of people with multiple sclerosis and their families.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nThe Committee heard from the patient experts that fingolimod would allow greater flexibility and decrease discomfort because it is given orally whereas other currently available treatments are administered by injection.\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee accepted that fingolimod is a valuable new therapy and that its oral formulation represents innovation in the treatment of multiple sclerosis.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee understood that although clinical practice varies among neurologists, many clinical specialists would consider fingolimod as a second or subsequent line of treatment for people with high disease activity despite treatment with beta interferon or glatiramer acetate. It heard from the clinical specialists that fingolimod would provide the greatest benefit to people with rapidly evolving severe relapsing–remitting multiple sclerosis, because they currently have very few treatment options. The Committee acknowledged the clinical specialists' disappointment that a specific recommendation for the use of fingolimod in this population could not be made because the manufacturer had not submitted an analysis of fingolimod compared with natalizumab in this population.\n\n\n\nAdverse reactions\n\nThe Committee understood from the clinical specialists and patient experts that fingolimod is generally well tolerated and that the adverse reactions expected during treatment could be managed in routine clinical practice.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee noted that only part of the population covered by the marketing authorisation for fingolimod was considered in the manufacturer's submission (population\xa01b). The Committee also noted that the manufacturer compared fingolimod with only one formulation of beta interferon (Avonex) in its original base-case analysis, and that it included no other comparators from the decision problem. The Committee concluded that limiting the analyses to comparisons with Avonex only was not appropriate, and instead comparisons with other beta interferons and best supportive care need to be included as a basis for any recommendations in this appraisal.\n\n\n\nThe manufacturer derived data from two clinical trials that assessed the efficacy and safety of fingolimod compared with placebo over 24\xa0months (FREEDOMS trial), and with beta interferon-1a (Avonex) over 12\xa0months (TRANSFORMS trial) in adults with relapsing–remitting multiple sclerosis.\n\n\n\nIn response to clarification the manufacturer provided revised analyses for people in population\xa01b who did not have rapidly evolving severe relapsing–remitting multiple sclerosis (that is population\xa01b, with people who also met the criteria for population\xa02 excluded). However, separate analyses were not provided for populations 1a or 2. The manufacturer also conducted a mixed treatment comparison, which assessed treatment effects between comparators in the absence of direct evidence.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe populations in the clinical trials were broader than those in the marketing authorisation for fingolimod. The manufacturer identified subgroups after the trials had finished which approximated the populations in the marketing authorisation. The ERG noted that the populations were not mutually exclusive. The Committee heard from the manufacturer that the European Medicines Agency had judged that the clinical trial data demonstrated consistent treatment effects with fingolimod in all of the subgroups with highly active disease covered by the marketing authorisation. The Committee concluded that the available evidence shows that fingolimod improves outcomes for the whole population in the clinical trials, and in those with highly active disease defined by the marketing authorisation.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee concluded that limiting the analyses to comparisons with Avonex only was not appropriate, and instead comparisons with other beta interferons and best supportive care need to be included as a basis for any recommendations in this appraisal.\n\n\n\nThe Committee concluded that it was clinically plausible to see non-significant changes in health-related quality-of-life measures in the FREEDOMS and TRANSFORMS trials, and that the impact of fingolimod on health-related quality of life remained uncertain.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nAn analysis of population\xa01b that excluded people who also met the criteria for population\xa02 (that is, a population in which people with rapidly evolving severe disease were excluded) was provided by the manufacturer in response to a request for clarification. The Committee noted that this analysis generated lower ICERs than those for the whole of population\xa01b, but was aware of reservations expressed by the manufacturer and the ERG about the small samples on which the subgroup analysis was based.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that the available evidence shows that people who are treated with fingolimod have lower relapse rates than people treated with Avonex or placebo. The Committee also agreed that fingolimod was shown to reduce disability progression compared with placebo in the whole population of the FREEDOMS trial; however, there was no significant impact on disability progression compared with Avonex in the TRANSFORMS trial. There were no statistically significant changes from baseline for EQ-5D measures observed for people with relapsing–remitting multiple sclerosis treated with fingolimod or placebo in the FREEDOMS trial. Only a slight non-statistically significant improvement in health-related quality of life according to the PRIMUS-QoL scale was observed for people treated with fingolimod or Avonex in the TRANSFORMS trial.\n\n, 4.8\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer provided a probabilistic Markov model that was structurally similar to other models used in previous NICE technology appraisal guidance on treatments for multiple sclerosis.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted the concerns of the clinical specialists that the model may not reflect the natural history of multiple sclerosis, because it does not allow for improvement in EDSS scores. The Committee concluded that the manufacturer's approach was reasonable because few people experience an improvement in EDSS score in clinical practice.\n\n\n\nThe Committee was concerned that the data set used by the manufacturer to estimate disability progression rates in the model may have given more rapid disability progression rates than those seen in the clinical trials and in the current UK patient population. The Committee noted from sensitivity analyses carried out by the manufacturer that the ICERs increased only slightly with changes in the assumptions on natural history of disease progression. The Committee was persuaded that disease progression in people initially treated with disease-modifying treatments may be less rapid in current clinical practice than in the Ontario data set and concluded that the data on the natural history of disability progression were a source of uncertainty in the model.\n\n\n\nThe Committee was concerned about the assumption in the manufacturer's original model that the treatment effect observed for the duration of the trials (1 or 2\xa0years) was maintained at the same level during the on-treatment periods. The Committee heard from the manufacturer that there is currently no evidence to support the hypothesis that the efficacy of fingolimod will reduce over time and preliminary results from the FREEDOMS extension study show that there is no loss of efficacy over 4\xa0years. In the absence of data beyond 4\xa0years, the Committee decided to be cautious and include a 50% waning of treatment effect after 5\xa0years in the base-case analysis. However, it acknowledged that if the treatment effect did not wane over time then this would overestimate the base-case ICER.\n\n\n\nThe Committee noted potential inaccuracies in some of the administration costs included in the manufacturer's original model. The Committee noted that the manufacturer had corrected these inaccuracies in the revised analyses submitted in response to the appraisal consultation documents and was persuaded that revising the costs in the model had a minimal impact on the ICER.\n\n\n\nThe Committee considered exploratory analyses from the ERG, which incrementally compared fingolimod with best supportive care and Rebif-44. The Committee noted comments from the manufacturer which suggested that the Rebif-44 data used in the comparison with fingolimod were from patients with relapsing–remitting multiple sclerosis regardless of previous treatment, rather than from those whose disease had a suboptimal response to disease-modifying therapy (that is, population\xa01b). The Committee was persuaded that this may have resulted in an overestimation of the ICER for fingolimod compared with Rebif-44.\n\n\n\nThe Committee acknowledged that there was variation in current practice and therefore concluded that fingolimod should be compared with a weighted average of the comparators currently used in UK clinical practice to manage relapsing–remitting multiple sclerosis. This includes best supportive care together with a mix of beta interferons (with the proportions for the beta interferons based on market share data from the Prescription Pricing Authority).\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee noted that the manufacturer did not use utility data from the FREEDOMS or TRANSFORMS trials in the original model. Additional analyses from the manufacturer in response to the appraisal consultation documents indicated the base-case ICER for population\xa01b slightly decreased when utility data from the FREEDOMS and TRANSFORMS trials were used for EDSS states up to 6 and data from Orme et al. (2007) were used for EDSS scores above 6. The Committee concluded that the manufacturer's revised approach to incorporating utility estimates in the model was reasonable.\n\n\n\nThe Committee heard from the patient experts that people who receive fingolimod have fewer adverse reactions than those who receive beta-interferon therapy. In addition, treatment with fingolimod significantly reduces relapses and could allow people to lead an active and fulfilling life and contribute more fully to society. The Committee also heard from the manufacturer that any impact of treatment with fingolimod on the severity of relapses had not been captured in the model. In addition, the benefits from a decreased need for informal care provided by family and friends of people with multiple sclerosis had not been considered. In the manufacturer's view, inclusion of these factors would decrease the ICER.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNone\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nOne-way sensitivity analyses conducted by the manufacturer suggested that the ICER for fingolimod compared with Avonex was most sensitive to the relative risks of disease progression assumed for fingolimod and Avonex, and the relative risk of relapse for Avonex.\n\n\n\nThe Committee acknowledged that the choice of comparator in the manufacturer's model was a key driver of cost effectiveness.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee concluded that depending on the proportions assumed for the comparator treatments, and the assumptions included in the model about the natural history of disability progression and the waning of treatment effect after 5\xa0years, the most plausible ICER for fingolimod compared with the weighted average of the comparators from the manufacturer's model was likely to be in the range of £25,000 to £35,000 per QALY gained. The Committee recognised that including all of the benefits of fingolimod which may not be adequately captured in the QALY calculation (as suggested by the manufacturer and the patient experts) could decrease the ICER to a level that would be considered a cost-effective use of NHS resources.\n\n, 4.19\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe manufacturer agreed a patient access scheme with the Department of Health in which a simple confidential discount is applied to the list price of fingolimod.\n\n\n\nEnd-of-life considerations\n\nNot applicable.\n\n\n\nEqualities considerations and social value judgements\n\nNo equality issues were raised during the scoping exercise or during the course of the appraisal.\n\n", 'Recommendations for further research': 'The Committee recommends the development of patient registries for multiple sclerosis to capture long-term treatment-related outcomes.\n\nThe Committee recommends that a new model for multiple sclerosis is developed, ideally based on UK patient cohorts, which uses the best available evidence (including experience to date from the risk-sharing scheme) and includes all currently available treatments.', 'Related NICE guidance': '# Published\n\nNatalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis. NICE technology appraisal guidance 127 (2007).\n\nMultiple sclerosis: management of multiple sclerosis in primary and secondary care. NICE clinical guideline 8 (2003).\n\nBeta interferon and glatiramer acetate for the treatment of multiple sclerosis. NICE technology appraisal guidance 32 (2002).', 'Review of guidance': 'The guidance on this technology will be considered for review by the Guidance Executive at the same time as Beta interferon and glatiramer acetate for the treatment of multiple sclerosis (NICE technology appraisal guidance 32) and Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 127). The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveApril 2012', 'Changes after publication': 'January 2014: implementation section updated to clarify that fingolimod is recommended as an option for treating highly active relapsing–remitting multiple sclerosis. Additional minor maintenance update also carried out.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta254
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Evidence-based recommendations on fingolimod (Gilenya) for highly active relapsing-remitting multiple sclerosis.
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25565b34557f108b365f1b269019080e6aa66e06
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nice
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Incisionless otoplasty
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Incisionless otoplasty
# Guidance
Incisionless otoplasty comprises a variety of surgical techniques, carried out via minimal percutaneous access, that have been poorly described in the evidence, which includes a very small number of patients. The evidence on efficacy and safety is inadequate both in quality and quantity, and therefore the procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake incisionless otoplasty should take the following actions.
Inform the clinical governance leads in their Trusts.
Ensure that patients and/or their parents or carers understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.
Audit and review clinical outcomes of all patients having incisionless otoplasty (see section 3.1).
Further research on incisionless otoplasty should describe the precise surgical techniques used and should report both short- and long-term outcomes, including the need for further procedures.# The procedure
# Indications and current treatments
Protruding or prominent ears result when normal cartilaginous folds fail to form within the ear.
Surgery to correct protruding ears aims to reposition the elastic cartilage permanently while preserving a natural appearance. Cartilage-sparing techniques avoid radical excision, but reduce the cartilage spring by such measures as scoring, drilling and suturing. All techniques usually involve a post-auricular incision of the skin.
# Outline of the procedure
Incisionless otoplasty avoids the use of a standard incision, which can sometimes be complicated by anterior skin necrosis or keloid scar formation.
The procedure is usually carried out with the patient under general anaesthesia, but it can also be done under local anaesthesia. Precise details of the procedure depend on the nature of the ear abnormalities, the needs of the individual patient and the preferences of the surgeon. In an optional first stage, a needle is inserted into the anterior aspect of the ear and used to score the anterior surface of the cartilage and render it more malleable. A posterior approach is then used to insert subcutaneous retention sutures (usually non-absorbable) to create a natural looking antihelix with less ear protrusion. Conchal cartilage may also be anchored onto the mastoid bone by a subcutaneous stitch attached to non-elastic tissue such as the periosteum.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A case series of 13 patients (5 of whom were treated by incisionless otoplasty) reported that photographs showed good correction and that all patients and their families were satisfied with the outcome.
A case series of 11 patients reported that all results were 'satisfactory' with no recurrence during 6- to 30-month follow-up.
The Specialist Advisers listed key efficacy outcomes as aesthetic ear correction and avoidance of recurrence.
# Safety
No safety concerns were reported in the published literature.
The Specialist Advisers listed anecdotal adverse events as anterior skin necrosis, collapse of the ear necessitating reconstruction with costal cartilage, poor aesthetic outcome and bleeding.
# Other comments
The Committee noted the psychological distress caused by protruding ears and the potential benefit of effective treatment, in particular by procedures that minimise scarring. However, the limited publications available provided inadequate evidence to suggest that incisionless otoplasty is an efficacious procedure. The Committee expressed particular disappointment at the paucity of the evidence base.# Further information
This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedures guidance process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Changes after publicationMay 2012: minor maintenance
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICENational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BTwww.nice.org.uknice@nice.org.uk0845 033 7780
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{'Guidance': "Incisionless otoplasty comprises a variety of surgical techniques, carried out via minimal percutaneous access, that have been poorly described in the evidence, which includes a very small number of patients. The evidence on efficacy and safety is inadequate both in quality and quantity, and therefore the procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake incisionless otoplasty should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and/or their parents or carers understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having incisionless otoplasty (see section 3.1).\n\nFurther research on incisionless otoplasty should describe the precise surgical techniques used and should report both short- and long-term outcomes, including the need for further procedures.", 'The procedure': "# Indications and current treatments\n\nProtruding or prominent ears result when normal cartilaginous folds fail to form within the ear.\n\nSurgery to correct protruding ears aims to reposition the elastic cartilage permanently while preserving a natural appearance. Cartilage-sparing techniques avoid radical excision, but reduce the cartilage spring by such measures as scoring, drilling and suturing. All techniques usually involve a post-auricular incision of the skin.\n\n# Outline of the procedure\n\nIncisionless otoplasty avoids the use of a standard incision, which can sometimes be complicated by anterior skin necrosis or keloid scar formation.\n\nThe procedure is usually carried out with the patient under general anaesthesia, but it can also be done under local anaesthesia. Precise details of the procedure depend on the nature of the ear abnormalities, the needs of the individual patient and the preferences of the surgeon. In an optional first stage, a needle is inserted into the anterior aspect of the ear and used to score the anterior surface of the cartilage and render it more malleable. A posterior approach is then used to insert subcutaneous retention sutures (usually non-absorbable) to create a natural looking antihelix with less ear protrusion. Conchal cartilage may also be anchored onto the mastoid bone by a subcutaneous stitch attached to non-elastic tissue such as the periosteum.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 13 patients (5 of whom were treated by incisionless otoplasty) reported that photographs showed good correction and that all patients and their families were satisfied with the outcome.\n\nA case series of 11 patients reported that all results were 'satisfactory' with no recurrence during 6- to 30-month follow-up.\n\nThe Specialist Advisers listed key efficacy outcomes as aesthetic ear correction and avoidance of recurrence.\n\n# Safety\n\nNo safety concerns were reported in the published literature.\n\nThe Specialist Advisers listed anecdotal adverse events as anterior skin necrosis, collapse of the ear necessitating reconstruction with costal cartilage, poor aesthetic outcome and bleeding.\n\n# Other comments\n\nThe Committee noted the psychological distress caused by protruding ears and the potential benefit of effective treatment, in particular by procedures that minimise scarring. However, the limited publications available provided inadequate evidence to suggest that incisionless otoplasty is an efficacious procedure. The Committee expressed particular disappointment at the paucity of the evidence base.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nInformation for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges after publicationMay 2012: minor maintenance\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICENational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BTwww.nice.org.uknice@nice.org.uk0845 033 7780'}
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Pharmalgen for the treatment of bee and wasp venom allergy
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Pharmalgen for the treatment of bee and wasp venom allergy
Evidence-based recommendations on bee venom and wasp venom (Pharmalgen) for treating bee and wasp venom allergy.
# Guidance
Pharmalgen is recommended as an option for the treatment of IgE-mediated bee and wasp venom allergy in people who have had:
a severe systemic reaction to bee or wasp venom, or
a moderate systemic reaction to bee or wasp venom and who have one or more of the following: a raised baseline serum tryptase, a high risk of future stings or anxiety about future stings.
Treatment with Pharmalgen should be initiated and monitored in a specialist centre experienced in venom immunotherapy.# Clinical need and practice
Bees and wasps inject venom when they sting. When a person is stung by a bee or wasp they typically have an intense, burning pain followed by erythema (redness) and oedema (swelling) at the site of the sting. This usually subsides within a few hours. After an initial sting, some people have an immune response and produce IgE antibodies. In these people, subsequent stings can trigger a rapid inflammatory response referred to as a 'type I' hypersensitivity reaction.
Hypersensitivity reactions to bee or wasp venom can be local or systemic, can vary in severity, and are typically of rapid onset. Large local reactions are characterised by oedema, erythema and pruritus, cover more than 10 cm in diameter and peak at between 24 and 48 hours after the sting. Systemic reactions can be measured using the Mueller grading system. Severity ranges from grade I to grade IV. A grade I systemic reaction is characterised by generalised urticaria or erythema, itching, malaise or anxiety. Grade II reactions may include symptoms associated with grade I reactions as well as generalised oedema, tightness in the chest, wheezing, abdominal pain, nausea and vomiting, and dizziness. Grade III reactions may include symptoms associated with grade I or II reactions as well as symptoms of dyspnoea, dysarthria, hoarseness, weakness, confusion, and a feeling of impending doom. Grade IV reactions may include symptoms associated with grade I, II or III reactions as well as loss of consciousness, incontinence of urine or faeces, or cyanosis.
Recently published guidelines for the treatment of bee and wasp venom allergy issued by the British Society for Allergy and Clinical Immunology classify systemic reactions as mild, moderate or severe. A mild systemic reaction is characterised by pruritus, urticaria, erythema, mild angio-oedema, rhinitis and conjunctivitis. Moderate systemic reactions may include mild asthma, moderate angio-oedema, abdominal pain, vomiting, diarrhoea and minor or transient hypotensive symptoms such as light-headedness and dizziness. Severe systemic reactions may include respiratory difficulty such as asthma or laryngeal oedema, hypotension, collapse or loss of consciousness, as well as double incontinence, seizures, or loss of colour vision. Anaphylaxis is defined by the European Resuscitation Council as a severe, life-threatening, generalised or systemic hypersensitivity reaction.
Data from the USA suggest that the prevalence of allergy to bee and wasp venom is between 0.4% and 3.3%. In the UK, insect stings are the second most frequent cause of anaphylaxis outside medical settings. It is estimated that of all deaths from anaphylaxis between 1992 and 2001 in the UK, approximately 62% were a result of reactions to wasp venom and approximately 9% were caused by reactions to bee venom. Some people who have a systemic reaction after being stung do not have another reaction when re-stung. It is estimated that after a large local reaction 5–15% of people go on to develop a systemic reaction when next stung. Approximately 14–20% of those who have a mild systemic reaction have another systemic reaction when next stung. For people who have experienced an anaphylactic reaction, the risk of having a recurrent episode is estimated to be between 60% and 70%.
The main method for diagnosing an allergy to bee and/or wasp venom is skin testing with venom. Another less sensitive method is measurement of allergen-specific IgE antibodies in serum. Clinicians may also measure serum tryptase at baseline (after a reaction to a sting has subsided) because this may predict the severity of a response to a subsequent sting.
Clinicians typically give an emergency kit to people with a venom allergy who are considered at risk of systemic reactions. The kit includes adrenaline (epinephrine; intramuscular injection) and can also include other emergency treatments such as a high-dose antihistamine (oral), a corticosteroid (inhaled), and/or a bronchodilator (inhaled). Preventive measures include advice on how to avoid bee and/or wasp stings.
In the UK, clinicians consider offering venom immunotherapy to people with a history of systemic allergic reactions to bee venom and/or wasp venom. Venom immunotherapy aims to reduce the risk of future systemic reactions and the severity of a systemic reaction when one occurs. People considered for venom immunotherapy are usually those who have had severe systemic reactions, or those who have experienced moderate systemic reactions and have additional risk factors, such as a high baseline serum tryptase or a high risk of future stings, or whose quality of life is significantly affected by venom allergy.# The technologies
Pharmalgen bee venom extract (ALK-Abelló) has a marketing authorisation for the treatment of IgE-mediated allergy to bee venom. Pharmalgen wasp venom extract (ALK-Abelló) has a marketing authorisation for the treatment of IgE-mediated allergy to wasp venom. Pharmalgen bee venom extract and Pharmalgen wasp venom extract (from now on referred to as Pharmalgen) also have marketing authorisations for the diagnosis of IgE-mediated allergy to bee or wasp venom, but this indication is outside the scope of this appraisal.
Treatment with Pharmalgen is in two phases: an initial phase and a maintenance phase. Before people receive Pharmalgen treatment, IgE-mediated allergy to bee or wasp venom must be confirmed by case history and by in vivo and/or in vitro diagnosis. Pharmalgen is given by subcutaneous injection.
During the initial phase, an increasing dose of Pharmalgen is given until the maximum tolerated dose is reached. The following types of dosing schedules can be used during the initial phase: conventional (one injection every 3–7 days), modified rush (clustered; two to four injections weekly given at intervals of 30 minutes) or rush (injections at 2-hour intervals with a maximum of four injections per day). During the maintenance phase, Pharmalgen is administered at a dose of 100 micrograms every 4–6 weeks for at least 3 years. The dosage may be adjusted depending on the person's history of allergic reactions and sensitivity to the specific allergen used.
The summary of product characteristics (SPC) as provided by the manufacturer states that Pharmalgen is contraindicated in people with malignancies, severe chronic or seasonal asthma, and immunological conditions. It is also contraindicated in people with diseases or conditions that prevent the treatment of possible anaphylactic reactions, such as chronic heart and lung disease, severe arterial hypertension and treatment with beta-blockers. Pharmalgen is also contraindicated in people taking tricyclic antidepressants, monoamine oxidase inhibitors, and angiotensin-converting enzyme inhibitors, and should not be initiated during pregnancy. Pharmalgen treatment may be associated with local or systemic immunological reactions, which can include anaphylaxis. The SPC recommends that people be observed for at least 60 minutes after an injection of Pharmalgen. For full details of adverse effects and contraindications see the SPC.
Pharmalgen bee venom costs £54.81 for an initial treatment set and £63.76 for a maintenance treatment set (excluding VAT; 'British national formulary' edition 61).The maintenance treatment set includes four vials; therefore, the cost per injection in the maintenance phase is £15.94. Pharmalgen wasp venom costs £67.20 for an initial treatment set and £82.03 for a maintenance treatment set (excluding VAT; BNF edition 61). The maintenance treatment set also includes four vials; therefore, the cost per injection in the maintenance phase is £20.51. Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). The manufacturer of Pharmalgen, ALK-Abelló, did not provide a submission for this appraisal. The Assessment Group (Liverpool Reviews and Implementation Group, LRiG) produced an assessment report of the clinical effectiveness and cost effectiveness of Pharmalgen within its licensed indication for the treatment of bee and wasp venom allergy.
# Clinical effectiveness
The Assessment Group conducted a systematic review of the evidence on the clinical effectiveness of Pharmalgen compared with other treatment options in people with bee and/or wasp venom allergy. Nine studies reported in 11 publications were identified that met the inclusion criteria of the systematic review. All nine of the studies compared Pharmalgen with an active treatment: five compared different doses or dosing schedules of Pharmalgen with each other, one compared Pharmalgen with a modified form of Pharmalgen, and three compared Pharmalgen with other venom immunotherapy. Therefore, none of the studies identified compared Pharmalgen with a non-venom immunotherapy intervention. Of the nine studies identified, four were randomised controlled trials (RCTs), two compared an intervention group with historical controls, and three were quasi-experimental studies. The Assessment Group explored the possibility of conducting a mixed treatment comparison or an indirect comparison, but did not consider either appropriate because of the limitations in the data.
The type of allergy and the severity of systemic reactions to stings were specified as inclusion criteria in four of the studies. None of the studies was conducted in the UK. The number of people recruited in each study ranged between 30 and 65. Seven studies included adults only, one study included people aged 15–68 years, and one study included people aged 6–70 years. The average age of participants was similar across studies and ranged between 35 and 49 years. All studies recruited people with allergies to bee or wasp venom confirmed by skin tests, and seven studies also confirmed this with IgE testing. The protocols for the initial phase of treatment differed between studies and varied between 6 and 35 doses, over a period of 3 hours to 16 weeks. Most studies used a maintenance dose of 100 micrograms every 4 weeks. The studies measured outcomes at different time points from 4 days to more than 3 years.
The outcome from eight studies in people allergic to bee or wasp venom included the proportion of stings that resulted in systemic reactions. This ranged from 0 to 36.4% depending on the dose of immunotherapy or dosing schedule. Three studies reported proportions of stings that resulted in systemic reactions after approximately 3 years of maintenance therapy; these ranged between 0 and 36.4%. In the study with a rate of 36.4%, three of the four participants with a systemic reaction had a diminished response with mild symptoms. The proportions of stings that resulted in large local reactions was reported in two studies, and ranged from 35.7% to 88.9% across the treatment groups.
The Assessment Group presented data on systemic reactions to stings from observational non-comparative studies of Pharmalgen. The Assessment Group found 17 studies that reported the proportion of stings that resulted in systemic reactions before, during or after venom immunotherapy. The reported proportion of stings that resulted in systemic reactions ranged from 0 to 32.7%. For the studies that reported systemic reactions after Pharmalgen treatment, the proportion of stings that resulted in systemic reaction ranged from 0 to 12.5%.
People receiving venom immunotherapy may develop an allergic systemic reaction (adverse reaction) to the treatment. Adverse reactions were reported in eight of the studies: in one study during the initial phase only, in five studies during the initial or maintenance phase and in two studies during maintenance only. The proportion of people developing adverse reactions during the initial and maintenance phases of venom immunotherapy ranged from 0 to 38.1%.
The Assessment Group also presented evidence from comparative studies of venom immunotherapy other than Pharmalgen. Searches identified one meta-analysis and two systematic reviews of venom immunotherapy (specific brands not specified) in the population of interest. One of the reviews is an ongoing unpublished Cochrane review. The Assessment Group noted that the systematic reviews and the meta-analysis concluded that venom immunotherapy is effective in lowering the risk of future systemic reactions to venom in people with venom allergies.
None of the studies identified in the systematic review by the Assessment Group reported data on health-related quality of life. However, the ongoing Cochrane review included two studies that included health-related quality of life data. These studies compared venom immunotherapy (Pharmalgen or non-Pharmalgen venom immunotherapy) with an adrenaline auto-injector, and assessed quality of life using the Vespid Allergy Quality of Life Questionnaire (VQLQ). A meta-analysis of the two studies by the Cochrane group for the outcome change in VQLQ over 1 year concluded that venom immunotherapy was associated with a statistically significant improvement in quality of life compared with an adrenaline auto-injector.
# Cost effectiveness
The Assessment Group undertook a systematic review of existing cost-effectiveness evidence and developed an economic model of Pharmalgen for the treatment of bee and wasp venom allergy. The systematic review identified three studies, of which two were full papers and one an abstract. The studies were US based with costs expressed in US dollars. The Assessment Group did not find any health economic studies that compared venom immunotherapy with adrenaline auto-injectors, high-dose antihistamine or advice on how to avoid bee and wasp stings (avoidance advice).
The Assessment Group developed a de novo economic model to evaluate the cost effectiveness of Pharmalgen. The model is deterministic and constructed as a 1-year decision tree that is extrapolated to a 10-year time horizon, with changes to the size of the cohort at the end of each year because of sting-related deaths or death from other causes. The Assessment Group chose a 10-year horizon because it identified evidence to support the maintenance of effect over 10 years, and it did not identify any studies that considered a longer follow-up. The analyses were conducted from a UK NHS and personal social services perspective, with costs and benefits discounted at a rate of 3.5%.
The Assessment Group used the clinical effectiveness evidence and the results from its own survey of 32 immunology clinicians in allergy centres in the UK, a published audit of UK allergy clinics, and published guidelines to inform the treatment pathway in its economic model. The economic model starts with a person receiving one of three therapies:
venom immunotherapy with Pharmalgen, an emergency kit containing an adrenaline auto-injector and high-dose antihistamine, plus advice on how to avoid being stung, or
an emergency kit containing an adrenaline auto-injector and high-dose antihistamine, plus advice on how to avoid being stung, or
advice on how to avoid being stung.
For people treated with Pharmalgen, there is an initial phase with stepwise increases in dosage and a subsequent 3-year maintenance phase. The model includes two forms of dosing in the initial phase: conventional dosing, which lasts 12 weeks with 1 injection per week, and modified rush (clustered) dosing with 16 injections over a 7-week period. The model assumes that 92% of people receive conventional dosing and 8% receive modified rush dosing.
The model assumes that a person experiences an average of 0.095 stings per year irrespective of their treatment, based on a weighted average from six studies. A separate analysis explored a scenario in which a person experiences five stings a year. In the model, the probability of a systemic reaction after a sting is 56.4% for people given advice on avoidance only. For people given an emergency kit plus advice on avoidance, the probability of a systemic reaction after a sting is 43.9%. The probability of a systemic reaction after a sting for people receiving Pharmalgen is 6.5%. If a systemic reaction occurs, the likelihood of a Mueller grade I reaction is 6.5%, 9.8% and 38.5% for the advice only, emergency kit and Pharmalgen groups respectively; the likelihood of a Mueller grade II reaction is 80.3%, 83.6% and 54.0%; the likelihood of a Mueller grade III reaction is 12.1%, 6.05% and 7.5%; and the likelihood of a Mueller grade IV reaction is 1.1%, 0.55% and 0%. The model assumes that 1.25% of Mueller grade IV reactions result in death regardless of previous treatment.
During venom immunotherapy with Pharmalgen a person may experience an adverse reaction to treatment. The model assumes that the probability of a treatment-related adverse reaction is 2.0% per injection in the initial phase and 0.26% per injection in the maintenance phase. Systemic adverse reactions are classified by Mueller grade; each grade is associated with a particular cost. Of people who experience systemic adverse reactions to treatment, 37.5% experience (by Mueller grade) grade I, 37.5% experience grade II, 12.5% experience grade III, and 12.5% experience grade IV. The model assumes that no deaths result from adverse reactions to venom immunotherapy. The model assumes that treatment with adrenaline auto-injector or high-dose antihistamine is not associated with adverse reactions.
The model assumes that bee and wasp venom immunotherapy reduces the risk of a systemic reaction following a sting to the same extent. However, because the cost of bee and wasp venom immunotherapy is different, it was necessary to differentiate between the two venom types. The model assumes that 23% of those with a bee and/or wasp allergy are allergic to bee venom, 70% are allergic to wasp venom and 7% are allergic to both (based on the results of the Assessment Group's survey of immunology clinicians in the UK). The average age of the modelled population is 37 years, and 80% are men.
Because no data on health-related quality of life were available, in the base case the model assumes that there are no changes in quality of life associated with venom allergy or venom immunotherapy. The model also assumes no change in quality of life associated with any grade of systemic reaction, either as a result of Pharmalgen treatment or a sting. Therefore, in the base case the model assumes that all health benefits from treatments result from reducing the number of anaphylaxis-related deaths.
The Assessment Group undertook a separate analysis for a scenario in which people are assumed to be less anxious about future allergic reactions after receiving Pharmalgen than before receiving therapy, and therefore experience an improvement in quality of life. The analysis quantified quality of life using results of a survey of norms of EQ-5D undertaken by the University. This survey estimated a reduction in utility of 0.16 based on a 'health state characterising level 2 anxiety/depression' which lowers utility by 0.07 per year, and a 'health state characterising usual activities level 2' which lowers utility by 0.036. The Assessment Group assumed that anxiety about stings would reduce utility by 25% of 0.16 (that is, a reduction in utility of 0.04 associated with venom allergy), and that treatment with Pharmalgen would increase utility by 0.01 per person per year.
No published information was available on actual resource use so the Assessment Group chose values based on discussions with a clinical specialist. The Assessment Group assumed that the emergency kit contains an adrenaline auto-injector, which is replaced every 18 months, and a high-dose antihistamine, which is replaced annually. The model also included costs for attending accident and emergency and for inpatient stays.
The cost of each adverse reaction to Pharmalgen was estimated as £32.81 for a Mueller grade I, II or III reaction and £239.81 for a Mueller grade IV reaction. For all three groups in the model, each systemic reaction to a sting was associated with the cost of attending accident and emergency, with inpatient stays and with antihistamines. The avoidance advice only group included the cost of adrenaline whereas the other two groups included the cost of an adrenaline auto-injector. Costs differed according to severity of the systemic reaction.
The Assessment Group presented deterministic pairwise results comparing Pharmalgen plus an emergency kit (adrenaline auto-injector and high-dose antihistamine) plus avoidance advice with two comparators: an emergency kit plus advice or advice alone.
The Assessment Group presented base-case results for a simulated 1000 patient cohort. The results showed that treatment with Pharmalgen plus an emergency kit plus avoidance advice provides an additional 0.11 quality-adjusted life years (QALYs) per 1000 patients compared with an emergency kit plus avoidance advice, with additional costs of £2,028,808, and an incremental cost-effectiveness ratio (ICER) of £18,065,527 per QALY gained. Compared with advice only, Pharmalgen plus an emergency kit plus avoidance advice provided an additional 0.29 QALYs per 1000 patients, with additional costs of £2,185,444, leading to an ICER of £7,627,835 per QALY gained.
For the scenario assuming five stings per year, the reduction in costs associated with fewer systemic reactions to stings over 10 years, coupled with the additional QALYs generated from fewer deaths, resulted in Pharmalgen dominating both alternatives (that is, it was more effective and less costly than the alternatives).
For the scenario assuming that Pharmalgen improves quality of life by reducing anxiety about future stings, the ICER for Pharmalgen plus an emergency kit plus avoidance advice compared with an emergency kit plus avoidance advice was £23,868 per QALY gained (based on incremental costs of £2,028,808 and incremental QALYs of 85.00 for a 1000 patient cohort). The ICER for Pharmalgen plus an emergency kit plus avoidance advice compared with advice only was £25,661 per QALY gained (incremental costs of £2,185,444 and incremental QALYs of 85.17 for a 1000 patient cohort).
The Assessment Group conducted sensitivity analyses. In the base case, all ICERs for Pharmalgen plus an emergency kit and avoidance advice, compared with an emergency kit and advice, exceeded £1 million per QALY gained irrespective of the scenario or values for parameters used within the model. When compared with advice alone, the ICERs for Pharmalgen plus an emergency kit and advice still exceeded £700,000 per QALY gained.
In the sensitivity analyses for the scenario assuming a high rate of stings (five per year), for most changes to parameters in the model, treatment with Pharmalgen dominated the alternatives (being more effective and less costly). The exceptions included a shortened time horizon (5 years), reduced treatment costs for a systemic reaction (50% of the base case) or using the most pessimistic values for all parameters in the model. Assuming 3.3 stings per year, treatment with Pharmalgen plus an emergency kit and avoidance advice no longer dominated the alternatives. Assuming 3.1 stings per year, the ICER for Pharmalgen plus an emergency kit plus avoidance advice was over £30,000 per QALY gained when compared with an emergency kit and advice. Assuming 2.8 stings per year, the ICER for Pharmalgen plus an emergency kit and advice was over £30,000 per QALY gained when compared with advice alone.
In the sensitivity analyses for the scenario assuming that Pharmalgen improves quality of life by reducing anxiety about future stings, for most parameters Pharmalgen plus emergency kit plus advice was associated with an ICER of £20,000 to £30,000 per QALY gained. The ICER was above £40,000 per QALY gained when the time horizon was 5 years and below £20,000 per QALY gained when the time horizon was 15 years or longer.
# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of Pharmalgen, having considered evidence on the nature of bee and wasp venom allergy and the value placed on the benefits of Pharmalgen by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
## Clinical effectiveness
The Committee discussed current clinical practice for the diagnosis of bee or wasp venom allergy. The Committee heard from the clinical specialists that people who have had a systemic reaction following a bee or wasp sting should be referred to an allergy specialist for the diagnosis of venom-specific IgE allergy to bee and/or wasp venom by skin or intradermal testing and serum-specific IgE testing. The clinical specialists stated that raised serum tryptase at baseline (after a reaction to a sting has subsided) is associated with an increased probability of severe systemic reactions to future stings. However the Committee also noted the consultation comment that the immunological condition mastocytosis may be associated with a raised baseline serum tryptase, and a diagnosis of mastocytosis may be a contraindication to Pharmalgen. The Committee understood that before treatment with Pharmalgen, a positive test for specific IgE antibodies is required, and that clinicians would also take into account baseline serum tryptase and other comorbid conditions when deciding whether to offer treatment with Pharmalgen.
The Committee discussed the treatment of bee and wasp venom allergy in current clinical practice. The Committee heard from the clinical specialists that people who have had a moderate or severe systemic reaction to bee or wasp venom are normally given an emergency kit containing adrenaline. The kit can also include other emergency treatments such as a high-dose antihistamine. Clinicians also advise people on how to avoid being stung, but they do not consider this advice to be effective on its own. The Committee discussed the use of venom immunotherapy in current clinical practice in the UK. The Committee heard from the clinical specialists that Pharmalgen, the only venom immunotherapy with a UK marketing authorisation, is an established therapy for venom allergy which should be initiated and monitored by healthcare professionals within a specialist centre with experience in venom immunotherapy and treating systemic reactions. The clinical specialists stated that they give Pharmalgen in accordance with the SPCs, most frequently using a conventional dosing schedule in the initial phase, followed by a maintenance period of 3 years. The Committee heard that in children and adults Pharmalgen is considered to provide immunity for at least 15 years. The Committee understood that the regimen of most relevance to the appraisal was an initial phase using a conventional dosing regimen and a maintenance phase lasting 3 years, with the treatment administered within a specialist centre.
The Committee discussed which patients currently receive Pharmalgen in clinical practice. It heard from the clinical specialists that Pharmalgen is offered to people with a history of severe systemic reactions to bee or wasp venom, or to people with moderate systemic reactions to bee or wasp venom if they have other risk factors such as raised baseline serum tryptase, a high risk of future stings, or anxiety about future stings. The Committee noted consultation comments that following publication of British Society for Allergy and Clinical Immunology guidelines, Pharmalgen may also be offered to people with a history of moderate systemic reactions to bee or wasp venom if they live far from emergency medical care, have certain comorbid conditions or request treatment with Pharmalgen. The Committee heard from the clinical specialists that children generally have a less severe reaction to venom than adults and a better prognosis over time. However, it is not possible to identify in advance which children will 'outgrow' their allergy to bee and/or wasp venom, and therefore Pharmalgen is an appropriate treatment for some children. The Committee understood that Pharmalgen is indicated for both adults and children, and that Pharmalgen is offered to people who have had severe systemic reactions or to people who have had moderate systemic reactions, and have additional risk factors for future systemic reactions such as raised baseline serum tryptase, or an increased risk of future stings, or whose quality of life is affected by anxiety about future stings.
The Committee discussed the impact of an allergy to bee and/or wasp venom on quality of life. The clinical specialists and patient experts stressed how frightening it is to be stung when there is an expectation of a possible systemic reaction following a sting, and that anaphylaxis can be accompanied by a sense of impending doom. The Committee heard from the patient experts that many people who have experienced a systemic reaction to bee or wasp venom are anxious about the possibility of systemic reactions following future stings, regardless of the actual risk of a reaction. The Committee heard that this anxiety affects usual daily activities of those affected and their family members. The Committee heard that people willingly tolerate the adverse effects of Pharmalgen treatment and the length and intensity of the administration schedule to reduce the probability of a systemic reaction to future stings. The Committee heard from patient experts that after treatment with Pharmalgen, anxiety levels return to normal for many people, and that carrying and having to administer an adrenaline auto-injector does not reduce anxiety to the same degree as having venom immunotherapy. The Committee heard from the clinical specialists that published trials have reported an improvement in quality of life in people who received venom immunotherapy compared with those who received an adrenaline auto-injector only. On balance, the Committee was persuaded that although the extent to which people might feel anxious following a systemic reaction would vary, and the risk of a sting might be very low, many people with a history of systemic reactions to bee or wasp venom would be anxious about the possibility of systemic reactions following future stings.
The Committee discussed the relevant comparator in the appraisal. The comparator as set out in the scope is a package of care without venom immunotherapy, including advice on avoidance of insect venom, and high-dose antihistamines and/or adrenaline auto-injectors (with training before use) to be used if stung. The Committee heard from the clinical specialists that the British Society for Allergy and Clinical Immunology recently issued guidelines for the treatment of bee and wasp venom allergy. It heard that clinicians advise people with a history of systemic reactions to bee or wasp venom on ways of minimising their risk of further stings, but do not provide advice alone. Instead clinicians offer people an adrenaline auto-injector (and training in its use) to carry and use following a bee or wasp sting that is accompanied by symptoms of a systemic reaction. The Committee concluded that an adrenaline auto-injector given alongside avoidance advice was the most appropriate comparator for Pharmalgen treatment.
The Committee discussed the clinical effectiveness evidence for Pharmalgen and noted that no RCTs or controlled studies had been identified that compared Pharmalgen with standard care without venom immunotherapy, as defined in the scope. The Committee discussed the available non-comparative data for Pharmalgen and the comparative data for non-Pharmalgen venom immunotherapy. The Committee heard from the clinical specialists that they considered that the results of non-Pharmalgen studies would also apply to Pharmalgen, and that venom immunotherapy is associated with changes in IgE production and a reduced risk of a systemic reaction following a sting. The Committee considered that the available evidence base for Pharmalgen was of poor quality and was limited. On balance, it was persuaded that Pharmalgen had demonstrated some efficacy in reducing the rate and severity of systemic reactions following a bee or wasp sting. However, the Committee considered that the relative efficacy could not be quantified with certainty.
## Cost effectiveness
The Committee discussed the economic model developed by the Assessment Group. It noted that in the base-case analysis, Pharmalgen plus an adrenaline auto-injector plus high-dose antihistamine and avoidance advice had an ICER of £18,070,000 per QALY gained compared with an adrenaline auto-injector plus high-dose antihistamine and advice. The Committee heard from the Assessment Group that this estimate was robust to changes in parameters associated with costs and effects. However, the estimate was particularly sensitive to assumptions about utility and about how frequently a person is stung. The Committee considered the importance of the assumption in the base-case analysis that Pharmalgen treatment did not affect health-related quality of life. The Committee noted its earlier conclusions that having a venom allergy increases anxiety and affects daily activities, and that treatment with Pharmalgen may reduce some of this anxiety. The Committee concluded that the assumption in the base-case analysis that Pharmalgen had no effect on health-related quality of life underestimated the cost effectiveness of Pharmalgen compared with alternative treatments.
The Committee discussed comments received during the consultation about the robustness of the Assessment Group's model. The Committee noted the consultation comments that some of the inputs in the economic model relating to costs, efficacy and the likelihood of having a systemic reaction while receiving treatment with Pharmalgen were not plausible. The Committee considered that although there are some uncertainties as to the plausibility of assumptions and inputs, the Assessment Group's sensitivity analyses showed that the estimates of cost effectiveness were not sensitive to changes in these parameters. The Committee understood from the Assessment Group that the key drivers of cost effectiveness were assumptions about utility and about how frequently a person is stung. On this basis the Committee concluded that the Assessment Group's model was an appropriate basis for decision-making despite uncertainties around the plausibility of some parameter estimates.
The Committee considered the Assessment Group's scenario analyses that had assumed that people have five bee or wasp stings per year. The Committee heard from clinical specialists that some people are stung at least five times per year. These may include beekeepers plus their children and neighbours, roofers and gardeners. However, the risk of being stung varies. The Committee noted that in these scenario analyses, treatment with Pharmalgen dominated the alternatives (that is, it was more effective and less costly), and that this remained the case until the average frequency of stings dropped to approximately three per year. The Committee concluded that Pharmalgen is an appropriate use of NHS resources for people with IgE-mediated allergy to bee and wasp venom, who have a high risk of stings.
The Committee then considered the scenario analyses that included an effect on health-related quality of life related to anxiety about re-stings and Pharmalgen treatment. The Committee noted that in these analyses the ICER for Pharmalgen decreased to less than £30,000 per QALY gained. The Committee was aware that the Assessment Group had been unable to identify any data on anxiety associated with venom allergy or changes in anxiety as a result of venom immunotherapy that could be used in the economic model. Therefore the Assessment Group had used the EQ-5D survey of norms to explore how much disutility was generated when a person went from having no problems with anxiety and daily activities to moderate anxiety with some effect on daily activities (0.16). The Committee considered that the Assessment Group's assumption that fear of being stung would generate a quarter of that value (0.04), and that venom immunotherapy would reduce this anxiety by a quarter (0.01), was plausible and, given the testimony of the patient experts, may even underestimate the gains in utility associated with treatment with Pharmalgen. The Committee concluded that for people who do not have a high risk of future stings the analyses that assume reduced anxiety about re-stings with Pharmalgen treatment are the most appropriate on which to base the most plausible estimate of the ICER.
The Committee considered the 10-year time horizon in the economic model. It was aware that it had not been presented with evidence of the duration of immunity; but it also considered the testimony of the clinical specialists that immunity was likely to be longer than 10 years. The Committee was presented with a scenario analysis with a time horizon of 20 years for people who have a gain in health-related quality of life associated with reduced anxiety about re-stings and treatment with Pharmalgen. In this scenario, the ICER was £13,800 per QALY gained for treatment with Pharmalgen plus an emergency kit plus advice compared with an emergency kit and advice alone. The Committee concluded that it is appropriate to use a time horizon of longer than 10 years, and that with reduced anxiety about re-stings after treatment with Pharmalgen the most plausible ICER would be less than £20,000 per QALY gained. The Committee concluded that Pharmalgen is an appropriate use of NHS resources for people with IgE-mediated allergy to bee and wasp venom, who are anxious about future stings.
The Committee then discussed its conclusions on the cost-effectiveness modelling and the use of Pharmalgen in current clinical practice (see section 4.3.4). The Committee took into account the evidence from the clinical specialists and patient experts. It concluded that it was appropriate to assume a health-related quality of life benefit from Pharmalgen for people with a history of severe systemic reactions and for people who have a history of moderate systemic reactions to bee and/or wasp venom and who have other risk factors for future systemic reactions such as anxiety about the possibility of systemic reactions following future stings, a higher risk of being stung or raised baseline serum tryptase. The Committee therefore concluded that Pharmalgen could be considered an appropriate use of NHS resources for the treatment of people with IgE-mediated bee and/or wasp venom allergy with the above characteristics. The Committee considered that anxiety about the possibility of systemic reactions following future stings should be such that it affects usual daily activities.
The Committee discussed comments received during consultation, noting that Pharmalgen may also be offered to people with a history of moderate systemic reactions to bee or wasp venom if they live far from emergency medical care, have comorbid conditions or request treatment with Pharmalgen. The Committee discussed the patient expert testimony, and concluded that these people would have heightened awareness of their situation and be anxious about the possible effects of having a systemic reaction from future stings. Therefore the Committee concluded that these groups were covered in its recommendation for people with a history of moderate systemic reactions, who are anxious about future stings.
The Committee discussed whether it should make a separate recommendation for people with raised baseline serum tryptase. The Committee noted that people with raised baseline serum tryptase are at higher risk of more severe reactions to future stings but that a person would only be aware of an increased risk once raised baseline serum tryptase had been diagnosed. The Committee also noted the consultation comment that a raised baseline serum tryptase may indicate mastocytosis, which is a possible contraindication for Pharmalgen. The Committee concluded that comorbid conditions, including mastocytosis, would be identified by the responsible clinician when considering whether to offer treatment with Pharmalgen. The Committee concluded that it was appropriate to include in its recommendations raised baseline serum tryptase as an additional risk factor for people who have had a moderate systemic reaction.
The Committee supported the statement made by the clinical specialists that treatment with Pharmalgen should be initiated and monitored in a specialist centre experienced in venom immunotherapy. The Committee discussed comments from consultation about the need for specialist centres to have staff appropriately trained in resuscitation or immediate access to age-appropriate resuscitation facilities. It noted that the SPCs specify that Pharmalgen should be provided under supervision of a doctor experienced in specific immunotherapy and that because of the risk of potentially fatal anaphylaxis, treatment with Pharmalgen must be carried out in clinics or hospitals where full facilities for cardiopulmonary resuscitation are immediately available for use by adequately trained personnel. The Committee therefore concluded that Pharmalgen should be provided within a specialist centre and that the details of the provision of resuscitation equipment were sufficiently specified in the SPC.
# Summary of Appraisal Committee's key conclusions
TA246
Appraisal title: Pharmalgen for the treatment of bee and wasp venom allergy
Section
Key conclusion
Pharmalgen is recommended as an option for the treatment of IgE-mediated bee and wasp venom allergy in people who have had:
a severe systemic reaction to bee or wasp venom, or
a moderate systemic reaction to bee or wasp venom and who have one or more of the following: a raised baseline serum tryptase, a high risk of future stings or anxiety about future stings.
Treatment with Pharmalgen should be initiated and monitored in a specialist centre experienced in venom immunotherapy.
The Committee considered the available evidence to be of poor quality and limited. It was persuaded that Pharmalgen had demonstrated efficacy in reducing the rate and severity of systemic reactions. However, the relative effect could not be quantified with certainty. The Committee concluded that it is appropriate to use a time horizon of longer than 10 years, and that with reduced anxiety about re-stings after treatment with Pharmalgen the most plausible ICER would be less than £20,000 per QALY gained.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee heard from the clinical specialists that people who have had a moderate or severe systemic reaction to bee or wasp venom are normally given an emergency kit containing adrenaline. The kit can also include other emergency treatments such as high-dose antihistamine. Clinicians also advise on how to avoid being stung, but they do not consider this advice to be effective on its own.
Pharmalgen is the only venom immunotherapy with UK marketing authorisation and is an established therapy for venom allergy.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee heard that that in children and adults Pharmalgen is considered to provide immunity for at least 15 years.
The Committee concluded that having a venom allergy increases anxiety and affects daily activities, and that treatment with Pharmalgen may reduce this anxiety.
The Committee heard that carrying and having to administer an adrenaline auto-injector does not reduce anxiety to the same degree as having venom immunotherapy.
What is the position of the treatment in the pathway of care for the condition?
The Committee heard from the clinical specialists that Pharmalgen is offered to people with a history of severe systemic reactions to bee or wasp venom, or to people who have had moderate systemic reactions to bee or wasp venom and have other risk factors such as a raised baseline serum tryptase, a high risk of future stings, or anxiety about future stings.
Adverse effects
The Committee heard that people willingly tolerate the adverse effects of Pharmalgen treatment and the length and intensity of the administration schedule to reduce the probability of a systemic reaction to future stings and their anxiety about future stings.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
No randomised controlled trials or controlled studies were identified that compared Pharmalgen with standard care without venom immunotherapy, as defined in the scope.
The Committee heard from the clinical specialists that they considered that the results of non-Pharmalgen venom immunotherapy studies were also relevant to Pharmalgen.
Relevance to general clinical practice in the NHS
The Committee considered that the available clinical evidence base for Pharmalgen was of poor quality and was limited.
Uncertainties generated by the evidence
The Committee did not consider that the relative efficacy of Pharmalgen compared with standard care without venom immunotherapy could be quantified with certainty.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee was persuaded that many people with a history of systemic reactions to bee or wasp venom would be anxious about the possibility of future stings.
The clinical specialists stated that elevated serum tryptase at baseline (after a reaction to a sting has subsided) is associated with an increased probability of severe systemic reactions to future stings.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee was persuaded that Pharmalgen had demonstrated some efficacy in reducing the rate and severity of systemic reactions following a bee or wasp sting. However, it considered that the relative efficacy could not be quantified with certainty.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee considered that the economic model developed by the Assessment Group was appropriate to form the basis of its decision-making, despite uncertainties around the plausibility of some parameter estimates.
The Assessment Group was unable to identify any data on anxiety associated with venom allergy or changes in anxiety as a result of venom immunotherapy that could be used in the economic model.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee concluded that the assumption in the base-case analysis that Pharmalgen had no effect on health-related quality of life underestimated the cost effectiveness of Pharmalgen compared with alternative treatments.
The Committee considered the scenario analyses that had assumed that people have five bee or wasp stings per year. It heard from clinical specialists that there are people who are stung at least five times per year and that these may include beekeepers plus their children and neighbours, roofers and gardeners.
The Committee concluded that it is appropriate to use a time horizon of longer than 10 years.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
In a scenario analysis the Assessment Group assumed that a history of systemic reactions to bee or wasp stings reduced utility by 0.04 per person per year, and that treatment with Pharmalgen increased utility by 0.01 per person per year.
The Committee recognised the limitations of the evidence, but accepted on balance that this utility estimate was plausible and, given the testimony of the patient experts, may even underestimate the gains in utility associated with treatment with Pharmalgen.
Are there specific groups of people for whom the technology is particularly cost effective?
Not applicable.
What are the key drivers of cost effectiveness?
Effect on quality of life
Risk of stings
Time horizon
Most likely cost-effectiveness estimate (given as an ICER)
For people with a high risk of stings, treatment with Pharmalgen dominated the alternatives (that is, it was more effective and less costly). For people without a high risk of stings but reduced anxiety about re-stings after treatment with Pharmalgen, the most plausible ICER was less than £20,000 per QALY gained.
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
No equality issues were identified during the scoping process or during the course of the appraisal.
# Related NICE guidance
Anaphylaxis: assessment to confirm an anaphylactic episode and the decision to refer after emergency treatment for a suspected anaphylactic episode. NICE clinical guideline 134 (2011).# Review of guidance
The guidance on this technology will be considered for review in January 2017. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveFebruary 2012# Changes after publication
February 2014: implementation section updated to clarify that pharmalgen is recommended as an option for treating bee and wasp venom allergy. Additional minor maintenance update also carried out.
June 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE multiple technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance ': 'Pharmalgen is recommended as an option for the treatment of IgE-mediated bee and wasp venom allergy in people who have had:\n\na severe systemic reaction to bee or wasp venom, or\n\na moderate systemic reaction to bee or wasp venom and who have one or more of the following: a raised baseline serum tryptase, a high risk of future stings or anxiety about future stings.\n\nTreatment with Pharmalgen should be initiated and monitored in a specialist centre experienced in venom immunotherapy.', 'Clinical need and practice': "Bees and wasps inject venom when they sting. When a person is stung by a bee or wasp they typically have an intense, burning pain followed by erythema (redness) and oedema (swelling) at the site of the sting. This usually subsides within a few hours. After an initial sting, some people have an immune response and produce IgE antibodies. In these people, subsequent stings can trigger a rapid inflammatory response referred to as a 'type I' hypersensitivity reaction.\n\nHypersensitivity reactions to bee or wasp venom can be local or systemic, can vary in severity, and are typically of rapid onset. Large local reactions are characterised by oedema, erythema and pruritus, cover more than 10\xa0cm in diameter and peak at between 24 and 48\xa0hours after the sting. Systemic reactions can be measured using the Mueller grading system. Severity ranges from grade I to grade IV. A grade I systemic reaction is characterised by generalised urticaria or erythema, itching, malaise or anxiety. Grade II reactions may include symptoms associated with grade I reactions as well as generalised oedema, tightness in the chest, wheezing, abdominal pain, nausea and vomiting, and dizziness. Grade III reactions may include symptoms associated with grade I or II reactions as well as symptoms of dyspnoea, dysarthria, hoarseness, weakness, confusion, and a feeling of impending doom. Grade IV reactions may include symptoms associated with grade I, II or III reactions as well as loss of consciousness, incontinence of urine or faeces, or cyanosis.\n\nRecently published guidelines for the treatment of bee and wasp venom allergy issued by the British Society for Allergy and Clinical Immunology classify systemic reactions as mild, moderate or severe. A mild systemic reaction is characterised by pruritus, urticaria, erythema, mild angio-oedema, rhinitis and conjunctivitis. Moderate systemic reactions may include mild asthma, moderate angio-oedema, abdominal pain, vomiting, diarrhoea and minor or transient hypotensive symptoms such as light-headedness and dizziness. Severe systemic reactions may include respiratory difficulty such as asthma or laryngeal oedema, hypotension, collapse or loss of consciousness, as well as double incontinence, seizures, or loss of colour vision. Anaphylaxis is defined by the European Resuscitation Council as a severe, life-threatening, generalised or systemic hypersensitivity reaction.\n\nData from the USA suggest that the prevalence of allergy to bee and wasp venom is between 0.4% and 3.3%. In the UK, insect stings are the second most frequent cause of anaphylaxis outside medical settings. It is estimated that of all deaths from anaphylaxis between 1992 and 2001 in the UK, approximately 62% were a result of reactions to wasp venom and approximately 9% were caused by reactions to bee venom. Some people who have a systemic reaction after being stung do not have another reaction when re-stung. It is estimated that after a large local reaction 5–15% of people go on to develop a systemic reaction when next stung. Approximately 14–20% of those who have a mild systemic reaction have another systemic reaction when next stung. For people who have experienced an anaphylactic reaction, the risk of having a recurrent episode is estimated to be between 60% and 70%.\n\nThe main method for diagnosing an allergy to bee and/or wasp venom is skin testing with venom. Another less sensitive method is measurement of allergen-specific IgE antibodies in serum. Clinicians may also measure serum tryptase at baseline (after a reaction to a sting has subsided) because this may predict the severity of a response to a subsequent sting.\n\nClinicians typically give an emergency kit to people with a venom allergy who are considered at risk of systemic reactions. The kit includes adrenaline (epinephrine; intramuscular injection) and can also include other emergency treatments such as a high-dose antihistamine (oral), a corticosteroid (inhaled), and/or a bronchodilator (inhaled). Preventive measures include advice on how to avoid bee and/or wasp stings.\n\nIn the UK, clinicians consider offering venom immunotherapy to people with a history of systemic allergic reactions to bee venom and/or wasp venom. Venom immunotherapy aims to reduce the risk of future systemic reactions and the severity of a systemic reaction when one occurs. People considered for venom immunotherapy are usually those who have had severe systemic reactions, or those who have experienced moderate systemic reactions and have additional risk factors, such as a high baseline serum tryptase or a high risk of future stings, or whose quality of life is significantly affected by venom allergy.", 'The technologies': "Pharmalgen bee venom extract (ALK-Abelló) has a marketing authorisation for the treatment of IgE-mediated allergy to bee venom. Pharmalgen wasp venom extract (ALK-Abelló) has a marketing authorisation for the treatment of IgE-mediated allergy to wasp venom. Pharmalgen bee venom extract and Pharmalgen wasp venom extract (from now on referred to as Pharmalgen) also have marketing authorisations for the diagnosis of IgE-mediated allergy to bee or wasp venom, but this indication is outside the scope of this appraisal.\n\nTreatment with Pharmalgen is in two phases: an initial phase and a maintenance phase. Before people receive Pharmalgen treatment, IgE-mediated allergy to bee or wasp venom must be confirmed by case history and by in vivo and/or in vitro diagnosis. Pharmalgen is given by subcutaneous injection.\n\nDuring the initial phase, an increasing dose of Pharmalgen is given until the maximum tolerated dose is reached. The following types of dosing schedules can be used during the initial phase: conventional (one injection every 3–7\xa0days), modified rush (clustered; two to four injections weekly given at intervals of 30 minutes) or rush (injections at 2-hour intervals with a maximum of four injections per day). During the maintenance phase, Pharmalgen is administered at a dose of 100\xa0micrograms every 4–6\xa0weeks for at least 3\xa0years. The dosage may be adjusted depending on the person's history of allergic reactions and sensitivity to the specific allergen used.\n\nThe summary of product characteristics (SPC) as provided by the manufacturer states that Pharmalgen is contraindicated in people with malignancies, severe chronic or seasonal asthma, and immunological conditions. It is also contraindicated in people with diseases or conditions that prevent the treatment of possible anaphylactic reactions, such as chronic heart and lung disease, severe arterial hypertension and treatment with beta-blockers. Pharmalgen is also contraindicated in people taking tricyclic antidepressants, monoamine oxidase inhibitors, and angiotensin-converting enzyme inhibitors, and should not be initiated during pregnancy. Pharmalgen treatment may be associated with local or systemic immunological reactions, which can include anaphylaxis. The SPC recommends that people be observed for at least 60\xa0minutes after an injection of Pharmalgen. For full details of adverse effects and contraindications see the SPC.\n\nPharmalgen bee venom costs £54.81 for an initial treatment set and £63.76 for a maintenance treatment set (excluding VAT; 'British national formulary' [BNF] edition 61).The maintenance treatment set includes four vials; therefore, the cost per injection in the maintenance phase is £15.94. Pharmalgen wasp venom costs £67.20 for an initial treatment set and £82.03 for a maintenance treatment set (excluding VAT; BNF edition 61). The maintenance treatment set also includes four vials; therefore, the cost per injection in the maintenance phase is £20.51. Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). The manufacturer of Pharmalgen, ALK-Abelló, did not provide a submission for this appraisal. The Assessment Group (Liverpool Reviews and Implementation Group, LRiG) produced an assessment report of the clinical effectiveness and cost effectiveness of Pharmalgen within its licensed indication for the treatment of bee and wasp venom allergy.\n\n# Clinical effectiveness\n\nThe Assessment Group conducted a systematic review of the evidence on the clinical effectiveness of Pharmalgen compared with other treatment options in people with bee and/or wasp venom allergy. Nine studies reported in 11 publications were identified that met the inclusion criteria of the systematic review. All nine of the studies compared Pharmalgen with an active treatment: five compared different doses or dosing schedules of Pharmalgen with each other, one compared Pharmalgen with a modified form of Pharmalgen, and three compared Pharmalgen with other venom immunotherapy. Therefore, none of the studies identified compared Pharmalgen with a non-venom immunotherapy intervention. Of the nine studies identified, four were randomised controlled trials (RCTs), two compared an intervention group with historical controls, and three were quasi-experimental studies. The Assessment Group explored the possibility of conducting a mixed treatment comparison or an indirect comparison, but did not consider either appropriate because of the limitations in the data.\n\nThe type of allergy and the severity of systemic reactions to stings were specified as inclusion criteria in four of the studies. None of the studies was conducted in the UK. The number of people recruited in each study ranged between 30 and 65. Seven studies included adults only, one study included people aged 15–68\xa0years, and one study included people aged 6–70\xa0years. The average age of participants was similar across studies and ranged between 35 and 49\xa0years. All studies recruited people with allergies to bee or wasp venom confirmed by skin tests, and seven studies also confirmed this with IgE testing. The protocols for the initial phase of treatment differed between studies and varied between 6 and 35 doses, over a period of 3\xa0hours to 16\xa0weeks. Most studies used a maintenance dose of 100\xa0micrograms every 4\xa0weeks. The studies measured outcomes at different time points from 4\xa0days to more than 3\xa0years.\n\nThe outcome from eight studies in people allergic to bee or wasp venom included the proportion of stings that resulted in systemic reactions. This ranged from 0 to 36.4% depending on the dose of immunotherapy or dosing schedule. Three studies reported proportions of stings that resulted in systemic reactions after approximately 3\xa0years of maintenance therapy; these ranged between 0 and 36.4%. In the study with a rate of 36.4%, three of the four participants with a systemic reaction had a diminished response with mild symptoms. The proportions of stings that resulted in large local reactions was reported in two studies, and ranged from 35.7% to 88.9% across the treatment groups.\n\nThe Assessment Group presented data on systemic reactions to stings from observational non-comparative studies of Pharmalgen. The Assessment Group found 17 studies that reported the proportion of stings that resulted in systemic reactions before, during or after venom immunotherapy. The reported proportion of stings that resulted in systemic reactions ranged from 0 to 32.7%. For the studies that reported systemic reactions after Pharmalgen treatment, the proportion of stings that resulted in systemic reaction ranged from 0 to 12.5%.\n\nPeople receiving venom immunotherapy may develop an allergic systemic reaction (adverse reaction) to the treatment. Adverse reactions were reported in eight of the studies: in one study during the initial phase only, in five studies during the initial or maintenance phase and in two studies during maintenance only. The proportion of people developing adverse reactions during the initial and maintenance phases of venom immunotherapy ranged from 0 to 38.1%.\n\nThe Assessment Group also presented evidence from comparative studies of venom immunotherapy other than Pharmalgen. Searches identified one meta-analysis and two systematic reviews of venom immunotherapy (specific brands not specified) in the population of interest. One of the reviews is an ongoing unpublished Cochrane review. The Assessment Group noted that the systematic reviews and the meta-analysis concluded that venom immunotherapy is effective in lowering the risk of future systemic reactions to venom in people with venom allergies.\n\nNone of the studies identified in the systematic review by the Assessment Group reported data on health-related quality of life. However, the ongoing Cochrane review included two studies that included health-related quality of life data. These studies compared venom immunotherapy (Pharmalgen or non-Pharmalgen venom immunotherapy) with an adrenaline auto-injector, and assessed quality of life using the Vespid Allergy Quality of Life Questionnaire (VQLQ). A meta-analysis of the two studies by the Cochrane group for the outcome change in VQLQ over 1\xa0year concluded that venom immunotherapy was associated with a statistically significant improvement in quality of life compared with an adrenaline auto-injector.\n\n# Cost effectiveness\n\nThe Assessment Group undertook a systematic review of existing cost-effectiveness evidence and developed an economic model of Pharmalgen for the treatment of bee and wasp venom allergy. The systematic review identified three studies, of which two were full papers and one an abstract. The studies were US based with costs expressed in US dollars. The Assessment Group did not find any health economic studies that compared venom immunotherapy with adrenaline auto-injectors, high-dose antihistamine or advice on how to avoid bee and wasp stings (avoidance advice).\n\nThe Assessment Group developed a de novo economic model to evaluate the cost effectiveness of Pharmalgen. The model is deterministic and constructed as a 1-year decision tree that is extrapolated to a 10-year time horizon, with changes to the size of the cohort at the end of each year because of sting-related deaths or death from other causes. The Assessment Group chose a 10-year horizon because it identified evidence to support the maintenance of effect over 10\xa0years, and it did not identify any studies that considered a longer follow-up. The analyses were conducted from a UK NHS and personal social services perspective, with costs and benefits discounted at a rate of 3.5%.\n\nThe Assessment Group used the clinical effectiveness evidence and the results from its own survey of 32 immunology clinicians in allergy centres in the UK, a published audit of UK allergy clinics, and published guidelines to inform the treatment pathway in its economic model. The economic model starts with a person receiving one of three therapies:\n\nvenom immunotherapy with Pharmalgen, an emergency kit containing an adrenaline auto-injector and high-dose antihistamine, plus advice on how to avoid being stung, or\n\nan emergency kit containing an adrenaline auto-injector and high-dose antihistamine, plus advice on how to avoid being stung, or\n\nadvice on how to avoid being stung.\n\nFor people treated with Pharmalgen, there is an initial phase with stepwise increases in dosage and a subsequent 3-year maintenance phase. The model includes two forms of dosing in the initial phase: conventional dosing, which lasts 12\xa0weeks with 1 injection per week, and modified rush (clustered) dosing with 16 injections over a 7-week period. The model assumes that 92% of people receive conventional dosing and 8% receive modified rush dosing.\n\nThe model assumes that a person experiences an average of 0.095 stings per year irrespective of their treatment, based on a weighted average from six studies. A separate analysis explored a scenario in which a person experiences five stings a year. In the model, the probability of a systemic reaction after a sting is 56.4% for people given advice on avoidance only. For people given an emergency kit plus advice on avoidance, the probability of a systemic reaction after a sting is 43.9%. The probability of a systemic reaction after a sting for people receiving Pharmalgen is 6.5%. If a systemic reaction occurs, the likelihood of a Mueller grade I reaction is 6.5%, 9.8% and 38.5% for the advice only, emergency kit and Pharmalgen groups respectively; the likelihood of a Mueller grade II reaction is 80.3%, 83.6% and 54.0%; the likelihood of a Mueller grade III reaction is 12.1%, 6.05% and 7.5%; and the likelihood of a Mueller grade IV reaction is 1.1%, 0.55% and 0%. The model assumes that 1.25% of Mueller grade IV reactions result in death regardless of previous treatment.\n\nDuring venom immunotherapy with Pharmalgen a person may experience an adverse reaction to treatment. The model assumes that the probability of a treatment-related adverse reaction is 2.0% per injection in the initial phase and 0.26% per injection in the maintenance phase. Systemic adverse reactions are classified by Mueller grade; each grade is associated with a particular cost. Of people who experience systemic adverse reactions to treatment, 37.5% experience (by Mueller grade) grade I, 37.5% experience grade II, 12.5% experience grade III, and 12.5% experience grade IV. The model assumes that no deaths result from adverse reactions to venom immunotherapy. The model assumes that treatment with adrenaline auto-injector or high-dose antihistamine is not associated with adverse reactions.\n\nThe model assumes that bee and wasp venom immunotherapy reduces the risk of a systemic reaction following a sting to the same extent. However, because the cost of bee and wasp venom immunotherapy is different, it was necessary to differentiate between the two venom types. The model assumes that 23% of those with a bee and/or wasp allergy are allergic to bee venom, 70% are allergic to wasp venom and 7% are allergic to both (based on the results of the Assessment Group's survey of immunology clinicians in the UK). The average age of the modelled population is 37\xa0years, and 80% are men.\n\nBecause no data on health-related quality of life were available, in the base case the model assumes that there are no changes in quality of life associated with venom allergy or venom immunotherapy. The model also assumes no change in quality of life associated with any grade of systemic reaction, either as a result of Pharmalgen treatment or a sting. Therefore, in the base case the model assumes that all health benefits from treatments result from reducing the number of anaphylaxis-related deaths.\n\nThe Assessment Group undertook a separate analysis for a scenario in which people are assumed to be less anxious about future allergic reactions after receiving Pharmalgen than before receiving therapy, and therefore experience an improvement in quality of life. The analysis quantified quality of life using results of a survey of norms of EQ-5D undertaken by the University. This survey estimated a reduction in utility of 0.16 based on a 'health state characterising level 2 anxiety/depression' which lowers utility by 0.07 per year, and a 'health state characterising usual activities level 2' which lowers utility by 0.036. The Assessment Group assumed that anxiety about stings would reduce utility by 25% of 0.16 (that is, a reduction in utility of 0.04 associated with venom allergy), and that treatment with Pharmalgen would increase utility by 0.01 per person per year.\n\nNo published information was available on actual resource use so the Assessment Group chose values based on discussions with a clinical specialist. The Assessment Group assumed that the emergency kit contains an adrenaline auto-injector, which is replaced every 18\xa0months, and a high-dose antihistamine, which is replaced annually. The model also included costs for attending accident and emergency and for inpatient stays.\n\nThe cost of each adverse reaction to Pharmalgen was estimated as £32.81 for a Mueller grade I, II or III reaction and £239.81 for a Mueller grade IV reaction. For all three groups in the model, each systemic reaction to a sting was associated with the cost of attending accident and emergency, with inpatient stays and with antihistamines. The avoidance advice only group included the cost of adrenaline whereas the other two groups included the cost of an adrenaline auto-injector. Costs differed according to severity of the systemic reaction.\n\nThe Assessment Group presented deterministic pairwise results comparing Pharmalgen plus an emergency kit (adrenaline auto-injector and high-dose antihistamine) plus avoidance advice with two comparators: an emergency kit plus advice or advice alone.\n\nThe Assessment Group presented base-case results for a simulated 1000 patient cohort. The results showed that treatment with Pharmalgen plus an emergency kit plus avoidance advice provides an additional 0.11 quality-adjusted life years (QALYs) per 1000 patients compared with an emergency kit plus avoidance advice, with additional costs of £2,028,808, and an incremental cost-effectiveness ratio (ICER) of £18,065,527 per QALY gained. Compared with advice only, Pharmalgen plus an emergency kit plus avoidance advice provided an additional 0.29 QALYs per 1000 patients, with additional costs of £2,185,444, leading to an ICER of £7,627,835 per QALY gained.\n\nFor the scenario assuming five stings per year, the reduction in costs associated with fewer systemic reactions to stings over 10\xa0years, coupled with the additional QALYs generated from fewer deaths, resulted in Pharmalgen dominating both alternatives (that is, it was more effective and less costly than the alternatives).\n\nFor the scenario assuming that Pharmalgen improves quality of life by reducing anxiety about future stings, the ICER for Pharmalgen plus an emergency kit plus avoidance advice compared with an emergency kit plus avoidance advice was £23,868 per QALY gained (based on incremental costs of £2,028,808 and incremental QALYs of 85.00 for a 1000 patient cohort). The ICER for Pharmalgen plus an emergency kit plus avoidance advice compared with advice only was £25,661 per QALY gained (incremental costs of £2,185,444 and incremental QALYs of 85.17 for a 1000 patient cohort).\n\nThe Assessment Group conducted sensitivity analyses. In the base case, all ICERs for Pharmalgen plus an emergency kit and avoidance advice, compared with an emergency kit and advice, exceeded £1 million per QALY gained irrespective of the scenario or values for parameters used within the model. When compared with advice alone, the ICERs for Pharmalgen plus an emergency kit and advice still exceeded £700,000 per QALY gained.\n\nIn the sensitivity analyses for the scenario assuming a high rate of stings (five per year), for most changes to parameters in the model, treatment with Pharmalgen dominated the alternatives (being more effective and less costly). The exceptions included a shortened time horizon (5\xa0years), reduced treatment costs for a systemic reaction (50% of the base case) or using the most pessimistic values for all parameters in the model. Assuming 3.3 stings per year, treatment with Pharmalgen plus an emergency kit and avoidance advice no longer dominated the alternatives. Assuming 3.1 stings per year, the ICER for Pharmalgen plus an emergency kit plus avoidance advice was over £30,000 per QALY gained when compared with an emergency kit and advice. Assuming 2.8 stings per year, the ICER for Pharmalgen plus an emergency kit and advice was over £30,000 per QALY gained when compared with advice alone.\n\nIn the sensitivity analyses for the scenario assuming that Pharmalgen improves quality of life by reducing anxiety about future stings, for most parameters Pharmalgen plus emergency kit plus advice was associated with an ICER of £20,000 to £30,000 per QALY gained. The ICER was above £40,000 per QALY gained when the time horizon was 5\xa0years and below £20,000 per QALY gained when the time horizon was 15\xa0years or longer.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of Pharmalgen, having considered evidence on the nature of bee and wasp venom allergy and the value placed on the benefits of Pharmalgen by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n## Clinical effectiveness\n\nThe Committee discussed current clinical practice for the diagnosis of bee or wasp venom allergy. The Committee heard from the clinical specialists that people who have had a systemic reaction following a bee or wasp sting should be referred to an allergy specialist for the diagnosis of venom-specific IgE allergy to bee and/or wasp venom by skin or intradermal testing and serum-specific IgE testing. The clinical specialists stated that raised serum tryptase at baseline (after a reaction to a sting has subsided) is associated with an increased probability of severe systemic reactions to future stings. However the Committee also noted the consultation comment that the immunological condition mastocytosis may be associated with a raised baseline serum tryptase, and a diagnosis of mastocytosis may be a contraindication to Pharmalgen. The Committee understood that before treatment with Pharmalgen, a positive test for specific IgE antibodies is required, and that clinicians would also take into account baseline serum tryptase and other comorbid conditions when deciding whether to offer treatment with Pharmalgen.\n\nThe Committee discussed the treatment of bee and wasp venom allergy in current clinical practice. The Committee heard from the clinical specialists that people who have had a moderate or severe systemic reaction to bee or wasp venom are normally given an emergency kit containing adrenaline. The kit can also include other emergency treatments such as a high-dose antihistamine. Clinicians also advise people on how to avoid being stung, but they do not consider this advice to be effective on its own. The Committee discussed the use of venom immunotherapy in current clinical practice in the UK. The Committee heard from the clinical specialists that Pharmalgen, the only venom immunotherapy with a UK marketing authorisation, is an established therapy for venom allergy which should be initiated and monitored by healthcare professionals within a specialist centre with experience in venom immunotherapy and treating systemic reactions. The clinical specialists stated that they give Pharmalgen in accordance with the SPCs, most frequently using a conventional dosing schedule in the initial phase, followed by a maintenance period of 3\xa0years. The Committee heard that in children and adults Pharmalgen is considered to provide immunity for at least 15\xa0years. The Committee understood that the regimen of most relevance to the appraisal was an initial phase using a conventional dosing regimen and a maintenance phase lasting 3\xa0years, with the treatment administered within a specialist centre.\n\nThe Committee discussed which patients currently receive Pharmalgen in clinical practice. It heard from the clinical specialists that Pharmalgen is offered to people with a history of severe systemic reactions to bee or wasp venom, or to people with moderate systemic reactions to bee or wasp venom if they have other risk factors such as raised baseline serum tryptase, a high risk of future stings, or anxiety about future stings. The Committee noted consultation comments that following publication of British Society for Allergy and Clinical Immunology guidelines, Pharmalgen may also be offered to people with a history of moderate systemic reactions to bee or wasp venom if they live far from emergency medical care, have certain comorbid conditions or request treatment with Pharmalgen. The Committee heard from the clinical specialists that children generally have a less severe reaction to venom than adults and a better prognosis over time. However, it is not possible to identify in advance which children will 'outgrow' their allergy to bee and/or wasp venom, and therefore Pharmalgen is an appropriate treatment for some children. The Committee understood that Pharmalgen is indicated for both adults and children, and that Pharmalgen is offered to people who have had severe systemic reactions or to people who have had moderate systemic reactions, and have additional risk factors for future systemic reactions such as raised baseline serum tryptase, or an increased risk of future stings, or whose quality of life is affected by anxiety about future stings.\n\nThe Committee discussed the impact of an allergy to bee and/or wasp venom on quality of life. The clinical specialists and patient experts stressed how frightening it is to be stung when there is an expectation of a possible systemic reaction following a sting, and that anaphylaxis can be accompanied by a sense of impending doom. The Committee heard from the patient experts that many people who have experienced a systemic reaction to bee or wasp venom are anxious about the possibility of systemic reactions following future stings, regardless of the actual risk of a reaction. The Committee heard that this anxiety affects usual daily activities of those affected and their family members. The Committee heard that people willingly tolerate the adverse effects of Pharmalgen treatment and the length and intensity of the administration schedule to reduce the probability of a systemic reaction to future stings. The Committee heard from patient experts that after treatment with Pharmalgen, anxiety levels return to normal for many people, and that carrying and having to administer an adrenaline auto-injector does not reduce anxiety to the same degree as having venom immunotherapy. The Committee heard from the clinical specialists that published trials have reported an improvement in quality of life in people who received venom immunotherapy compared with those who received an adrenaline auto-injector only. On balance, the Committee was persuaded that although the extent to which people might feel anxious following a systemic reaction would vary, and the risk of a sting might be very low, many people with a history of systemic reactions to bee or wasp venom would be anxious about the possibility of systemic reactions following future stings.\n\nThe Committee discussed the relevant comparator in the appraisal. The comparator as set out in the scope is a package of care without venom immunotherapy, including advice on avoidance of insect venom, and high-dose antihistamines and/or adrenaline auto-injectors (with training before use) to be used if stung. The Committee heard from the clinical specialists that the British Society for Allergy and Clinical Immunology recently issued guidelines for the treatment of bee and wasp venom allergy. It heard that clinicians advise people with a history of systemic reactions to bee or wasp venom on ways of minimising their risk of further stings, but do not provide advice alone. Instead clinicians offer people an adrenaline auto-injector (and training in its use) to carry and use following a bee or wasp sting that is accompanied by symptoms of a systemic reaction. The Committee concluded that an adrenaline auto-injector given alongside avoidance advice was the most appropriate comparator for Pharmalgen treatment.\n\nThe Committee discussed the clinical effectiveness evidence for Pharmalgen and noted that no RCTs or controlled studies had been identified that compared Pharmalgen with standard care without venom immunotherapy, as defined in the scope. The Committee discussed the available non-comparative data for Pharmalgen and the comparative data for non-Pharmalgen venom immunotherapy. The Committee heard from the clinical specialists that they considered that the results of non-Pharmalgen studies would also apply to Pharmalgen, and that venom immunotherapy is associated with changes in IgE production and a reduced risk of a systemic reaction following a sting. The Committee considered that the available evidence base for Pharmalgen was of poor quality and was limited. On balance, it was persuaded that Pharmalgen had demonstrated some efficacy in reducing the rate and severity of systemic reactions following a bee or wasp sting. However, the Committee considered that the relative efficacy could not be quantified with certainty.\n\n## Cost effectiveness\n\nThe Committee discussed the economic model developed by the Assessment Group. It noted that in the base-case analysis, Pharmalgen plus an adrenaline auto-injector plus high-dose antihistamine and avoidance advice had an ICER of £18,070,000 per QALY gained compared with an adrenaline auto-injector plus high-dose antihistamine and advice. The Committee heard from the Assessment Group that this estimate was robust to changes in parameters associated with costs and effects. However, the estimate was particularly sensitive to assumptions about utility and about how frequently a person is stung. The Committee considered the importance of the assumption in the base-case analysis that Pharmalgen treatment did not affect health-related quality of life. The Committee noted its earlier conclusions that having a venom allergy increases anxiety and affects daily activities, and that treatment with Pharmalgen may reduce some of this anxiety. The Committee concluded that the assumption in the base-case analysis that Pharmalgen had no effect on health-related quality of life underestimated the cost effectiveness of Pharmalgen compared with alternative treatments.\n\nThe Committee discussed comments received during the consultation about the robustness of the Assessment Group's model. The Committee noted the consultation comments that some of the inputs in the economic model relating to costs, efficacy and the likelihood of having a systemic reaction while receiving treatment with Pharmalgen were not plausible. The Committee considered that although there are some uncertainties as to the plausibility of assumptions and inputs, the Assessment Group's sensitivity analyses showed that the estimates of cost effectiveness were not sensitive to changes in these parameters. The Committee understood from the Assessment Group that the key drivers of cost effectiveness were assumptions about utility and about how frequently a person is stung. On this basis the Committee concluded that the Assessment Group's model was an appropriate basis for decision-making despite uncertainties around the plausibility of some parameter estimates.\n\nThe Committee considered the Assessment Group's scenario analyses that had assumed that people have five bee or wasp stings per year. The Committee heard from clinical specialists that some people are stung at least five times per year. These may include beekeepers plus their children and neighbours, roofers and gardeners. However, the risk of being stung varies. The Committee noted that in these scenario analyses, treatment with Pharmalgen dominated the alternatives (that is, it was more effective and less costly), and that this remained the case until the average frequency of stings dropped to approximately three per year. The Committee concluded that Pharmalgen is an appropriate use of NHS resources for people with IgE-mediated allergy to bee and wasp venom, who have a high risk of stings.\n\nThe Committee then considered the scenario analyses that included an effect on health-related quality of life related to anxiety about re-stings and Pharmalgen treatment. The Committee noted that in these analyses the ICER for Pharmalgen decreased to less than £30,000 per QALY gained. The Committee was aware that the Assessment Group had been unable to identify any data on anxiety associated with venom allergy or changes in anxiety as a result of venom immunotherapy that could be used in the economic model. Therefore the Assessment Group had used the EQ-5D survey of norms to explore how much disutility was generated when a person went from having no problems with anxiety and daily activities to moderate anxiety with some effect on daily activities (0.16). The Committee considered that the Assessment Group's assumption that fear of being stung would generate a quarter of that value (0.04), and that venom immunotherapy would reduce this anxiety by a quarter (0.01), was plausible and, given the testimony of the patient experts, may even underestimate the gains in utility associated with treatment with Pharmalgen. The Committee concluded that for people who do not have a high risk of future stings the analyses that assume reduced anxiety about re-stings with Pharmalgen treatment are the most appropriate on which to base the most plausible estimate of the ICER.\n\nThe Committee considered the 10-year time horizon in the economic model. It was aware that it had not been presented with evidence of the duration of immunity; but it also considered the testimony of the clinical specialists that immunity was likely to be longer than 10\xa0years. The Committee was presented with a scenario analysis with a time horizon of 20\xa0years for people who have a gain in health-related quality of life associated with reduced anxiety about re-stings and treatment with Pharmalgen. In this scenario, the ICER was £13,800 per QALY gained for treatment with Pharmalgen plus an emergency kit plus advice compared with an emergency kit and advice alone. The Committee concluded that it is appropriate to use a time horizon of longer than 10\xa0years, and that with reduced anxiety about re-stings after treatment with Pharmalgen the most plausible ICER would be less than £20,000 per QALY gained. The Committee concluded that Pharmalgen is an appropriate use of NHS resources for people with IgE-mediated allergy to bee and wasp venom, who are anxious about future stings.\n\nThe Committee then discussed its conclusions on the cost-effectiveness modelling and the use of Pharmalgen in current clinical practice (see section 4.3.4). The Committee took into account the evidence from the clinical specialists and patient experts. It concluded that it was appropriate to assume a health-related quality of life benefit from Pharmalgen for people with a history of severe systemic reactions and for people who have a history of moderate systemic reactions to bee and/or wasp venom and who have other risk factors for future systemic reactions such as anxiety about the possibility of systemic reactions following future stings, a higher risk of being stung or raised baseline serum tryptase. The Committee therefore concluded that Pharmalgen could be considered an appropriate use of NHS resources for the treatment of people with IgE-mediated bee and/or wasp venom allergy with the above characteristics. The Committee considered that anxiety about the possibility of systemic reactions following future stings should be such that it affects usual daily activities.\n\nThe Committee discussed comments received during consultation, noting that Pharmalgen may also be offered to people with a history of moderate systemic reactions to bee or wasp venom if they live far from emergency medical care, have comorbid conditions or request treatment with Pharmalgen. The Committee discussed the patient expert testimony, and concluded that these people would have heightened awareness of their situation and be anxious about the possible effects of having a systemic reaction from future stings. Therefore the Committee concluded that these groups were covered in its recommendation for people with a history of moderate systemic reactions, who are anxious about future stings.\n\nThe Committee discussed whether it should make a separate recommendation for people with raised baseline serum tryptase. The Committee noted that people with raised baseline serum tryptase are at higher risk of more severe reactions to future stings but that a person would only be aware of an increased risk once raised baseline serum tryptase had been diagnosed. The Committee also noted the consultation comment that a raised baseline serum tryptase may indicate mastocytosis, which is a possible contraindication for Pharmalgen. The Committee concluded that comorbid conditions, including mastocytosis, would be identified by the responsible clinician when considering whether to offer treatment with Pharmalgen. The Committee concluded that it was appropriate to include in its recommendations raised baseline serum tryptase as an additional risk factor for people who have had a moderate systemic reaction.\n\nThe Committee supported the statement made by the clinical specialists that treatment with Pharmalgen should be initiated and monitored in a specialist centre experienced in venom immunotherapy. The Committee discussed comments from consultation about the need for specialist centres to have staff appropriately trained in resuscitation or immediate access to age-appropriate resuscitation facilities. It noted that the SPCs specify that Pharmalgen should be provided under supervision of a doctor experienced in specific immunotherapy and that because of the risk of potentially fatal anaphylaxis, treatment with Pharmalgen must be carried out in clinics or hospitals where full facilities for cardiopulmonary resuscitation are immediately available for use by adequately trained personnel. The Committee therefore concluded that Pharmalgen should be provided within a specialist centre and that the details of the provision of resuscitation equipment were sufficiently specified in the SPC.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA246\n\nAppraisal title: Pharmalgen for the treatment of bee and wasp venom allergy\n\nSection\n\nKey conclusion\n\nPharmalgen is recommended as an option for the treatment of IgE-mediated bee and wasp venom allergy in people who have had:\n\n\n\na severe systemic reaction to bee or wasp venom, or\n\n\n\na moderate systemic reaction to bee or wasp venom and who have one or more of the following: a raised baseline serum tryptase, a high risk of future stings or anxiety about future stings.\n\n\n\nTreatment with Pharmalgen should be initiated and monitored in a specialist centre experienced in venom immunotherapy.\n\n\n\nThe Committee considered the available evidence to be of poor quality and limited. It was persuaded that Pharmalgen had demonstrated efficacy in reducing the rate and severity of systemic reactions. However, the relative effect could not be quantified with certainty. The Committee concluded that it is appropriate to use a time horizon of longer than 10\xa0years, and that with reduced anxiety about re-stings after treatment with Pharmalgen the most plausible ICER would be less than £20,000 per QALY gained.\n\n, 4.3.12\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard from the clinical specialists that people who have had a moderate or severe systemic reaction to bee or wasp venom are normally given an emergency kit containing adrenaline. The kit can also include other emergency treatments such as high-dose antihistamine. Clinicians also advise on how to avoid being stung, but they do not consider this advice to be effective on its own.\n\nPharmalgen is the only venom immunotherapy with UK marketing authorisation and is an established therapy for venom allergy.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee heard that that in children and adults Pharmalgen is considered to provide immunity for at least 15\xa0years.\n\n\n\n\n\nThe Committee concluded that having a venom allergy increases anxiety and affects daily activities, and that treatment with Pharmalgen may reduce this anxiety.\n\n\n\n\n\nThe Committee heard that carrying and having to administer an adrenaline auto-injector does not reduce anxiety to the same degree as having venom immunotherapy.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee heard from the clinical specialists that Pharmalgen is offered to people with a history of severe systemic reactions to bee or wasp venom, or to people who have had moderate systemic reactions to bee or wasp venom and have other risk factors such as a raised baseline serum tryptase, a high risk of future stings, or anxiety about future stings.\n\n\n\nAdverse effects\n\nThe Committee heard that people willingly tolerate the adverse effects of Pharmalgen treatment and the length and intensity of the administration schedule to reduce the probability of a systemic reaction to future stings and their anxiety about future stings.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nNo randomised controlled trials or controlled studies were identified that compared Pharmalgen with standard care without venom immunotherapy, as defined in the scope.\n\nThe Committee heard from the clinical specialists that they considered that the results of non-Pharmalgen venom immunotherapy studies were also relevant to Pharmalgen.\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee considered that the available clinical evidence base for Pharmalgen was of poor quality and was limited.\n\n\n\n\n\nUncertainties generated by the evidence\n\nThe Committee did not consider that the relative efficacy of Pharmalgen compared with standard care without venom immunotherapy could be quantified with certainty.\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee was persuaded that many people with a history of systemic reactions to bee or wasp venom would be anxious about the possibility of future stings.\n\n\n\nThe clinical specialists stated that elevated serum tryptase at baseline (after a reaction to a sting has subsided) is associated with an increased probability of severe systemic reactions to future stings.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee was persuaded that Pharmalgen had demonstrated some efficacy in reducing the rate and severity of systemic reactions following a bee or wasp sting. However, it considered that the relative efficacy could not be quantified with certainty.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered that the economic model developed by the Assessment Group was appropriate to form the basis of its decision-making, despite uncertainties around the plausibility of some parameter estimates.\n\n\n\nThe Assessment Group was unable to identify any data on anxiety associated with venom allergy or changes in anxiety as a result of venom immunotherapy that could be used in the economic model.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee concluded that the assumption in the base-case analysis that Pharmalgen had no effect on health-related quality of life underestimated the cost effectiveness of Pharmalgen compared with alternative treatments.\n\n\n\nThe Committee considered the scenario analyses that had assumed that people have five bee or wasp stings per year. It heard from clinical specialists that there are people who are stung at least five times per year and that these may include beekeepers plus their children and neighbours, roofers and gardeners.\n\n\n\n\n\nThe Committee concluded that it is appropriate to use a time horizon of longer than 10\xa0years.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nIn a scenario analysis the Assessment Group assumed that a history of systemic reactions to bee or wasp stings reduced utility by 0.04 per person per year, and that treatment with Pharmalgen increased utility by 0.01 per person per year.\n\nThe Committee recognised the limitations of the evidence, but accepted on balance that this utility estimate was plausible and, given the testimony of the patient experts, may even underestimate the gains in utility associated with treatment with Pharmalgen.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nEffect on quality of life\n\n, 4.3.11\n\nRisk of stings\n\n\n\nTime horizon\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nFor people with a high risk of stings, treatment with Pharmalgen dominated the alternatives (that is, it was more effective and less costly). For people without a high risk of stings but reduced anxiety about re-stings after treatment with Pharmalgen, the most plausible ICER was less than £20,000 per QALY gained.\n\n, 4.3.12\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n\n\nEnd-of-life considerations\n\nNot applicable.\n\n\n\nEqualities considerations and social value judgements\n\nNo equality issues were identified during the scoping process or during the course of the appraisal.\n\n", 'Related NICE guidance': 'Anaphylaxis: assessment to confirm an anaphylactic episode and the decision to refer after emergency treatment for a suspected anaphylactic episode. NICE clinical guideline 134 (2011).', 'Review of guidance': 'The guidance on this technology will be considered for review in January 2017. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveFebruary 2012', 'Changes after publication': 'February 2014: implementation section updated to clarify that pharmalgen is recommended as an option for treating bee and wasp venom allergy. Additional minor maintenance update also carried out.\n\nJune 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta246
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Evidence-based recommendations on bee venom and wasp venom (Pharmalgen) for treating bee and wasp venom allergy.
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Tocilizumab for the treatment of rheumatoid arthritis
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Tocilizumab for the treatment of rheumatoid arthritis
Evidence-based recommendations on tocilizumab (RoActemra) for treating rheumatoid arthritis in adults.
# Guidance
Tocilizumab in combination with methotrexate is recommended as an option for the treatment of rheumatoid arthritis in adults if:
the disease has responded inadequately to DMARDs and a TNF inhibitor and the person cannot receive rituximab because of a contraindication to rituximab, or because rituximab is withdrawn because of an adverse event, and tocilizumab is used as described for TNF inhibitor treatments in the NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor, specifically the recommendations on disease activity or
the disease has responded inadequately to one or more TNF inhibitor treatments and to rituximab
and the manufacturer provides tocilizumab with the discount agreed as part of the patient access scheme.
People currently receiving tocilizumab for the treatment of rheumatoid arthritis who do not meet the criteria in 1.1 should have the option to continue treatment until they and their clinicians consider it appropriate to stop.
Take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the disease activity score and make any appropriate adjustments.# The technology
Tocilizumab (RoActemra, Roche) is a humanised monoclonal antibody that inhibits cytokine interleukin‑6 (IL‑6). Reducing the activity of IL‑6 may reduce inflammation in the joints, prevent long-term damage, improve quality of life and function, and relieve certain systemic effects of rheumatoid arthritis. Tocilizumab, in combination with methotrexate, has a UK marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis in adults whose disease has not responded adequately to, or who were intolerant to, previous therapy with one or more DMARDs or TNF-alpha antagonists. In these people, tocilizumab can be given as monotherapy in case of intolerance to methotrexate or if continued treatment with methotrexate is inappropriate. Tocilizumab has been shown to reduce the rate of progression of joint damage as measured by X‑ray and to improve physical function when given in combination with methotrexate.
Tocilizumab is contraindicated in people with active, severe infections. The summary of product characteristics (SPC) lists the following as the most commonly reported adverse drug reactions associated with tocilizumab treatment: upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased alanine transaminase. For full details of side effects and contraindications, see the SPC.
Tocilizumab is administered as an intravenous infusion, given over 1 hour. The recommended dosage is 8 mg/kg, given once every 4 weeks. For people whose body weight is more than 100 kg, doses exceeding 800 mg per infusion are not recommended. Tocilizumab is available in three vial sizes, which are priced at £102.40 for an 80-mg vial, £256 for a 200-mg vial and £512 for a 400-mg vial ('British national formulary' edition 59, excluding VAT). The cost for tocilizumab as reported by the manufacturer is £9295 per year for a patient weighing approximately 70 kg. Costs may vary in different settings because of negotiated procurement discounts.
The Department of Health and the manufacturer have agreed that tocilizumab will be available to the NHS with a patient access scheme in which a discount from the list price is applied to original invoices. The level of the discount is commercial in confidence (see section 5.2). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this NICE technology appraisal guidance is published.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of tocilizumab, a review of this submission by the Evidence Review Group (ERG; appendix B), and two additional analyses by the Decision Support Unit (DSU; appendix B).
# Clinical effectiveness
In the submission, the manufacturer presented evidence on the clinical effectiveness of tocilizumab in combination with DMARDs for two populations: people whose rheumatoid arthritis had responded inadequately to previous DMARDs but before treatment with a TNF‑alpha inhibitor (the 'DMARD‑IR' population) and people whose rheumatoid arthritis had responded inadequately to previous TNF‑alpha inhibitors but before treatment with rituximab (the 'TNF‑IR' population). The manufacturer also presented evidence on the clinical effectiveness of tocilizumab as monotherapy. The submission focused on the tocilizumab 8 mg/kg treatment arms of the included studies because this is the recommended dose in the SPC. Some of the studies also included doses other than the licensed dose. Results for doses other than the licensed dose are not considered in this appraisal.
## Tocilizumab plus methotrexate as a treatment option after an inadequate response to conventional DMARDs
The main clinical-effectiveness evidence for the DMARD‑IR population came from three randomised controlled trials (RCTs). All three RCTs were double-blind, placebo-controlled parallel-group studies in adults with moderate to severe active rheumatoid arthritis whose condition had responded inadequately to treatment with methotrexate (OPTION and LITHE) or traditional DMARDs (TOWARD). The OPTION trial assessed the effects of tocilizumab 8 mg/kg plus methotrexate (n=205) compared with placebo plus methotrexate (n=204). The LITHE trial assessed the effects of tocilizumab 8 mg/kg plus methotrexate (n=398) compared with placebo plus methotrexate (n=393). The TOWARD trial assessed the effects of tocilizumab 8 mg/kg plus DMARDs (n=805) compared with placebo plus DMARDs (n=415).
The primary outcome in the RCTs was the proportion of people with an American of Rheumatology (ACR) 20 response at week 24. This was defined as at least a 20% improvement in both the tender joint count and the swollen joint count and at least a 20% improvement in three of the other five core set measures included in the ACR score. In all three RCTs, the same outcome measure and data collection instruments were used. The manufacturer stated that the RCTs had similar patient populations. This was demonstrated by general demographics and the effect of various factors on the ACR20 response rate, which was examined by logistic regression analysis. No statistically significant differences were found in treatment effects between studies and the manufacturer inferred that pooling the results of the three RCTs for the primary outcome was appropriate. The manufacturer's submission stated that the adjusted odds ratio for the ACR20 response of tocilizumab 8 mg/kg plus DMARD compared with placebo plus DMARD was approximately 4.2. Averaged ACR20 response rates, described as pooled results, were 59.2% in the tocilizumab 8‑mg/kg arm compared with 25.8% in the placebo arm (p≤0.0001) at week 24.
Secondary outcomes of the RCTs, measured at 24 weeks, were pooled across the three RCTs by the manufacturer. Pooled ACR response rates were: 37.0% compared with 9.6% for ACR50 response rates (p<0.0001), 18.5% compared with 2.4% for ACR70 response rates (p≤0.0001), and 4.2% compared with 0.3% for ACR90 response rates (p≤0.0001), for the tocilizumab 8‑mg/kg plus DMARD arms and placebo plus DMARD arms respectively. The manufacturer also presented averaged disease activity score 28 (DAS28) results from the three RCTs. Approximately half of all people in the RCTs reached low disease activity, defined as DAS28 of less than 3.2. Approximately one-third of people in the RCTs went into remission, defined as DAS28 of less than 2.6. The proportion of participants going into remission while on tocilizumab was reported to increase during the study period. There was a greater decrease (improvement) in averaged health assessment questionnaire (HAQ) results from baseline HAQ score in the tocilizumab groups than in the placebo groups. In the pooled population at week 24, the proportion of participants with a clinically relevant improvement in HAQ (defined as a decrease of at least 0.25 in an individual's total score) was higher in the tocilizumab groups (68%) than in the placebo groups (52%).
Additionally, European quality of life (EuroQoL) health-state questionnaire (EQ‑5D) scores were collected in the OPTION and LITHE RCTs. In the OPTION RCT, the baseline mean EQ‑5D was 0.393 (standard deviation 0.327) in the tocilizumab 8 mg/kg plus methotrexate arm, and 0.391 (standard deviation 0.329) in the placebo plus methotrexate arm. At follow-up, the mean EQ‑5D was 0.671 (standard deviation 0.237) in the tocilizumab 8 mg/kg arm and 0.534 (standard deviation 0.318) in the placebo arm. The manufacturer did not provide EQ‑5D results from the LITHE RCT separately by treatment arm.
Two single-arm extension studies assessed maintenance of clinical benefit of tocilizumab beyond 24 weeks. Overall, response rates for those remaining on tocilizumab plus DMARD treatment were maintained or continued to improve with duration of treatment, with an increasing proportion of people achieving higher ACR scores over time. The manufacturer reported that improvements in HAQ scores were observed for up to 132 weeks in the pooled tocilizumab 8 mg/kg plus DMARD arm.
No head-to-head studies were identified that provided evidence on the clinical effectiveness of tocilizumab compared with TNF‑alpha inhibitors and abatacept for the DMARD‑IR population. Therefore, the manufacturer conducted a mixed treatment comparison. A total of 18 RCTs (including OPTION, LITHE and TOWARD) were identified for inclusion. All studies were randomised, placebo-controlled, double-blind trials and all had a follow-up period of either 24 or 30 weeks. Participants were predominantly female (approximately 80%), older than 50 years, had experienced more than 6 years' duration of rheumatoid arthritis, were previously treated with an average of two or more DMARDs, and more than half had used non-steroidal anti-inflammatory drugs or glucocorticoids concomitantly. The manufacturer reported that the baseline characteristics across the trials were comparable to ACR core parameters. Results for TNF‑alpha inhibitors were pooled, because it was assumed there was no difference in efficacy between these drugs. This assumption was reported to be informed by the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130).
The mixed treatment comparison suggested that tocilizumab showed efficacy (measured by ACR20 and ACR50 response rates) comparable to all included biological treatments. For the ACR70 response rate, tocilizumab treatment was associated with a higher response rate than the TNF‑alpha inhibitors and abatacept (relative risks of 1.77 and 1.98 respectively). In the base-case comparison, there was a greater than 99% probability that tocilizumab was more efficacious than biological treatments (that is, etanercept, infliximab and adalimumab), as measured by ACR70 response rates. The manufacturer stated that homogeneity at each ACR response level was assessed using Cochran's Q‑statistic (ACR20: 44.1857, p=0.0002; ACR50: 41.6878, p=0.0004; ACR70: 25.5752, p=0.0603). Based on these results, the manufacturer used random-effects methods to estimate ACR20 and ACR50 response rates, and fixed-effect methods to estimate ACR70 response rates. As well as the base-case mixed treatment comparison, the manufacturer also presented three scenario analyses, which included or excluded data from certain trials included in the base case. The manufacturer stated that overall the results from these alternative scenarios were consistent with the initial findings.
## Tocilizumab plus methotrexate as a treatment option after an inadequate response to a TNF‑alpha inhibitor
The main clinical-effectiveness evidence for the TNF‑IR population came from one RCT, known as RADIATE. RADIATE was a double-blind, placebo-controlled, parallel-group study in adults with moderate to severe rheumatoid arthritis. The participants' rheumatoid arthritis had responded inadequately to previous TNF‑alpha inhibitor therapy. RADIATE assessed the effects of tocilizumab 8 mg/kg plus methotrexate (n=170) compared with placebo plus methotrexate (n=158).
The primary outcome of the RADIATE trial was ACR20 response rate. At 24 weeks, 50% of people in the tocilizumab arm compared with 10% of people in the placebo arm had experienced an ACR20 response (p<0.0001). Additionally, at 24 weeks, 28.8% compared with 3.8% had experienced an ACR50 response (p<0.0001), and 12.4% compared with 1.3% had experienced an ACR70 response (p<0.0002), for the tocilizumab arm and the placebo arm respectively. At week 24, the mean change from baseline in DAS28 was -3.16 for tocilizumab and -0.95 for placebo. The manufacturer stated that the remission rates were similar to those seen in the DMARD-IR population at 24 weeks. The mean decrease in HAQ from baseline at 24 weeks for the tocilizumab group was 0.39, compared with 0.05 for the placebo group.
Two single-arm extension studies assessed the maintenance of clinical benefit of tocilizumab plus DMARDs beyond 24 weeks. Response rates to therapy with tocilizumab were maintained or continued to improve with duration of treatment (as in the DMARD‑IR population). Results similar to those for the DMARD‑IR population were reported and the manufacturer noted that the pattern of improvement in mean HAQ score was also observed for up to 132 weeks.
## Tocilizumab as a monotherapy
One RCT (AMBITION) assessed the effects of tocilizumab 8 mg/kg alone (n=288) compared with methotrexate alone (n=284). This was a double-blind, placebo-controlled trial that included a sub-study tocilizumab arm in which placebo was given first for 8 weeks and then tocilizumab was given for 16 weeks. Most of the people in the AMBITION RCT had not received treatment with methotrexate before or had stopped methotrexate treatment for reasons other than toxicity or lack of efficacy.
The ACR20 response rate at 24 weeks in the intention-to-treat population was 69.9% in the tocilizumab arm compared with 52.5% in the methotrexate arm. The weighted difference in ACR20 response was 0.19 (95% confidence interval 0.11 to 0.27). The manufacturer concluded that treatment with tocilizumab was non-inferior to treatment with methotrexate. The manufacturer also stated that the trial population of AMBITION was not in accordance with the SPC of tocilizumab. This was because the AMBITION trial had recruited people who had not received any previous treatment with methotrexate; the SPC states that tocilizumab can be given as monotherapy in case of intolerance to methotrexate or if continued treatment with methotrexate is inappropriate.
## Adverse events
The manufacturer reported that adverse events associated with the mechanism of IL‑6 receptor (IL‑6R) inhibition were observed in all tocilizumab treatment groups. These adverse events included transient hepatic transaminase elevations, asymptomatic elevations of indirect bilirubin, transient neutropenia, and lipid elevations that appear to occur in association with marked decreases in acute phase proteins. In addition, serious infections associated with the immunomodulatory effects of tocilizumab were comparable with the incidence of serious infections with TNF-alpha inhibitors. Adverse events reported more frequently with tocilizumab 8 mg/kg monotherapy than in the methotrexate group were abdominal pain and discomfort, headache, dizziness, rash, pruritis and elevated blood pressure, neutropenia, leukopenia and hyperlipidaemia. Most of these events were mild and transient. The manufacturer reported that there was no increase in the severity or frequency of adverse events with prolonged exposure to the tocilizumab 8 mg/kg dose.
## Follow-up data
In addition to the original submission, the manufacturer of tocilizumab provided updated data with a maximum of 180 weeks of follow-up. The response rates of all people who received at least one dose of tocilizumab in the OPTION, AMBITION, RADIATE and TOWARD trials were analysed. A total of 3986 people were included in the long-term analyses. Approximately 14% of people discontinued tocilizumab treatment for safety reasons (including intercurrent illness). The manufacturer stated that tocilizumab increased or maintained ACR response rates in the DMARD‑IR, TNF-IR and tocilizumab monotherapy populations. This was demonstrated by the increased proportion of people with ACR50 and ACR70 responses and with an ACR70 response maintained for 24 consecutive weeks. The manufacturer also used the long-term follow-up data to re-estimate the HAQ progression with tocilizumab. The manufacturer stated that there was a negative trend (an improvement) in HAQ progression for both the DMARD‑IR and TNF‑IR populations.
# Cost effectiveness
The manufacturer did not identify any economic evaluations of tocilizumab and developed an economic model for the submission. This was an individual sampling model with a hypothetical homogenous cohort. The model used a lifetime horizon for costs and benefits. It considered the DMARD‑IR and TNF‑IR populations separately. No evidence on the cost effectiveness of tocilizumab monotherapy was presented.
The manufacturer's initial economic model compared a treatment sequence that included tocilizumab with the same treatment sequence without tocilizumab for two populations. For the DMARD‑IR population, tocilizumab plus methotrexate was the first biological treatment and if the condition did not respond or if the ACR20 response rate was no longer achieved then etanercept plus methotrexate was the next treatment. This was followed by rituximab plus methotrexate, then leflunomide, then gold, then ciclosporin until people withdrew from the last treatment (ciclosporin) and moved on to palliative care. The sequence was the same for the comparator arm, but excluded tocilizumab plus methotrexate at the beginning. For the TNF‑IR population, the sequence was the same as the DMARD‑IR population, except for the omission of etanercept plus methotrexate (that is, the first treatment in the comparator arm was rituximab plus methotrexate).
The probabilities of response were derived from the adjusted ACR response rates (adjusted for placebo differences across trials) from the base-case mixed treatment comparison. There were four categories of response: non-response, ACR20 response, ACR50 response, and ACR70 response. People were assigned a predefined drop in HAQ score (that is, an improvement in physical function) based on their ACR responses. Data from four RCTs (OPTION, TOWARD, LITHE and RADIATE) were analysed to estimate the relationship between ACR response and HAQ score in the first 24 weeks. People whose condition responded were assumed to have a constant probability of withdrawal owing to lack of efficacy. The probability of withdrawing from treatment was the same for the biological treatments (infliximab, etanercept, adalimumab, rituximab and tocilizumab) and was calculated as the average of two withdrawal rate estimates for etanercept and infliximab. At the point of switching to the next treatment, people were assumed to experience an increase in their HAQ score (rebound) equal to the initial HAQ improvement. After the initial 24‑week period the HAQ score with tocilizumab plus methotrexate was assumed to decrease linearly (improve) based on the observational extensions to the RCTs. Because of substantial uncertainty in the data for weeks 132–156, this continued improvement was only assumed for the first 3 years in the DMARD-IR cohort and 2.5 years in the TNF-IR cohort. Beyond this (3 years after initial treatment in the DMARD-IR cohort and 2.5 years after initial treatment in the TNF-IR cohort), the HAQ score was assumed to stay constant (that is, zero HAQ improvement) with tocilizumab plus methotrexate treatment. After the initial 24‑week treatment period, no change in HAQ score was assumed (zero HAQ improvement) for biological treatments such as etanercept and rituximab. After the initial 24‑week treatment period, an increase in HAQ score (that is, a worsening of physical function) was assumed for traditional DMARDs. The manufacturer also carried out sensitivity analyses using an assumption of zero HAQ progression (no improvement or worsening) while on treatment.
Tocilizumab plus methotrexate was assumed to be given for a minimum of 6 months and the administration cost of each infusion of tocilizumab was assumed to be £142 (see section 3.25 for subsequent considerations of administration costs). The costs of treating any adverse events were not included in the economic model presented by the manufacturer. The manufacturer reported that EQ‑5D scores from the tocilizumab OPTION and LITHE trials were mapped to HAQ scores using a quadratic regression model. Alternative mapping equations as used in the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130) and other submissions to NICE were examined in scenario analyses. Utility weights were derived from the EQ‑5D scores using the UK time trade-off tariff. Adverse events associated with tocilizumab treatment were assumed to generate an insignificant burden on people's quality of life, and therefore were not included in the model.
For the DMARD‑IR population, the treatment sequence including tocilizumab plus methotrexate compared with the sequence without tocilizumab produced incremental costs of £23,253 and incremental quality-adjusted life years (QALYs) of 1.17. This resulted in a base-case incremental cost-effectiveness ratio (ICER) of £19,870 per QALY gained. For the TNF‑IR population, the treatment sequence including tocilizumab plus methotrexate compared with the sequence without tocilizumab produced incremental costs of £26,640 and incremental QALYs of 1.21. This resulted in a base-case ICER of £22,003 per QALY gained. Probabilistic sensitivity analyses suggested that the addition of tocilizumab and methotrexate to the treatment sequences had a 56.4% and 22.4% probability of being cost effective (for the DMARD‑IR and TNF‑IR populations respectively) if the maximum acceptable amount to pay for a QALY gained is £20,000. All scenario analyses presented by the manufacturer resulted in ICERs of less than £30,000 per QALY gained. The ICERs increased to £24,905 and £24,739 per QALY gained for the DMARD‑IR and TNF‑IR populations respectively, using an assumption of no change in HAQ score (that is, no continued improvement on tocilizumab after the initial ACR response).
# Evidence Review Group comments
The ERG highlighted the following key areas of concern with the manufacturer's submission.
The selection of the studies and the pooling of the TNF‑alpha inhibitors in the mixed treatment comparison.
The long-term estimates of HAQ score.
Mapping HAQ scores to EQ‑5D to derive utility estimates for the economic model.
The rebound effect on discontinuation (defined as an increase in a person's HAQ score when treatment is withdrawn).
The non-inclusion of adverse events in the economic model.
The ERG explored the combined adjusted ACR response rates for TNF‑alpha inhibitors used in the mixed treatment comparison (DMARD‑IR population) and considered that etanercept appeared less efficacious in the comparison than the literature suggested. The ERG commented that the reason for the apparent low efficacy of etanercept compared with both tocilizumab and the other TNF‑alpha inhibitors was a single large trial with a very high response rate in the placebo arm (the Klareskog trial). The ERG noted that this trial only included people who were likely to benefit from methotrexate and had an aggressive dosing schedule of methotrexate if the signs and symptoms of rheumatoid arthritis reappeared. When the ERG removed the Klareskog trial from the analysis, etanercept appeared more efficacious than tocilizumab and all the other treatments in the comparison. The ERG then questioned the validity of assuming that all TNF‑alpha inhibitors had the same efficacy in the model, because this lowered the estimate of the effectiveness of the TNF‑alpha inhibitor used in the model.
The ERG commented that the follow-up period of 24 weeks in the five included tocilizumab studies could be considered too short. It noted that the longer-term data on tocilizumab came from single-arm studies with no comparator of placebo, conventional DMARDs or biological agents, so the long-term effectiveness of tocilizumab was unclear. The manufacturer estimated the medium-term HAQ progression (up to 3 years for the DMARD‑IR population and 2.5 years for the TNF‑IR population) using linear functions. However, the ERG suggested that an exponential function was equally plausible. The ERG noted that any functions fitted to the data needed to be constructed carefully because even small changes to the predictions would have a significant impact on the ICER.
The ERG was also concerned about the way the relationship between HAQ and EQ‑5D was modelled. The manufacturer's submission used a quadratic equation for this. The quadratic model predicted that EQ‑5D scores would be lower at high HAQ scores compared with a linear model. In addition, literature has shown that EQ‑5D and HAQ are closely correlated at baseline and that when quality of life worsened over time the EQ‑5D became more variable (resulting in a weaker correlation). The ERG noted that the modelled relationship between HAQ and EQ‑5D scores resulted in negative utilities for health states (that is, health states that are considered to be worse than death). The ERG stated that using negative utility values is questionable because a certain amount of disability (because of irreversible characteristics such as damaged joints) may remain despite optimal control of inflammatory disease. The ERG concluded that algorithms for modelling the relationship between HAQ and EQ‑5D should only be used when there are no direct utility scores; however, the trials for tocilizumab (OPTION and LITHE) measured EQ‑5D directly.
The manufacturer assumed the cost of administering each infusion of tocilizumab was £142. This was derived by adjusting for inflation the cost of an infusion as used in the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130). However, the ERG commented that this cost should have been adjusted for inflation from 2001 and not from 2004 as was presented by the manufacturer.
The manufacturer's submission assumed that the rebound after withdrawal from treatment was equal to the initial HAQ improvement only. The manufacturer's submission also assumed that the HAQ score for people treated with tocilizumab improved over the course of treatment, but that for other treatments the HAQ score either remained the same (biological treatments) or worsened (conventional DMARDs and palliative care). Therefore, it was assumed that the short- to medium-term HAQ benefit was retained in the long term. The guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130) accepted a similar assumption that people would lose their initial HAQ improvement when treatment was withdrawn, and also that biological treatments delayed disease progression more than conventional DMARDs. However, whereas the HAQ score representing underlying disease progression for all biological treatments in the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130) remained the same or worsened only slightly while on treatment, the manufacturer assumed that HAQ score improvement was possible for tocilizumab only. The ERG commented that the assumptions about rebound effect and HAQ progression disproportionately favoured tocilizumab by not only allowing the drug to delay disease progression, but also by allowing for a lasting improvement of the condition.
In addition, the ERG considered that excluding adverse events in the manufacturer's model was questionable because biological treatments are known to be associated with adverse events. It reported that it was unclear whether the adverse-event rate is higher or lower for tocilizumab than for other biological treatments. The manufacturer's submission states that the mean and median duration of treatment with tocilizumab in the clinical trials was 1.08 years. The ERG commented that the risks of longer-term treatment with tocilizumab were unknown.
# Manufacturer's response to consultation
In response to three rounds of consultation for the original guidance on tocilizumab for rheumatoid arthritis (NICE technology appraisal guidance 198), the manufacturer presented revised ICERs for the DMARD‑IR and TNF‑IR populations incorporating some of the ERG's suggested changes. The manufacturer also provided ICERs for positioning tocilizumab after an inadequate response to rituximab, and tocilizumab for people who are intolerant to rituximab or for whom rituximab is contraindicated. The clinical-effectiveness data for tocilizumab used in these positions were taken from the RADIATE trial. All of the revised and new ICERs incorporated degraded ACR response rates for tocilizumab, etanercept and rituximab when they are used later in the treatment sequence. Estimates for etanercept were based on treatment response to a second or third TNF‑alpha inhibitor reported from the South Swedish Arthritis Treatment Group. These downgraded the efficacy of etanercept from 62%, 38% and 16% to 49%, 26% and 7% for ACR20, ACR50 and ACR70 response rates respectively when used after one biological treatment. For tocilizumab when used after two biological treatments, degraded rates were based on the subgroup of people from the RADIATE trial whose rheumatoid arthritis had responded inadequately to more than one TNF‑alpha inhibitor. Based on these data, tocilizumab response rates changed from 62%, 31% and 12% to 50%, 31% and 15% for ACR20, ACR50 and ACR70 response rates respectively. For rituximab used after two biological treatments, the manufacturer provided downgraded response rates based on a subgroup of people whose rheumatoid arthritis had responded inadequately to more than one TNF‑alpha inhibitor from a trial comparing rituximab plus methotrexate with placebo plus methotrexate (REFLEX). Based on these data, the rituximab response rates were downgraded from 46%, 23% and 14% to 42%, 22% and 10% respectively.
The revised ICERs were based on the adjusted ACR rates from the mixed treatment comparison, and included a long-term HAQ improvement for tocilizumab and a stable HAQ score (that is, zero HAQ progression) for all other biological treatments. This was not the case for the ICER for tocilizumab given after rituximab, for which no HAQ improvement for treatment with any biological treatment, including tocilizumab, was assumed. All of the revised ICERs were calculated using the HAQ to EQ‑5D mapping and included negative utilities that represented states worse than death. The ICERs were subject to the assumption that a person would experience the same adverse events during treatment as during palliative care, and that the cost of administration of tocilizumab was £154.
The manufacturer's revised ICER for the DMARD‑IR population increased from £19,870 to £21,733 per QALY gained and increased from £22,003 to £23,285 per QALY gained for the TNF‑IR population. The ICER for tocilizumab used after rituximab was £23,735 per QALY gained. The ICER for tocilizumab for people who are intolerant to rituximab or for whom rituximab is contraindicated was £20,242 per QALY gained.
# Decision Support Unit report 2010
In 2010, the DSU was asked to undertake additional cost-effectiveness analyses to validate the manufacturer's ICERs submitted following the third round of consultation, and to conduct sensitivity analyses to address the Appraisal Committee's concerns about key parameter assumptions. The 2010 report highlighted a key issue with the calculation of the ICERs presented by the manufacturer. This concerned the 'pair-wise' calculation of sequences containing tocilizumab plus methotrexate with the same sequence excluding tocilizumab rather than an 'incremental' comparison of all strategies containing tocilizumab plus methotrexate with each other and with a base-case strategy without tocilizumab. The DSU considered that the incremental approach was the most appropriate, not only to determine whether tocilizumab plus methotrexate was cost effective, but also in what circumstances, given the availability of a number of other treatments that are used sequentially. The DSU's 2010 report explained that an ICER calculated through a pair-wise comparison does not demonstrate that the sequence can be considered cost effective because there are a series of mutually exclusive sequences available and only one can be selected at any one time.
For etanercept, the mixed treatment comparison analysis combined all TNF‑alpha inhibitors (etanercept, infliximab and adalimumab) but excluded the Klareskog trial of etanercept that the Committee had requested to be removed because of its unusually high placebo response rate. The DSU noted in the 2010 report that the adjusted mixed treatment comparison rates were lower than the unadjusted trial ACR, or point estimate, rates for etanercept. The adjusted etanercept ACR20, ACR50 and ACR70 response rates were 62%, 38% and 16% respectively and the unadjusted ACR20, ACR50 and ACR70 response rates were 71%, 39% and 17% respectively. In 2010 the DSU reported that the unadjusted rates in the model were taken from a single etanercept trial, without justification for the sole use of this particular trial. The DSU provided an alternative set of unadjusted response rates for etanercept, which were based on the two etanercept trials from the mixed treatment comparison (rather than the single trial chosen by the manufacturer). The DSU stated in the 2010 report that this appeared to represent the most robust data. The resulting unadjusted ACR response rates were 73%, 47% and 22% for ACR20, ACR50 and ACR70 respectively. For rituximab, the adjusted mixed treatment comparison ACR response rates were also lower than the unadjusted ACR trial response rates. The percentage of people reaching an ACR20, ACR50 and ACR70 response rate was 51%, 27% and 12% respectively in the unadjusted analysis and 46%, 23% and 14% respectively in the adjusted analysis. The unadjusted data were taken from the REFLEX trial.
The DSU highlighted in the 2010 report that the opposite effect was observed with the adjusted and unadjusted ACR rates for tocilizumab, that is, the adjusted rates from the mixed treatment comparison were higher than the unadjusted rates. For tocilizumab given as the first biological treatment in the sequence, the adjusted rates were 63%, 41% and 26% for ACR20, ACR50 and ACR70 response rates respectively and the unadjusted rates for tocilizumab, which were based on a separate meta-analysis of OPTION, TOWARD and LITHE (submitted as part of the manufacturer's licence application), were 59%, 37% and 19% respectively. For tocilizumab used as the second biological treatment in a sequence (that is, after a TNF‑alpha inhibitor), the mixed treatment comparison had the same effect of increasing the tocilizumab ACR response rates. The adjusted rates were 62%, 31% and 12%, whereas the unadjusted rates were 50%, 29% and 12% for ACR20, ACR50 and ACR70 response rates respectively. The unadjusted rates for tocilizumab used as the second biological treatment in the sequence were taken from the RADIATE trial.
The DSU also commented on the degradation rates provided by the manufacturer. These rates were all from single data sources, without justification given for the selection of the sources. The DSU highlighted that the degraded response rates for etanercept were based on the reported ACR rates for the TNF‑alpha inhibitors as a group and may not have been generalisable to etanercept. The DSU also noted that the degraded ACR70 response rate for tocilizumab used after two biological treatments assumed by the manufacturer (15%) was marginally better than when used after a single biological treatment (12%). The DSU stated that this appeared to be counterintuitive and that it would be more appropriate to assume the same ACR70 response rate when tocilizumab is given after two biological treatments as for when it is given after one.
In the 2010 report the DSU considered four separate approaches that varied the ACR response rates and degradation rates used to calculate the incremental ICERs (approaches to evidence synthesis).
Approach 1 was the same as the manufacturer's revised base case and used the adjusted mixed treatment comparison results with the degradation rates supplied by the manufacturer.
Approach 2 used the unadjusted single trial ACR response rates for etanercept when used first in the treatment sequence as supplied by the manufacturer. All other estimates remained the same as in approach 1.
Approach 3 used the unadjusted trial ACR response rates for all treatments in the sequence as supplied by the manufacturer. In addition, this approach replaced the degraded effect for tocilizumab when used after two biological treatments with the same effect assumed after one biological treatment to account for the counterintuitive change in response rate assumed by the manufacturer (see section 3.34).
Approach 4 was the same as approach 3, except that the DSU used the alternative unadjusted ACR response rates for etanercept from the two trials (described in section 3.32).
For each of the four approaches to evidence synthesis, the DSU undertook four sets of sensitivity analyses to assess the robustness of the ICER results to other key parameter assumptions in the 2010 report. These were:
employing the same set of parameter assumptions employed by the manufacturer in its base case
assuming no long-term HAQ improvement with tocilizumab
assuming no long-term HAQ improvement with tocilizumab and excluding negative utilities from the HAQ to EQ-5D mapping
assuming no long-term HAQ improvement with tocilizumab and doubling the administration costs for tocilizumab to £308.60 per infusion.
The DSU in the 2010 report calculated the incremental ICERs for each approach using the four sensitivity analyses and presented the incremental results separately for each of the 16 possible analyses. In each incremental analysis, the treatment strategies compared with each other were:
etanercept followed by rituximab (strategy 1)
tocilizumab, followed by etanercept, followed by rituximab (strategy 2)
etanercept, followed by tocilizumab, followed by rituximab (strategy 3)
etanercept, followed by rituximab, followed by tocilizumab (strategy 4).
For all treatment strategies, the calculation of the ICER included the costs and QALYs associated with treatment with conventional DMARDs and palliative care at the end of the sequence. All treatment strategies were in combination with methotrexate.
Using the threshold for cost effectiveness (£30,000 per QALY gained), the results of the fully incremental analysis undertaken by the DSU in the 2010 report indicated that using tocilizumab as a first-line treatment before etanercept would not be cost effective for any approach and with any set of parameter assumptions (including the manufacturer's base-case assumptions). Using tocilizumab as a second-line treatment before rituximab would only be cost effective if it is assumed that tocilizumab has long-term HAQ improvement and there is no HAQ improvement assumed with other biological treatments. However, if tocilizumab has zero HAQ improvement, then tocilizumab would only be cost effective when used as a third-line treatment after rituximab. If tocilizumab has zero HAQ improvement and the administration costs of tocilizumab are doubled, then tocilizumab is never cost effective (that is, standard care is the most cost-effective sequence). For people who have an intolerance to rituximab, or for whom rituximab is contraindicated, adding tocilizumab to the current standard care is cost effective. However, if tocilizumab does not have a different effect on long-term HAQ and the administration costs of tocilizumab are doubled, then the current standard care would be more cost effective for this population.
# Rapid review of NICE technology appraisal guidance 198: patient access scheme
In the Appraisal Committee's original guidance on tocilizumab for rheumatoid arthritis (NICE technology appraisal guidance 198) tocilizumab plus methotrexate was recommended for the treatment of rheumatoid arthritis that has not responded adequately to one or more TNF‑alpha inhibitors or to rituximab, or in whom rituximab is contraindicated or is withdrawn because of an adverse effect. Following publication of this guidance, the manufacturer submitted a patient access scheme in which a discount was applied to all indications for tocilizumab (see section 2.4) to be considered as a rapid review of the original guidance.
As part of the rapid review, the manufacturer did not submit any additional clinical-effectiveness data. However, the manufacturer did clarify the ACR and non-response rates for each drug for each position in the treatment sequences. This highlighted that when tocilizumab is the first biological treatment in the sequence, the non-response rate is approximately 40% compared with 27% when etanercept is the first biological treatment in the sequence.
The manufacturer submitted revised ICERs using the assumptions that the Committee agreed at the final Committee meeting before issuing NICE technology appraisal guidance 198, which included:
using approach 4 to evidence synthesis (see section 3.35)
assuming no long-term HAQ improvement with tocilizumab.
The manufacturer presented the results of an incremental analysis for the DMARD‑IR population in which the following treatment sequences were included:
etanercept then rituximab (baseline sequence)
tocilizumab then etanercept then rituximab
etanercept then tocilizumab then rituximab
etanercept then rituximab then tocilizumab.
The manufacturer was requested to include an additional baseline treatment sequence of tocilizumab, followed by etanercept. In this analysis the ICER for tocilizumab as the first treatment in the sequence was £5716 per QALY gained. As the second treatment in the sequence it was £30,716 per QALY gained, and as the third treatment in the sequence the ICER was £8134 per QALY gained. All ICERs incorporated the discount for tocilizumab agreed as part of the patient access scheme.
The manufacturer also responded to a request from the DSU as part of this rapid review to provide ICERs for the TNF‑IR population in which the following treatment sequences were included:
rituximab (baseline sequence)
tocilizumab then rituximab.
In this analysis the costs and QALYs associated with prior treatment with a TNF‑alpha inhibitor were assumed to be the same for both treatment strategies and were therefore not modelled. The ICER for the tocilizumab sequence compared with the baseline sequence (incorporating the discount for tocilizumab agreed as part of the patient access scheme) was £22,690 per QALY gained.
# Decision Support Unit report 2011
In 2011, the DSU was asked to undertake a review of whether the manufacturer had correctly implemented the Department of Health approved patient access scheme within their cost-effectiveness analysis. Additionally the DSU critiqued the changes to the costs of tocilizumab and ensured the Committee's agreed assumptions from the guidance on tocilizumab for rheumatoid arthritis (NICE technology appraisal guidance 198) had been used as the starting point within the economic analysis.
The DSU confirmed in the 2011 report that these conditions were met. However it raised the following issues with the manufacturer's analyses:
No results had been presented for the subgroup of people intolerant to rituximab or who have had rituximab withdrawn because of a contraindication. The ICERs were incorrect because no account had been taken of sequences that were extendedly dominated (less effective than and at least as costly as a combination of other drug sequences).
Within the TNF-IR analysis a sequence of rituximab followed by tocilizumab had not been included.
The DSU also corrected for a minor inaccuracy in the unadjusted trial rates used in NICE technology appraisal guidance 198. This changed the ACR20, ACR50 and ACR70 response rates for tocilizumab following two biologicals from 0.50, 0.31 and 0.15 to 0.50, 0.29 and 0.12 respectively.
In 2011, the DSU reported the results of their exploratory analysis for the DMARD‑IR population, which included the same treatment sequences in an incremental analysis as those modelled by the manufacturer (see section 3.42). All ICERs incorporated the discount for tocilizumab agreed as part of the patient access scheme. In this analysis, three sequences were extendedly dominated (first: etanercept followed by rituximab; second: tocilizumab as the first treatment; third: tocilizumab as the second treatment). The ICER for tocilizumab as the third treatment in the sequence was £28,380 per QALY gained compared with £8134 per QALY gained from the manufacturer's analysis.
The DSU provided an additional exploratory analysis in the 2011 report. This was an exploratory analysis for the rituximab-intolerant DMARD-IR population. All ICERs incorporated the discount for tocilizumab agreed as part of the patient access scheme. In this analysis etanercept alone was extendedly dominated. The ICER for tocilizumab followed by etanercept compared with tocilizumab alone was £10,698 per QALY gained, and the ICER for etanercept followed by tocilizumab compared with tocilizumab followed by etanercept was £30,121 per QALY gained.
The DSU reported the results of their exploratory analysis for the TNF-IR population, which included the same treatment sequences in an incremental analysis as those modelled by the manufacturer (see section 3.43). All ICERs incorporated the discount for tocilizumab agreed as part of the patient access scheme. In this analysis, tocilizumab followed by rituximab was dominated (was less effective than and at least as costly) by rituximab followed by tocilizumab. The ICER for rituximab followed by tocilizumab was £18,527 per QALY gained compared with the manufacturer's estimate of £22,690 per QALY gained.
Full details of all the evidence are in the manufacturer's submissions, the ERG report, and the reports from the DSU, which are available from the NICE website.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of tocilizumab, having considered evidence on the nature of rheumatoid arthritis and the value placed on the benefits of tocilizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee understood that the main purpose of treatment for rheumatoid arthritis is to suppress inflammation, which in turn can slow disease progression and prevent irreversible joint damage. The Committee heard from the clinical specialists and patient experts that the primary concern with tocilizumab treatment was the potential for infectious complications, but that trial data suggested that most adverse events were relatively minor, and, in most cases, did not limit treatment use. The Committee noted the safety data presented by the manufacturer, which reported 27 deaths and a serious adverse event rate of 5.8%. The Committee considered that this adverse event rate was high, but heard that it was comparable with other biological treatments.
The Committee understood the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130) recommends TNF‑alpha inhibitors adalimumab, etanercept and infliximab as options for the treatment of adults whose rheumatoid arthritis has responded inadequately to two DMARDs (unless DMARDs are contraindicated), and with a DAS28 score greater than 5.1. The Committee noted that in NICE technology appraisal guidance 130, treatment should normally be initiated with the least expensive drug (taking into account administration costs, required dose and product price per dose) and this may need to be varied in individual cases because of differences in the mode of administration and treatment schedules. It was also aware of:
Certolizumab pegol for the treatment of rheumatoid arthritis (NICE technology appraisal guidance 186) and
Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs (NICE technology appraisal guidance 225).
It noted the recommendations for the TNF‑alpha inhibitors certolizumab pegol and golimumab to be used as described in the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130), including the specific considerations concerning disease activity and choice of treatment. For treatment following an inadequate response to DMARDs (including at least one TNF‑alpha inhibitor), the guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for rheumatoid arthritis (NICE technology appraisal guidance 195) recommends rituximab plus methotrexate.
The Committee discussed the treatment options for people with moderate to severe active rheumatoid arthritis. It was aware that after an inadequate response to rituximab, additional DMARDs and best supportive care would be offered. The Committee heard from the manufacturer that it was seeking a recommendation for tocilizumab as an option along with other biological treatments in the treatment pathway. The Committee concluded that there were four possible scenarios for including tocilizumab in the treatment pathway:
Tocilizumab after two DMARDs as an alternative to TNF‑alpha inhibitors.
Tocilizumab after TNF‑alpha inhibitors as an alternative to rituximab.
Tocilizumab after TNF‑alpha inhibitors when a person is intolerant to rituximab or for whom rituximab is contraindicated.
Tocilizumab as an addition to the treatment pathway after rituximab.
# Clinical effectiveness
The Committee first discussed tocilizumab given as monotherapy. It noted that the only clinical evidence for tocilizumab monotherapy came from a trial that included people who had not been previously treated with methotrexate and that tocilizumab monotherapy treatment for this population was outside the licensed indication of tocilizumab. The Committee also noted that no cost-effectiveness estimates of tocilizumab given as monotherapy had been presented by the manufacturer. It concluded that no evidence for tocilizumab monotherapy within its licensed indication was available, and therefore no recommendations for tocilizumab as a monotherapy could be made.
The Committee considered the evidence on the clinical effectiveness of tocilizumab plus DMARDs compared with placebo plus DMARDs. The Committee concluded that tocilizumab plus methotrexate was clinically effective compared with placebo plus DMARDs when given before TNF‑alpha inhibitors and when given before rituximab.
The Committee then considered the evidence for the relative efficacy of tocilizumab compared with etanercept and compared with rituximab when all treatment strategies were in combination with methotrexate. It understood that tocilizumab had not been compared head-to-head with etanercept (or any other TNF‑alpha inhibitor) or rituximab, and that indirect evidence had been combined in a mixed treatment comparison for this purpose. It noted the concerns raised by the ERG and clinical specialists regarding the mixed treatment comparison. The mixed treatment comparison assumed that the TNF‑alpha results could be regarded as a class; however, when merged, the overall results reduced the efficacy of etanercept. The Committee noted that the manufacturers had responded to its requests to remove the Klareskog trial of etanercept from the analysis because this was a large RCT with unusually high control-arm response rates and did not correspond with the inclusion criteria of the mixed treatment comparison. With this trial removed, the Committee noted that etanercept appeared at least equal to, and possibly had higher efficacy than, tocilizumab.
The Committee further noted the concerns of the DSU in its 2010 report regarding the adjusted ACR response rates from the mixed treatment comparison compared with the 'unadjusted' point estimates from the individual trials. It understood that the proportions of people achieving ACR20, ACR50 and ACR70 response rates for etanercept and rituximab resulting from the mixed treatment comparison were lower than the corresponding unadjusted trial ACR response rates. Conversely, the proportions of people achieving ACR20, ACR50 and ACR70 response rates were higher for tocilizumab in the adjusted mixed treatment comparison analysis than the unadjusted trial rates. The 2010 DSU report clarified that the counterintuitive results of the mixed treatment comparison had possibly arisen when the comparator response rates from all of the trials had been pooled. The Committee considered that the mixed treatment comparison included a set of heterogeneous trials, which meant that the results were subject to considerable uncertainty, and that limited confidence could be placed in the adjusted ACR response rates in the manufacturer's revised base case. The Committee concluded that using the unadjusted trial estimates in the analyses was more appropriate.
The Committee considered the relative efficacy of tocilizumab compared with etanercept and also with rituximab using the unadjusted trial estimates of ACR rates. It considered that the evidence was not conclusive of a benefit of any one drug over another. The Committee concluded that no convincing evidence had been presented to demonstrate the superiority of tocilizumab over etanercept or rituximab, but that the estimates were in a similar range to etanercept and rituximab.
The Committee considered the clinical evidence for tocilizumab after treatment with rituximab. Based on previous discussions it recognised that tocilizumab plus methotrexate is clinically effective compared with placebo plus methotrexate (see section 4.7). It noted the evidence from the RADIATE trial in which a subgroup of people had rheumatoid arthritis that had responded inadequately to two TNF‑alpha inhibitors. It understood that this was the only available evidence to consider the effectiveness of tocilizumab after rituximab. The Committee considered that it indicated a benefit of tocilizumab after two biological treatments. In view of this evidence and considering the comments from patient experts and clinical specialists, the Committee, on balance, agreed that tocilizumab was likely to benefit people whose rheumatoid arthritis has responded inadequately to rituximab.
# Cost effectiveness
The Committee discussed the appropriate approach for determining the cost effectiveness of tocilizumab. It understood that before the 2010 DSU report the manufacturer's ICERs were based on adjusted trial response rates from the mixed treatment comparison. It also understood that the 2010 DSU report presented analyses using four different approaches to evidence synthesis (see section 3.35). The Committee considered, on the basis of previous discussions (see section 4.8), that approach 1, in which the ACR response rates came from the mixed treatment comparison, was not appropriate. The remaining three approaches to evidence synthesis used the unadjusted trial response rates for all treatments and incorporated degradation rates. The Committee understood that approaches 2 and 3 only used the unadjusted ACR response rate from a single trial for etanercept, rather than from the two available trials. The Committee had a strong preference for approach 4, which used data from both of the etanercept trials. Approach 4 also corrected the counterintuitive ACR70 response rate for tocilizumab used as a third biological treatment in the treatment sequence noted by the DSU in the 2010 report. The Committee concluded that approach 4 to evidence synthesis (see section 3.35) was the most appropriate for consideration.
The Committee also discussed the two sensitivity analyses presented by the DSU within approach 4 in the 2010 report. The first concerned evidence supplied by the manufacturer for a long-term HAQ improvement. It understood that the data for a HAQ improvement with tocilizumab treatment came from open-label extension studies in which only the HAQ scores for people who remained on treatment were available. It noted that, for the open-label extension trial assessing the benefits of tocilizumab after the failure of conventional DMARDs (that is, before etanercept), approximately 30% of people had stopped treatment. It further noted that the confidence intervals around the mean HAQ scores at each point in time were wide. The Committee therefore considered that the manufacturer's evidence was not a robust estimate of the long-term HAQ improvement on tocilizumab and was subject to uncertainty. Furthermore, the manufacturer had not provided any comparable investigation into long-term HAQ trends for the comparator biological treatments other than rituximab. The manufacturer presented a graph of a stable HAQ trend for people on rituximab from the REFLEX trial. However, no data had been supplied by the manufacturer to support the graph. The Committee questioned the comparability of the rituximab and tocilizumab HAQ trend lines, and considered that single-arm extension trial data did not provide a direct comparison of the relative benefits between the two treatments. In addition, the Committee heard from patient experts and clinical specialists that it was unlikely that tocilizumab would provide a long-term HAQ benefit over and above that of any other biological treatment. Overall, the Committee could not support the assumption that there is a long-term HAQ gain with tocilizumab (that is, a HAQ improvement with tocilizumab) compared with no HAQ improvement with other biological treatments. It concluded, on the basis of the evidence presented, that the long-term HAQ improvement on tocilizumab treatment had not been demonstrated. The Committee agreed that the analyses that assumed no long-term HAQ improvement with tocilizumab were therefore the most appropriate for consideration.
The second sensitivity analysis that the Committee considered concerned the exclusion of negative utilities (health states worse than death) from the incremental analysis. The Committee noted that the manufacturer's mapping of HAQ scores to EQ-5D utility values resulted in negative utility values. It discussed that excluding negative utility values could be considered counterintuitive and did not allow for a worsening of quality of life when a person had rheumatoid arthritis. The Committee heard from the manufacturer that it was possible that there were some people with rheumatoid arthritis who may experience negative utility values. The Committee noted that the impact of removing the negative utilities from the incremental analysis was minimal. The Committee agreed that although the exclusion of negative utility values was subject to some debate, it was not a key issue in determining the cost effectiveness of tocilizumab. The Committee therefore accepted that the calculation of some ICERs would include negative utility values but concluded that this was acceptable because of the low impact on the ICERs.
The Committee considered the administration costs of tocilizumab. It noted comments received during consultation in 2010 that, although the infusion took 1 hour, the total time taken to administer tocilizumab in an organised unit would be at least 2 hours. The Committee then discussed the 2010 DSU analysis using approach 4 with no long-term HAQ improvement and the administration costs doubled. It heard from the DSU that the decision to double the cost was not based on a robust estimate of the time taken to administer tocilizumab, but was intended to illustrate the sensitivity of the ICERs to this assumption. Although the Committee agreed that a cost based on an administration time of 1 hour represented the minimum cost to the NHS, it did not agree that the true cost would be as much as double. The Committee therefore considered that it was not appropriate to double the administration cost of tocilizumab and concluded that the manufacturer's revised estimate of £154 was acceptable.
The Committee noted that some modelling assumptions in the manufacturer's submission had not been investigated by the DSU in the 2010 report. These included, first, any difference in the adverse events that may occur on biological treatment compared with those that might occur in palliative care. Second, that despite previous requests to the manufacturer to use directly observed EQ‑5D data, the revised base-case ICERs from the manufacturer were still subject to a HAQ mapping algorithm. The Committee highlighted its concern with this, but acknowledged that the data had not been available to investigate these assumptions.
In summary the Committee concluded that the best estimate of cost effectiveness of tocilizumab in any position in the treatment pathway should be based on approach 4 to evidence synthesis in which the ACR response rates came from the trials rather than the mixed treatment comparison and used a corrected degradation factor for tocilizumab (see section 3.35). In addition, it concluded that no long-term HAQ improvements with tocilizumab should be assumed.
The Committee considered the cost-effectiveness analyses submitted by the manufacturer in 2011 that were based on the preferred approach (see section 4.17) and that incorporated tocilizumab at the discount agreed as part of the patient access scheme (see section 2.4). It also considered the DSU 2011 report when reviewing the manufacturer's submission. It discussed the manufacturer's analyses, which the DSU replicated including fully incremental calculations (see sections 3.45 to 3.47) for all three patient subgroups: people whose rheumatoid arthritis has responded inadequately to one or more conventional DMARDs (DMARD-IR analysis); people who are intolerant to rituximab, or for whom rituximab is contraindicated (DMARD-IR rituximab intolerant); people whose rheumatoid arthritis has responded inadequately to TNF‑alpha inhibitors (TNF-IR analysis). The Committee accepted the DSU separate exploratory incremental analyses. It noted the DSU's comment from the 2011 report that the manufacturer's analysis had not taken into account extended dominance (when one or more drug sequences are less effective than and at least as costly as another sequence) and that this had an impact on the ICERs. The Committee concluded that the DSU's 2011 exploratory analyses should be used as the basis for determining the cost effectiveness of tocilizumab.
The Committee also considered the straightforward inferences that could be made from its separate clinical effectiveness and costing conclusions. These were that for the DMARD-IR population (who had not received a TNF‑alpha inhibitor or any other biological treatment) tocilizumab was similar in clinical effectiveness (see section 4.10) to the TNF‑alpha inhibitors and could be considered a plausible alternative. In the case of the TNF‑IR population (whose condition had failed to respond to a TNF‑alpha inhibitor but who had not yet tried rituximab), the position was different. Although tocilizumab might be as clinically effective as rituximab, it was also more expensive and so the Committee concluded tocilizumab could not be considered an option unless rituximab was contraindicated, not tolerated or had failed.
The Committee considered the DMARD-IR ICERs in the DSU's 2011 exploratory analysis. It noted from the total costs and QALYs for the sequences that when tocilizumab was the first biological treatment rather than etanercept, it was associated with fewer QALYs and less cost. It understood that this was because of the percentage of non-responders on tocilizumab (approximately 40%) when taken as a first-line biological treatment, which resulted in reduced time on tocilizumab treatment and therefore lower cost of the sequence. The Committee noted that this improved the cost effectiveness of tocilizumab. However, on the basis of previous discussions (see section 4.10) the Committee was not convinced that the clinical effectiveness of tocilizumab would be superior to that of etanercept. The Committee concluded that the improved cost effectiveness of tocilizumab as the first biological treatment compared with etanercept was due to the cost of time on treatment, rather than any substantial differences in clinical or cost effectiveness between tocilizumab and etanercept.
The Committee further considered the DMARD-IR ICERs from the DSU's 2011 exploratory analysis. It noted that although tocilizumab appeared cost effective as the first biological treatment (£5700 per QALY gained), this sequence had rituximab as the third biological treatment in the sequence, rather than the second. The Committee raised concerns that this was counterintuitive because the total drug treatment cost of rituximab is approximately half that of either tocilizumab or etanercept. On the basis of previous discussions (see section 4.11) the Committee was not convinced that the clinical effectiveness of etanercept or tocilizumab would be sufficiently superior to rituximab such that a sequence in which rituximab was third would be more cost effective than one in which rituximab was second. The Committee noted that a sequence in which tocilizumab was the first biological treatment, followed by rituximab, followed by etanercept, had not been included in either the manufacturer's or the DSU's 2011 analyses. It was aware that in clinical practice this sequence would involve off-licence use of rituximab because the marketing authorisation restricts rituximab to use after an inadequate response or intolerance to other DMARDs including one or more TNF‑alpha inhibitors. However the Committee considered that to understand the impact on the cost effectiveness of placing tocilizumab first in the sequence, it was important to consider all possible treatment sequences. It noted that in their exploratory incremental analysis from 2011, the DSU had incorporated an alternative baseline sequence of tocilizumab followed by rituximab. The Committee accepted this sequence as a proxy for tocilizumab, followed by rituximab, followed by etanercept. It noted that when this alternative baseline sequence was included in the exploratory analysis, three sequences were extendedly dominated (see section 3.49) leaving the baseline sequence of tocilizumab followed by rituximab, and the sequence of etanercept, followed by rituximab, followed by tocilizumab. Comparing these two sequences, tocilizumab as the third biological in the sequence had an ICER of £28,400 per QALY gained, compared with tocilizumab as the first biological treatment in the sequence. It accepted that some uncertainty around the point estimates of the ICERs was likely. However the conclusion to this analysis was consistent with the reasoning in section 4.18. The Committee concluded that tocilizumab should be recommended as an option when used in the same way as the TNF‑alpha inhibitors etanercept, adalimumab, infliximab, golimumab and certolizumab pegol recommended in NICE technology appraisal guidance 130, 186 and 225. The Committee understood that its recommendation would apply to people whose rheumatoid arthritis has a DAS28 score of greater than 5.1. It also understood that treatment should normally be initiated with the least expensive drug (taking into account administration costs, required dose and product price per dose) and this may need to be varied in individual cases because of differences in the mode of administration and treatment schedules.
The Committee discussed the cost effectiveness of tocilizumab when a person is intolerant to rituximab or for whom rituximab is contraindicated (that is, the DMARD‑IR rituximab intolerant population). The Committee again took the view that, assuming that etanercept and tocilizumab have approximately equal effectiveness (see section 4.19) and cost, it would be reasonable for either to be an option in this position. The Committee noted that the DSU's 2011 analyses broadly corroborated these conclusions. It noted that in this population the ICER from the DSU's 2011 exploratory incremental analysis was £30,100 per QALY gained for a sequence in which etanercept was followed by tocilizumab, and £10,700 per QALY gained for a sequence in which tocilizumab was followed by etanercept (see section 3.50). The Committee concluded that tocilizumab should be recommended as an option for the DMARD-IR rituximab intolerant population. It further concluded that this recommendation should be in line with the guidance on adalimumab, etanercept, infliximab, rituximab and abatacept (NICE technology appraisal guidance 195), specifically the recommendations on disease activity when a second TNF‑alpha inhibitor is recommended for people in whom rituximab is contraindicated or when rituximab is withdrawn because of an adverse event.
Finally, the Committee considered the DSU's 2011 exploratory analysis for the TNF‑IR population. It understood that in this analysis, the costs and QALYs associated with earlier treatment on a TNF‑alpha inhibitor were assumed to be the same and so the analysis comprised two sequences containing tocilizumab (one in which tocilizumab is followed by rituximab and one in which rituximab is followed by tocilizumab) and a baseline treatment sequence of rituximab alone. The Committee noted from this analysis that the treatment strategy that placed tocilizumab before rituximab was dominated by treating with rituximab before tocilizumab (in people who had previously only had a TNF‑alpha inhibitor). The Committee accepted the ICER from this analysis as the most plausible estimate of tocilizumab following rituximab in this population (that is, £18,500 per QALY gained). The Committee also compared this ICER with the manufacturer's estimate of £22,700 per QALY gained. In view of this, the Committee concluded that tocilizumab could be considered an option after an inadequate response to treatment with rituximab but should not be recommended as an alternative to rituximab.
The Committee noted that, in clinical practice and as recommended in the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130), treatment should normally be initiated with the least expensive drug; this would not necessarily be the same drug in individual cases because of differences in the mode of administration and treatment schedules. The Committee therefore concluded that it was appropriate to recommend tocilizumab as an option following the same considerations as for the drugs recommended as options in NICE technology appraisal guidance 130.
The Committee concluded that it was appropriate to recommend tocilizumab plus methotrexate as an option for people whose rheumatoid arthritis has a DAS28 score greater than 5.1 and has responded inadequately to one or more previous DMARDs if used as described for TNF inhibitor treatments in NICE technology appraisal guidance 130, specifically the recommendations on disease activity and choice of treatment. It concluded that tocilizumab plus methotrexate could be recommended as an option for people whose rheumatoid arthritis has responded inadequately to treatment with DMARDs and a TNF inhibitor and in whom rituximab is contraindicated or who had rituximab withdrawn because of an adverse event. The Committee concluded that, for people whose rheumatoid arthritis has responded inadequately to previous TNF inhibitors, and for whom rituximab is an option, tocilizumab plus methotrexate could not be recommended because although it might be as effective as rituximab, it was more expensive and so could not be considered unless rituximab was contraindicated, not tolerated or had failed. The Committee also concluded that tocilizumab plus methotrexate could be recommended for people whose rheumatoid arthritis has responded inadequately to treatment with one or more previous TNF inhibitors and rituximab. It also decided that a recommendation about tocilizumab as monotherapy could not be made because there was not enough evidence of its efficacy as a monotherapy.
TA247
Appraisal title: Tocilizumab for the treatment of rheumatoid arthritis (rapid review of technology appraisal guidance 198)
Section
Key conclusion
Tocilizumab in combination with methotrexate is recommended as an option for the treatment of rheumatoid arthritis in adults if:
the disease has responded inadequately to disease-modifying anti-rheumatic drugs (DMARDs) and it is used as described for tumour necrosis factor (TNF) inhibitor treatments in Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis (NICE technology appraisal guidance 130), specifically the recommendations on disease activity and choice of treatment or
January 2016: This bullet point has been updated by NICE technology appraisal guidance 375.
the disease has responded inadequately to DMARDs and a TNF inhibitor and the person cannot receive rituximab because of a contraindication to rituximab, or because rituximab is withdrawn because of an adverse event, and tocilizumab is used as described for TNF inhibitor treatments in NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor, specifically the recommendations on disease activity or
the disease has responded inadequately to one or more TNF inhibitor treatments and to rituximab
and the manufacturer provides tocilizumab with the discount agreed as part of the patient access scheme.
People currently receiving tocilizumab for the treatment of rheumatoid arthritis who do not meet the criteria in 1.1 should have the option to continue treatment until they and their clinicians consider it appropriate to stop.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee understood the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130) recommends TNF‑alpha inhibitors adalimumab, etanercept and infliximab as options for the treatment of adults whose rheumatoid arthritis has responded inadequately to two DMARDs (unless DMARDs are contraindicated), and with a DAS28 score greater than 5.1. The Committee noted that in NICE technology appraisal guidance 130, treatment should normally be initiated with the least expensive drug (taking into account administration costs, required dose and product price per dose) and this may need to be varied in individual cases because of differences in the mode of administration and treatment schedules. It was also aware of certolizumab pegol for the treatment of rheumatoid arthritis (NICE technology appraisal guidance 186) and golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs (NICE technology appraisal guidance 225).
For treatment following an inadequate response to DMARDs (including at least one TNF‑alpha inhibitor), the guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for rheumatoid arthritis (NICE technology appraisal guidance 195) recommends rituximab plus methotrexate.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
Tocilizumab has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function when given in combination with methotrexate.
What is the position of the treatment in the pathway of care for the condition?
The Committee concluded that there were four possible scenarios for including tocilizumab in the treatment pathway:
Tocilizumab after two DMARDs as an alternative to TNF‑alpha inhibitors.
Tocilizumab after TNF‑alpha inhibitors as an alternative to rituximab.
Tocilizumab after TNF‑alpha inhibitors when a person is intolerant to rituximab or for whom rituximab is contraindicated.
Tocilizumab as an addition to the treatment pathway after rituximab.
Adverse effects
The Committee noted the safety data presented by the manufacturer, which reported 27 deaths and a serious adverse event rate of 5.8%. The Committee considered that this adverse event rate was high, but heard that it was comparable with other biological treatments.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee concluded that no evidence for tocilizumab monotherapy within its licensed indication was available, and therefore no recommendations for tocilizumab as a monotherapy could be made.
The Committee considered the evidence on the clinical effectiveness of tocilizumab plus DMARDs compared with placebo plus DMARDs. The Committee concluded that tocilizumab plus methotrexate was clinically effective compared with placebo plus DMARDs when given before TNF‑alpha inhibitors and when given before rituximab.
The Committee then considered the evidence for the relative efficacy of tocilizumab compared with etanercept and compared with rituximab when all treatment strategies were in combination with methotrexate. It understood that tocilizumab had not been compared head-to-head with either etanercept (or any other TNF‑alpha inhibitor) or rituximab, and that indirect evidence had been combined in a mixed treatment comparison for this purpose.
Relevance to general clinical practice in the NHS
The Committee did not raise any issues about the relevance of the clinical-effectiveness data to general clinical practice in the NHS.
N/A
Uncertainties generated by the evidence
The mixed treatment comparison assumed that the TNF‑alpha results could be regarded as a class. The Committee noted that the manufacturers had responded to requests to remove the Klareskog trial of etanercept from the analysis because this was a large RCT with unusually high control-arm response rates and did not correspond with the inclusion criteria of the mixed treatment comparison. With this trial removed, the Committee noted that etanercept appeared at least equal to, and possibly had higher efficacy than, tocilizumab.
The Committee considered that limited confidence could be placed in the adjusted ACR response rates in the manufacturer's revised base case. The Committee concluded that using the unadjusted trial estimates in the analyses was more appropriate.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
N/A
N/A
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that no convincing evidence had been presented to demonstrate the superiority of tocilizumab over etanercept or rituximab, but that the estimates were in a similar range to etanercept and rituximab.
The Committee noted the evidence from the RADIATE trial and, on balance, agreed that tocilizumab was likely to benefit people whose rheumatoid arthritis has responded inadequately to rituximab.
Evidence for cost effectiveness
Availability and nature of evidence
The manufacturer did not identify any economic evaluations of tocilizumab and developed an economic model for the submission. This was an individual sampling model with a hypothetical homogenous cohort. The model used a lifetime horizon for costs and benefits. It considered the DMARD-IR and TNF-IR populations separately. No evidence on the cost effectiveness of tocilizumab monotherapy was presented.
Uncertainties around and plausibility of assumptions and inputs in the economic model
In summary the Committee concluded that the best estimate of cost effectiveness of tocilizumab in any position in the treatment pathway should be based on approach 4 to evidence synthesis in which the ACR response rates came from the trials rather than the mixed treatment comparison and used a corrected degradation factor for tocilizumab (see section 3.35). In addition, it concluded that no long-term HAQ improvements with tocilizumab should be assumed.
The economic model incorporated tocilizumab at the discount agreed as part of the patient access scheme.
The manufacturer's analysis had not taken into account extended dominance and that this had an impact on the ICERs. The Committee concluded that the DSU's 2011 exploratory analyses should be used as the basis for determining the cost effectiveness of tocilizumab.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee noted that the manufacturer's mapping of HAQ scores to EQ‑5D utility values resulted in negative utility values. The Committee heard from the manufacturer that it was possible that there were some people with rheumatoid arthritis who may experience negative utility values. The Committee therefore accepted that the calculation of some ICERs would include negative utility values but concluded that this was acceptable because of the low impact on the ICERs.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee heard from the manufacturer that it was seeking a recommendation for tocilizumab as an option along with other biological treatments in the treatment pathway. It therefore considered that there were four possible scenarios for including tocilizumab in the treatment pathway:
Tocilizumab after two DMARDs as an alternative to TNF‑alpha inhibitors.
Tocilizumab after TNF‑alpha inhibitors as an alternative to rituximab.
Tocilizumab after TNF‑alpha inhibitors when a person is intolerant to rituximab or for whom rituximab is contraindicated.
Tocilizumab as an addition to the treatment pathway after rituximab.
What are the key drivers of cost effectiveness?
The Committee concluded that the improved cost effectiveness of tocilizumab as the first biological treatment compared with etanercept was due to the cost of time on treatment, rather than any substantial differences in clinical or cost effectiveness between tocilizumab and etanercept.
Most likely cost-effectiveness estimate (given as an ICER)
For the DMARD‑IR population: three sequences were extendedly dominated (less effective than and at least as costly as a combination of other drug sequences). When tocilizumab is the third biological in the sequence the most plausible estimate of the ICER is £28,400 per QALY gained. The Committee accepted that some uncertainty around the point estimates of the ICERs was likely.
For the DMARD‑IR rituximab intolerant population: the Committee noted that the most plausible estimate for the ICER ranged from £10,700 per QALY gained for the sequence in which etanercept followed tocilizumab to £30,100 per QALY gained in the sequence where tocilizumab followed etanercept.
For the TNF‑IR population: the Committee accepted the ICER of £18,500 per QALY gained as the most plausible ICER estimate for tocilizumab following rituximab in this population.
Additional factors taken into account
Patient access schemes (PPRS)
The Department of Health and the manufacturer have agreed that tocilizumab will be available to the NHS with a patient access scheme in which a discount from the list price is applied to original invoices. The level of the discount is commercial in confidence.
End-of-life considerations
N/A
N/A
Equalities considerations and social value judgements
No equalities issues were raised in the appraisal.
N/A
|
{'Guidance': 'Tocilizumab in combination with methotrexate is recommended as an option for the treatment of rheumatoid arthritis in adults if:\n\n[this part of the recommendation has been replaced by the recommendations in the NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed]\n\nthe disease has responded inadequately to DMARDs and a TNF inhibitor and the person cannot receive rituximab because of a contraindication to rituximab, or because rituximab is withdrawn because of an adverse event, and tocilizumab is used as described for TNF inhibitor treatments in the NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor, specifically the recommendations on disease activity or\n\nthe disease has responded inadequately to one or more TNF inhibitor treatments and to rituximab\n\nand the manufacturer provides tocilizumab with the discount agreed as part of the patient access scheme.\n\nPeople currently receiving tocilizumab for the treatment of rheumatoid arthritis who do not meet the criteria in 1.1 should have the option to continue treatment until they and their clinicians consider it appropriate to stop.\n\nTake into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the disease activity score and make any appropriate adjustments.', 'The technology ': "Tocilizumab (RoActemra, Roche) is a humanised monoclonal antibody that inhibits cytokine interleukin‑6 (IL‑6). Reducing the activity of IL‑6 may reduce inflammation in the joints, prevent long-term damage, improve quality of life and function, and relieve certain systemic effects of rheumatoid arthritis. Tocilizumab, in combination with methotrexate, has a UK marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis in adults whose disease has not responded adequately to, or who were intolerant to, previous therapy with one or more DMARDs or TNF-alpha antagonists. In these people, tocilizumab can be given as monotherapy in case of intolerance to methotrexate or if continued treatment with methotrexate is inappropriate. Tocilizumab has been shown to reduce the rate of progression of joint damage as measured by X‑ray and to improve physical function when given in combination with methotrexate.\n\nTocilizumab is contraindicated in people with active, severe infections. The summary of product characteristics (SPC) lists the following as the most commonly reported adverse drug reactions associated with tocilizumab treatment: upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased alanine transaminase. For full details of side effects and contraindications, see the SPC.\n\nTocilizumab is administered as an intravenous infusion, given over 1\xa0hour. The recommended dosage is 8\xa0mg/kg, given once every 4\xa0weeks. For people whose body weight is more than 100\xa0kg, doses exceeding 800\xa0mg per infusion are not recommended. Tocilizumab is available in three vial sizes, which are priced at £102.40 for an 80-mg vial, £256 for a 200-mg vial and £512 for a 400-mg vial ('British national formulary' [BNF] edition 59, excluding VAT). The cost for tocilizumab as reported by the manufacturer is £9295 per year for a patient weighing approximately 70\xa0kg. Costs may vary in different settings because of negotiated procurement discounts.\n\nThe Department of Health and the manufacturer have agreed that tocilizumab will be available to the NHS with a patient access scheme in which a discount from the list price is applied to original invoices. The level of the discount is commercial in confidence (see section\xa05.2). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this NICE technology appraisal guidance is published.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of tocilizumab, a review of this submission by the Evidence Review Group (ERG; appendix B), and two additional analyses by the Decision Support Unit (DSU; appendix B).\n\n# Clinical effectiveness\n\nIn the submission, the manufacturer presented evidence on the clinical effectiveness of tocilizumab in combination with DMARDs for two populations: people whose rheumatoid arthritis had responded inadequately to previous DMARDs but before treatment with a TNF‑alpha inhibitor (the 'DMARD‑IR' population) and people whose rheumatoid arthritis had responded inadequately to previous TNF‑alpha inhibitors but before treatment with rituximab (the 'TNF‑IR' population). The manufacturer also presented evidence on the clinical effectiveness of tocilizumab as monotherapy. The submission focused on the tocilizumab 8\xa0mg/kg treatment arms of the included studies because this is the recommended dose in the SPC. Some of the studies also included doses other than the licensed dose. Results for doses other than the licensed dose are not considered in this appraisal.\n\n## Tocilizumab plus methotrexate as a treatment option after an inadequate response to conventional DMARDs\n\nThe main clinical-effectiveness evidence for the DMARD‑IR population came from three randomised controlled trials (RCTs). All three RCTs were double-blind, placebo-controlled parallel-group studies in adults with moderate to severe active rheumatoid arthritis whose condition had responded inadequately to treatment with methotrexate (OPTION and LITHE) or traditional DMARDs (TOWARD). The OPTION trial assessed the effects of tocilizumab 8\xa0mg/kg plus methotrexate (n=205) compared with placebo plus methotrexate (n=204). The LITHE trial assessed the effects of tocilizumab 8\xa0mg/kg plus methotrexate (n=398) compared with placebo plus methotrexate (n=393). The TOWARD trial assessed the effects of tocilizumab 8\xa0mg/kg plus DMARDs (n=805) compared with placebo plus DMARDs (n=415).\n\nThe primary outcome in the RCTs was the proportion of people with an American of Rheumatology (ACR) 20 response at week\xa024. This was defined as at least a 20% improvement in both the tender joint count and the swollen joint count and at least a 20% improvement in three of the other five core set measures included in the ACR score. In all three RCTs, the same outcome measure and data collection instruments were used. The manufacturer stated that the RCTs had similar patient populations. This was demonstrated by general demographics and the effect of various factors on the ACR20 response rate, which was examined by logistic regression analysis. No statistically significant differences were found in treatment effects between studies and the manufacturer inferred that pooling the results of the three RCTs for the primary outcome was appropriate. The manufacturer's submission stated that the adjusted odds ratio for the ACR20 response of tocilizumab 8\xa0mg/kg plus DMARD compared with placebo plus DMARD was approximately 4.2. Averaged ACR20 response rates, described as pooled results, were 59.2% in the tocilizumab 8‑mg/kg arm compared with 25.8% in the placebo arm (p≤0.0001) at week\xa024.\n\nSecondary outcomes of the RCTs, measured at 24\xa0weeks, were pooled across the three RCTs by the manufacturer. Pooled ACR response rates were: 37.0% compared with 9.6% for ACR50 response rates (p<0.0001), 18.5% compared with 2.4% for ACR70 response rates (p≤0.0001), and 4.2% compared with 0.3% for ACR90 response rates (p≤0.0001), for the tocilizumab 8‑mg/kg plus DMARD arms and placebo plus DMARD arms respectively. The manufacturer also presented averaged disease activity score\xa028 (DAS28) results from the three RCTs. Approximately half of all people in the RCTs reached low disease activity, defined as DAS28 of less than 3.2. Approximately one-third of people in the RCTs went into remission, defined as DAS28 of less than 2.6. The proportion of participants going into remission while on tocilizumab was reported to increase during the study period. There was a greater decrease (improvement) in averaged health assessment questionnaire (HAQ) results from baseline HAQ score in the tocilizumab groups than in the placebo groups. In the pooled population at week\xa024, the proportion of participants with a clinically relevant improvement in HAQ (defined as a decrease of at least 0.25 in an individual's total score) was higher in the tocilizumab groups (68%) than in the placebo groups (52%).\n\nAdditionally, European quality of life (EuroQoL) health-state questionnaire (EQ‑5D) scores were collected in the OPTION and LITHE RCTs. In the OPTION RCT, the baseline mean EQ‑5D was 0.393 (standard deviation 0.327) in the tocilizumab 8\xa0mg/kg plus methotrexate arm, and 0.391 (standard deviation 0.329) in the placebo plus methotrexate arm. At follow-up, the mean EQ‑5D was 0.671 (standard deviation 0.237) in the tocilizumab 8\xa0mg/kg arm and 0.534 (standard deviation 0.318) in the placebo arm. The manufacturer did not provide EQ‑5D results from the LITHE RCT separately by treatment arm.\n\nTwo single-arm extension studies assessed maintenance of clinical benefit of tocilizumab beyond 24\xa0weeks. Overall, response rates for those remaining on tocilizumab plus DMARD treatment were maintained or continued to improve with duration of treatment, with an increasing proportion of people achieving higher ACR scores over time. The manufacturer reported that improvements in HAQ scores were observed for up to 132\xa0weeks in the pooled tocilizumab 8\xa0mg/kg plus DMARD arm.\n\nNo head-to-head studies were identified that provided evidence on the clinical effectiveness of tocilizumab compared with TNF‑alpha inhibitors and abatacept for the DMARD‑IR population. Therefore, the manufacturer conducted a mixed treatment comparison. A total of 18\xa0RCTs (including OPTION, LITHE and TOWARD) were identified for inclusion. All studies were randomised, placebo-controlled, double-blind trials and all had a follow-up period of either 24 or 30\xa0weeks. Participants were predominantly female (approximately 80%), older than 50\xa0years, had experienced more than 6\xa0years' duration of rheumatoid arthritis, were previously treated with an average of two or more DMARDs, and more than half had used non-steroidal anti-inflammatory drugs or glucocorticoids concomitantly. The manufacturer reported that the baseline characteristics across the trials were comparable to ACR core parameters. Results for TNF‑alpha inhibitors were pooled, because it was assumed there was no difference in efficacy between these drugs. This assumption was reported to be informed by the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130).\n\nThe mixed treatment comparison suggested that tocilizumab showed efficacy (measured by ACR20 and ACR50 response rates) comparable to all included biological treatments. For the ACR70 response rate, tocilizumab treatment was associated with a higher response rate than the TNF‑alpha inhibitors and abatacept (relative risks of 1.77 and 1.98 respectively). In the base-case comparison, there was a greater than 99% probability that tocilizumab was more efficacious than biological treatments (that is, etanercept, infliximab and adalimumab), as measured by ACR70 response rates. The manufacturer stated that homogeneity at each ACR response level was assessed using Cochran's Q‑statistic (ACR20: 44.1857, p=0.0002; ACR50: 41.6878, p=0.0004; ACR70: 25.5752, p=0.0603). Based on these results, the manufacturer used random-effects methods to estimate ACR20 and ACR50 response rates, and fixed-effect methods to estimate ACR70 response rates. As well as the base-case mixed treatment comparison, the manufacturer also presented three scenario analyses, which included or excluded data from certain trials included in the base case. The manufacturer stated that overall the results from these alternative scenarios were consistent with the initial findings.\n\n## Tocilizumab plus methotrexate as a treatment option after an inadequate response to a TNF‑alpha inhibitor\n\nThe main clinical-effectiveness evidence for the TNF‑IR population came from one RCT, known as RADIATE. RADIATE was a double-blind, placebo-controlled, parallel-group study in adults with moderate to severe rheumatoid arthritis. The participants' rheumatoid arthritis had responded inadequately to previous TNF‑alpha inhibitor therapy. RADIATE assessed the effects of tocilizumab 8\xa0mg/kg plus methotrexate (n=170) compared with placebo plus methotrexate (n=158).\n\nThe primary outcome of the RADIATE trial was ACR20 response rate. At 24\xa0weeks, 50% of people in the tocilizumab arm compared with 10% of people in the placebo arm had experienced an ACR20 response (p<0.0001). Additionally, at 24\xa0weeks, 28.8% compared with 3.8% had experienced an ACR50 response (p<0.0001), and 12.4% compared with 1.3% had experienced an ACR70 response (p<0.0002), for the tocilizumab arm and the placebo arm respectively. At week\xa024, the mean change from baseline in DAS28 was -3.16 for tocilizumab and -0.95 for placebo. The manufacturer stated that the remission rates were similar to those seen in the DMARD-IR population at 24\xa0weeks. The mean decrease in HAQ from baseline at 24\xa0weeks for the tocilizumab group was 0.39, compared with 0.05 for the placebo group.\n\nTwo single-arm extension studies assessed the maintenance of clinical benefit of tocilizumab plus DMARDs beyond 24\xa0weeks. Response rates to therapy with tocilizumab were maintained or continued to improve with duration of treatment (as in the DMARD‑IR population). Results similar to those for the DMARD‑IR population were reported and the manufacturer noted that the pattern of improvement in mean HAQ score was also observed for up to 132\xa0weeks.\n\n## Tocilizumab as a monotherapy\n\nOne RCT (AMBITION) assessed the effects of tocilizumab 8\xa0mg/kg alone (n=288) compared with methotrexate alone (n=284). This was a double-blind, placebo-controlled trial that included a sub-study tocilizumab arm in which placebo was given first for 8\xa0weeks and then tocilizumab was given for 16\xa0weeks. Most of the people in the AMBITION RCT had not received treatment with methotrexate before or had stopped methotrexate treatment for reasons other than toxicity or lack of efficacy.\n\nThe ACR20 response rate at 24\xa0weeks in the intention-to-treat population was 69.9% in the tocilizumab arm compared with 52.5% in the methotrexate arm. The weighted difference in ACR20 response was 0.19 (95% confidence interval 0.11 to 0.27). The manufacturer concluded that treatment with tocilizumab was non-inferior to treatment with methotrexate. The manufacturer also stated that the trial population of AMBITION was not in accordance with the SPC of tocilizumab. This was because the AMBITION trial had recruited people who had not received any previous treatment with methotrexate; the SPC states that tocilizumab can be given as monotherapy in case of intolerance to methotrexate or if continued treatment with methotrexate is inappropriate.\n\n## Adverse events\n\nThe manufacturer reported that adverse events associated with the mechanism of IL‑6 receptor (IL‑6R) inhibition were observed in all tocilizumab treatment groups. These adverse events included transient hepatic transaminase elevations, asymptomatic elevations of indirect bilirubin, transient neutropenia, and lipid elevations that appear to occur in association with marked decreases in acute phase proteins. In addition, serious infections associated with the immunomodulatory effects of tocilizumab were comparable with the incidence of serious infections with TNF-alpha inhibitors. Adverse events reported more frequently with tocilizumab 8\xa0mg/kg monotherapy than in the methotrexate group were abdominal pain and discomfort, headache, dizziness, rash, pruritis and elevated blood pressure, neutropenia, leukopenia and hyperlipidaemia. Most of these events were mild and transient. The manufacturer reported that there was no increase in the severity or frequency of adverse events with prolonged exposure to the tocilizumab 8\xa0mg/kg dose.\n\n## Follow-up data\n\nIn addition to the original submission, the manufacturer of tocilizumab provided updated data with a maximum of 180\xa0weeks of follow-up. The response rates of all people who received at least one dose of tocilizumab in the OPTION, AMBITION, RADIATE and TOWARD trials were analysed. A total of 3986\xa0people were included in the long-term analyses. Approximately 14% of people discontinued tocilizumab treatment for safety reasons (including intercurrent illness). The manufacturer stated that tocilizumab increased or maintained ACR response rates in the DMARD‑IR, TNF-IR and tocilizumab monotherapy populations. This was demonstrated by the increased proportion of people with ACR50 and ACR70 responses and with an ACR70 response maintained for 24\xa0consecutive weeks. The manufacturer also used the long-term follow-up data to re-estimate the HAQ progression with tocilizumab. The manufacturer stated that there was a negative trend (an improvement) in HAQ progression for both the DMARD‑IR and TNF‑IR populations.\n\n# Cost effectiveness\n\nThe manufacturer did not identify any economic evaluations of tocilizumab and developed an economic model for the submission. This was an individual sampling model with a hypothetical homogenous cohort. The model used a lifetime horizon for costs and benefits. It considered the DMARD‑IR and TNF‑IR populations separately. No evidence on the cost effectiveness of tocilizumab monotherapy was presented.\n\nThe manufacturer's initial economic model compared a treatment sequence that included tocilizumab with the same treatment sequence without tocilizumab for two populations. For the DMARD‑IR population, tocilizumab plus methotrexate was the first biological treatment and if the condition did not respond or if the ACR20 response rate was no longer achieved then etanercept plus methotrexate was the next treatment. This was followed by rituximab plus methotrexate, then leflunomide, then gold, then ciclosporin until people withdrew from the last treatment (ciclosporin) and moved on to palliative care. The sequence was the same for the comparator arm, but excluded tocilizumab plus methotrexate at the beginning. For the TNF‑IR population, the sequence was the same as the DMARD‑IR population, except for the omission of etanercept plus methotrexate (that is, the first treatment in the comparator arm was rituximab plus methotrexate).\n\nThe probabilities of response were derived from the adjusted ACR response rates (adjusted for placebo differences across trials) from the base-case mixed treatment comparison. There were four categories of response: non-response, ACR20 response, ACR50 response, and ACR70 response. People were assigned a predefined drop in HAQ score (that is, an improvement in physical function) based on their ACR responses. Data from four RCTs (OPTION, TOWARD, LITHE and RADIATE) were analysed to estimate the relationship between ACR response and HAQ score in the first 24\xa0weeks. People whose condition responded were assumed to have a constant probability of withdrawal owing to lack of efficacy. The probability of withdrawing from treatment was the same for the biological treatments (infliximab, etanercept, adalimumab, rituximab and tocilizumab) and was calculated as the average of two withdrawal rate estimates for etanercept and infliximab. At the point of switching to the next treatment, people were assumed to experience an increase in their HAQ score (rebound) equal to the initial HAQ improvement. After the initial 24‑week period the HAQ score with tocilizumab plus methotrexate was assumed to decrease linearly (improve) based on the observational extensions to the RCTs. Because of substantial uncertainty in the data for weeks\xa0132–156, this continued improvement was only assumed for the first 3\xa0years in the DMARD-IR cohort and 2.5\xa0years in the TNF-IR cohort. Beyond this (3\xa0years after initial treatment in the DMARD-IR cohort and 2.5\xa0years after initial treatment in the TNF-IR cohort), the HAQ score was assumed to stay constant (that is, zero HAQ improvement) with tocilizumab plus methotrexate treatment. After the initial 24‑week treatment period, no change in HAQ score was assumed (zero HAQ improvement) for biological treatments such as etanercept and rituximab. After the initial 24‑week treatment period, an increase in HAQ score (that is, a worsening of physical function) was assumed for traditional DMARDs. The manufacturer also carried out sensitivity analyses using an assumption of zero HAQ progression (no improvement or worsening) while on treatment.\n\nTocilizumab plus methotrexate was assumed to be given for a minimum of 6\xa0months and the administration cost of each infusion of tocilizumab was assumed to be £142 (see section\xa03.25 for subsequent considerations of administration costs). The costs of treating any adverse events were not included in the economic model presented by the manufacturer. The manufacturer reported that EQ‑5D scores from the tocilizumab OPTION and LITHE trials were mapped to HAQ scores using a quadratic regression model. Alternative mapping equations as used in the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130) and other submissions to NICE were examined in scenario analyses. Utility weights were derived from the EQ‑5D scores using the UK time trade-off tariff. Adverse events associated with tocilizumab treatment were assumed to generate an insignificant burden on people's quality of life, and therefore were not included in the model.\n\nFor the DMARD‑IR population, the treatment sequence including tocilizumab plus methotrexate compared with the sequence without tocilizumab produced incremental costs of £23,253 and incremental quality-adjusted life years (QALYs) of 1.17. This resulted in a base-case incremental cost-effectiveness ratio (ICER) of £19,870 per QALY gained. For the TNF‑IR population, the treatment sequence including tocilizumab plus methotrexate compared with the sequence without tocilizumab produced incremental costs of £26,640 and incremental QALYs of 1.21. This resulted in a base-case ICER of £22,003 per QALY gained. Probabilistic sensitivity analyses suggested that the addition of tocilizumab and methotrexate to the treatment sequences had a 56.4% and 22.4% probability of being cost effective (for the DMARD‑IR and TNF‑IR populations respectively) if the maximum acceptable amount to pay for a QALY gained is £20,000. All scenario analyses presented by the manufacturer resulted in ICERs of less than £30,000 per QALY gained. The ICERs increased to £24,905 and £24,739 per QALY gained for the DMARD‑IR and TNF‑IR populations respectively, using an assumption of no change in HAQ score (that is, no continued improvement on tocilizumab after the initial ACR response).\n\n# Evidence Review Group comments\n\nThe ERG highlighted the following key areas of concern with the manufacturer's submission.\n\nThe selection of the studies and the pooling of the TNF‑alpha inhibitors in the mixed treatment comparison.\n\nThe long-term estimates of HAQ score.\n\nMapping HAQ scores to EQ‑5D to derive utility estimates for the economic model.\n\nThe rebound effect on discontinuation (defined as an increase in a person's HAQ score when treatment is withdrawn).\n\nThe non-inclusion of adverse events in the economic model.\n\nThe ERG explored the combined adjusted ACR response rates for TNF‑alpha inhibitors used in the mixed treatment comparison (DMARD‑IR population) and considered that etanercept appeared less efficacious in the comparison than the literature suggested. The ERG commented that the reason for the apparent low efficacy of etanercept compared with both tocilizumab and the other TNF‑alpha inhibitors was a single large trial with a very high response rate in the placebo arm (the Klareskog trial). The ERG noted that this trial only included people who were likely to benefit from methotrexate and had an aggressive dosing schedule of methotrexate if the signs and symptoms of rheumatoid arthritis reappeared. When the ERG removed the Klareskog trial from the analysis, etanercept appeared more efficacious than tocilizumab and all the other treatments in the comparison. The ERG then questioned the validity of assuming that all TNF‑alpha inhibitors had the same efficacy in the model, because this lowered the estimate of the effectiveness of the TNF‑alpha inhibitor used in the model.\n\nThe ERG commented that the follow-up period of 24\xa0weeks in the five included tocilizumab studies could be considered too short. It noted that the longer-term data on tocilizumab came from single-arm studies with no comparator of placebo, conventional DMARDs or biological agents, so the long-term effectiveness of tocilizumab was unclear. The manufacturer estimated the medium-term HAQ progression (up to 3\xa0years for the DMARD‑IR population and 2.5\xa0years for the TNF‑IR population) using linear functions. However, the ERG suggested that an exponential function was equally plausible. The ERG noted that any functions fitted to the data needed to be constructed carefully because even small changes to the predictions would have a significant impact on the ICER.\n\nThe ERG was also concerned about the way the relationship between HAQ and EQ‑5D was modelled. The manufacturer's submission used a quadratic equation for this. The quadratic model predicted that EQ‑5D scores would be lower at high HAQ scores compared with a linear model. In addition, literature has shown that EQ‑5D and HAQ are closely correlated at baseline and that when quality of life worsened over time the EQ‑5D became more variable (resulting in a weaker correlation). The ERG noted that the modelled relationship between HAQ and EQ‑5D scores resulted in negative utilities for health states (that is, health states that are considered to be worse than death). The ERG stated that using negative utility values is questionable because a certain amount of disability (because of irreversible characteristics such as damaged joints) may remain despite optimal control of inflammatory disease. The ERG concluded that algorithms for modelling the relationship between HAQ and EQ‑5D should only be used when there are no direct utility scores; however, the trials for tocilizumab (OPTION and LITHE) measured EQ‑5D directly.\n\nThe manufacturer assumed the cost of administering each infusion of tocilizumab was £142. This was derived by adjusting for inflation the cost of an infusion as used in the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130). However, the ERG commented that this cost should have been adjusted for inflation from 2001 and not from 2004 as was presented by the manufacturer.\n\nThe manufacturer's submission assumed that the rebound after withdrawal from treatment was equal to the initial HAQ improvement only. The manufacturer's submission also assumed that the HAQ score for people treated with tocilizumab improved over the course of treatment, but that for other treatments the HAQ score either remained the same (biological treatments) or worsened (conventional DMARDs and palliative care). Therefore, it was assumed that the short- to medium-term HAQ benefit was retained in the long term. The guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130) accepted a similar assumption that people would lose their initial HAQ improvement when treatment was withdrawn, and also that biological treatments delayed disease progression more than conventional DMARDs. However, whereas the HAQ score representing underlying disease progression for all biological treatments in the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130) remained the same or worsened only slightly while on treatment, the manufacturer assumed that HAQ score improvement was possible for tocilizumab only. The ERG commented that the assumptions about rebound effect and HAQ progression disproportionately favoured tocilizumab by not only allowing the drug to delay disease progression, but also by allowing for a lasting improvement of the condition.\n\nIn addition, the ERG considered that excluding adverse events in the manufacturer's model was questionable because biological treatments are known to be associated with adverse events. It reported that it was unclear whether the adverse-event rate is higher or lower for tocilizumab than for other biological treatments. The manufacturer's submission states that the mean and median duration of treatment with tocilizumab in the clinical trials was 1.08\xa0years. The ERG commented that the risks of longer-term treatment with tocilizumab were unknown.\n\n# Manufacturer's response to consultation\n\nIn response to three rounds of consultation for the original guidance on tocilizumab for rheumatoid arthritis (NICE technology appraisal guidance 198), the manufacturer presented revised ICERs for the DMARD‑IR and TNF‑IR populations incorporating some of the ERG's suggested changes. The manufacturer also provided ICERs for positioning tocilizumab after an inadequate response to rituximab, and tocilizumab for people who are intolerant to rituximab or for whom rituximab is contraindicated. The clinical-effectiveness data for tocilizumab used in these positions were taken from the RADIATE trial. All of the revised and new ICERs incorporated degraded ACR response rates for tocilizumab, etanercept and rituximab when they are used later in the treatment sequence. Estimates for etanercept were based on treatment response to a second or third TNF‑alpha inhibitor reported from the South Swedish Arthritis Treatment Group. These downgraded the efficacy of etanercept from 62%, 38% and 16% to 49%, 26% and 7% for ACR20, ACR50 and ACR70 response rates respectively when used after one biological treatment. For tocilizumab when used after two biological treatments, degraded rates were based on the subgroup of people from the RADIATE trial whose rheumatoid arthritis had responded inadequately to more than one TNF‑alpha inhibitor. Based on these data, tocilizumab response rates changed from 62%, 31% and 12% to 50%, 31% and 15% for ACR20, ACR50 and ACR70 response rates respectively. For rituximab used after two biological treatments, the manufacturer provided downgraded response rates based on a subgroup of people whose rheumatoid arthritis had responded inadequately to more than one TNF‑alpha inhibitor from a trial comparing rituximab plus methotrexate with placebo plus methotrexate (REFLEX). Based on these data, the rituximab response rates were downgraded from 46%, 23% and 14% to 42%, 22% and 10% respectively.\n\nThe revised ICERs were based on the adjusted ACR rates from the mixed treatment comparison, and included a long-term HAQ improvement for tocilizumab and a stable HAQ score (that is, zero HAQ progression) for all other biological treatments. This was not the case for the ICER for tocilizumab given after rituximab, for which no HAQ improvement for treatment with any biological treatment, including tocilizumab, was assumed. All of the revised ICERs were calculated using the HAQ to EQ‑5D mapping and included negative utilities that represented states worse than death. The ICERs were subject to the assumption that a person would experience the same adverse events during treatment as during palliative care, and that the cost of administration of tocilizumab was £154.\n\nThe manufacturer's revised ICER for the DMARD‑IR population increased from £19,870 to £21,733 per QALY gained and increased from £22,003 to £23,285 per QALY gained for the TNF‑IR population. The ICER for tocilizumab used after rituximab was £23,735 per QALY gained. The ICER for tocilizumab for people who are intolerant to rituximab or for whom rituximab is contraindicated was £20,242 per QALY gained.\n\n# Decision Support Unit report 2010\n\nIn 2010, the DSU was asked to undertake additional cost-effectiveness analyses to validate the manufacturer's ICERs submitted following the third round of consultation, and to conduct sensitivity analyses to address the Appraisal Committee's concerns about key parameter assumptions. The 2010 report highlighted a key issue with the calculation of the ICERs presented by the manufacturer. This concerned the 'pair-wise' calculation of sequences containing tocilizumab plus methotrexate with the same sequence excluding tocilizumab rather than an 'incremental' comparison of all strategies containing tocilizumab plus methotrexate with each other and with a base-case strategy without tocilizumab. The DSU considered that the incremental approach was the most appropriate, not only to determine whether tocilizumab plus methotrexate was cost effective, but also in what circumstances, given the availability of a number of other treatments that are used sequentially. The DSU's 2010 report explained that an ICER calculated through a pair-wise comparison does not demonstrate that the sequence can be considered cost effective because there are a series of mutually exclusive sequences available and only one can be selected at any one time.\n\nFor etanercept, the mixed treatment comparison analysis combined all TNF‑alpha inhibitors (etanercept, infliximab and adalimumab) but excluded the Klareskog trial of etanercept that the Committee had requested to be removed because of its unusually high placebo response rate. The DSU noted in the 2010 report that the adjusted mixed treatment comparison rates were lower than the unadjusted trial ACR, or point estimate, rates for etanercept. The adjusted etanercept ACR20, ACR50 and ACR70 response rates were 62%, 38% and 16% respectively and the unadjusted ACR20, ACR50 and ACR70 response rates were 71%, 39% and 17% respectively. In 2010 the DSU reported that the unadjusted rates in the model were taken from a single etanercept trial, without justification for the sole use of this particular trial. The DSU provided an alternative set of unadjusted response rates for etanercept, which were based on the two etanercept trials from the mixed treatment comparison (rather than the single trial chosen by the manufacturer). The DSU stated in the 2010 report that this appeared to represent the most robust data. The resulting unadjusted ACR response rates were 73%, 47% and 22% for ACR20, ACR50 and ACR70 respectively. For rituximab, the adjusted mixed treatment comparison ACR response rates were also lower than the unadjusted ACR trial response rates. The percentage of people reaching an ACR20, ACR50 and ACR70 response rate was 51%, 27% and 12% respectively in the unadjusted analysis and 46%, 23% and 14% respectively in the adjusted analysis. The unadjusted data were taken from the REFLEX trial.\n\nThe DSU highlighted in the 2010 report that the opposite effect was observed with the adjusted and unadjusted ACR rates for tocilizumab, that is, the adjusted rates from the mixed treatment comparison were higher than the unadjusted rates. For tocilizumab given as the first biological treatment in the sequence, the adjusted rates were 63%, 41% and 26% for ACR20, ACR50 and ACR70 response rates respectively and the unadjusted rates for tocilizumab, which were based on a separate meta-analysis of OPTION, TOWARD and LITHE (submitted as part of the manufacturer's licence application), were 59%, 37% and 19% respectively. For tocilizumab used as the second biological treatment in a sequence (that is, after a TNF‑alpha inhibitor), the mixed treatment comparison had the same effect of increasing the tocilizumab ACR response rates. The adjusted rates were 62%, 31% and 12%, whereas the unadjusted rates were 50%, 29% and 12% for ACR20, ACR50 and ACR70 response rates respectively. The unadjusted rates for tocilizumab used as the second biological treatment in the sequence were taken from the RADIATE trial.\n\nThe DSU also commented on the degradation rates provided by the manufacturer. These rates were all from single data sources, without justification given for the selection of the sources. The DSU highlighted that the degraded response rates for etanercept were based on the reported ACR rates for the TNF‑alpha inhibitors as a group and may not have been generalisable to etanercept. The DSU also noted that the degraded ACR70 response rate for tocilizumab used after two biological treatments assumed by the manufacturer (15%) was marginally better than when used after a single biological treatment (12%). The DSU stated that this appeared to be counterintuitive and that it would be more appropriate to assume the same ACR70 response rate when tocilizumab is given after two biological treatments as for when it is given after one.\n\nIn the 2010 report the DSU considered four separate approaches that varied the ACR response rates and degradation rates used to calculate the incremental ICERs (approaches to evidence synthesis).\n\nApproach 1 was the same as the manufacturer's revised base case and used the adjusted mixed treatment comparison results with the degradation rates supplied by the manufacturer.\n\nApproach 2 used the unadjusted single trial ACR response rates for etanercept when used first in the treatment sequence as supplied by the manufacturer. All other estimates remained the same as in approach\xa01.\n\nApproach 3 used the unadjusted trial ACR response rates for all treatments in the sequence as supplied by the manufacturer. In addition, this approach replaced the degraded effect for tocilizumab when used after two biological treatments with the same effect assumed after one biological treatment to account for the counterintuitive change in response rate assumed by the manufacturer (see section\xa03.34).\n\nApproach 4 was the same as approach\xa03, except that the DSU used the alternative unadjusted ACR response rates for etanercept from the two trials (described in section\xa03.32).\n\nFor each of the four approaches to evidence synthesis, the DSU undertook four sets of sensitivity analyses to assess the robustness of the ICER results to other key parameter assumptions in the 2010 report. These were:\n\nemploying the same set of parameter assumptions employed by the manufacturer in its base case\n\nassuming no long-term HAQ improvement with tocilizumab\n\nassuming no long-term HAQ improvement with tocilizumab and excluding negative utilities from the HAQ to EQ-5D mapping\n\nassuming no long-term HAQ improvement with tocilizumab and doubling the administration costs for tocilizumab to £308.60 per infusion.\n\nThe DSU in the 2010 report calculated the incremental ICERs for each approach using the four sensitivity analyses and presented the incremental results separately for each of the 16\xa0possible analyses. In each incremental analysis, the treatment strategies compared with each other were:\n\netanercept followed by rituximab (strategy\xa01)\n\ntocilizumab, followed by etanercept, followed by rituximab (strategy\xa02)\n\netanercept, followed by tocilizumab, followed by rituximab (strategy\xa03)\n\netanercept, followed by rituximab, followed by tocilizumab (strategy\xa04).\n\nFor all treatment strategies, the calculation of the ICER included the costs and QALYs associated with treatment with conventional DMARDs and palliative care at the end of the sequence. All treatment strategies were in combination with methotrexate.\n\nUsing the threshold for cost effectiveness (£30,000 per QALY gained), the results of the fully incremental analysis undertaken by the DSU in the 2010 report indicated that using tocilizumab as a first-line treatment before etanercept would not be cost effective for any approach and with any set of parameter assumptions (including the manufacturer's base-case assumptions). Using tocilizumab as a second-line treatment before rituximab would only be cost effective if it is assumed that tocilizumab has long-term HAQ improvement and there is no HAQ improvement assumed with other biological treatments. However, if tocilizumab has zero HAQ improvement, then tocilizumab would only be cost effective when used as a third-line treatment after rituximab. If tocilizumab has zero HAQ improvement and the administration costs of tocilizumab are doubled, then tocilizumab is never cost effective (that is, standard care is the most cost-effective sequence). For people who have an intolerance to rituximab, or for whom rituximab is contraindicated, adding tocilizumab to the current standard care is cost effective. However, if tocilizumab does not have a different effect on long-term HAQ and the administration costs of tocilizumab are doubled, then the current standard care would be more cost effective for this population.\n\n# Rapid review of NICE technology appraisal guidance 198: patient access scheme\n\nIn the Appraisal Committee's original guidance on tocilizumab for rheumatoid arthritis (NICE technology appraisal guidance 198) tocilizumab plus methotrexate was recommended for the treatment of rheumatoid arthritis that has not responded adequately to one or more TNF‑alpha inhibitors or to rituximab, or in whom rituximab is contraindicated or is withdrawn because of an adverse effect. Following publication of this guidance, the manufacturer submitted a patient access scheme in which a discount was applied to all indications for tocilizumab (see section\xa02.4) to be considered as a rapid review of the original guidance.\n\nAs part of the rapid review, the manufacturer did not submit any additional clinical-effectiveness data. However, the manufacturer did clarify the ACR and non-response rates for each drug for each position in the treatment sequences. This highlighted that when tocilizumab is the first biological treatment in the sequence, the non-response rate is approximately 40% compared with 27% when etanercept is the first biological treatment in the sequence.\n\nThe manufacturer submitted revised ICERs using the assumptions that the Committee agreed at the final Committee meeting before issuing NICE technology appraisal guidance 198, which included:\n\nusing approach\xa04 to evidence synthesis (see section\xa03.35)\n\nassuming no long-term HAQ improvement with tocilizumab.\n\nThe manufacturer presented the results of an incremental analysis for the DMARD‑IR population in which the following treatment sequences were included:\n\netanercept then rituximab (baseline sequence)\n\ntocilizumab then etanercept then rituximab\n\netanercept then tocilizumab then rituximab\n\netanercept then rituximab then tocilizumab.\n\nThe manufacturer was requested to include an additional baseline treatment sequence of tocilizumab, followed by etanercept. In this analysis the ICER for tocilizumab as the first treatment in the sequence was £5716 per QALY gained. As the second treatment in the sequence it was £30,716 per QALY gained, and as the third treatment in the sequence the ICER was £8134 per QALY gained. All ICERs incorporated the discount for tocilizumab agreed as part of the patient access scheme.\n\nThe manufacturer also responded to a request from the DSU as part of this rapid review to provide ICERs for the TNF‑IR population in which the following treatment sequences were included:\n\nrituximab (baseline sequence)\n\ntocilizumab then rituximab.\n\nIn this analysis the costs and QALYs associated with prior treatment with a TNF‑alpha inhibitor were assumed to be the same for both treatment strategies and were therefore not modelled. The ICER for the tocilizumab sequence compared with the baseline sequence (incorporating the discount for tocilizumab agreed as part of the patient access scheme) was £22,690 per QALY gained.\n\n# Decision Support Unit report 2011\n\nIn 2011, the DSU was asked to undertake a review of whether the manufacturer had correctly implemented the Department of Health approved patient access scheme within their cost-effectiveness analysis. Additionally the DSU critiqued the changes to the costs of tocilizumab and ensured the Committee's agreed assumptions from the guidance on tocilizumab for rheumatoid arthritis (NICE technology appraisal guidance 198) had been used as the starting point within the economic analysis.\n\nThe DSU confirmed in the 2011 report that these conditions were met. However it raised the following issues with the manufacturer's analyses:\n\nNo results had been presented for the subgroup of people intolerant to rituximab or who have had rituximab withdrawn because of a contraindication. The ICERs were incorrect because no account had been taken of sequences that were extendedly dominated (less effective than and at least as costly as a combination of other drug sequences).\n\nWithin the TNF-IR analysis a sequence of rituximab followed by tocilizumab had not been included.\n\nThe DSU also corrected for a minor inaccuracy in the unadjusted trial rates used in NICE technology appraisal guidance 198. This changed the ACR20, ACR50 and ACR70 response rates for tocilizumab following two biologicals from 0.50, 0.31 and 0.15 to 0.50, 0.29 and 0.12 respectively.\n\nIn 2011, the DSU reported the results of their exploratory analysis for the DMARD‑IR population, which included the same treatment sequences in an incremental analysis as those modelled by the manufacturer (see section\xa03.42). All ICERs incorporated the discount for tocilizumab agreed as part of the patient access scheme. In this analysis, three sequences were extendedly dominated (first: etanercept followed by rituximab; second: tocilizumab as the first treatment; third: tocilizumab as the second treatment). The ICER for tocilizumab as the third treatment in the sequence was £28,380 per QALY gained compared with £8134 per QALY gained from the manufacturer's analysis.\n\nThe DSU provided an additional exploratory analysis in the 2011 report. This was an exploratory analysis for the rituximab-intolerant DMARD-IR population. All ICERs incorporated the discount for tocilizumab agreed as part of the patient access scheme. In this analysis etanercept alone was extendedly dominated. The ICER for tocilizumab followed by etanercept compared with tocilizumab alone was £10,698 per QALY gained, and the ICER for etanercept followed by tocilizumab compared with tocilizumab followed by etanercept was £30,121 per QALY gained.\n\nThe DSU reported the results of their exploratory analysis for the TNF-IR population, which included the same treatment sequences in an incremental analysis as those modelled by the manufacturer (see section\xa03.43). All ICERs incorporated the discount for tocilizumab agreed as part of the patient access scheme. In this analysis, tocilizumab followed by rituximab was dominated (was less effective than and at least as costly) by rituximab followed by tocilizumab. The ICER for rituximab followed by tocilizumab was £18,527 per QALY gained compared with the manufacturer's estimate of £22,690 per QALY gained.\n\nFull details of all the evidence are in the manufacturer's submissions, the ERG report, and the reports from the DSU, which are available from the NICE website.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of tocilizumab, having considered evidence on the nature of rheumatoid arthritis and the value placed on the benefits of tocilizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee understood that the main purpose of treatment for rheumatoid arthritis is to suppress inflammation, which in turn can slow disease progression and prevent irreversible joint damage. The Committee heard from the clinical specialists and patient experts that the primary concern with tocilizumab treatment was the potential for infectious complications, but that trial data suggested that most adverse events were relatively minor, and, in most cases, did not limit treatment use. The Committee noted the safety data presented by the manufacturer, which reported 27\xa0deaths and a serious adverse event rate of 5.8%. The Committee considered that this adverse event rate was high, but heard that it was comparable with other biological treatments.\n\nThe Committee understood the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130) recommends TNF‑alpha inhibitors adalimumab, etanercept and infliximab as options for the treatment of adults whose rheumatoid arthritis has responded inadequately to two DMARDs (unless DMARDs are contraindicated), and with a DAS28 score greater than 5.1. The Committee noted that in NICE technology appraisal guidance 130, treatment should normally be initiated with the least expensive drug (taking into account administration costs, required dose and product price per dose) and this may need to be varied in individual cases because of differences in the mode of administration and treatment schedules. It was also aware of:\n\nCertolizumab pegol for the treatment of rheumatoid arthritis (NICE technology appraisal guidance 186) and\n\nGolimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs (NICE technology appraisal guidance 225).\n\nIt noted the recommendations for the TNF‑alpha inhibitors certolizumab pegol and golimumab to be used as described in the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130), including the specific considerations concerning disease activity and choice of treatment. For treatment following an inadequate response to DMARDs (including at least one TNF‑alpha inhibitor), the guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for rheumatoid arthritis (NICE technology appraisal guidance 195) recommends rituximab plus methotrexate.\n\nThe Committee discussed the treatment options for people with moderate to severe active rheumatoid arthritis. It was aware that after an inadequate response to rituximab, additional DMARDs and best supportive care would be offered. The Committee heard from the manufacturer that it was seeking a recommendation for tocilizumab as an option along with other biological treatments in the treatment pathway. The Committee concluded that there were four possible scenarios for including tocilizumab in the treatment pathway:\n\nTocilizumab after two DMARDs as an alternative to TNF‑alpha inhibitors.\n\nTocilizumab after TNF‑alpha inhibitors as an alternative to rituximab.\n\nTocilizumab after TNF‑alpha inhibitors when a person is intolerant to rituximab or for whom rituximab is contraindicated.\n\nTocilizumab as an addition to the treatment pathway after rituximab.\n\n# Clinical effectiveness\n\nThe Committee first discussed tocilizumab given as monotherapy. It noted that the only clinical evidence for tocilizumab monotherapy came from a trial that included people who had not been previously treated with methotrexate and that tocilizumab monotherapy treatment for this population was outside the licensed indication of tocilizumab. The Committee also noted that no cost-effectiveness estimates of tocilizumab given as monotherapy had been presented by the manufacturer. It concluded that no evidence for tocilizumab monotherapy within its licensed indication was available, and therefore no recommendations for tocilizumab as a monotherapy could be made.\n\nThe Committee considered the evidence on the clinical effectiveness of tocilizumab plus DMARDs compared with placebo plus DMARDs. The Committee concluded that tocilizumab plus methotrexate was clinically effective compared with placebo plus DMARDs when given before TNF‑alpha inhibitors and when given before rituximab.\n\nThe Committee then considered the evidence for the relative efficacy of tocilizumab compared with etanercept and compared with rituximab when all treatment strategies were in combination with methotrexate. It understood that tocilizumab had not been compared head-to-head with etanercept (or any other TNF‑alpha inhibitor) or rituximab, and that indirect evidence had been combined in a mixed treatment comparison for this purpose. It noted the concerns raised by the ERG and clinical specialists regarding the mixed treatment comparison. The mixed treatment comparison assumed that the TNF‑alpha results could be regarded as a class; however, when merged, the overall results reduced the efficacy of etanercept. The Committee noted that the manufacturers had responded to its requests to remove the Klareskog trial of etanercept from the analysis because this was a large RCT with unusually high control-arm response rates and did not correspond with the inclusion criteria of the mixed treatment comparison. With this trial removed, the Committee noted that etanercept appeared at least equal to, and possibly had higher efficacy than, tocilizumab.\n\nThe Committee further noted the concerns of the DSU in its 2010 report regarding the adjusted ACR response rates from the mixed treatment comparison compared with the 'unadjusted' point estimates from the individual trials. It understood that the proportions of people achieving ACR20, ACR50 and ACR70 response rates for etanercept and rituximab resulting from the mixed treatment comparison were lower than the corresponding unadjusted trial ACR response rates. Conversely, the proportions of people achieving ACR20, ACR50 and ACR70 response rates were higher for tocilizumab in the adjusted mixed treatment comparison analysis than the unadjusted trial rates. The 2010 DSU report clarified that the counterintuitive results of the mixed treatment comparison had possibly arisen when the comparator response rates from all of the trials had been pooled. The Committee considered that the mixed treatment comparison included a set of heterogeneous trials, which meant that the results were subject to considerable uncertainty, and that limited confidence could be placed in the adjusted ACR response rates in the manufacturer's revised base case. The Committee concluded that using the unadjusted trial estimates in the analyses was more appropriate.\n\nThe Committee considered the relative efficacy of tocilizumab compared with etanercept and also with rituximab using the unadjusted trial estimates of ACR rates. It considered that the evidence was not conclusive of a benefit of any one drug over another. The Committee concluded that no convincing evidence had been presented to demonstrate the superiority of tocilizumab over etanercept or rituximab, but that the estimates were in a similar range to etanercept and rituximab.\n\nThe Committee considered the clinical evidence for tocilizumab after treatment with rituximab. Based on previous discussions it recognised that tocilizumab plus methotrexate is clinically effective compared with placebo plus methotrexate (see section\xa04.7). It noted the evidence from the RADIATE trial in which a subgroup of people had rheumatoid arthritis that had responded inadequately to two TNF‑alpha inhibitors. It understood that this was the only available evidence to consider the effectiveness of tocilizumab after rituximab. The Committee considered that it indicated a benefit of tocilizumab after two biological treatments. In view of this evidence and considering the comments from patient experts and clinical specialists, the Committee, on balance, agreed that tocilizumab was likely to benefit people whose rheumatoid arthritis has responded inadequately to rituximab.\n\n# Cost effectiveness\n\nThe Committee discussed the appropriate approach for determining the cost effectiveness of tocilizumab. It understood that before the 2010 DSU report the manufacturer's ICERs were based on adjusted trial response rates from the mixed treatment comparison. It also understood that the 2010 DSU report presented analyses using four different approaches to evidence synthesis (see section\xa03.35). The Committee considered, on the basis of previous discussions (see section\xa04.8), that approach\xa01, in which the ACR response rates came from the mixed treatment comparison, was not appropriate. The remaining three approaches to evidence synthesis used the unadjusted trial response rates for all treatments and incorporated degradation rates. The Committee understood that approaches\xa02 and 3 only used the unadjusted ACR response rate from a single trial for etanercept, rather than from the two available trials. The Committee had a strong preference for approach\xa04, which used data from both of the etanercept trials. Approach\xa04 also corrected the counterintuitive ACR70 response rate for tocilizumab used as a third biological treatment in the treatment sequence noted by the DSU in the 2010 report. The Committee concluded that approach\xa04 to evidence synthesis (see section\xa03.35) was the most appropriate for consideration.\n\nThe Committee also discussed the two sensitivity analyses presented by the DSU within approach\xa04 in the 2010 report. The first concerned evidence supplied by the manufacturer for a long-term HAQ improvement. It understood that the data for a HAQ improvement with tocilizumab treatment came from open-label extension studies in which only the HAQ scores for people who remained on treatment were available. It noted that, for the open-label extension trial assessing the benefits of tocilizumab after the failure of conventional DMARDs (that is, before etanercept), approximately 30% of people had stopped treatment. It further noted that the confidence intervals around the mean HAQ scores at each point in time were wide. The Committee therefore considered that the manufacturer's evidence was not a robust estimate of the long-term HAQ improvement on tocilizumab and was subject to uncertainty. Furthermore, the manufacturer had not provided any comparable investigation into long-term HAQ trends for the comparator biological treatments other than rituximab. The manufacturer presented a graph of a stable HAQ trend for people on rituximab from the REFLEX trial. However, no data had been supplied by the manufacturer to support the graph. The Committee questioned the comparability of the rituximab and tocilizumab HAQ trend lines, and considered that single-arm extension trial data did not provide a direct comparison of the relative benefits between the two treatments. In addition, the Committee heard from patient experts and clinical specialists that it was unlikely that tocilizumab would provide a long-term HAQ benefit over and above that of any other biological treatment. Overall, the Committee could not support the assumption that there is a long-term HAQ gain with tocilizumab (that is, a HAQ improvement with tocilizumab) compared with no HAQ improvement with other biological treatments. It concluded, on the basis of the evidence presented, that the long-term HAQ improvement on tocilizumab treatment had not been demonstrated. The Committee agreed that the analyses that assumed no long-term HAQ improvement with tocilizumab were therefore the most appropriate for consideration.\n\nThe second sensitivity analysis that the Committee considered concerned the exclusion of negative utilities (health states worse than death) from the incremental analysis. The Committee noted that the manufacturer's mapping of HAQ scores to EQ-5D utility values resulted in negative utility values. It discussed that excluding negative utility values could be considered counterintuitive and did not allow for a worsening of quality of life when a person had rheumatoid arthritis. The Committee heard from the manufacturer that it was possible that there were some people with rheumatoid arthritis who may experience negative utility values. The Committee noted that the impact of removing the negative utilities from the incremental analysis was minimal. The Committee agreed that although the exclusion of negative utility values was subject to some debate, it was not a key issue in determining the cost effectiveness of tocilizumab. The Committee therefore accepted that the calculation of some ICERs would include negative utility values but concluded that this was acceptable because of the low impact on the ICERs.\n\nThe Committee considered the administration costs of tocilizumab. It noted comments received during consultation in 2010 that, although the infusion took 1\xa0hour, the total time taken to administer tocilizumab in an organised unit would be at least 2\xa0hours. The Committee then discussed the 2010 DSU analysis using approach\xa04 with no long-term HAQ improvement and the administration costs doubled. It heard from the DSU that the decision to double the cost was not based on a robust estimate of the time taken to administer tocilizumab, but was intended to illustrate the sensitivity of the ICERs to this assumption. Although the Committee agreed that a cost based on an administration time of 1\xa0hour represented the minimum cost to the NHS, it did not agree that the true cost would be as much as double. The Committee therefore considered that it was not appropriate to double the administration cost of tocilizumab and concluded that the manufacturer's revised estimate of £154 was acceptable.\n\nThe Committee noted that some modelling assumptions in the manufacturer's submission had not been investigated by the DSU in the 2010 report. These included, first, any difference in the adverse events that may occur on biological treatment compared with those that might occur in palliative care. Second, that despite previous requests to the manufacturer to use directly observed EQ‑5D data, the revised base-case ICERs from the manufacturer were still subject to a HAQ mapping algorithm. The Committee highlighted its concern with this, but acknowledged that the data had not been available to investigate these assumptions.\n\nIn summary the Committee concluded that the best estimate of cost effectiveness of tocilizumab in any position in the treatment pathway should be based on approach\xa04 to evidence synthesis in which the ACR response rates came from the trials rather than the mixed treatment comparison and used a corrected degradation factor for tocilizumab (see section\xa03.35). In addition, it concluded that no long-term HAQ improvements with tocilizumab should be assumed.\n\nThe Committee considered the cost-effectiveness analyses submitted by the manufacturer in 2011 that were based on the preferred approach (see section\xa04.17) and that incorporated tocilizumab at the discount agreed as part of the patient access scheme (see section\xa02.4). It also considered the DSU 2011 report when reviewing the manufacturer's submission. It discussed the manufacturer's analyses, which the DSU replicated including fully incremental calculations (see sections\xa03.45 to 3.47) for all three patient subgroups: people whose rheumatoid arthritis has responded inadequately to one or more conventional DMARDs (DMARD-IR analysis); people who are intolerant to rituximab, or for whom rituximab is contraindicated (DMARD-IR rituximab intolerant); people whose rheumatoid arthritis has responded inadequately to TNF‑alpha inhibitors (TNF-IR analysis). The Committee accepted the DSU separate exploratory incremental analyses. It noted the DSU's comment from the 2011 report that the manufacturer's analysis had not taken into account extended dominance (when one or more drug sequences are less effective than and at least as costly as another sequence) and that this had an impact on the ICERs. The Committee concluded that the DSU's 2011 exploratory analyses should be used as the basis for determining the cost effectiveness of tocilizumab.\n\nThe Committee also considered the straightforward inferences that could be made from its separate clinical effectiveness and costing conclusions. These were that for the DMARD-IR population (who had not received a TNF‑alpha inhibitor or any other biological treatment) tocilizumab was similar in clinical effectiveness (see section\xa04.10) to the TNF‑alpha inhibitors and could be considered a plausible alternative. In the case of the TNF‑IR population (whose condition had failed to respond to a TNF‑alpha inhibitor but who had not yet tried rituximab), the position was different. Although tocilizumab might be as clinically effective as rituximab, it was also more expensive and so the Committee concluded tocilizumab could not be considered an option unless rituximab was contraindicated, not tolerated or had failed.\n\nThe Committee considered the DMARD-IR ICERs in the DSU's 2011 exploratory analysis. It noted from the total costs and QALYs for the sequences that when tocilizumab was the first biological treatment rather than etanercept, it was associated with fewer QALYs and less cost. It understood that this was because of the percentage of non-responders on tocilizumab (approximately 40%) when taken as a first-line biological treatment, which resulted in reduced time on tocilizumab treatment and therefore lower cost of the sequence. The Committee noted that this improved the cost effectiveness of tocilizumab. However, on the basis of previous discussions (see section\xa04.10) the Committee was not convinced that the clinical effectiveness of tocilizumab would be superior to that of etanercept. The Committee concluded that the improved cost effectiveness of tocilizumab as the first biological treatment compared with etanercept was due to the cost of time on treatment, rather than any substantial differences in clinical or cost effectiveness between tocilizumab and etanercept.\n\nThe Committee further considered the DMARD-IR ICERs from the DSU's 2011 exploratory analysis. It noted that although tocilizumab appeared cost effective as the first biological treatment (£5700 per QALY gained), this sequence had rituximab as the third biological treatment in the sequence, rather than the second. The Committee raised concerns that this was counterintuitive because the total drug treatment cost of rituximab is approximately half that of either tocilizumab or etanercept. On the basis of previous discussions (see section\xa04.11) the Committee was not convinced that the clinical effectiveness of etanercept or tocilizumab would be sufficiently superior to rituximab such that a sequence in which rituximab was third would be more cost effective than one in which rituximab was second. The Committee noted that a sequence in which tocilizumab was the first biological treatment, followed by rituximab, followed by etanercept, had not been included in either the manufacturer's or the DSU's 2011 analyses. It was aware that in clinical practice this sequence would involve off-licence use of rituximab because the marketing authorisation restricts rituximab to use after an inadequate response or intolerance to other DMARDs including one or more TNF‑alpha inhibitors. However the Committee considered that to understand the impact on the cost effectiveness of placing tocilizumab first in the sequence, it was important to consider all possible treatment sequences. It noted that in their exploratory incremental analysis from 2011, the DSU had incorporated an alternative baseline sequence of tocilizumab followed by rituximab. The Committee accepted this sequence as a proxy for tocilizumab, followed by rituximab, followed by etanercept. It noted that when this alternative baseline sequence was included in the exploratory analysis, three sequences were extendedly dominated (see section\xa03.49) leaving the baseline sequence of tocilizumab followed by rituximab, and the sequence of etanercept, followed by rituximab, followed by tocilizumab. Comparing these two sequences, tocilizumab as the third biological in the sequence had an ICER of £28,400 per QALY gained, compared with tocilizumab as the first biological treatment in the sequence. It accepted that some uncertainty around the point estimates of the ICERs was likely. However the conclusion to this analysis was consistent with the reasoning in section\xa04.18. The Committee concluded that tocilizumab should be recommended as an option when used in the same way as the TNF‑alpha inhibitors etanercept, adalimumab, infliximab, golimumab and certolizumab pegol recommended in NICE technology appraisal guidance 130, 186 and 225. The Committee understood that its recommendation would apply to people whose rheumatoid arthritis has a DAS28 score of greater than 5.1. It also understood that treatment should normally be initiated with the least expensive drug (taking into account administration costs, required dose and product price per dose) and this may need to be varied in individual cases because of differences in the mode of administration and treatment schedules.\n\nThe Committee discussed the cost effectiveness of tocilizumab when a person is intolerant to rituximab or for whom rituximab is contraindicated (that is, the DMARD‑IR rituximab intolerant population). The Committee again took the view that, assuming that etanercept and tocilizumab have approximately equal effectiveness (see section\xa04.19) and cost, it would be reasonable for either to be an option in this position. The Committee noted that the DSU's 2011 analyses broadly corroborated these conclusions. It noted that in this population the ICER from the DSU's 2011 exploratory incremental analysis was £30,100 per QALY gained for a sequence in which etanercept was followed by tocilizumab, and £10,700 per QALY gained for a sequence in which tocilizumab was followed by etanercept (see section\xa03.50). The Committee concluded that tocilizumab should be recommended as an option for the DMARD-IR rituximab intolerant population. It further concluded that this recommendation should be in line with the guidance on adalimumab, etanercept, infliximab, rituximab and abatacept (NICE technology appraisal guidance 195), specifically the recommendations on disease activity when a second TNF‑alpha inhibitor is recommended for people in whom rituximab is contraindicated or when rituximab is withdrawn because of an adverse event.\n\nFinally, the Committee considered the DSU's 2011 exploratory analysis for the TNF‑IR population. It understood that in this analysis, the costs and QALYs associated with earlier treatment on a TNF‑alpha inhibitor were assumed to be the same and so the analysis comprised two sequences containing tocilizumab (one in which tocilizumab is followed by rituximab and one in which rituximab is followed by tocilizumab) and a baseline treatment sequence of rituximab alone. The Committee noted from this analysis that the treatment strategy that placed tocilizumab before rituximab was dominated by treating with rituximab before tocilizumab (in people who had previously only had a TNF‑alpha inhibitor). The Committee accepted the ICER from this analysis as the most plausible estimate of tocilizumab following rituximab in this population (that is, £18,500 per QALY gained). The Committee also compared this ICER with the manufacturer's estimate of £22,700 per QALY gained. In view of this, the Committee concluded that tocilizumab could be considered an option after an inadequate response to treatment with rituximab but should not be recommended as an alternative to rituximab.\n\nThe Committee noted that, in clinical practice and as recommended in the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130), treatment should normally be initiated with the least expensive drug; this would not necessarily be the same drug in individual cases because of differences in the mode of administration and treatment schedules. The Committee therefore concluded that it was appropriate to recommend tocilizumab as an option following the same considerations as for the drugs recommended as options in NICE technology appraisal guidance\xa0130.\n\nThe Committee concluded that it was appropriate to recommend tocilizumab plus methotrexate as an option for people whose rheumatoid arthritis has a DAS28 score greater than 5.1 and has responded inadequately to one or more previous DMARDs if used as described for TNF inhibitor treatments in NICE technology appraisal guidance 130, specifically the recommendations on disease activity and choice of treatment. It concluded that tocilizumab plus methotrexate could be recommended as an option for people whose rheumatoid arthritis has responded inadequately to treatment with DMARDs and a TNF inhibitor and in whom rituximab is contraindicated or who had rituximab withdrawn because of an adverse event. The Committee concluded that, for people whose rheumatoid arthritis has responded inadequately to previous TNF inhibitors, and for whom rituximab is an option, tocilizumab plus methotrexate could not be recommended because although it might be as effective as rituximab, it was more expensive and so could not be considered unless rituximab was contraindicated, not tolerated or had failed. The Committee also concluded that tocilizumab plus methotrexate could be recommended for people whose rheumatoid arthritis has responded inadequately to treatment with one or more previous TNF inhibitors and rituximab. It also decided that a recommendation about tocilizumab as monotherapy could not be made because there was not enough evidence of its efficacy as a monotherapy.\n\nTA247\n\nAppraisal title: Tocilizumab for the treatment of rheumatoid arthritis (rapid review of technology appraisal guidance 198)\n\nSection\n\nKey conclusion\n\nTocilizumab in combination with methotrexate is recommended as an option for the treatment of rheumatoid arthritis in adults if:\n\nthe disease has responded inadequately to disease-modifying anti-rheumatic drugs (DMARDs) and it is used as described for tumour necrosis factor (TNF) inhibitor treatments in Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis (NICE technology appraisal guidance 130), specifically the recommendations on disease activity and choice of treatment or\n\nJanuary 2016: This bullet point has been updated by NICE technology appraisal guidance 375.\n\nthe disease has responded inadequately to DMARDs and a TNF inhibitor and the person cannot receive rituximab because of a contraindication to rituximab, or because rituximab is withdrawn because of an adverse event, and tocilizumab is used as described for TNF inhibitor treatments in NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor, specifically the recommendations on disease activity or\n\nthe disease has responded inadequately to one or more TNF inhibitor treatments and to rituximab\n\nand the manufacturer provides tocilizumab with the discount agreed as part of the patient access scheme.\n\n\n\nPeople currently receiving tocilizumab for the treatment of rheumatoid arthritis who do not meet the criteria in 1.1 should have the option to continue treatment until they and their clinicians consider it appropriate to stop.\n\n, 1.2\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee understood the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130) recommends TNF‑alpha inhibitors adalimumab, etanercept and infliximab as options for the treatment of adults whose rheumatoid arthritis has responded inadequately to two DMARDs (unless DMARDs are contraindicated), and with a DAS28 score greater than 5.1. The Committee noted that in NICE technology appraisal guidance 130, treatment should normally be initiated with the least expensive drug (taking into account administration costs, required dose and product price per dose) and this may need to be varied in individual cases because of differences in the mode of administration and treatment schedules. It was also aware of certolizumab pegol for the treatment of rheumatoid arthritis (NICE technology appraisal guidance 186) and golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs (NICE technology appraisal guidance 225).\n\n\n\nFor treatment following an inadequate response to DMARDs (including at least one TNF‑alpha inhibitor), the guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for rheumatoid arthritis (NICE technology appraisal guidance 195) recommends rituximab plus methotrexate.\n\n, 4.4\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nTocilizumab has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function when given in combination with methotrexate.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee concluded that there were four possible scenarios for including tocilizumab in the treatment pathway:\n\nTocilizumab after two DMARDs as an alternative to TNF‑alpha inhibitors.\n\nTocilizumab after TNF‑alpha inhibitors as an alternative to rituximab.\n\nTocilizumab after TNF‑alpha inhibitors when a person is intolerant to rituximab or for whom rituximab is contraindicated.\n\nTocilizumab as an addition to the treatment pathway after rituximab.\n\n\n\nAdverse effects\n\nThe Committee noted the safety data presented by the manufacturer, which reported 27\xa0deaths and a serious adverse event rate of 5.8%. The Committee considered that this adverse event rate was high, but heard that it was comparable with other biological treatments.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee concluded that no evidence for tocilizumab monotherapy within its licensed indication was available, and therefore no recommendations for tocilizumab as a monotherapy could be made.\n\nThe Committee considered the evidence on the clinical effectiveness of tocilizumab plus DMARDs compared with placebo plus DMARDs. The Committee concluded that tocilizumab plus methotrexate was clinically effective compared with placebo plus DMARDs when given before TNF‑alpha inhibitors and when given before rituximab.\n\nThe Committee then considered the evidence for the relative efficacy of tocilizumab compared with etanercept and compared with rituximab when all treatment strategies were in combination with methotrexate. It understood that tocilizumab had not been compared head-to-head with either etanercept (or any other TNF‑alpha inhibitor) or rituximab, and that indirect evidence had been combined in a mixed treatment comparison for this purpose.\n\n, 4.7, 4.8\n\nRelevance to general clinical practice in the NHS\n\nThe Committee did not raise any issues about the relevance of the clinical-effectiveness data to general clinical practice in the NHS.\n\nN/A\n\nUncertainties generated by the evidence\n\nThe mixed treatment comparison assumed that the TNF‑alpha results could be regarded as a class. The Committee noted that the manufacturers had responded to requests to remove the Klareskog trial of etanercept from the analysis because this was a large RCT with unusually high control-arm response rates and did not correspond with the inclusion criteria of the mixed treatment comparison. With this trial removed, the Committee noted that etanercept appeared at least equal to, and possibly had higher efficacy than, tocilizumab.\n\nThe Committee considered that limited confidence could be placed in the adjusted ACR response rates in the manufacturer's revised base case. The Committee concluded that using the unadjusted trial estimates in the analyses was more appropriate.\n\n, 4.9\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nN/A\n\nN/A\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that no convincing evidence had been presented to demonstrate the superiority of tocilizumab over etanercept or rituximab, but that the estimates were in a similar range to etanercept and rituximab.\n\nThe Committee noted the evidence from the RADIATE trial and, on balance, agreed that tocilizumab was likely to benefit people whose rheumatoid arthritis has responded inadequately to rituximab.\n\n, 4.11\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer did not identify any economic evaluations of tocilizumab and developed an economic model for the submission. This was an individual sampling model with a hypothetical homogenous cohort. The model used a lifetime horizon for costs and benefits. It considered the DMARD-IR and TNF-IR populations separately. No evidence on the cost effectiveness of tocilizumab monotherapy was presented.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nIn summary the Committee concluded that the best estimate of cost effectiveness of tocilizumab in any position in the treatment pathway should be based on approach 4 to evidence synthesis in which the ACR response rates came from the trials rather than the mixed treatment comparison and used a corrected degradation factor for tocilizumab (see section\xa03.35). In addition, it concluded that no long-term HAQ improvements with tocilizumab should be assumed.\n\nThe economic model incorporated tocilizumab at the discount agreed as part of the patient access scheme.\n\nThe manufacturer's analysis had not taken into account extended dominance and that this had an impact on the ICERs. The Committee concluded that the DSU's 2011 exploratory analyses should be used as the basis for determining the cost effectiveness of tocilizumab.\n\n, 4.18, 4.18\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee noted that the manufacturer's mapping of HAQ scores to EQ‑5D utility values resulted in negative utility values. The Committee heard from the manufacturer that it was possible that there were some people with rheumatoid arthritis who may experience negative utility values. The Committee therefore accepted that the calculation of some ICERs would include negative utility values but concluded that this was acceptable because of the low impact on the ICERs.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee heard from the manufacturer that it was seeking a recommendation for tocilizumab as an option along with other biological treatments in the treatment pathway. It therefore considered that there were four possible scenarios for including tocilizumab in the treatment pathway:\n\nTocilizumab after two DMARDs as an alternative to TNF‑alpha inhibitors.\n\nTocilizumab after TNF‑alpha inhibitors as an alternative to rituximab.\n\nTocilizumab after TNF‑alpha inhibitors when a person is intolerant to rituximab or for whom rituximab is contraindicated.\n\nTocilizumab as an addition to the treatment pathway after rituximab.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee concluded that the improved cost effectiveness of tocilizumab as the first biological treatment compared with etanercept was due to the cost of time on treatment, rather than any substantial differences in clinical or cost effectiveness between tocilizumab and etanercept.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nFor the DMARD‑IR population: three sequences were extendedly dominated (less effective than and at least as costly as a combination of other drug sequences). When tocilizumab is the third biological in the sequence the most plausible estimate of the ICER is £28,400 per QALY gained. The Committee accepted that some uncertainty around the point estimates of the ICERs was likely.\n\nFor the DMARD‑IR rituximab intolerant population: the Committee noted that the most plausible estimate for the ICER ranged from £10,700 per QALY gained for the sequence in which etanercept followed tocilizumab to £30,100 per QALY gained in the sequence where tocilizumab followed etanercept.\n\nFor the TNF‑IR population: the Committee accepted the ICER of £18,500 per QALY gained as the most plausible ICER estimate for tocilizumab following rituximab in this population.\n\n, 4.22, 4.23\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe Department of Health and the manufacturer have agreed that tocilizumab will be available to the NHS with a patient access scheme in which a discount from the list price is applied to original invoices. The level of the discount is commercial in confidence.\n\n, 5.2\n\nEnd-of-life considerations\n\nN/A\n\nN/A\n\nEqualities considerations and social value judgements\n\nNo equalities issues were raised in the appraisal.\n\nN/A"}
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https://www.nice.org.uk/guidance/ta247
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Evidence-based recommendations on tocilizumab (RoActemra) for treating rheumatoid arthritis in adults.
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Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults
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Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults
Evidence-based recommendations on apixaban (Eliquis) for preventing venous thromboembolism after total hip or knee replacement in adults.
# Guidance
Apixaban is recommended as an option for the prevention of venous thromboembolism in adults after elective hip or knee replacement surgery.# The technology
Apixaban (Eliquis, Bristol-Myers Squibb and Pfizer) is an anticoagulant that affects the blood coagulation cascade by directly inhibiting activated factor X (factor Xa), so inhibiting thrombin formation and the development of thrombi. Apixaban has a marketing authorisation for the 'prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery'.
The recommended dosage of apixaban in the summary of product characteristics is 2.5 mg orally twice daily. The initial dose should be taken 12–24 hours after surgery. The duration of treatment depends on the individual risk of the patient for venous thromboembolism, which is determined by the type of orthopaedic surgery. Recommended treatment durations are 32–38 days for patients having hip replacement surgery and 10–14 days for patients having knee replacement surgery.
According to the summary of product characteristics, 11% of patients treated with apixaban 2.5 mg twice daily in clinical trials experienced adverse reactions. As with other anticoagulants, bleeding may occur during apixaban therapy in patients with risk factors such as lesions liable to bleed. Common adverse reactions are anaemia, haemorrhage, contusion and nausea. For full details of side effects and contraindications, see the summary of product characteristics.
Apixaban costs £17.15, £34.30 and £102.90 for packs of 10, 20 and 60 tablets respectively excluding VAT (NHS list price as reported by the manufacturer). The cost of treatment is estimated to be £41.16 (based on 12 days' treatment) for knee replacement surgery and £116.62 for hip replacement surgery (based on 34 days' treatment). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of apixaban and a review of this submission by the Evidence Review Group (ERG; appendix B).
The manufacturer's submission compared apixaban with enoxaparin, a low molecular weight heparin (LMWH), using direct evidence from randomised controlled trials, and with dabigatran etexilate, rivaroxaban and fondaparinux, using evidence from randomised controlled trials that had been incorporated into an adjusted indirect comparison and a mixed treatment comparison. Outcomes analysed included mortality, incidence of venous thromboembolism and adverse reactions to treatment. All of these were specified in the decision problem for this appraisal. The clinical evidence submitted by the manufacturer did not include analysis of outcomes such as joint infection, length of hospital stay, complications after deep vein thrombosis or health-related quality of life because these were not available from the clinical trials of apixaban. However, the manufacturer included complications after deep vein thrombosis and health-related quality of life in its economic submission.
The manufacturer identified four randomised controlled trials comparing apixaban with enoxaparin for the prevention of venous thromboembolism. ADVANCE 1 ('Apixaban dosed orally versus anticoagulation with enoxaparin'), ADVANCE 2 and APROPOS ('Apixaban prophylaxis in patients undergoing total knee replacement surgery') recruited patients having total knee replacement surgery. ADVANCE 3 recruited patients having total hip replacement surgery.
ADVANCE 1 (n = 3195) and ADVANCE 2 (n = 3057) were multicentre parallel-group randomised controlled trials. In ADVANCE 1, apixaban was given at a dosage of 2.5 mg twice daily for 12 days and enoxaparin at a dosage of 30 mg twice daily for 12 days. Treatment in both arms was started 12–24 hours after surgery. In ADVANCE 2, apixaban was given at a dosage of 2.5 mg twice daily for 11 days and enoxaparin at a dosage of 40 mg once daily for 11 days. Apixaban was started 12–24 hours after surgery and enoxaparin 9–15 hours before surgery. APROPOS (n = 305) was a dose-finding clinical study in which patients were randomised to receive one of several doses of apixaban (5 mg, 10 mg, 20 mg, once or twice daily), enoxaparin 30 mg twice daily or warfarin. ADVANCE 2 used the UK dosing regimen for enoxaparin (40 mg once daily) whereas ADVANCE 1 and APROPOS used the US dosing regimen (30 mg twice daily). The manufacturer considered ADVANCE 2 to be the most relevant study for the prevention of venous thromboembolism after total knee replacement surgery in the context of UK clinical practice because it was the only study that compared apixaban with the UK licensed dose of enoxaparin.
ADVANCE 3 (n = 5407) was a multicentre parallel-group randomised controlled trial comparing apixaban with enoxaparin for the prevention of venous thromboembolism after total hip replacement surgery. Apixaban was given at a dosage of 2.5 mg twice daily for 32–38 days and enoxaparin at a dosage of 40 mg once daily for 32–38 days. Apixaban was started 12–24 hours after surgery and enoxaparin 9–15 hours before surgery.
The primary efficacy end point for ADVANCE 1 and ADVANCE 2 was the composite of all incidences of venous thromboembolism (pulmonary embolism, symptomatic and asymptomatic deep vein thrombosis), and death from any cause during the intended treatment period. The primary safety end point was bleeding and included confirmed major bleeding events, a composite of confirmed major bleeding events and confirmed non-major bleeding events, and all bleeding events. The primary efficacy end point for ADVANCE 3 was the composite of symptomatic or asymptomatic deep vein thrombosis, non-fatal pulmonary embolism, and death from any cause during the intended treatment period. The primary safety end point was bleeding during treatment or within 2 days of the last dose of study medication. The primary efficacy end point for APROPOS was the composite of symptomatic or asymptomatic deep vein thrombosis, non-fatal pulmonary embolism and death from any cause. The primary safety end point was major bleeding.
The primary efficacy analysis dataset included all randomised patients who had a bilateral venogram that was evaluable, venous thromboembolism, or who died from any cause. The manufacturer stated that the intention-to-treat analysis assumed that no readable venogram represented no event, which potentially underestimated the number of venous thromboembolic events in the intention-to-treat population. The remaining efficacy and safety analyses were conducted on the intention-to-treat population.
ADVANCE 2 showed that apixaban was statistically significantly superior to enoxaparin in terms of the primary composite end point of all venous thromboembolism and death from any cause (relative risk 0.62, 95% confidence interval 0.51 to 0.74), as well as in terms of major venous thromboembolism (RR 0.5, 95% CI 0.26 to 0.97) and all deep vein thrombosis (RR 0.6, 95% CI 0.5 to 0.72). For major bleeding events and all bleeding events, the relative risks were 0.65 (95% CI 0.28 to 1.49) and 0.83 (95% CI 0.65 to 1.06) respectively. ADVANCE 1 and APROPOS both used the US dosing regimen for enoxaparin and neither reported significant differences for any of the outcomes reported.
ADVANCE 3 showed that apixaban was statistically significantly superior to enoxaparin in terms of the primary composite end point of all venous thromboembolism and death from any cause (RR 0.36, 95% CI 0.23 to 0.56), as well as in terms of major venous thromboembolism (RR 0.4, 95% CI 0.19 to 0.83) and all deep vein thrombosis (RR academic in confidence). For major bleeding events and all bleeding events the relative risks were 1.22 (95% CI 0.65 to 2.26) and 0.93 (95% CI 0.81 to 1.08) respectively.
In the absence of direct evidence comparing apixaban with dabigatran etexilate, rivaroxaban and fondaparinux, the manufacturer presented results of an adjusted indirect comparison using enoxaparin as the common comparator. The manufacturer did not include an assessment of apixaban compared with other LMWHs in the indirect comparison. It considered enoxaparin to be the most widely used LMWH in the UK. Moreover, enoxaparin was the comparator used in the apixaban registration trials (ADVANCE 2 and 3). The manufacturer identified 15 randomised controlled trials for inclusion in the indirect comparison. Of these, nine compared the treatment of interest with enoxaparin at the UK dosage of 40 mg once daily. The remaining six studies compared the treatment of interest with enoxaparin 30 mg twice daily.
The manufacturer reported adjusted indirect comparisons using pooled data from studies using the UK dosage of enoxaparin alone, US dosage of enoxaparin alone and combined UK and US dosages of enoxaparin as the common comparator. Results were expressed as odds ratios for apixaban versus the other treatments of interest. For the outcome of composite venous thromboembolic events, and other end points of any deep vein thrombosis, asymptomatic deep vein thrombosis and major venous thromboembolism, results from the primary efficacy population were reported. For symptomatic deep vein thrombosis, pulmonary embolism, any bleeding, major bleeding, clinically relevant non-major bleeding and minor bleeding, results were reported from the intention-to-treat population.
The manufacturer stated that it considered the adjusted indirect comparisons of apixaban 2.5 mg twice daily against other anticoagulants of interest using the UK dosage of enoxaparin to be the most relevant to UK clinical practice. The results of such analyses for hip replacement showed that there were no significant differences for apixaban when compared with rivaroxaban for total venous thromboembolism and death from any cause, any deep vein thrombosis, major venous thromboembolism, pulmonary embolism, any bleeding or major bleeding. These results were the same for total knee replacement, except for the number of pulmonary embolic events, which was statistically significantly reduced with rivaroxaban. When compared with dabigatran etexilate, total venous thromboembolism, death from any cause and any deep vein thrombosis were statistically significantly reduced with apixaban; there were no significant differences for the other main outcomes (major venous thromboembolism, pulmonary embolism, any bleeding and major bleeding). These results were the same for total hip replacement and total knee replacement. When compared with fondaparinux in patients with total hip replacement, apixaban showed no significant differences for any deep vein thrombosis, pulmonary embolism or major bleeding. Other main outcomes (total venous thromboembolism and death from any cause, major venous thromboembolism and any bleeding) were not reported using indirect comparisons. There were no randomised controlled trials comparing fondaparinux with the UK dosage (40 mg daily) of enoxaparin in patients having total knee replacement surgery, therefore an adjusted indirect comparison was not possible. The results of the adjusted indirect comparisons using data with US dosages of enoxaparin and pooled data with UK and US dosages of enoxaparin were considered to be academic in confidence by the manufacturer and therefore cannot be presented.
The manufacturer also undertook a mixed treatment comparison that included 43 studies. Results were expressed as odds ratios and were for the same outcomes as for the adjusted indirect comparisons. The manufacturer reported mixed treatment comparisons using only the UK dosage of enoxaparin and also using pooled data for UK and US dosages. The results of the mixed treatment comparisons cannot be reported because the manufacturer considers the results to be academic in confidence.
The manufacturer considered the adjusted indirect comparison using the UK dosage of enoxaparin to be the most appropriate analysis for informing the relative efficacy and safety of apixaban compared with enoxaparin, rivaroxaban, dabigatran etexilate and fondaparinux. This was because results from the mixed treatment comparison were inconsistent with some of the head-to-head data from the randomised controlled trials. The manufacturer noted that the inconsistent results and wider credibility intervals may be a result of the large number of trials contributing to the enoxaparin 40 mg once daily node in the network analysis. These trials tended to be older, with fewer study criteria reported and small sample sizes, and compared enoxaparin 40 mg once daily with treatments other than the comparators in the scope. The manufacturer highlighted inconsistencies between the results of the mixed treatment comparison and the head-to-head trial for the following comparisons: apixaban 2.5 mg twice daily compared with enoxaparin 40 mg once daily, and rivaroxaban 10 mg once daily compared with enoxaparin 40 mg once daily for the primary composite end point (venous thromboembolism plus death from any cause) and on some of the secondary outcomes.
The ERG considered that the three clinical trials, ADVANCE 1, 2 and 3, which represent the main clinical efficacy evidence, were of reasonable methodological quality and measured a range of outcomes that were appropriate and clinically relevant. It stated that processes and validation of study screening and data extraction appeared to be appropriate. The ERG agreed with the chosen doses for each treatment included in the adjusted indirect and mixed treatment comparisons. The ERG commented that the statistical methods were explicitly described for the meta-analyses and indirect comparisons, and all relevant analyses were performed. In addition, the ERG commented that the manufacturer's conclusion that the mixed treatment comparison was less reliable than the adjusted indirect comparison seemed reasonable.
The manufacturer submitted an economic model assessing the cost effectiveness of apixaban compared with enoxaparin, dabigatran etexilate and rivaroxaban. A two-stage modelling approach was adopted, based on an approach previously used for 'Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults' (NICE technology appraisal guidance 157). A decision tree was used to model treatment in the prophylactic phase (from the time of surgery to 90 days after surgery) and a Markov model was used to model long-term events (90 days after surgery and beyond). The differential effects of treatment are only realised in the prophylactic phase of the model. The Markov model has a cycle length of 1 year and a maximum time horizon of 60 years (base case 35 years).
In the decision tree model, a hypothetical patient can experience a venous thromboembolic event (total venous thromboembolic events or death from any cause) or no event. When death is not a result of venous thromboembolism, death can result from a major bleed or other cause. Deaths from other causes refer to deaths not related to venous thromboembolism and deaths not related to anticoagulation during the prophylactic phase. A venous thromboembolic event can be a pulmonary embolism, symptomatic or asymptomatic deep vein thrombosis (both either distal or proximal). Pulmonary embolism may or may not result in death. A cohort of hypothetical patients surviving pulmonary embolism and a cohort with symptomatic deep vein thrombosis receive treatment and progress to the non-fatal bleeding events state of the model. A cohort of hypothetical patients with asymptomatic deep vein thrombosis progress to the non-fatal bleeding events state without treatment. A cohort of hypothetical patients without venous thromboembolic events also progress directly to the non-fatal bleeding state. Probabilities of bleeding are independent of what happened earlier in the model. A cohort of hypothetical patients experiencing an intracranial haemorrhage proceed immediately to the 'disabled' health state and remain there for the duration of the model or until they die. Alternatively, hypothetical patients can experience no bleeding, minor bleeding, a non-major clinically relevant bleed or a major bleed (other than an intracranial haemorrhage). In the period between the end of treatment and 90 days after surgery, hypothetical patients without symptoms can become symptomatic. Asymptomatic deep vein thrombosis that becomes symptomatic after prophylactic treatment is assumed to be of the same type (distal thrombosis remains distal and proximal thrombosis remains proximal).
At 90 days after surgery a cohort of hypothetical patients leave the decision tree model and enter the long-term Markov model. Hypothetical patients who have not experienced a venous thromboembolic event enter the Markov model in the 'well' state, whereas hypothetical patients who have asymptomatic deep vein thrombosis enter the Markov model in the untreated venous thromboembolic state. Hypothetical patients who have had a pulmonary embolism or a deep vein thrombosis or have made the transition from asymptomatic to symptomatic deep vein thrombosis enter the Markov model in the treated venous thromboembolic state. Hypothetical patients who have had an intracranial haemorrhage enter in the 'disabled' health state. A cohort of hypothetical patients who died while in the decision tree model enter the Markov model in the 'dead' state. In the long-term Markov model, a cohort of hypothetical patients can remain well, die, have a pulmonary embolism, a deep vein thrombosis, mild-to-moderate post-thrombotic syndrome (divided into year 1 and subsequent years) or a severe post-thrombotic syndrome (divided into year 1 and subsequent years). The same transitions are possible for treated and untreated patients. Once a hypothetical patient has a pulmonary embolism or deep vein thrombosis they make the transition to the treated venous thromboembolic state. There is no differential treatment effect in this long-term phase of the model.
Key assumptions in the economic evaluation included the assumption that during the prophylactic phase, deaths from pulmonary embolism and other causes occur at 35 days for total hip replacement and 14 days for total knee replacement in each treatment arm. It was assumed that during the phase after prophylaxis, deaths from pulmonary embolism occur at 63 days for total hip replacement and 52 days for total knee replacement. These are the midpoints of the post-prophylactic phase for each indication. It was also assumed that deaths from major bleeds occur at 35 days for total hip replacement and 14 days for total knee replacement, regardless of whether the bleeding rates were based on the duration of prophylaxis or 90 days.
The manufacturer modelled the efficacy (total venous thromboembolic events and all deaths) and safety (total bleeds) of the treatments in line with the corresponding end points in the two clinical trials of apixaban (ADVANCE 2 and 3) and in the indirect comparison of apixaban with rivaroxaban and with dabigatran etexilate. The manufacturer stated that because data were not available for an indirect comparison of apixaban with fondaparinux in patients having total knee replacement surgery, apixaban could not be compared with fondaparinux in the economic model. The manufacturer also stated that relative risks were used in the economic model rather than odds ratios because they can be directly applied to an absolute probability of an event to generate the absolute event rate for the comparator treatment. The manufacturer's original economic model did not distinguish between types of bleed and types of venous thromboembolism for each comparator individually, but assumed that they were all the same. Since this assumption may favour apixaban, the ERG asked the manufacturer to provide an adjusted model that allowed the differences in type of bleed and type of venous thromboembolism. This adapted model was provided by the manufacturer.
The probabilities of other clinical events in the decision tree element of the model were assumed to be treatment independent and assumed not to differ between apixaban, enoxaparin, rivaroxaban and dabigatran etexilate. Where possible, the probabilities for the post-event treatment-independent probabilities were obtained from a synthesis of all the trials on rivaroxaban and dabigatran etexilate. The manufacturer undertook a literature review to identify parameter estimates of long-term recurrent venous thromboembolism and post-thrombotic syndrome.
The manufacturer presented drug acquisition costs for a course of treatment depending on the treatment durations assumed for each treatment. The treatment durations applied were: for apixaban, total knee replacement 12 days and total hip replacement 34 days (mean duration in ADVANCE 2 and 3 trials); for enoxaparin, total knee replacement 12 days and total hip replacement 34 days (mean duration in ADVANCE 2 and 3 trials); for rivaroxaban total knee replacement 12 days and total hip replacement 33 days (mean duration in RECORD 1 and 3 trials); for dabigatran etexilate ,and total knee replacement 8 days and total hip replacement 32 days (median duration in RE-MODEL and RE-NOVATE). The costs per course of treatment for total knee replacement were £48.48, £52.97, £33.60 and £41.16 for enoxaparin, rivaroxaban, dabigatran etexilate and apixaban respectively. For total hip replacement the costs per course of treatment were £137.36, £145.68, £134.40 and £116.62 for enoxaparin, rivaroxaban dabigatran etexilate and apixaban respectively.
The manufacturer presented base-case analyses for people having total hip replacement surgery and for those having total knee replacement surgery. In the base-case analyses a comparison was made between enoxaparin, apixaban, dabigatran etexilate and rivaroxaban. For both total hip replacement surgery and total knee replacement surgery, apixaban, dabigatran etexilate and rivaroxaban were less expensive than enoxaparin. The quality-adjusted life year (QALY) differences between the treatments were small. For people having total hip replacement surgery, total QALYs ranged from 9.520 for enoxaparin to 9.536 for rivaroxaban. For patients having total knee replacement surgery, total QALYs ranged from 9.023 for enoxaparin to 9.090 for rivaroxaban.
For patients having total hip replacement, apixaban, rivaroxaban and dabigatran etexilate all dominated enoxaparin, that is they were less expensive and provided more benefit than enoxaparin. Apixaban was the least expensive technology. Both apixaban and rivaroxaban were more effective and less costly, and thus dominant, compared with dabigatran etexilate and enoxaparin. Rivaroxaban generated more QALYs compared with apixaban. The incremental cost-effectiveness ratio (ICER) of rivaroxaban was £21,661 per QALY gained compared with apixaban. For people having total knee replacement surgery, apixaban was less expensive than dabigatran etexilate and enoxaparin, but more expensive than rivaroxaban. Apixaban was also more clinically effective than dabigatran etexilate and enoxaparin. Both apixaban and rivaroxaban dominated dabigatran etexilate and enoxaparin in the analyses for total knee replacement.
The manufacturer conducted deterministic one-way sensitivity analysis, which included an assessment of the impact of a 50% reduction in the cost of dabigatran etexilate. For patients having total hip replacement, apixaban remained dominant compared with enoxaparin and dabigatran etexilate for all changes in the sensitivity analysis. Rivaroxaban was cost effective compared with apixaban, except when the time horizon was 10 years or less, when the age at surgery was 80 years, or when a smaller relative difference in the risk of the primary end point (total venous thromboembolic events and death from any cause) was assumed. For patients having total knee replacement, apixaban remained dominant compared with enoxaparin and dabigatran etexilate for all changes in the deterministic sensitivity analysis, whereas rivaroxaban dominated apixaban for all changes.
The manufacturer also presented probabilistic sensitivity analysis, which showed that in total hip replacement apixaban had a 53% probability of being the most cost-effective drug at a maximum acceptable ICER of £20,000 per QALY gained and rivaroxaban had a probability of 47%. At a maximum acceptable ICER of £30,000 per QALY gained these probabilities were 47% and 53% respectively. For total knee replacement, at a maximum acceptable ICER of £20,000 per QALY gained, apixaban had an 11% probability of being the most cost-effective drug. For rivaroxaban this probability was 89%. At a maximum acceptable ICER of £30,000 per QALY gained, these probabilities were 10% and 90% respectively.
The ERG considered the modelling approach to be reasonable because it had followed previous economic models, including a previous submission to NICE for NICE technology appraisal guidance 157. The ERG considered that the health states modelled were appropriate. The ERG also considered it appropriate for enoxaparin to be restricted to 40 mg once daily, which is the dosage licensed in Europe. The ERG considered it reasonable that the manufacturer had used enoxaparin to represent LMWHs. The ERG noted that the model does not allow movement from mild-to-moderate post-thrombotic syndrome to severe post-thrombotic syndrome and that there are no bleeding events in the long-term Markov model.
The ERG noted that all parameter uncertainty was not reflected in the probabilistic sensitivity analyses. The ERG therefore commented that the probabilistic sensitivity analyses probably underestimate the total uncertainty.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of apixaban for the prevention of venous thromboembolism after elective total hip or knee replacement surgery in adults having considered evidence on the nature of the condition and the value placed on the benefits of apixaban by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee discussed the decision problem and agreed that this appraisal would focus on choice among drugs for preventing venous thromboembolism. The Committee discussed 'Venous thromboembolism: reducing the risk' (NICE clinical guideline 92). It noted the recommendation that in addition to mechanical prophylaxis, people having elective hip replacement or elective knee replacement should be offered LMWH, dabigatran etexilate, rivaroxaban or fondaparinux. It also noted the written comments received from one of the clinical specialists that the newer oral anticoagulant agents for the prevention of venous thromboembolism are not used by all surgical units because some surgeons are concerned that they may increase the incidence of bleeding at the operation site, increasing the risk of infection, delayed wound healing and delayed mobilisation. The Committee was aware of these concerns, but concluded that any recommendations made would be limited to situations in which drugs for the prevention of venous thromboembolism were already recommended in 'Venous thromboembolism: reducing the risk' (NICE clinical guideline 92).
The Committee discussed the benefits of oral treatments compared with subcutaneous injection, in particular the greater acceptability and ease of management of oral administration. The Committee noted the written evidence from one of the clinical specialists and the patient expert that for treatments given by subcutaneous injection, people would have to be taught to self-inject before discharge from hospital or a district nurse would have to continue the treatment after discharge. The Committee heard from patient experts and the clinical specialist present at the Committee meeting that people prefer oral dosing to subcutaneous injection and therefore adherence to treatment after discharge might improve, although this remained uncertain. The Committee noted the twice-daily regimen for apixaban compared with the once-daily regimens for rivaroxaban and dabigatran etexilate. The Committee heard from the patient experts that if people received enough information about the effectiveness of apixaban and the importance of preventing venous thromboembolism they would be likely to adhere to apixaban treatment even though they needed to take it twice a day.
The Committee discussed the clinical effectiveness of apixaban compared with LMWH, rivaroxaban, dabigatran etexilate and fondaparinux in people having elective hip or knee surgery. It noted the direct evidence from randomised controlled trials of apixaban and enoxaparin, and the indirect and mixed treatment comparison of apixaban versus rivaroxaban, dabigatran etexilate and fondaparinux. It also noted that the direct evidence was limited to a comparison of apixaban and enoxaparin and that the manufacturer assumed that all LMWHs were equivalent in terms of their clinical effectiveness. The Committee heard that enoxaparin is the most widely used LMWH in the UK, and agreed that the comparison using enoxaparin as the only LMWH was appropriate. It discussed the applicability of the clinical trials to UK clinical practice, understanding that there is variation in strategies for preventing venous thromboembolism. The Committee agreed that data from the ADVANCE 2 and ADVANCE 3 randomised controlled trials, in which the patients in the control arm received 40 mg enoxaparin once daily, were applicable to UK clinical practice. It agreed that the ADVANCE 1 and APROPOS trials, which used an alternative dosing regimen of 30 mg enoxaparin twice daily, did not use the UK licensed dosage, and that they were less relevant to the evaluation of clinical effectiveness of apixaban than ADVANCE 2 and 3.
The Committee discussed the outcome data from these trials. It noted the written concerns of one of the clinical specialists about the use of surrogate markers as valid predictors of clinically relevant outcomes. The clinical specialist highlighted that there were limited data available to show a relationship between one of the major components of the composite primary outcome of the studies (asymptomatic deep vein thrombosis) and clinically relevant venous thromboembolic events, and that the data that were available did not suggest that asymptomatic deep vein thrombosis was a good predictor of clinical thromboembolic events after joint-replacement surgery. The clinical specialist present at the meeting stated that in his opinion there was sufficient evidence to suggest an association between asymptomatic deep vein thrombosis and acute pulmonary embolism. The Committee acknowledged the difference of opinion expressed by clinician specialists about asymptomatic deep vein thrombosis but agreed that asymptomatic deep vein thrombosis was widely used as an outcome measure in research studies, and was relevant for consideration.
The Committee discussed the results of the ADVANCE trials and concluded that apixaban was significantly more effective than enoxaparin in preventing venous thromboembolism. The Committee considered adverse events such as bleeding, noting that the bleeding rates were lower for apixaban than for enoxaparin, although the difference was not statistically significant. It concluded that apixaban could, using the evidence available, be considered more clinically effective than enoxaparin in preventing venous thromboembolic events, but was broadly comparable to enoxaparin in terms of short-term adverse effects.
The Committee considered the evidence on the clinical effectiveness of apixaban compared with rivaroxaban, dabigatran etexilate and fondaparinux through the indirect and mixed treatment comparisons. The Committee noted the ERG's critique of the indirect and mixed treatment comparisons and the manufacturer's response to the clarification requested by the ERG. It also noted that the manufacturer had undertaken three indirect and two mixed treatment comparison analyses which took account of the differences in UK and USA dosages of enoxaparin. The Committee agreed with the manufacturer and the ERG that the indirect and mixed treatment comparisons using the UK dosage of enoxaparin were most relevant to UK clinical practice and therefore it was reasonable to consider the results of these comparisons. The Committee was aware of the uncertainty associated with the results from the indirect comparison and the mixed treatment comparison as demonstrated by the wide confidence intervals (surrounding the point estimates from the indirect comparison analysis) and the credibility intervals (surrounding the point estimates from the mixed treatment comparison). The Committee was also aware of the inconsistency of some results between the indirect comparison and the mixed treatment comparison and between the indirect comparison and the direct randomised controlled trials, and the manufacturer's explanation for these inconsistencies. The Committee agreed that based on the evidence presented it was not possible to estimate the relative effectiveness of apixaban compared with rivaroxaban, dabigatran etexilate or fondaparinux.
The Committee then considered the factors that clinicians take into account when prescribing anticoagulant therapy for people having total hip and knee replacement surgery. The Committee discussed the concerns raised by orthopaedic surgeons about the effect of anticoagulants on local bleeding, infection and wound healing. The Committee noted the written statement from one clinical specialist that bleeding caused by anticoagulation is clinically important because it can contribute to deep surgical site infection. The Committee also noted from the written statement that some orthopaedic surgeons believed that new oral antithrombotic agents such as rivaroxaban and dabigatran etexilate may be associated with more treatment-related bleeds than enoxaparin and result in worse patient outcomes. The Committee heard from the clinical specialist present at the meeting that there was a 'trade-off' to be made between the benefits of reduced thrombotic events and increased risk of bleeding.
The Committee discussed the risk of bleeding into the joint and the association between the time between surgery and anticoagulant therapy taking effect, that is, the greater the time between surgery and anticoagulant therapy taking effect the lower the risk of bleeding. The Committee was aware of the different starting times in the summaries of product characteristics for each of the anticoagulants and noted that apixaban had the longest time window for administration following surgery (12–24 hours after surgery, compared with rivaroxaban 6–10 hours after surgery, dabigatran etexilate 1–4 hours after surgery and enoxaparin 6–12 hours after surgery). The Committee had not seen any evidence assessing the association between the different drug regimens and the risk of bleeding. The Committee agreed that the longer time window for administration of apixaban could allow clinicians to assess a patient's bleeding risk before starting thromboprophylaxis after total hip or knee replacement surgery.
The Committee then discussed the choice of anticoagulants for people with renal disease. The Committee heard from the clinical specialist that in patients with severe renal disease all anticoagulant therapy carries additional risks and oral agents would be unsuitable. The Committee noted that for mild-to-moderate renal disease, the summary of product characteristics for apixaban did not specify a dose adjustment whereas the summary of product characteristics for dabigatran etexilate did. The Committee agreed that although there was insufficient evidence to determine the relative clinical effectiveness of the oral anticoagulants, apixaban and rivaroxaban shared a potential benefit for clinical practice in that there is no need to modify the dose in people with mild to moderate kidney function impairment.
The Committee discussed the evidence submitted by the manufacturer on the cost effectiveness of apixaban for the prevention of venous thromboembolism in people having hip or knee replacement, the ERG's critique of the manufacturer's submission, and the manufacturer's response to the clarification requested by the ERG. The Committee noted the two-phase structure of the economic model and accepted that the modelling approach used by the manufacturer was appropriate for modelling the prevention of venous thromboembolism.
The Committee discussed the base-case analysis in the manufacturer's submission. It noted that the manufacturer had not included fondaparinux in the economic evaluation because there was insufficient clinical evidence available for the indirect comparison of apixaban and fondaparinux in patients having total knee replacement surgery. It also noted that the manufacturer had highlighted that fondaparinux was used in less than 1% of people in current UK clinical practice. The Committee was aware that the cost of dabigatran etexilate used in the base-case analysis did not reflect the current NHS list price of dabigatran etexilate. It was also aware that the 40% reduction in the cost of dabigatran etexilate occurred after the manufacturer of apixaban had provided its submission to NICE, but that the submission included a one-way sensitivity analysis that anticipated the price reduction (see section 3.24). The Committee noted that in the base-case analysis apixaban dominated enoxaparin and dabigatran etexilate in both total hip and knee replacement, that is, apixaban was associated with larger QALY gains and lower costs. It further noted that for total knee replacement the ICER for rivaroxaban compared with apixaban was £21,700 per QALY gained, but for total hip replacement rivaroxaban dominated apixaban. The Committee then considered the one-way sensitivity analysis provided by the manufacturer, and in particular that relating to a 50% reduction in the price of dabigatran etexilate. The Committee noted that for patients having total hip replacement or total knee replacement, apixaban still remained dominant compared with enoxaparin and dabigatran etexilate for all changes in the sensitivity analysis. The Committee then considered the plausibility of the cost-effectiveness results, in particular in relation to the strength of the evidence for clinical effectiveness. The Committee recognised that there were uncertainties associated with the ICERs for rivaroxaban and dabigatran etexilate because the clinical data for these drugs included in the model were originally derived from the indirect comparison, unlike the ICER for enoxaparin which was derived from direct head-to-head trials. The Committee therefore agreed that the cost-effectiveness results for apixaban compared with enoxaparin were the most robust, and that there were significant uncertainties in the comparisons of cost effectiveness with rivaroxaban and dabigatran etexilate.
The Committee concluded that apixaban was more clinically effective and cheaper than enoxaparin. It also concluded that there was insufficient clinical evidence to determine whether or not apixaban was more or less clinically effective than rivaroxaban or dabigatran etexilate and therefore the ICERs presented for these anticoagulants had to be interpreted with caution. However, the Committee did accept that any differences in clinical effectiveness between the agents were likely to be small, and apixaban may provide some clinical advantages compared with the other agents. The Committee therefore concluded that apixaban should be recommended as an option for preventing venous thromboembolism in adults after elective total hip and total knee replacement surgery.
The Committee considered whether its recommendation was associated with any issues related to equality legislation and the requirement for fairness. The Committee noted that no issues had been highlighted during the scoping exercise or during the course of the appraisal. The Committee was aware that consultees and commentators had raised the issue of providing non-injectable medication for people with needle phobia but concluded that the recommendations do not affect access to the technology for any specific groups.
# Summary of Appraisal Committee's key conclusions
TA245
Appraisal title: 'Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults'
Section
Key conclusion
Apixaban is recommended as an option for the prevention of venous thromboembolism in adults after elective hip or knee replacement surgery.
The Committee concluded that apixaban was more clinically effective and cheaper than enoxaparin. It also concluded that there was insufficient clinical evidence to determine whether or not apixaban was more or less clinically effective than rivaroxaban and dabigatran etexilate and therefore the ICERs presented for these anticoagulants had to be interpreted with caution.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee noted the recommendation in the NICE clinical guideline 'Venous thromboembolism' (NICE clinical guideline 92) that people having elective hip replacement or elective knee replacement should be offered LMWH, dabigatran etexilate, rivaroxaban or fondaparinux.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
Apixaban appeared to provide a potential benefit for clinical practice. The dose does not need to be adjusted for people with compromised renal function.
What is the position of the treatment in the pathway of care for the condition?
Apixaban has a marketing authorisation for the 'prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery'.
Adverse effects
Common adverse events include anaemia, haemorrhage, contusion and nausea. See the summary of product characteristics for full details.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
Four good quality randomised controlled trials were identified comparing apixaban with enoxaparin. Fifteen randomised controlled trials were identified for inclusion in the indirect comparison of apixaban with dabigatran etexilate, rivaroxaban and fondaparinux. The manufacturer included 43 studies for the mixed treatment comparison.
Relevance to general clinical practice in the NHS
Of the fifteen studies identified for inclusion in the indirect comparison, nine compared the treatment of interest with enoxaparin at the UK dosage of 40 mg once daily.
The Committee agreed that the ADVANCE 2 and ADVANCE 3 randomised controlled trials, in which patients in the control arm received enoxaparin 40 mg once daily, were applicable to UK clinical practice.
Uncertainties generated by the evidence
The manufacturer highlighted inconsistencies among the results of the mixed treatment comparisons and the head-to-head trials.
The Committee was aware of the inconsistency of some results between the indirect comparison and the mixed treatment comparison and between the indirect comparison and the head-to-head trials, and the manufacturer's explanation for these inconsistencies.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
No subgroups were identified.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee agreed that based on the evidence presented it was not possible to determine an estimate of relative effectiveness of apixaban compared with rivaroxaban, dabigatran etexilate or fondaparinux.
Evidence for cost effectiveness
Availability and nature of evidence
The manufacturer submitted an economic model assessing the cost effectiveness of apixaban compared with enoxaparin, dabigatran etexilate and rivaroxaban. The manufacturer adopted a two-stage modelling approach. A decision tree to model treatment in the prophylactic phase (from the time of surgery to 90 days after surgery) and a Markov model to model the long-term events (90 days after surgery).
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee recognised uncertainties associated with ICERs for rivaroxaban and dabigatran etexilate because the clinical data were derived from indirect comparison analysis, unlike the ICER for enoxaparin, which was derived from direct head-to-head trials.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The QALY differences between the treatments were small. For people having total hip replacement surgery, total QALYs ranged from 9.520 for enoxaparin to 9.536 for rivaroxaban. For patients having total knee replacement surgery, total QALYs ranged from 9.023 for enoxaparin to 9.090 for rivaroxaban.
Are there specific groups of people for whom the technology is particularly cost effective?
No subgroups were identified.
What are the key drivers of cost effectiveness?
Rivaroxaban was cost effective compared with apixaban, except when the time horizon was 10 years or less, when the age at surgery was 80 years or when a smaller relative difference in the risk of the primary end point (total venous thromboembolism and death from any cause) was assumed.
Most likely cost-effectiveness estimate (given as an ICER)
In base-case analyses apixaban dominated enoxaparin. The Committee agreed that because the ICER for enoxaparin was derived from data from direct head-to-head trials, the cost-effectiveness results for apixaban compared with enoxaparin were the most robust.
Additional factors taken into account
Patient access schemes (PPRS)
The manufacturer did not submit a patient access scheme.
End-of-life considerations
The supplementary advice was not relevant to this appraisal.
Equalities considerations and social value judgements
No equalities issues were raised in this appraisal.
# Recommendations for further research
More trials of apixaban compared with other LMWHs in total hip and knee replacement would decrease the uncertainty of the clinical and cost effectiveness of these treatments. Trials directly comparing apixaban with rivaroxaban, dabigatran etexilate and fondaparinux would strengthen the evidence base for these comparisons.# Related NICE guidance
Published
Venous thromboembolism: reducing the risk. NICE clinical guideline 92 (2010).
Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. NICE technology appraisal guidance 157 (2008).
Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement surgery in adults. NICE technology appraisal guidance 170 (2009).# Review of guidance
The guidance on this technology will be considered for review in January 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveJanuary 2012# Changes after publication
February 2014: implementation section updated to clarify that apixaban is recommended as an option for preventing venous thromboembolism after total hip or knee replacement. Additional minor maintenance update also carried out.
June 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Apixaban is recommended as an option for the prevention of venous thromboembolism in adults after elective hip or knee replacement surgery.', 'The technology ': "Apixaban (Eliquis, Bristol-Myers Squibb and Pfizer) is an anticoagulant that affects the blood coagulation cascade by directly inhibiting activated factor X (factor Xa), so inhibiting thrombin formation and the development of thrombi. Apixaban has a marketing authorisation for the 'prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery'.\n\nThe recommended dosage of apixaban in the summary of product characteristics is 2.5 mg orally twice daily. The initial dose should be taken 12–24 hours after surgery. The duration of treatment depends on the individual risk of the patient for venous thromboembolism, which is determined by the type of orthopaedic surgery. Recommended treatment durations are 32–38 days for patients having hip replacement surgery and 10–14 days for patients having knee replacement surgery.\n\nAccording to the summary of product characteristics, 11% of patients treated with apixaban 2.5 mg twice daily in clinical trials experienced adverse reactions. As with other anticoagulants, bleeding may occur during apixaban therapy in patients with risk factors such as lesions liable to bleed. Common adverse reactions are anaemia, haemorrhage, contusion and nausea. For full details of side effects and contraindications, see the summary of product characteristics.\n\nApixaban costs £17.15, £34.30 and £102.90 for packs of 10, 20 and 60 tablets respectively excluding VAT (NHS list price as reported by the manufacturer). The cost of treatment is estimated to be £41.16 (based on 12 days' treatment) for knee replacement surgery and £116.62 for hip replacement surgery (based on 34 days' treatment). Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of apixaban and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer's submission compared apixaban with enoxaparin, a low molecular weight heparin (LMWH), using direct evidence from randomised controlled trials, and with dabigatran etexilate, rivaroxaban and fondaparinux, using evidence from randomised controlled trials that had been incorporated into an adjusted indirect comparison and a mixed treatment comparison. Outcomes analysed included mortality, incidence of venous thromboembolism and adverse reactions to treatment. All of these were specified in the decision problem for this appraisal. The clinical evidence submitted by the manufacturer did not include analysis of outcomes such as joint infection, length of hospital stay, complications after deep vein thrombosis or health-related quality of life because these were not available from the clinical trials of apixaban. However, the manufacturer included complications after deep vein thrombosis and health-related quality of life in its economic submission.\n\nThe manufacturer identified four randomised controlled trials comparing apixaban with enoxaparin for the prevention of venous thromboembolism. ADVANCE 1 ('Apixaban dosed orally versus anticoagulation with enoxaparin'), ADVANCE 2 and APROPOS ('Apixaban prophylaxis in patients undergoing total knee replacement surgery') recruited patients having total knee replacement surgery. ADVANCE 3 recruited patients having total hip replacement surgery.\n\nADVANCE 1 (n = 3195) and ADVANCE 2 (n = 3057) were multicentre parallel-group randomised controlled trials. In ADVANCE 1, apixaban was given at a dosage of 2.5 mg twice daily for 12 days and enoxaparin at a dosage of 30 mg twice daily for 12 days. Treatment in both arms was started 12–24 hours after surgery. In ADVANCE 2, apixaban was given at a dosage of 2.5 mg twice daily for 11 days and enoxaparin at a dosage of 40 mg once daily for 11 days. Apixaban was started 12–24 hours after surgery and enoxaparin 9–15 hours before surgery. APROPOS (n = 305) was a dose-finding clinical study in which patients were randomised to receive one of several doses of apixaban (5 mg, 10 mg, 20 mg, once or twice daily), enoxaparin 30 mg twice daily or warfarin. ADVANCE 2 used the UK dosing regimen for enoxaparin (40 mg once daily) whereas ADVANCE 1 and APROPOS used the US dosing regimen (30 mg twice daily). The manufacturer considered ADVANCE 2 to be the most relevant study for the prevention of venous thromboembolism after total knee replacement surgery in the context of UK clinical practice because it was the only study that compared apixaban with the UK licensed dose of enoxaparin.\n\nADVANCE 3 (n = 5407) was a multicentre parallel-group randomised controlled trial comparing apixaban with enoxaparin for the prevention of venous thromboembolism after total hip replacement surgery. Apixaban was given at a dosage of 2.5 mg twice daily for 32–38 days and enoxaparin at a dosage of 40 mg once daily for 32–38 days. Apixaban was started 12–24 hours after surgery and enoxaparin 9–15 hours before surgery.\n\nThe primary efficacy end point for ADVANCE 1 and ADVANCE 2 was the composite of all incidences of venous thromboembolism (pulmonary embolism, symptomatic and asymptomatic deep vein thrombosis), and death from any cause during the intended treatment period. The primary safety end point was bleeding and included confirmed major bleeding events, a composite of confirmed major bleeding events and confirmed non-major bleeding events, and all bleeding events. The primary efficacy end point for ADVANCE 3 was the composite of symptomatic or asymptomatic deep vein thrombosis, non-fatal pulmonary embolism, and death from any cause during the intended treatment period. The primary safety end point was bleeding during treatment or within 2 days of the last dose of study medication. The primary efficacy end point for APROPOS was the composite of symptomatic or asymptomatic deep vein thrombosis, non-fatal pulmonary embolism and death from any cause. The primary safety end point was major bleeding.\n\nThe primary efficacy analysis dataset included all randomised patients who had a bilateral venogram that was evaluable, venous thromboembolism, or who died from any cause. The manufacturer stated that the intention-to-treat analysis assumed that no readable venogram represented no event, which potentially underestimated the number of venous thromboembolic events in the intention-to-treat population. The remaining efficacy and safety analyses were conducted on the intention-to-treat population.\n\nADVANCE 2 showed that apixaban was statistically significantly superior to enoxaparin in terms of the primary composite end point of all venous thromboembolism and death from any cause (relative risk [RR] 0.62, 95% confidence interval [CI] 0.51 to 0.74), as well as in terms of major venous thromboembolism (RR 0.5, 95% CI 0.26 to 0.97) and all deep vein thrombosis (RR 0.6, 95% CI 0.5 to 0.72). For major bleeding events and all bleeding events, the relative risks were 0.65 (95% CI 0.28 to 1.49) and 0.83 (95% CI 0.65 to 1.06) respectively. ADVANCE 1 and APROPOS both used the US dosing regimen for enoxaparin and neither reported significant differences for any of the outcomes reported.\n\nADVANCE 3 showed that apixaban was statistically significantly superior to enoxaparin in terms of the primary composite end point of all venous thromboembolism and death from any cause (RR 0.36, 95% CI 0.23 to 0.56), as well as in terms of major venous thromboembolism (RR 0.4, 95% CI 0.19 to 0.83) and all deep vein thrombosis (RR academic in confidence). For major bleeding events and all bleeding events the relative risks were 1.22 (95% CI 0.65 to 2.26) and 0.93 (95% CI 0.81 to 1.08) respectively.\n\nIn the absence of direct evidence comparing apixaban with dabigatran etexilate, rivaroxaban and fondaparinux, the manufacturer presented results of an adjusted indirect comparison using enoxaparin as the common comparator. The manufacturer did not include an assessment of apixaban compared with other LMWHs in the indirect comparison. It considered enoxaparin to be the most widely used LMWH in the UK. Moreover, enoxaparin was the comparator used in the apixaban registration trials (ADVANCE 2 and 3). The manufacturer identified 15 randomised controlled trials for inclusion in the indirect comparison. Of these, nine compared the treatment of interest with enoxaparin at the UK dosage of 40 mg once daily. The remaining six studies compared the treatment of interest with enoxaparin 30 mg twice daily.\n\nThe manufacturer reported adjusted indirect comparisons using pooled data from studies using the UK dosage of enoxaparin alone, US dosage of enoxaparin alone and combined UK and US dosages of enoxaparin as the common comparator. Results were expressed as odds ratios for apixaban versus the other treatments of interest. For the outcome of composite venous thromboembolic events, and other end points of any deep vein thrombosis, asymptomatic deep vein thrombosis and major venous thromboembolism, results from the primary efficacy population were reported. For symptomatic deep vein thrombosis, pulmonary embolism, any bleeding, major bleeding, clinically relevant non-major bleeding and minor bleeding, results were reported from the intention-to-treat population.\n\nThe manufacturer stated that it considered the adjusted indirect comparisons of apixaban 2.5 mg twice daily against other anticoagulants of interest using the UK dosage of enoxaparin to be the most relevant to UK clinical practice. The results of such analyses for hip replacement showed that there were no significant differences for apixaban when compared with rivaroxaban for total venous thromboembolism and death from any cause, any deep vein thrombosis, major venous thromboembolism, pulmonary embolism, any bleeding or major bleeding. These results were the same for total knee replacement, except for the number of pulmonary embolic events, which was statistically significantly reduced with rivaroxaban. When compared with dabigatran etexilate, total venous thromboembolism, death from any cause and any deep vein thrombosis were statistically significantly reduced with apixaban; there were no significant differences for the other main outcomes (major venous thromboembolism, pulmonary embolism, any bleeding and major bleeding). These results were the same for total hip replacement and total knee replacement. When compared with fondaparinux in patients with total hip replacement, apixaban showed no significant differences for any deep vein thrombosis, pulmonary embolism or major bleeding. Other main outcomes (total venous thromboembolism and death from any cause, major venous thromboembolism and any bleeding) were not reported using indirect comparisons. There were no randomised controlled trials comparing fondaparinux with the UK dosage (40 mg daily) of enoxaparin in patients having total knee replacement surgery, therefore an adjusted indirect comparison was not possible. The results of the adjusted indirect comparisons using data with US dosages of enoxaparin and pooled data with UK and US dosages of enoxaparin were considered to be academic in confidence by the manufacturer and therefore cannot be presented.\n\nThe manufacturer also undertook a mixed treatment comparison that included 43 studies. Results were expressed as odds ratios and were for the same outcomes as for the adjusted indirect comparisons. The manufacturer reported mixed treatment comparisons using only the UK dosage of enoxaparin and also using pooled data for UK and US dosages. The results of the mixed treatment comparisons cannot be reported because the manufacturer considers the results to be academic in confidence.\n\nThe manufacturer considered the adjusted indirect comparison using the UK dosage of enoxaparin to be the most appropriate analysis for informing the relative efficacy and safety of apixaban compared with enoxaparin, rivaroxaban, dabigatran etexilate and fondaparinux. This was because results from the mixed treatment comparison were inconsistent with some of the head-to-head data from the randomised controlled trials. The manufacturer noted that the inconsistent results and wider credibility intervals may be a result of the large number of trials contributing to the enoxaparin 40 mg once daily node in the network analysis. These trials tended to be older, with fewer study criteria reported and small sample sizes, and compared enoxaparin 40 mg once daily with treatments other than the comparators in the scope. The manufacturer highlighted inconsistencies between the results of the mixed treatment comparison and the head-to-head trial for the following comparisons: apixaban 2.5 mg twice daily compared with enoxaparin 40 mg once daily, and rivaroxaban 10 mg once daily compared with enoxaparin 40 mg once daily for the primary composite end point (venous thromboembolism plus death from any cause) and on some of the secondary outcomes.\n\nThe ERG considered that the three clinical trials, ADVANCE 1, 2 and 3, which represent the main clinical efficacy evidence, were of reasonable methodological quality and measured a range of outcomes that were appropriate and clinically relevant. It stated that processes and validation of study screening and data extraction appeared to be appropriate. The ERG agreed with the chosen doses for each treatment included in the adjusted indirect and mixed treatment comparisons. The ERG commented that the statistical methods were explicitly described for the meta-analyses and indirect comparisons, and all relevant analyses were performed. In addition, the ERG commented that the manufacturer's conclusion that the mixed treatment comparison was less reliable than the adjusted indirect comparison seemed reasonable.\n\nThe manufacturer submitted an economic model assessing the cost effectiveness of apixaban compared with enoxaparin, dabigatran etexilate and rivaroxaban. A two-stage modelling approach was adopted, based on an approach previously used for 'Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults' (NICE technology appraisal guidance 157). A decision tree was used to model treatment in the prophylactic phase (from the time of surgery to 90 days after surgery) and a Markov model was used to model long-term events (90 days after surgery and beyond). The differential effects of treatment are only realised in the prophylactic phase of the model. The Markov model has a cycle length of 1 year and a maximum time horizon of 60 years (base case 35 years).\n\nIn the decision tree model, a hypothetical patient can experience a venous thromboembolic event (total venous thromboembolic events or death from any cause) or no event. When death is not a result of venous thromboembolism, death can result from a major bleed or other cause. Deaths from other causes refer to deaths not related to venous thromboembolism and deaths not related to anticoagulation during the prophylactic phase. A venous thromboembolic event can be a pulmonary embolism, symptomatic or asymptomatic deep vein thrombosis (both either distal or proximal). Pulmonary embolism may or may not result in death. A cohort of hypothetical patients surviving pulmonary embolism and a cohort with symptomatic deep vein thrombosis receive treatment and progress to the non-fatal bleeding events state of the model. A cohort of hypothetical patients with asymptomatic deep vein thrombosis progress to the non-fatal bleeding events state without treatment. A cohort of hypothetical patients without venous thromboembolic events also progress directly to the non-fatal bleeding state. Probabilities of bleeding are independent of what happened earlier in the model. A cohort of hypothetical patients experiencing an intracranial haemorrhage proceed immediately to the 'disabled' health state and remain there for the duration of the model or until they die. Alternatively, hypothetical patients can experience no bleeding, minor bleeding, a non-major clinically relevant bleed or a major bleed (other than an intracranial haemorrhage). In the period between the end of treatment and 90 days after surgery, hypothetical patients without symptoms can become symptomatic. Asymptomatic deep vein thrombosis that becomes symptomatic after prophylactic treatment is assumed to be of the same type (distal thrombosis remains distal and proximal thrombosis remains proximal).\n\nAt 90 days after surgery a cohort of hypothetical patients leave the decision tree model and enter the long-term Markov model. Hypothetical patients who have not experienced a venous thromboembolic event enter the Markov model in the 'well' state, whereas hypothetical patients who have asymptomatic deep vein thrombosis enter the Markov model in the untreated venous thromboembolic state. Hypothetical patients who have had a pulmonary embolism or a deep vein thrombosis or have made the transition from asymptomatic to symptomatic deep vein thrombosis enter the Markov model in the treated venous thromboembolic state. Hypothetical patients who have had an intracranial haemorrhage enter in the 'disabled' health state. A cohort of hypothetical patients who died while in the decision tree model enter the Markov model in the 'dead' state. In the long-term Markov model, a cohort of hypothetical patients can remain well, die, have a pulmonary embolism, a deep vein thrombosis, mild-to-moderate post-thrombotic syndrome (divided into year 1 and subsequent years) or a severe post-thrombotic syndrome (divided into year 1 and subsequent years). The same transitions are possible for treated and untreated patients. Once a hypothetical patient has a pulmonary embolism or deep vein thrombosis they make the transition to the treated venous thromboembolic state. There is no differential treatment effect in this long-term phase of the model.\n\nKey assumptions in the economic evaluation included the assumption that during the prophylactic phase, deaths from pulmonary embolism and other causes occur at 35 days for total hip replacement and 14 days for total knee replacement in each treatment arm. It was assumed that during the phase after prophylaxis, deaths from pulmonary embolism occur at 63 days for total hip replacement and 52 days for total knee replacement. These are the midpoints of the post-prophylactic phase for each indication. It was also assumed that deaths from major bleeds occur at 35 days for total hip replacement and 14 days for total knee replacement, regardless of whether the bleeding rates were based on the duration of prophylaxis or 90 days.\n\nThe manufacturer modelled the efficacy (total venous thromboembolic events and all deaths) and safety (total bleeds) of the treatments in line with the corresponding end points in the two clinical trials of apixaban (ADVANCE 2 and 3) and in the indirect comparison of apixaban with rivaroxaban and with dabigatran etexilate. The manufacturer stated that because data were not available for an indirect comparison of apixaban with fondaparinux in patients having total knee replacement surgery, apixaban could not be compared with fondaparinux in the economic model. The manufacturer also stated that relative risks were used in the economic model rather than odds ratios because they can be directly applied to an absolute probability of an event to generate the absolute event rate for the comparator treatment. The manufacturer's original economic model did not distinguish between types of bleed and types of venous thromboembolism for each comparator individually, but assumed that they were all the same. Since this assumption may favour apixaban, the ERG asked the manufacturer to provide an adjusted model that allowed the differences in type of bleed and type of venous thromboembolism. This adapted model was provided by the manufacturer.\n\nThe probabilities of other clinical events in the decision tree element of the model were assumed to be treatment independent and assumed not to differ between apixaban, enoxaparin, rivaroxaban and dabigatran etexilate. Where possible, the probabilities for the post-event treatment-independent probabilities were obtained from a synthesis of all the trials on rivaroxaban and dabigatran etexilate. The manufacturer undertook a literature review to identify parameter estimates of long-term recurrent venous thromboembolism and post-thrombotic syndrome.\n\nThe manufacturer presented drug acquisition costs for a course of treatment depending on the treatment durations assumed for each treatment. The treatment durations applied were: for apixaban, total knee replacement 12 days and total hip replacement 34 days (mean duration in ADVANCE 2 and 3 trials); for enoxaparin, total knee replacement 12 days and total hip replacement 34 days (mean duration in ADVANCE 2 and 3 trials); for rivaroxaban total knee replacement 12 days and total hip replacement 33 days (mean duration in RECORD 1 and 3 trials); for dabigatran etexilate ,and total knee replacement 8 days and total hip replacement 32 days (median duration in RE-MODEL and RE-NOVATE). The costs per course of treatment for total knee replacement were £48.48, £52.97, £33.60 and £41.16 for enoxaparin, rivaroxaban, dabigatran etexilate and apixaban respectively. For total hip replacement the costs per course of treatment were £137.36, £145.68, £134.40 and £116.62 for enoxaparin, rivaroxaban dabigatran etexilate and apixaban respectively.\n\nThe manufacturer presented base-case analyses for people having total hip replacement surgery and for those having total knee replacement surgery. In the base-case analyses a comparison was made between enoxaparin, apixaban, dabigatran etexilate and rivaroxaban. For both total hip replacement surgery and total knee replacement surgery, apixaban, dabigatran etexilate and rivaroxaban were less expensive than enoxaparin. The quality-adjusted life year (QALY) differences between the treatments were small. For people having total hip replacement surgery, total QALYs ranged from 9.520 for enoxaparin to 9.536 for rivaroxaban. For patients having total knee replacement surgery, total QALYs ranged from 9.023 for enoxaparin to 9.090 for rivaroxaban.\n\nFor patients having total hip replacement, apixaban, rivaroxaban and dabigatran etexilate all dominated enoxaparin, that is they were less expensive and provided more benefit than enoxaparin. Apixaban was the least expensive technology. Both apixaban and rivaroxaban were more effective and less costly, and thus dominant, compared with dabigatran etexilate and enoxaparin. Rivaroxaban generated more QALYs compared with apixaban. The incremental cost-effectiveness ratio (ICER) of rivaroxaban was £21,661 per QALY gained compared with apixaban. For people having total knee replacement surgery, apixaban was less expensive than dabigatran etexilate and enoxaparin, but more expensive than rivaroxaban. Apixaban was also more clinically effective than dabigatran etexilate and enoxaparin. Both apixaban and rivaroxaban dominated dabigatran etexilate and enoxaparin in the analyses for total knee replacement.\n\nThe manufacturer conducted deterministic one-way sensitivity analysis, which included an assessment of the impact of a 50% reduction in the cost of dabigatran etexilate. For patients having total hip replacement, apixaban remained dominant compared with enoxaparin and dabigatran etexilate for all changes in the sensitivity analysis. Rivaroxaban was cost effective compared with apixaban, except when the time horizon was 10 years or less, when the age at surgery was 80 years, or when a smaller relative difference in the risk of the primary end point (total venous thromboembolic events and death from any cause) was assumed. For patients having total knee replacement, apixaban remained dominant compared with enoxaparin and dabigatran etexilate for all changes in the deterministic sensitivity analysis, whereas rivaroxaban dominated apixaban for all changes.\n\nThe manufacturer also presented probabilistic sensitivity analysis, which showed that in total hip replacement apixaban had a 53% probability of being the most cost-effective drug at a maximum acceptable ICER of £20,000 per QALY gained and rivaroxaban had a probability of 47%. At a maximum acceptable ICER of £30,000 per QALY gained these probabilities were 47% and 53% respectively. For total knee replacement, at a maximum acceptable ICER of £20,000 per QALY gained, apixaban had an 11% probability of being the most cost-effective drug. For rivaroxaban this probability was 89%. At a maximum acceptable ICER of £30,000 per QALY gained, these probabilities were 10% and 90% respectively.\n\nThe ERG considered the modelling approach to be reasonable because it had followed previous economic models, including a previous submission to NICE for NICE technology appraisal guidance 157. The ERG considered that the health states modelled were appropriate. The ERG also considered it appropriate for enoxaparin to be restricted to 40 mg once daily, which is the dosage licensed in Europe. The ERG considered it reasonable that the manufacturer had used enoxaparin to represent LMWHs. The ERG noted that the model does not allow movement from mild-to-moderate post-thrombotic syndrome to severe post-thrombotic syndrome and that there are no bleeding events in the long-term Markov model.\n\nThe ERG noted that all parameter uncertainty was not reflected in the probabilistic sensitivity analyses. The ERG therefore commented that the probabilistic sensitivity analyses probably underestimate the total uncertainty.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of apixaban for the prevention of venous thromboembolism after elective total hip or knee replacement surgery in adults having considered evidence on the nature of the condition and the value placed on the benefits of apixaban by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the decision problem and agreed that this appraisal would focus on choice among drugs for preventing venous thromboembolism. The Committee discussed 'Venous thromboembolism: reducing the risk' (NICE clinical guideline 92). It noted the recommendation that in addition to mechanical prophylaxis, people having elective hip replacement or elective knee replacement should be offered LMWH, dabigatran etexilate, rivaroxaban or fondaparinux. It also noted the written comments received from one of the clinical specialists that the newer oral anticoagulant agents for the prevention of venous thromboembolism are not used by all surgical units because some surgeons are concerned that they may increase the incidence of bleeding at the operation site, increasing the risk of infection, delayed wound healing and delayed mobilisation. The Committee was aware of these concerns, but concluded that any recommendations made would be limited to situations in which drugs for the prevention of venous thromboembolism were already recommended in 'Venous thromboembolism: reducing the risk' (NICE clinical guideline 92).\n\nThe Committee discussed the benefits of oral treatments compared with subcutaneous injection, in particular the greater acceptability and ease of management of oral administration. The Committee noted the written evidence from one of the clinical specialists and the patient expert that for treatments given by subcutaneous injection, people would have to be taught to self-inject before discharge from hospital or a district nurse would have to continue the treatment after discharge. The Committee heard from patient experts and the clinical specialist present at the Committee meeting that people prefer oral dosing to subcutaneous injection and therefore adherence to treatment after discharge might improve, although this remained uncertain. The Committee noted the twice-daily regimen for apixaban compared with the once-daily regimens for rivaroxaban and dabigatran etexilate. The Committee heard from the patient experts that if people received enough information about the effectiveness of apixaban and the importance of preventing venous thromboembolism they would be likely to adhere to apixaban treatment even though they needed to take it twice a day.\n\nThe Committee discussed the clinical effectiveness of apixaban compared with LMWH, rivaroxaban, dabigatran etexilate and fondaparinux in people having elective hip or knee surgery. It noted the direct evidence from randomised controlled trials of apixaban and enoxaparin, and the indirect and mixed treatment comparison of apixaban versus rivaroxaban, dabigatran etexilate and fondaparinux. It also noted that the direct evidence was limited to a comparison of apixaban and enoxaparin and that the manufacturer assumed that all LMWHs were equivalent in terms of their clinical effectiveness. The Committee heard that enoxaparin is the most widely used LMWH in the UK, and agreed that the comparison using enoxaparin as the only LMWH was appropriate. It discussed the applicability of the clinical trials to UK clinical practice, understanding that there is variation in strategies for preventing venous thromboembolism. The Committee agreed that data from the ADVANCE 2 and ADVANCE 3 randomised controlled trials, in which the patients in the control arm received 40 mg enoxaparin once daily, were applicable to UK clinical practice. It agreed that the ADVANCE 1 and APROPOS trials, which used an alternative dosing regimen of 30 mg enoxaparin twice daily, did not use the UK licensed dosage, and that they were less relevant to the evaluation of clinical effectiveness of apixaban than ADVANCE 2 and 3.\n\nThe Committee discussed the outcome data from these trials. It noted the written concerns of one of the clinical specialists about the use of surrogate markers as valid predictors of clinically relevant outcomes. The clinical specialist highlighted that there were limited data available to show a relationship between one of the major components of the composite primary outcome of the studies (asymptomatic deep vein thrombosis) and clinically relevant venous thromboembolic events, and that the data that were available did not suggest that asymptomatic deep vein thrombosis was a good predictor of clinical thromboembolic events after joint-replacement surgery. The clinical specialist present at the meeting stated that in his opinion there was sufficient evidence to suggest an association between asymptomatic deep vein thrombosis and acute pulmonary embolism. The Committee acknowledged the difference of opinion expressed by clinician specialists about asymptomatic deep vein thrombosis but agreed that asymptomatic deep vein thrombosis was widely used as an outcome measure in research studies, and was relevant for consideration.\n\nThe Committee discussed the results of the ADVANCE trials and concluded that apixaban was significantly more effective than enoxaparin in preventing venous thromboembolism. The Committee considered adverse events such as bleeding, noting that the bleeding rates were lower for apixaban than for enoxaparin, although the difference was not statistically significant. It concluded that apixaban could, using the evidence available, be considered more clinically effective than enoxaparin in preventing venous thromboembolic events, but was broadly comparable to enoxaparin in terms of short-term adverse effects.\n\nThe Committee considered the evidence on the clinical effectiveness of apixaban compared with rivaroxaban, dabigatran etexilate and fondaparinux through the indirect and mixed treatment comparisons. The Committee noted the ERG's critique of the indirect and mixed treatment comparisons and the manufacturer's response to the clarification requested by the ERG. It also noted that the manufacturer had undertaken three indirect and two mixed treatment comparison analyses which took account of the differences in UK and USA dosages of enoxaparin. The Committee agreed with the manufacturer and the ERG that the indirect and mixed treatment comparisons using the UK dosage of enoxaparin were most relevant to UK clinical practice and therefore it was reasonable to consider the results of these comparisons. The Committee was aware of the uncertainty associated with the results from the indirect comparison and the mixed treatment comparison as demonstrated by the wide confidence intervals (surrounding the point estimates from the indirect comparison analysis) and the credibility intervals (surrounding the point estimates from the mixed treatment comparison). The Committee was also aware of the inconsistency of some results between the indirect comparison and the mixed treatment comparison and between the indirect comparison and the direct randomised controlled trials, and the manufacturer's explanation for these inconsistencies. The Committee agreed that based on the evidence presented it was not possible to estimate the relative effectiveness of apixaban compared with rivaroxaban, dabigatran etexilate or fondaparinux.\n\nThe Committee then considered the factors that clinicians take into account when prescribing anticoagulant therapy for people having total hip and knee replacement surgery. The Committee discussed the concerns raised by orthopaedic surgeons about the effect of anticoagulants on local bleeding, infection and wound healing. The Committee noted the written statement from one clinical specialist that bleeding caused by anticoagulation is clinically important because it can contribute to deep surgical site infection. The Committee also noted from the written statement that some orthopaedic surgeons believed that new oral antithrombotic agents such as rivaroxaban and dabigatran etexilate may be associated with more treatment-related bleeds than enoxaparin and result in worse patient outcomes. The Committee heard from the clinical specialist present at the meeting that there was a 'trade-off' to be made between the benefits of reduced thrombotic events and increased risk of bleeding.\n\nThe Committee discussed the risk of bleeding into the joint and the association between the time between surgery and anticoagulant therapy taking effect, that is, the greater the time between surgery and anticoagulant therapy taking effect the lower the risk of bleeding. The Committee was aware of the different starting times in the summaries of product characteristics for each of the anticoagulants and noted that apixaban had the longest time window for administration following surgery (12–24 hours after surgery, compared with rivaroxaban 6–10 hours after surgery, dabigatran etexilate 1–4 hours after surgery and enoxaparin 6–12 hours after surgery). The Committee had not seen any evidence assessing the association between the different drug regimens and the risk of bleeding. The Committee agreed that the longer time window for administration of apixaban could allow clinicians to assess a patient's bleeding risk before starting thromboprophylaxis after total hip or knee replacement surgery.\n\nThe Committee then discussed the choice of anticoagulants for people with renal disease. The Committee heard from the clinical specialist that in patients with severe renal disease all anticoagulant therapy carries additional risks and oral agents would be unsuitable. The Committee noted that for mild-to-moderate renal disease, the summary of product characteristics for apixaban did not specify a dose adjustment whereas the summary of product characteristics for dabigatran etexilate did. The Committee agreed that although there was insufficient evidence to determine the relative clinical effectiveness of the oral anticoagulants, apixaban and rivaroxaban shared a potential benefit for clinical practice in that there is no need to modify the dose in people with mild to moderate kidney function impairment.\n\nThe Committee discussed the evidence submitted by the manufacturer on the cost effectiveness of apixaban for the prevention of venous thromboembolism in people having hip or knee replacement, the ERG's critique of the manufacturer's submission, and the manufacturer's response to the clarification requested by the ERG. The Committee noted the two-phase structure of the economic model and accepted that the modelling approach used by the manufacturer was appropriate for modelling the prevention of venous thromboembolism.\n\nThe Committee discussed the base-case analysis in the manufacturer's submission. It noted that the manufacturer had not included fondaparinux in the economic evaluation because there was insufficient clinical evidence available for the indirect comparison of apixaban and fondaparinux in patients having total knee replacement surgery. It also noted that the manufacturer had highlighted that fondaparinux was used in less than 1% of people in current UK clinical practice. The Committee was aware that the cost of dabigatran etexilate used in the base-case analysis did not reflect the current NHS list price of dabigatran etexilate. It was also aware that the 40% reduction in the cost of dabigatran etexilate occurred after the manufacturer of apixaban had provided its submission to NICE, but that the submission included a one-way sensitivity analysis that anticipated the price reduction (see section 3.24). The Committee noted that in the base-case analysis apixaban dominated enoxaparin and dabigatran etexilate in both total hip and knee replacement, that is, apixaban was associated with larger QALY gains and lower costs. It further noted that for total knee replacement the ICER for rivaroxaban compared with apixaban was £21,700 per QALY gained, but for total hip replacement rivaroxaban dominated apixaban. The Committee then considered the one-way sensitivity analysis provided by the manufacturer, and in particular that relating to a 50% reduction in the price of dabigatran etexilate. The Committee noted that for patients having total hip replacement or total knee replacement, apixaban still remained dominant compared with enoxaparin and dabigatran etexilate for all changes in the sensitivity analysis. The Committee then considered the plausibility of the cost-effectiveness results, in particular in relation to the strength of the evidence for clinical effectiveness. The Committee recognised that there were uncertainties associated with the ICERs for rivaroxaban and dabigatran etexilate because the clinical data for these drugs included in the model were originally derived from the indirect comparison, unlike the ICER for enoxaparin which was derived from direct head-to-head trials. The Committee therefore agreed that the cost-effectiveness results for apixaban compared with enoxaparin were the most robust, and that there were significant uncertainties in the comparisons of cost effectiveness with rivaroxaban and dabigatran etexilate.\n\nThe Committee concluded that apixaban was more clinically effective and cheaper than enoxaparin. It also concluded that there was insufficient clinical evidence to determine whether or not apixaban was more or less clinically effective than rivaroxaban or dabigatran etexilate and therefore the ICERs presented for these anticoagulants had to be interpreted with caution. However, the Committee did accept that any differences in clinical effectiveness between the agents were likely to be small, and apixaban may provide some clinical advantages compared with the other agents. The Committee therefore concluded that apixaban should be recommended as an option for preventing venous thromboembolism in adults after elective total hip and total knee replacement surgery.\n\nThe Committee considered whether its recommendation was associated with any issues related to equality legislation and the requirement for fairness. The Committee noted that no issues had been highlighted during the scoping exercise or during the course of the appraisal. The Committee was aware that consultees and commentators had raised the issue of providing non-injectable medication for people with needle phobia but concluded that the recommendations do not affect access to the technology for any specific groups.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA245\n\nAppraisal title: 'Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults'\n\nSection\n\nKey conclusion\n\nApixaban is recommended as an option for the prevention of venous thromboembolism in adults after elective hip or knee replacement surgery.\n\n\n\nThe Committee concluded that apixaban was more clinically effective and cheaper than enoxaparin. It also concluded that there was insufficient clinical evidence to determine whether or not apixaban was more or less clinically effective than rivaroxaban and dabigatran etexilate and therefore the ICERs presented for these anticoagulants had to be interpreted with caution.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee noted the recommendation in the NICE clinical guideline 'Venous thromboembolism' (NICE clinical guideline 92) that people having elective hip replacement or elective knee replacement should be offered LMWH, dabigatran etexilate, rivaroxaban or fondaparinux.\n\n\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nApixaban appeared to provide a potential benefit for clinical practice. The dose does not need to be adjusted for people with compromised renal function.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nApixaban has a marketing authorisation for the 'prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery'.\n\n\n\nAdverse effects\n\nCommon adverse events include anaemia, haemorrhage, contusion and nausea. See the summary of product characteristics for full details.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nFour good quality randomised controlled trials were identified comparing apixaban with enoxaparin. Fifteen randomised controlled trials were identified for inclusion in the indirect comparison of apixaban with dabigatran etexilate, rivaroxaban and fondaparinux. The manufacturer included 43 studies for the mixed treatment comparison.\n\n\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\nOf the fifteen studies identified for inclusion in the indirect comparison, nine compared the treatment of interest with enoxaparin at the UK dosage of 40 mg once daily.\n\n\n\n\n\n\n\nThe Committee agreed that the ADVANCE 2 and ADVANCE 3 randomised controlled trials, in which patients in the control arm received enoxaparin 40 mg once daily, were applicable to UK clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe manufacturer highlighted inconsistencies among the results of the mixed treatment comparisons and the head-to-head trials.\n\n\n\n\n\n\n\nThe Committee was aware of the inconsistency of some results between the indirect comparison and the mixed treatment comparison and between the indirect comparison and the head-to-head trials, and the manufacturer's explanation for these inconsistencies.\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo subgroups were identified.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee agreed that based on the evidence presented it was not possible to determine an estimate of relative effectiveness of apixaban compared with rivaroxaban, dabigatran etexilate or fondaparinux.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer submitted an economic model assessing the cost effectiveness of apixaban compared with enoxaparin, dabigatran etexilate and rivaroxaban. The manufacturer adopted a two-stage modelling approach. A decision tree to model treatment in the prophylactic phase (from the time of surgery to 90 days after surgery) and a Markov model to model the long-term events (90 days after surgery).\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee recognised uncertainties associated with ICERs for rivaroxaban and dabigatran etexilate because the clinical data were derived from indirect comparison analysis, unlike the ICER for enoxaparin, which was derived from direct head-to-head trials.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe QALY differences between the treatments were small. For people having total hip replacement surgery, total QALYs ranged from 9.520 for enoxaparin to 9.536 for rivaroxaban. For patients having total knee replacement surgery, total QALYs ranged from 9.023 for enoxaparin to 9.090 for rivaroxaban.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo subgroups were identified.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nRivaroxaban was cost effective compared with apixaban, except when the time horizon was 10 years or less, when the age at surgery was 80 years or when a smaller relative difference in the risk of the primary end point (total venous thromboembolism and death from any cause) was assumed.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nIn base-case analyses apixaban dominated enoxaparin. The Committee agreed that because the ICER for enoxaparin was derived from data from direct head-to-head trials, the cost-effectiveness results for apixaban compared with enoxaparin were the most robust.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe manufacturer did not submit a patient access scheme.\n\n\n\nEnd-of-life considerations\n\nThe supplementary advice was not relevant to this appraisal.\n\n\n\nEqualities considerations and social value judgements\n\nNo equalities issues were raised in this appraisal.\n\n", 'Recommendations for further research ': 'More trials of apixaban compared with other LMWHs in total hip and knee replacement would decrease the uncertainty of the clinical and cost effectiveness of these treatments. Trials directly comparing apixaban with rivaroxaban, dabigatran etexilate and fondaparinux would strengthen the evidence base for these comparisons.', 'Related NICE guidance': 'Published\n\nVenous thromboembolism: reducing the risk. NICE clinical guideline 92 (2010).\n\nDabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. NICE technology appraisal guidance 157 (2008).\n\nRivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement surgery in adults. NICE technology appraisal guidance 170 (2009).', 'Review of guidance': 'The guidance on this technology will be considered for review in January 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveJanuary 2012', 'Changes after publication': 'February 2014: implementation section updated to clarify that apixaban is recommended as an option for preventing venous thromboembolism after total hip or knee replacement. Additional minor maintenance update also carried out.\n\nJune 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta245
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Evidence-based recommendations on apixaban (Eliquis) for preventing venous thromboembolism after total hip or knee replacement in adults.
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87531ea6294d8d6e3e69607ec0e7e7cbe49c9091
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Cetuximab, bevacizumab and panitumumab for the treatment of metastatic colorectal cancer after first-line chemotherapy: Cetuximab (monotherapy or combination chemotherapy), bevacizumab (in combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy
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Cetuximab, bevacizumab and panitumumab for the treatment of metastatic colorectal cancer after first-line chemotherapy: Cetuximab (monotherapy or combination chemotherapy), bevacizumab (in combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy
Evidence-based recommendations on cetuximab (Erbitux), bevacizumab (Avastin) and panitumumab (Vectibix) for treating metastatic colorectal cancer in adults.
# Guidance
This guidance updates and replaces NICE technology appraisal 150 (published in June 2008). It also updates and replaces recommendations in NICE technology appraisal guidance 118 (published in January 2007) on the use of cetuximab for the treatment of colorectal cancer that has progressed after first-line chemotherapy. For details see About this guidance.
Cetuximab monotherapy or combination chemotherapy is not recommended for the treatment of people with metastatic colorectal cancer that has progressed after first-line chemotherapy.
Bevacizumab in combination with non-oxaliplatin (fluoropyrimidine-based) chemotherapy is not recommended for the treatment of people with metastatic colorectal cancer that has progressed after first-line chemotherapy.
Panitumumab monotherapy is not recommended for the treatment of people with metastatic colorectal cancer that has progressed after first-line chemotherapy.
People currently receiving cetuximab monotherapy or combination chemotherapy, bevacizumab in combination with non-oxaliplatin chemotherapy, or panitumumab monotherapy for the treatment of metastatic colorectal cancer that has progressed after first-line chemotherapy should have the option to continue treatment until they and their clinician consider it appropriate to stop.# Clinical need and practice
Colorectal cancer originates in the lower part of the digestive system, including the colon and rectum. In metastatic colorectal cancer, the tumour spreads beyond the local or regional lymph nodes to other parts of the body. Approximately 32,000 people were diagnosed with colorectal cancer in England and Wales in 2008. The prevalence of colorectal cancer increases with age, from 35 per 100,000 in people younger than 60 years, to 345 per 100,000 in people over 75 years. The median age of people at diagnosis is over 70 years.
The overall 5-year survival rate for colorectal cancer in England and Wales is approximately 50%; however, large differences in duration of survival exist according to the stage of disease at diagnosis. In 2007, over 93% of people in the UK diagnosed with Stage A on the modified Dukes' classification system (the earliest stage of the disease) survived for 5 years compared with less than 7% of people with metastatic disease.
At the time of diagnosis, an estimated 20–55% of people with colorectal cancer already have metastatic disease. In addition, of the people who have undergone surgery for early-stage colorectal cancer, approximately 50–60% will eventually develop metastatic disease, most commonly in the liver.
Advanced, or metastatic, colorectal cancer is cancer that has spread beyond the colon to other areas of the body. The management of metastatic colorectal cancer is mainly palliative, that is, to relieve symptoms, and combines specialist treatments (such as palliative surgery, chemotherapy and radiation) with control of symptoms and psychosocial support. However, approximately 8% of people with metastatic colorectal cancer have potentially resectable liver metastases and, in some, chemotherapy may make these liver metastases operable.
The aim of treatment is to improve both the length and quality of the patient's remaining life. People with metastatic disease in sufficiently good health (World Health Organization performance status 2 or better) are usually treated with first-line chemotherapy and then, if their cancer progresses, second-line chemotherapy. For other people, the harms from chemotherapy may outweigh the potential benefits. Therefore treatment depends on the person's individual circumstances.
Characteristics of the tumour that influence outcomes of treatment in people with metastatic colorectal cancer include the presence of: epidermal growth factor receptor (EGFR) and the 'wild-type' (non-mutated) form of the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene. Drugs that target EGFR are more effective against tumours expressing EGFR and a normal (wild-type) KRAS gene compared with those not expressing EGFR and with a mutated KRAS gene. Around 80% of people with metastatic colorectal cancer have EGFR-expressing disease and 30–50% have the KRAS wild-type gene.
As first-line treatment options for advanced colorectal cancer, NICE has recommended oxaliplatin in combination with 5-fluorouracil plus folinic acid (FOLFOX) and irinotecan in combination with 5-fluorouracil plus folinic acid (FOLFIRI) ('Irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer' (review of technology appraisal 33) ). Other first-line treatment options recommended for metastatic colorectal cancer are the oral analogues of 5-fluorouracil; capecitabine or tegafur with uracil (in combination with folinic acid) ('Guidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer' ). If metastatic disease is confined to the liver, and the patient has KRAS wild-type disease, the aim of first-line treatment is to make the metastases resectable surgically, and cetuximab may be given with FOLFOX or FOLFIRI ('Cetuximab for the first-line treatment of metastatic colorectal cancer' ).
For second-line therapy in people whose disease has progressed despite first-line treatment, TA93 recommends monotherapy with irinotecan as an option for people who received FOLFOX as first-line treatment, and FOLFOX as an option for people who received FOLFIRI as first-line treatment.# The technologies
Bevacizumab (Avastin, Roche Products) is a recombinant monoclonal antibody that inhibits angiogenesis by targeting the biological activity of human vascular endothelial growth factor, which stimulates formation of new blood vessels in the tumour. The UK marketing authorisation states that bevacizumab 'in combination with fluoropyrimidine-based chemotherapy is indicated for the treatment of patients with metastatic carcinoma of the colon or rectum'. Fluoropyrimidines are anti-metabolite drugs which include 5-fluorouracil (5-FU), folinic acid, capecitabine and tegafur.
Bevacizumab is contraindicated in people who have hypersensitivity to the active substance or to any of the excipients. The summary of product characteristics (SPC) lists the following as special warnings and precautions for use: gastrointestinal perforations, gastrointestinal fistulae, wound healing complications, hypertension, reversible posterior leukoencephalopathy syndrome, proteinuria, thromboembolism (arterial and venous), haemorrhage (including pulmonary haemorrhage and haemoptysis), congestive heart failure, neutropenia, hypersensitivity reactions (including infusion reactions), osteonecrosis of the jaw and eye disorders. For full details of side effects and contraindications, see the SPC.
Bevacizumab is administered by intravenous infusion. The recommended dosage is 5 or 10 mg/kg of body weight once every 2 weeks or 7.5 or 15 mg/kg of body weight once every 3 weeks. The price of a 100-mg vial is £242.66, and a 400-mg vial is £924.40 (excluding VAT; 'British national formulary' edition 61). Costs may vary in different settings because of negotiated procurement discounts.
Cetuximab (Erbitux, Merck Serono) is a recombinant monoclonal antibody that blocks the human EGFR and inhibits the proliferation of cells that depend on activation of EGFR for growth. Cetuximab has a UK marketing authorisation for the treatment of patients with EGFR-expressing, KRAS wild-type metastatic colorectal cancer, in combination with irinotecan-based chemotherapy or FOLFOX (5-FU and folinic acid and oxaliplatin) or as a single agent in patients whose disease has failed to respond to oxaliplatin and irinotecan-based therapy, and who are intolerant to irinotecan.
Cetuximab is contraindicated in people with known severe (grade 3 or 4) hypersensitivity reactions to cetuximab. The SPC lists the following as special warnings and precautions for use: infusion-related reactions, respiratory disorders, skin reactions, electrolyte disturbances, neutropenia and cardiovascular disorders. For full details of side effects and contraindications, see the SPC.
Cetuximab is administered by intravenous infusion. The recommended dosage is an initial dose of 400 mg/m2 of body surface area followed by 250 mg/m2 once a week. The list price of a 20-ml vial (100-mg) is £178.10, and a 100-ml vial (500-mg) is £890.50 (excluding VAT; BNF edition 61). The manufacturer of cetuximab has agreed with the Department of Health that the price to the NHS will be £136.50 for a 20-ml vial and £682.50 for a 100-ml vial. Because the reduced prices are in the public domain and are available across the NHS, all calculations in the economic model are based on these reduced prices. Costs may vary in different settings because of negotiated procurement discounts.
Panitumumab (Vectibix, Amgen) is a recombinant monoclonal antibody that blocks EGFR, inhibiting the growth of tumours expressing EGFR. It has a UK marketing authorisation as a 'monotherapy for the treatment of patients with EGFR-expressing metastatic colorectal cancer with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens'.
Panitumumab is contraindicated in people with severe hypersensitivity to the active substance or to any of the excipients and in people with interstitial pneumonitis or pulmonary fibrosis. The SPC lists the following as special warnings and precautions for use: 'dermatologic reactions, pulmonary complications, electrolyte disturbances, infusion-related reactions, acute renal failure and keratitis'. For full details of side effects and contraindications, see the SPC.
Panitumumab is administered by intravenous infusion. The recommended dosage is 6 mg/kg of body weight once every 14 days. The price of a 100-mg vial is £379.29, and a 400-mg vial is £1517.16 (excluding VAT; BNF edition 61). Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
The scope specified that this appraisal would evaluate the clinical and cost effectiveness of: cetuximab (monotherapy or in combination with chemotherapy); bevacizumab (in combination with non-oxaliplatin chemotherapy) and panitumumab monotherapy. The populations covered included people with EGFR-expressing and KRAS wild-type metastatic colorectal cancer that has progressed after first-line chemotherapy (cetuximab or panitumumab) and people with metastatic colorectal cancer that has progressed after first-line chemotherapy (bevacizumab). The comparators were chemotherapy with oxaliplatin or irinotecan. The interventions were compared with each other and with best supportive care. The relevant outcomes were overall survival, progression-free survival, response rate, adverse reactions to treatment, and health-related quality of life.
# Clinical effectiveness
The Assessment Group completed a systematic review of the efficacy of the technologies as second- and third-line treatments for metastatic colorectal cancer that has progressed after first-line chemotherapy. For cetuximab and panitumumab, the population of interest was limited to people with KRAS wild-type disease. For the three therapies under consideration, only two randomised clinical trials (RCTs) met the inclusion criteria and were judged to be of good quality. In neither study did people have their KRAS mutation status determined at the beginning of the trial. However, both trials retrospectively analysed this and reported results for the subgroup of people with KRAS wild-type tumours.
## Bevacizumab
The manufacturer identified one RCT (the E3200 trial) of bevacizumab as second-line treatment for metastatic colorectal cancer. The trial investigated the effectiveness of bevacizumab plus an oxaliplatin-containing chemotherapy regimen, which is outside the scope of this appraisal. People with metastatic colorectal cancer (n = 829) who had previously been treated with a fluoropyrimidine with or without irinotecan were randomised to receive bevacizumab plus FOLFOX4 (oxaliplatin plus 5-fluorouracil 400 mg, fluorouracil 600 mg and folinic acid), FOLFOX4 alone or bevacizumab alone. The primary endpoint was overall survival.
Median overall survival was 12.9 months in people randomised to bevacizumab plus FOLFOX4 (n = 286), 10.8 months in people randomised to FOLFOX4 alone (n = 291), and 10.2 months in people randomised to bevacizumab alone (n = 252). The incremental overall median survival for bevacizumab plus FOLFOX4 compared with FOLFOX4 was 2.1 months, with a hazard ratio (HR) of 0.75 (95% confidence interval not provided, p = 0.001). Median progression-free survival was 7.3 months in the bevacizumab plus FOLFOX4 arm, 4.7 months in the FOLFOX4 alone arm, and 2.7 months in the bevacizumab alone arm. The incremental median progression-free survival for bevacizumab plus FOLFOX4 compared with FOLFOX4 alone was 2.6 months (p < 0.0001). The bevacizumab alone arm of the study closed early after an interim analysis suggested inferior overall survival compared with the other arms.
The manufacturer identified three RCTs (Hurwitz et al. 2004, Kabbinavar et al. 2005, Saltz et al. 2008) that investigated the effectiveness of bevacizumab as first-line treatment for metastatic colorectal cancer. However, the scope for this appraisal specifies that bevacizumab should be considered as second-line and subsequent treatment. The manufacturer stated that, because no RCTs for metastatic colorectal cancer in the second-line setting studied bevacizumab in combination with chemotherapy regimens not containing oxaliplatin, these RCTs in the first-line setting only provide evidence to 'indicate that bevacizumab is safe and effective in combination with irinotecan in second-line metastatic colorectal cancer'. One study (Hurwitz et al. 2004) compared bevacizumab plus irinotecan, bolus 5-fluorouracil and folinic acid (n = 402) with placebo plus irinotecan, bolus 5-fluorouracil and folinic acid (n = 411). The primary endpoint was median overall survival, which was 20.3 months for people randomised to bevacizumab plus irinotecan, bolus 5-fluorouracil and folinic acid compared with 15.6 months for people randomised to placebo plus folinic acid (HR = 0.66, p < 0.001). The median progression-free survival was 10.6 months for people randomised to bevacizumab plus irinotecan, bolus 5-fluorouracil and folinic acid and 6.2 months for people randomised to placebo plus folinic acid (HR = 0.54, p < 0.001). The second RCT (Kabbinavar et al. 2005) evaluated bevacizumab plus bolus 5-fluorouracil and folinic acid (n = 105) compared with placebo plus bolus 5-fluorouracil and folinic acid (n = 104). Median overall survival was 16.6 months in people randomised to bevacizumab plus bolus 5-fluorouracil and folinic acid compared with 12.9 months in people randomised to placebo plus 5-fluorouracil and folinic acid (HR = 0.79, p = 0.16). The third RCT (Saltz et al. 2008) compared bevacizumab plus oxaliplatin-based chemotherapy (FOLFOX or capecitabine plus oxaliplatin , n = 699) with oxaliplatin-based chemotherapy alone (FOLFOX or XELOX, n = 667). Progression-free survival (the primary endpoint) was significantly greater in people randomised to bevacizumab plus chemotherapy compared with chemotherapy alone (median progression-free survival 9.4 months versus 8.0 months; HR = 0.83, p = 0.002). There was no significant difference in overall median survival between the two arms (21.3 months versus 19.9 months for the bevacizumab plus chemotherapy arm and chemotherapy alone arm respectively; HR = 0.89, p = 0.77).
The manufacturer identified two observational cohort studies that investigated the effectiveness of bevacizumab as second-line treatment for metastatic colorectal cancer in people with progressed disease. One study, which used data from the 'Bevacizumab Regimens: Investigation of Treatment Effects and Safety' (BRiTE) registry compared overall survival in people treated with bevacizumab as first- and second-line therapy (n = 642), with people treated with bevacizumab as first-line therapy but with other chemotherapy treatments in the second-line setting (n = 531). Overall survival was significantly greater in people who received bevacizumab as a second-line treatment compared with those receiving other second-line chemotherapy regimens (median overall survival post progression 31.8 months compared with 19.9 months; HR = 0.48, p < 0.001). The other observational study used data from the ARIES registry and compared overall survival in people with metastatic colorectal cancer who received bevacizumab as first- and second-line treatment (n = 208) with people treated with bevacizumab in the second-line setting only (n = 255). Overall survival was significantly greater in people who received bevacizumab as first- and second-line treatment compared with those who received it in the second-line setting only (median overall survival post progression 21.7 months (95% CI 17.8 to 27.0) compared with 17.5 months (95% CI 15.9 to 21.5). The manufacturer noted that the data from the registries were not available by type of chemotherapy, and therefore specific information about the effect of bevacizumab in combination with non-oxaliplatin-based chemotherapy could not be provided.
The Assessment Group did not identify any trials that met the inclusion criteria for its review (that is, bevacizumab plus non-oxaliplatin-based chemotherapy for the treatment of people with metastatic colorectal cancer whose disease had progressed after first-line chemotherapy).
## Cetuximab
The manufacturer and the Assessment Group identified one RCT (the CO.17 trial), which compared cetuximab plus best supportive care with best supportive care alone in people (n = 572) with metastatic colorectal cancer who had previously been treated with a fluoropyrimidine, irinotecan and oxaliplatin or who had contraindications to these treatments. This trial was mainly a trial of third-line and subsequent therapy, because 96−98% of people had received both irinotecan and oxaliplatin. Nearly half of the participants had received four or more chemotherapy regimens. The primary endpoint was overall survival.
The median overall survival in the whole trial population (irrespective of KRAS mutation status of the tumour) was 6.1 months with cetuximab plus best supportive care and 4.6 months with best supportive care alone, with an HR of 0.77 (95% CI 0.64 to 0.92; p = 0.005). Approximately 7% of people randomised to best supportive care alone were given cetuximab after crossover.
A total of 394 (68.9%) tumour specimens were retrospectively examined for KRAS mutation status after completion of the trial (Karapetis et al. 2008). Limiting analyses to people with KRAS wild-type status, the median overall survival was 9.5 months for people randomised to cetuximab plus best supportive care compared with 4.8 months for people randomised to best supportive care alone (HR = 0.55, 95% CI 0.41 to 0.74; p < 0.001). In an analysis that adjusted for both randomisation and potential prognostic factors (age, Eastern Cooperative Oncology Group performance status, previous chemotherapy), the HR increased to 0.62 (95% CI 0.44 to 0.87; p = 0.006).
To compare cetuximab plus best supportive care with cetuximab plus irinotecan in people with KRAS wild-type status, the manufacturer presented a published retrospective observational analysis (De Roock et al. 2008, referred to as the De Roock analysis) that analysed data on Belgian participants combined from four studies (EVEREST n = 50, BOND n = 44, SALVAGE n = 17 and BABEL n = 2). Approximately one-quarter of people had been treated with cextuximab monotherapy, and three-quarters with cetuximab (at varying dosages) plus irinotecan. The phase II EVEREST trial investigated the effect of cetuximab dose escalation on EGFR expression in people with metastatic colorectal cancer whose disease had not responded to prior treatment with irinotecan. The BOND study was a randomised open-label multicentre phase II RCT of cetuximab plus irinotecan versus cetuximab monotherapy in people with metastatic EGFR-expressing colorectal adenocarcinoma. The SALVAGE study was an uncontrolled trial of monotherapy with cetuximab in people with metastatic colorectal cancer, whose tumours expressed EGFR and were refractory to irinotecan, oxaliplatin and fluoropyrimidines. The BABEL study was an uncontrolled trial of cetuximab monotherapy in people with KRAS wild-type metastatic colorectal cancer. The De Roock analysis provided data for a total of 113 people (67 with KRAS wild-type status, 46 with the KRAS mutation) with irinotecan refractory metastatic colorectal cancer who had been treated with cetuximab monotherapy. The Assessment Group excluded the De Roock analysis from its review because it judged the analysis to have a number of limitations: the people selected may not have been representative of people treated in UK clinical practice, and two of the studies (BABEL and SALVAGE) were single arm (that is, uncontrolled) studies. Only the BOND study compared cetuximab plus irinotecan with cetuximab monotherapy.
## Panitumumab
The manufacturer and the Assessment Group identified one RCT (the 'Amgen' trial) that compared panitumumab plus best supportive care with best supportive care alone in 463 people with metastatic colorectal cancer that had progressed after standard first- and second-line chemotherapy (a fluoropyrimidine, irinotecan and oxaliplatin). The primary endpoint of the trial was progression-free survival. Overall survival was analysed as a secondary endpoint. No statistically significant difference was observed in overall survival in the whole population (irrespective of KRAS mutation status) (HR = 1.00, 95% CI 0.82 to 1.22).
Tumour samples from 427 (92%) people in the Amgen trial were retrospectively obtained for KRAS mutation status testing after the end of the trial. In the KRAS wild-type population, median progression-free survival was 12.3 weeks in people randomised to panitumumab plus best supportive care compared with 7.3 weeks in people randomised to best supportive care alone. When calculating overall survival in people randomised to the best supportive care arm, the manufacturer excluded people with wild-type KRAS who crossed over to receive panitumumab. Overall survival was estimated using two mutually exclusive time points: mean time to disease progression and mean time from progression to death. Survival estimates for best supportive care were based on people randomised to best supportive care with a KRAS mutation or wild-type KRAS for the time until disease progression (before any treatment crossover occurred), and people randomised to best supportive care with a KRAS mutation for the time from disease progression to death. Mean times to disease progression and from progression to death were estimated by fitting survival models to patient-level data from the clinical trial and then estimating the area under the best-fit curves and the mean survival for each distribution. The median overall survival from an intention-to-treat analysis in the KRAS wild-type population was 8.1 months for people randomised to panitumumab plus best supportive care compared with 7.6 months for people randomised to best supportive care alone. No statistically significant difference in median overall survival after disease progression between panitumumab and best supportive care was shown in this KRAS wild-type population (HR = 0.99; 95% CI 0.75 to 1.29).
There was significant crossover in the Amgen trial; of 219 people randomised to best supportive care alone, 166 (76%) crossed over after disease progression to receive treatment with panitumumab. Because panitumumab lengthened progression-free survival, and many people randomised to best supportive care also received panitumumab after progression, the estimates of effectiveness from intention-to-treat analyses (see section 4.2.11) were considered by the manufacturer to underestimate the effectiveness of panitumumab. Therefore, in an attempt to adjust for this bias, the manufacturer adjusted the overall survival results by including people with KRAS mutations randomised to best supportive care in the analysis, regardless of whether they crossed over to receive panitumumab treatment after disease progression. The manufacturer's rationale for this method was that the trial showed that people with a KRAS mutation did not benefit from treatment with panitumumab. Therefore people with a KRAS mutation in the best supportive care arm who crossed over to receive panitumumab after disease progression would also be less likely to benefit from it. The average survival gain adjusted for crossover was between 2.74 months (overall survival estimated by splitting response rates) and 3.13 months (overall survival estimated by aggregating survival across response rates) for panitumumab compared with best supportive care. The Assessment Group judged that the manufacturer's approach and assumptions to adjust for crossover were reasonable.
## Mixed treatment comparisons
The Assessment Group and the manufacturers did not identify any RCTs that directly compared each of the technologies included in this appraisal. Both the Assessment Group and the manufacturer of cetuximab carried out a mixed treatment comparison using the Bucher approach to estimate the relative effectiveness of the technologies relevant to the decision problem. Without clinical evidence for the use of bevacizumab as specified by the scope, there were four treatments or comparators:
best supportive care
monotherapy with cetuximab plus best supportive care
monotherapy with panitumumab plus best supportive care, and
cetuximab plus chemotherapy plus best supportive care. The manufacturers of panitumumab and bevacizumab did not submit a mixed treatment comparison because they did not consider it possible to conduct a robust mixed treatment comparison of the three technologies based on the evidence available.
## Manufacturer's (Merck Serono) mixed treatment comparison
To compare the clinical effectiveness of cetuximab plus chemotherapy with panitumumab plus best supportive care and best supportive care alone, the manufacturer (Merck Serono) used data from the CO.17 trial and from the Amgen trial. Although the scope of this appraisal covers cetuximab plus chemotherapy, the only evidence available was for cetuximab plus irinotecan. The manufacturer used data from 80 people in a retrospective analysis of the De Roock analysis to compare cetuximab plus best supportive care with cetuximab plus irinotecan in the KRAS wild-type population. The manufacturer did not identify any relevant evidence for bevacizumab.
The resulting HR for overall survival for cetuximab plus irinotecan and best supportive care compared with best supportive care alone was 0.29 (95% CI 0.14 to 0.59). Following advice from clinical specialists, the manufacturer concluded that the parametric model it had fitted to the Kaplan–Meier curve for overall survival (Weibull function) did not match the original data. The manufacturer therefore obtained additional data from the retrospective analysis of the De Roock analysis for 364 people. The resulting HR for overall survival for cetuximab plus irinotecan compared with best supportive care changed to 0.32 (confidence interval not reported). The manufacturer used the 95% CI from the original retrospective analysis of the De Roock analysis (that is, 95% CI 0.14 to 0.59). The resulting HR for overall survival for cetuximab plus best supportive care compared with panitumumab plus best supportive care was 0.56 (95% CI 0.37 to 0.83).
The Assessment Group expressed concerns about the validity of the manufacturer's approach to calculating progression-free survival and overall survival hazard ratios from the mixed treatment comparison because:
it combined randomised and non-randomised evidence, subjecting it to bias and confounding
it did not assess whether the populations in the chosen studies were comparable
for calculating the overall survival HR for cetuximab plus irinotecan compared with best supportive care, the manufacturer used data from a non-comparative study to adjust the HR to fit the model, but the statistical fit of the model was determined by clinical specialists rather than statistical testing, and the manufacturer did not clarify how adjustments were made to fit the data to the model
the manufacturer used unadjusted HRs from the cetuximab CO.17 RCT instead of values adjusted for patient characteristics, which may have overestimated the effectiveness of cetuximab
the BOND study, which was included in the observational retrospective analysis that combined four studies (the De Roock analysis) did not account for crossover, and this could have led to an underestimation of overall survival gain for cetuximab plus best supportive care compared with cetuximab plus irinotecan.
## Assessment Group's mixed treatment comparison
The Assessment Group also carried out a mixed treatment comparison for the four treatments: best supportive care, cetuximab monotherapy plus best supportive care, panitumumab monotherapy plus best supportive care, and cetuximab plus irinotecan and best supportive care. The Assessment Group used data from the two RCTs used by the manufacturer of cetuximab in its mixed treatment comparison: the CO.17 trial (cetuximab plus best supportive care compared with best supportive care alone) and the Amgen trial (panitumumab plus best supportive care compared with best supportive care alone). It also used data from the retrospective analysis of four studies (the De Roock analysis). The Assessment Group assumed that best supportive care was equivalent between the CO.17 trial and the Amgen trial. Unlike the manufacturer's analysis, the Assessment Group adjusted HRs in its mixed treatment comparison for the patient characteristics in the KRAS wild-type population. However, the HRs obtained from the indirect comparison were not adjusted using data from the retrospective analysis (De Roock analysis).
Results of the mixed treatment comparison showed that patients who received cetuximab plus best supportive care would be expected to have significantly longer overall survival than those receiving panitumumab plus best supportive care (unadjusted HR 0.56, 95% CI 0.37 to 0.83; adjusted HR 0.63, 95% CI 0.41 to 0.97). The Assessment Group highlighted that the HR for overall survival for panitumumab from the Amgen trial may have underestimated the effectiveness of panitumumab relative to best supportive care because most people randomised to best supportive care also received treatment with panitumumab after their disease had progressed. The Assessment Group reported an overall survival estimate of 16.2 months for cetuximab plus irinotecan in an appendix to the assessment report.
# Cost effectiveness
## Manufacturer's submission
Amgen and Roche Products did not submit health economic models. Roche Products submitted calculations outlining the treatment costs for bevacizumab plus FOLFIRI compared with cetuximab plus FOLFIRI. The treatment cost for cetuximab plus FOLFIRI was estimated to exceed that for bevacizumab plus FOLFIRI by £5408, with an incremental cost for KRAS testing of £462, additional drugs costs of £3357 and additional administration costs of £1589.
Merck Serono provided a Markov model to make four comparisons:
cetuximab plus best supportive care compared with best supportive care alone
cetuximab plus irinotecan plus best supportive care compared with best supportive care alone
cetuximab plus best supportive care compared with panitumumab plus best supportive care
cetuximab plus irinotecan plus best supportive care compared with panitumumab plus best supportive care.
The population modelled by Merck Serono included people with EGFR-expressing KRAS wild-type metastatic colorectal cancer who had received second- or subsequent-line chemotherapy for metastatic disease. The model had a 10-year time horizon and a UK National Health Service (NHS) perspective. The cycle length was 1 week and a half-cycle correction was not applied. The model had three health states: progression-free disease, progressive disease and death. Merck Serono based the transitions between health states on parametric approximations of Kaplan–Meier estimates of progression-free survival and overall survival from the relevant arms of the RCTs (with time spent by a patient in progressive disease defined as the difference between the two).
To compare cetuximab plus best supportive care with best supportive care alone, Merck Serono estimated separate probabilities for time to disease progression and time to death for people in the progression-free disease and progressive disease health states using patient-level data. Merck Serono chose different functions on the basis of goodness-of-fit measures for each transition (log-normal for time to progression; log-logistic for death from the health state of pre-progression; Weibull for death from the health state of progressive disease).
For the comparison of cetuximab plus irinotecan and best supportive care with best supportive care alone, Merck Serono modelled progression-free survival and overall survival using a two-stage process. First, it simulated progression-free survival and overall survival for people treated with best supportive care alone using a Weibull curve and then validated this curve using data from the best supportive care arm of the CO.17 trial. The corresponding values for progression-free survival and overall survival for cetuximab plus irinotecan and best supportive care were then estimated by applying the overall survival HRs for cetuximab plus irinotecan and best supportive care with the HR for best supportive care being drawn from the mixed treatment comparison. Merck Serono obtained estimates of utility for each health state using the Health Utility Index (HUI) scale (a generic preference-based measure of quality of life) by reanalysing data by health state in the CO.17 trial. These utility values were then applied to cetuximab plus irinotecan and best supportive care and panitumumab plus best supportive care. The manufacturer used utility values of 0.809 for progression-free disease, 0.789 for progressive disease and 0.000 for death.
The following assumptions were made in the model: the mean time on treatment with cetuximab plus best supportive care is 2.6 months and the mean time for cetuximab plus irinotecan is 4.4 months; active treatment stops at set cut-off time points, that is, 13 weeks for cetuximab plus best supportive care and 24 weeks for cetuximab plus irinotecan plus best supportive care, even if a patient's disease has not progressed.
Merck Serono produced a series of pairwise comparisons of cost effectiveness in people with KRAS wild-type metastatic colorectal cancer:
Cetuximab plus best supportive care compared with best supportive care alone produced a base-case incremental cost-effectiveness ratio (ICER) of £47,095 per quality-adjusted life year (QALY) gained.
Cetuximab plus irinotecan plus best supportive care compared with best supportive care alone produced a base-case ICER of £43,887 per QALY gained.
Cetuximab plus irinotecan plus best supportive care compared with panitumumab plus best supportive care produced a base-case ICER of £21,819 per QALY gained. When cetuximab plus best supportive care was compared with panitumumab plus best supportive care, panitumumab was associated with higher costs and fewer QALYs (–0.193 incremental QALYs and £2629 incremental costs). Merck Serono completed one-way sensitivity analyses on all the model parameters and the only factor found to significantly change the ICERs was varying the cost of cetuximab (which included changes to the price of the drug, its administration costs, and/or the duration of treatment).
Merck Serono's probabilistic sensitivity analyses indicated that, compared with best supportive care alone, cetuximab plus best supportive care and cetuximab plus irinotecan had a 64.7% and a 68% chance respectively of being cost effective at £50,000 per QALY gained. Compared with panitumumab plus best supportive care, cetuximab plus best supportive care had a 100% chance of being cost effective at £15,000 per QALY gained. Cetuximab plus irinotecan compared with panitumumab plus best supportive care has a 73.8% chance of being cost effective at £30,000 per QALY gained and a 93% chance of being cost effective at £50,000 per QALY gained.
## Assessment Group's report
From a literature review the Assessment Group identified one cost-effectiveness analysis of bevacizumab in previously untreated metastatic colorectal cancer, which was not relevant to this appraisal. It also identified a study by Mittman et al. (2008) which was a trial-based cost-effectiveness analysis that used data from the cetuximab CO.17 trial. The Assessment Group also identified three studies (Annemans et al. 2007, Norum et al. 2006, Starling et al. 2007) which assessed the cost effectiveness of cetuximab plus irinotecan compared with best supportive care. The base-case ICER in the Annemans et al. study was €40,273 per life year gained (based on 12 weeks of treatment). The base-case ICER was €205,536 per life year gained in the Norum et al. study and £57,608 per QALY gained in the Starling et al. study.
The Assessment Group noted that the Merck Serono model did not attempt to compare cetuximab plus irinotecan plus best supportive care with cetuximab plus best supportive care. Moreover, Merck Serono assessed the cost effectiveness of cetuximab only as third-line treatment and did not consider it as second-line treatment, but the scope for this appraisal allows any of the technologies to be considered as second-line treatment. The Assessment Group questioned the validity of the utility values obtained from the CO.17 trial by Merck Serono because they exceeded the values produced by the health economic evaluation that accompanied the CO.17 trial (Mittman et al. 2008).
The Assessment Group provided an area under the curve model that compares cetuximab plus best supportive care with best supportive care alone, cetuximab plus irinotecan plus best supportive care with best supportive care alone, and panitumumab plus best supportive care with best supportive care alone in people with EGFR-expressing KRAS wild-type metastatic colorectal cancer who had received at least second-line chemotherapy for metastatic disease. The Assessment Group did not include bevacizumab in the economic analysis because no clinical effectiveness evidence was available for bevacizumab plus chemotherapy without oxaliplatin in people who had received previous chemotherapy. The model had a 10-year time horizon and a UK NHS perspective. The cycle length was 1 month and a half-cycle correction was applied.
The model had three health states: progression-free disease, progressive disease and death. The Assessment Group used an 'area under the curve' or 'cohort partition' method to determine the number of people in each health state at each cycle of the model, rather than using transition probabilities. The Assessment Group obtained estimates of utility from the Mittman et al. (2008) study that used individual patient-level data and HUI data from the CO.17 trial. The Assessment Group used utility values for progression-free disease of 0.81 for cetuximab plus best supportive care, 0.75 for best supportive care, 0.75 for cetuximab plus irinotecan, and 0.87 for panitumumab plus best supportive care; a utility value of 0.69 was used for progressive disease (for all treatments).
The Assessment Group's model differed from the Merck Serono model in the following ways for the comparison of cetuximab plus best supportive care versus best supportive care alone:
the estimates of mean time on cetuximab varied: Assessment Group 4.8 months, Merck Serono 2.6 months
the estimates of drug costs varied because of differences in estimates of treatment duration: Assessment Group £14,400, Merck Serono £8200
the estimates of drug administration costs varied because of differences in estimates of treatment duration: Assessment Group £5500, Merck Serono £2000
the estimates of utility were taken directly from Mittman et al. (2008) by the Assessment Group; reanalysed estimates from the CO.17 trial were used by Merck Serono
the Assessment Group model included an adjustment for crossover for the overall survival HR for panitumumab compared with best supportive care whereas the Merck Serono model did not.
For the comparison of cetuximab plus irinotecan versus best supportive care, the main differences between the Assessment Group's model and the Merck Serono model were the:
estimates of mean time on cetuximab plus irinotecan varied: Assessment Group 8.8 months, Merck Serono 4.4 months
estimates of drug costs varied because of differences in estimates of treatment duration: Assessment Group £32,000, Merck Serono £17,400
estimates of drug administration costs varied because of differences in estimates of treatment duration: Assessment Group £12,700, Merck Serono £3800.
The Assessment Group produced a series of pairwise comparisons of cost effectiveness in people with KRAS wild-type metastatic colorectal cancer:
Cetuximab plus best supportive care compared with best supportive care alone produced a base-case ICER of £98,000 per QALY gained.
Cetuximab plus irinotecan plus best supportive care compared with best supportive care alone produced a base-case ICER of £88,000 per QALY gained.
Panitumumab plus best supportive care compared with best supportive care alone produced a base-case ICER of £150,000 per QALY gained. The Assessment Group completed deterministic one-way sensitivity analyses on model parameters and the only factor found to substantially change the ICER was the estimate of overall survival. The ICER for cetuximab plus best supportive care compared with best supportive care alone was more than £70,000 per QALY gained in all scenarios, the ICER for cetuximab plus irinotecan compared with best supportive care was more than £55,000 per QALY gained, and the ICER for panitumumab plus best supportive care compared with best supportive care was more than £110,000 per QALY gained. When the unadjusted progression-free survival estimates from the Amgen trial were used, the ICER for panitumumab plus best supportive care compared with best supportive care was reduced to £109,000 per QALY gained. In an additional analysis conducted in response to comments received from the manufacturers during consultation on the assessment report, the overall survival estimate for best supportive care was increased from 6.8 months to 7.2 months. This gave an ICER of £119,000 per QALY gained for panitumumab plus best supportive care compared with best supportive care.
The Assessment Group's probabilistic sensitivity analyses indicated that below £60,000 per QALY gained, none of the drugs appraised is the most cost-effective treatment for second-line or subsequent chemotherapy of metastatic colorectal cancer. Above £90,000 per QALY gained, cetuximab plus irinotecan is likely to be the most cost-effective treatment compared with best supportive care. Cetuximab monotherapy or panitumumab are never the most cost-effective option when compared with best supportive care.
# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab in combination with non-oxaliplatin chemotherapy, cetuximab either in combination with chemotherapy or as monotherapy, and panitumumab monotherapy. The Committee did so having considered evidence on the nature of metastatic colorectal cancer and the value placed on the benefits of bevacizumab, cetuximab and panitumumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee heard from the clinical specialists and patient experts that there are limited treatment options for people with metastatic colorectal cancer that has progressed after treatment with first-line chemotherapy (progression being defined as radiological evidence of tumour growth or spread, and/or by clinical symptoms). The second-line treatment options that NICE recommends currently (in TA93) are irinotecan monotherapy and FOLFOX. Irinotecan monotherapy is offered to people who received FOLFOX as first-line treatment, and FOLFOX is offered to people who received FOLFIRI as first-line treatment. TA93 also specifies that people may receive treatment with either FOLFOX or irinotecan as second-line and subsequent-line therapy if they have received 5-fluorouracil and folinic acid or oral analogues as first-line treatment. The Committee heard from the clinical specialists that frail people and older adults were more likely to be offered as first-line therapy 5-fluorouracil and folinic acid over FOLFIRI or FOLFOX, with FOLFOX (or the same combination of oral analogues) being less toxic than FOLFIRI. The Committee also heard that as second-line therapy, clinicians prefer to offer combination chemotherapy (for example, FOLFOX) over irinotecan monotherapy (partly because of irinotecan's toxicity), but that clinicians consider offering irinotecan monotherapy as third-line therapy after second-line combination chemotherapy.
The Committee heard from the clinical specialists that EGFR testing was not routinely carried out in clinical practice for people with colorectal cancer because the results had not been found to correlate with response to specific chemotherapy regimens. The Committee further heard from the clinical specialists that KRAS testing is now routinely offered in the NHS in some parts of England and Wales, that several proprietary test kits are available, and that NHS pathology laboratories can carry out this testing at low cost. The Committee was also aware that Merck Serono offers KRAS testing for free, and that accepting Merck Serono's test did not prevent clinicians from prescribing treatments from other manufacturers. The Committee concluded that the KRAS testing required by the marketing authorisations for treatment with cetuximab and panitumumab would not be a barrier to treatment.
The Committee heard from the patient experts that people who need to have second- and third-line chemotherapy particularly value even very small increases in life expectancy because this extra time allows them to put their affairs in order and help family and friends. The Committee also heard from the patient experts that the opportunity to receive active treatment rather than palliative care alone is very important to people with metastatic colorectal cancer. In addition, the Committee heard that people with colorectal cancer in England are becoming increasingly worried about what they perceive to be unequal access to treatment with biological drugs, which are currently only provided to some people through the Cancer Drugs Fund.
## Bevacizumab
The Committee discussed the clinical effectiveness of bevacizumab in people with metastatic colorectal cancer who have received first-line chemotherapy. The Committee discussed the results of the three RCTs (see section 4.2.4) presented in the Roche Products submission, which investigated the effectiveness of bevacizumab as first-line treatment for metastatic colorectal cancer. The Committee agreed that these trials demonstrated that bevacizumab is an effective first-line treatment for metastatic colorectal cancer, but recognised that the scope of this appraisal was to consider bevacizumab in the second- and third-line setting. The Committee understood that Roche Products, the regulatory authorities and the clinical specialists considered that if bevacizumab plus a non-oxaliplatin-containing regimen is effective in the first-line setting, the combination would also likely be effective in second- and third-line settings, despite not having been tested in these situations. The Committee heard that this assumption was the basis of the regulatory approval for bevacizumab as a second-line therapy. However, the Committee agreed that people receiving bevacizumab as second-line therapy would have more advanced disease than people receiving bevacizumab for first-line therapy. Therefore, the Committee concluded that people receiving bevacizumab as second-line therapy would likely have smaller gains in survival than people who have not previously received chemotherapy.
The Committee noted the results of two registry-based observational studies, BRiTE and ARIES. The Committee understood that Roche Products could not provide data from these registries specifically for bevacizumab in combination with non-oxaliplatin chemotherapy. In line with this, the manufacturer also informed the Committee that these registries were unlikely to inform the Committee's decision regarding the use of bevacizumab as second-line or subsequent therapy in combination with non-oxaliplatin chemotherapy. The Committee concluded that the observational evidence presented in the manufacturer's submission could not be used to establish the magnitude of the overall survival gain with bevacizumab plus non-oxaliplatin chemotherapy for people with metastatic colorectal cancer which had not responded to first-line chemotherapy.
The Committee then discussed the E3200 RCT presented in the Roche Products submission (see section 4.2.2), which investigated the effectiveness of bevacizumab plus an oxaliplatin-containing chemotherapy regimen as second-line treatment compared with placebo plus folinic acid for metastatic colorectal cancer. The Committee acknowledged that 'Bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer' (NICE technology appraisal guidance 212 ) has already evaluated the clinical and cost effectiveness of bevacizumab plus oxaliplatin-containing chemotherapy in metastatic colorectal cancer, and that the remit of the current appraisal is to appraise bevacizumab plus non-oxaliplatin chemotherapy. The Committee agreed that the results of the E3200 trial could not be used to establish the overall survival gain with bevacizumab plus non-oxaliplatin chemotherapy as second- or third-line treatment for people with metastatic colorectal cancer who had not responded to first-line or second-line chemotherapy. The Committee noted that this conclusion was supported by one of the clinical specialists, who pointed out that the effectiveness of biological drugs plus oxaliplatin differs from the effectiveness of biological drugs plus irinotecan. The Committee acknowledged that there is an ongoing RCT of bevacizumab plus FOLFIRI compared with panitumumab plus FOLFIRI as second-line treatment of metastatic colorectal cancer, which is due to finish in August 2012. However it agreed that it was not aware of any currently available evidence on which to base a decision about the clinical effectiveness of bevacizumab plus non-oxaliplatin chemotherapy in people with metastatic colorectal cancer who had previously received chemotherapy.
The Committee discussed the likely cost effectiveness of bevacizumab plus non-oxaliplatin chemotherapy compared with best supportive care and noted the Assessment Group's view that lack of relevant evidence on clinical effectiveness meant that it was not feasible to carry out a cost-effectiveness evaluation of bevacizumab. The Committee also heard from Roche Products that it had not submitted an economic model because it did not believe it would be possible to establish that bevacizumab plus non-oxaliplatin chemotherapy is cost effective as a second-line treatment for metastatic colorectal cancer. The Committee noted that previous NICE technology appraisal guidance (TA212 and 'Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer' ) had not found bevacizumab to be a cost-effective first-line or second-line treatment for metastatic colorectal cancer. In view of its previous judgement that bevacizumab is likely to be less effective as second-line therapy than as first-line therapy, on balance, the Committee felt that it was unlikely that bevacizumab would be a cost-effective treatment for people with metastatic colorectal cancer who had received first-line therapy. The Committee therefore concluded that the available clinical and cost-effectiveness evidence does not justify a positive recommendation for bevacizumab plus non-oxaliplatin chemotherapy as second-line treatment for metastatic colorectal cancer.
## Cetuximab
The Committee discussed the clinical effectiveness of cetuximab (monotherapy or combination chemotherapy) in people with KRAS wild-type metastatic colorectal cancer that has progressed after first-line chemotherapy. The Committee noted that the people in the CO.17 trial had previously received oxaliplatin- and irinotecan-based therapy, that is, cetuximab was used in the third-line or later setting. The trial had shown a median overall survival of 9.5 months for cetuximab plus best supportive care compared with 4.8 months for best supportive care alone. The Committee was aware that only 68.9% of people in the CO.17 trial were tested for KRAS mutation status, and was concerned that there may have been selection bias related to the KRAS mutation testing if those people tested were fundamentally different in a way which influenced their response to treatment. The Committee noted the Assessment Group's comment that the age of people in the trial, including people whose tumour displayed KRAS mutations and those not tested, averaged 63 years (range 28–88 years), which was on average 10 years younger than people with metastatic colorectal cancer typically seen in clinical practice in the NHS. The Committee heard from the clinical specialists that age at of the start of treatment was unlikely to affect clinical response. The Committee therefore agreed that although the trial population did not fully represent people seen in clinical practice in the NHS, the evidence of clinical effectiveness for cetuximab monotherapy was generalisable to UK clinical practice. The Committee concluded that there was sufficient evidence to show that cetuximab plus best supportive care gave greater benefit in terms of both progression-free survival and overall survival than best supportive care alone.
The Committee discussed the evidence available for the clinical effectiveness of cetuximab plus irinotecan chemotherapy. The Committee noted that there were no head-to-head trials of cetuximab plus irinotecan compared with best supportive care in KRAS wild-type colorectal cancer. The Committee therefore discussed the results of the manufacturer's mixed treatment comparison that compared cetuximab plus chemotherapy with panitumumab or best supportive care and cetuximab monotherapy with panitumumab in the KRAS wild-type population. The Committee noted the Assessment Group's concerns about the validity of the mixed treatment comparison (see section 4.2.17). The Assessment Group was particularly concerned about the reliance on the retrospective observational analysis (the De Roock analysis) for the effectiveness estimate for cetuximab plus irinotecan, which combined data from RCTs and non-RCTs (single-arm trials), not all of which included treatment with cetuximab plus irinotecan. The Committee therefore agreed that the results of the mixed treatment comparison should be interpreted with caution. The Committee concluded that the estimates of overall survival for cetuximab plus irinotecan were subject to a high degree of uncertainty.
The Committee discussed the economic model submitted by the manufacturer of cetuximab, and the Assessment Group's comments on this model. The Committee concluded that using best supportive care as one of the comparators in the model was appropriate. However, the Committee was concerned that the manufacturer had not submitted an economic comparison of cetuximab plus best supportive care versus cetuximab plus irinotecan plus best supportive care, despite having submitted estimates of clinical effectiveness, and had not given a reason for this. The Committee discussed two concerns about the total cost estimated by the manufacturer for cetuximab; that is, the administration costs and costs associated with duration of treatment. The Committee was aware that the Assessment Group model had used estimated administration costs for cetuximab that were two to three times higher than those estimated by the manufacturer. The Committee discussed its concerns about the assumptions in the manufacturer's model about the duration of treatment; particularly whether in clinical practice people would receive cetuximab for a fixed treatment period (as modelled) rather than until disease progresses (as specified in the SPC). The Committee heard from the clinical specialists that clinicians would offer people treatment with cetuximab monotherapy until their disease progressed, but would likely offer cetuximab plus irinotecan for a fixed period in view of the increased toxicity of combined treatment. The Committee therefore concluded that it did not accept the assumption in the manufacturer's model that a fixed treatment period for cetuximab represented UK clinical practice. The Committee also noted a comment made by Amgen during consultation that the NICE 'Guide to the methods of technology appraisal' states a preference for the use of the public list price for a technology and not the negotiated price to the NHS. The Committee noted that the lower NHS price for cetuximab was previously used in NICE technology appraisal 176 rather than the list price. It agreed that the most relevant price to be considered in this appraisal is the one that is nationally available and in the public domain, and therefore considered it appropriate to use the NHS price for cetuximab in the economic model.
The Committee discussed the utility estimates in the manufacturer's model, which were obtained from the CO.17 trial. The Committee was aware that using HUI deviated from the NICE reference case, which encourages the use of EQ-5D. However, it agreed that the HUI was a valid measure of utility and that values obtained from the trial population were likely to be generalisable to patients in the UK. The Committee noted that the utility estimates for each of the disease states were not consistent with the expectation that quality of life worsens with progression of disease. The Committee was aware of the Assessment Group's concern that the values of utility recalculated by the manufacturer from the CO.17 trial were higher for progression-free disease than those of Mittman et al. from the same trial. The Committee also noted that the utility estimates used in the model (for example, 0.81 for progression-free disease for cetuximab plus best supportive care) were similar to those expected for people of the same age without metastatic colorectal cancer. The Committee concluded that the utility values in the manufacturer's model were highly uncertain.
The Committee discussed the results of the manufacturer's sensitivity analyses and noted that the estimate of cost effectiveness was most sensitive to the estimate of overall drug costs, which was determined by the time on cetuximab treatment. The Committee heard from the manufacturer that the estimates of time on treatment in the model were based on clinical opinion rather than direct estimates from the CO.17 trial. The Committee agreed that the assumption of a fixed treatment period for cetuximab in the manufacturer's model did not represent UK clinical practice (see section 4.4.11).
The Committee considered the Assessment Group's economic model for cetuximab. The Committee heard that the utility estimates in the Assessment Group's model had been obtained from a published cost–utility study of the CO.17 trial (Mittman et al. 2008) and were in general lower than those used in the manufacturer's model. The Committee agreed that the utility values used by the manufacturer were implausibly high because they were similar to those of the general population of the same age without metastatic colorectal cancer. The Committee also noted that because the manufacturer did not provide an estimate of the average length of cetuximab treatment in the CO.17 trial, the Assessment Group contacted Dr Mittman to obtain this estimate after the assessment report had been submitted to the Committee. This estimate was provided to the Committee as an addendum, and is not given in this document because it is considered academic-in-confidence. The Committee agreed that this estimate of time on treatment was more appropriate because it was derived from trial data rather than from an assumption.
The Committee noted that one of the main factors affecting the cost effectiveness of cetuximab was the assumption about the duration of treatment. The Committee agreed that using the values provided as academic-in-confidence in the Assessment Group's analyses gave the most plausible ICER for cetuximab plus best supportive care of £90,000 per QALY gained and for cetuximab plus irinotecan plus best supportive care of £88,000 per QALY gained, both compared with best supportive care. The Committee was aware of another cost−utility analysis of the CO.17 trial (Mittman et al. 2008) that had estimated an ICER of £101,000 per QALY gained for cetuximab plus best supportive care compared with best supportive care. The Committee was also aware that the manufacturer, Merck Serono, noted in its comments during consultation that cetuximab 'is not cost effective under the usual threshold range for acceptability'.The Committee concluded that the most plausible ICERs for cetuximab monotherapy and cetuximab in combination chemotherapy did not represent a cost-effective use of NHS resources.
## Panitumumab
The Committee discussed the clinical effectiveness of panitumumab monotherapy in people with KRAS wild-type metastatic colorectal cancer that has progressed after first-line chemotherapy. It noted that the only trial evidence available applied to people who had previously received both oxaliplatin- and irinotecan-based therapy, that is, in the third-line or subsequent setting (the Amgen trial). The Committee heard from the manufacturer that over 90% of people in the trial were assessed for the KRAS mutation and concluded that selection bias associated with testing was unlikely. The Committee noted that although a benefit in progression-free survival of 5 weeks was associated with panitumumab monotherapy relative to best supportive care, no statistically significant effect on overall survival was observed in the trial. The Committee heard from one of the clinical specialists that in trials of metastatic colorectal cancer, gains in progression-free survival cannot reliably translate to gains in overall survival. The Committee was aware that most people in the study who had been randomised to receive best supportive care crossed over to receive panitumumab. The Committee noted that one consultee proposed that analyses adjusting for crossover did not adjust for the adverse reactions related to panitumumab treatment. It heard the Assessment Group's view that the manufacturer's analyses to adjust for crossover reflected a reasonable approach. The Committee concluded that panitumumab provided a survival benefit relative to best supportive care, but that the magnitude of this benefit was uncertain.
The Committee discussed the results of the Assessment Group's economic analysis for panitumumab, which was based on the HRs for panitumumab from the Assessment Group's mixed treatment comparison, adjusted for crossover. The Committee also noted the analyses carried out by the Assessment Group after public consultation on the assessment report, which used unadjusted HRs from the Amgen trial directly. These analyses resulted in a decrease in the ICER from £150,000 to £109,000 per QALY gained when panitumumab plus best supportive care was compared with best supportive care alone. The Committee also noted that the results of the Assessment Group's one-way sensitivity analyses showed that increasing the mean overall survival estimate for panitumumab plus best supportive care from the base-case value of 6.8 months to 7.2 months (based on an increase of 2 standard errors) resulted in an ICER of £110,000 per QALY gained. The Committee concluded that it was not possible to specify a precise ICER for panitumumab plus best supportive care compared with best supportive care alone, but that the most plausible ICER was likely to be between £110,000 and £150,000 per QALY gained.
## End-of-life considerations
The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations. In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.
The Committee discussed whether the technologies appraised fulfil the criteria for consideration as life-extending, end-of-life treatments. For metastatic colorectal cancer that has progressed after first-line treatment, the Committee agreed that the technologies fulfil the first criterion related to life expectancy, because estimates of life expectancy from people randomised to best supportive care in the second-line setting were less than 12 months.
For bevacizumab, the Committee agreed that there was no evidence to show how much bevacizumab plus non-oxaliplatin chemotherapy given as second-line treatment extends survival. In addition, the Committee understood that it should take into account all populations which are covered by all indications of the marketing authorisation for a given technology when considering the size of the patient population. The Committee noted that bevacizumab has a marketing authorisation for a number of indications and therefore does not fulfil the criterion of being indicated for a small patient group. The Committee concluded that bevacizumab plus non-oxaliplatin chemotherapy does not meet all of the criteria for a life-extending, end-of-life treatment.
For cetuximab, the Committee acknowledged that cetuximab plus best supportive care prolonged life by a median of 4.7 months in the third-line or later setting relative to best supportive care alone and therefore met the second end-of-life criterion. The Committee was aware from the manufacturer's data that approximately 7600 people have EGFR-positive, KRAS wild-type metastatic colorectal cancer in England and Wales, and only a small proportion of these (approximately 260 to 390 people) would be fit enough for third or subsequent lines of treatment. However, the Committee noted that cetuximab has a marketing authorisation for people with any stage of EGFR-positive KRAS wild-type metastatic colorectal cancer, and also for people with locally advanced and recurrent and/or metastatic head and neck cancer, which has previously been estimated to be a population of about 3000 (NICE technology appraisal guidance 172 ). The Committee discussed the decisions from two previous NICE technology appraisal appeals and noted that the Appeal Panel recognised that the criterion in the supplementary advice for end-of-life treatments for small patient populations indicated that 'Sufficient regard should be given to recognition of the desirability of developing new treatments in smaller disease areas and that higher prices, and therefore reduced cost effectiveness, were more likely to be justified given the need to recoup costs of development of the product from more limited licences'. The Appeal Panel had concluded that it was appropriate, according to the supplementary advice, to add together the potential patient populations covered by the marketing authorisation for different indications rather than on the basis of actual or recommended use. The Committee therefore concluded that the true size of the cumulative population covered by the marketing authorisation for cetuximab was likely to be over 10,000 patients and was not small, and that cetuximab does not meet all of the criteria for a life-extending, end-of-life treatment.
The Committee considered whether panitumumab provides a life extension of about 3 months. It noted that the manufacturer estimated that the mean life extension (after adjusting for crossover) was between 2.7 and 3.2 months, and that the Assessment Group judged the method used to derive this estimate to be reasonable. The Committee also noted that the progression-free survival benefit for panitumumab was similar to that for cetuximab and therefore there was sufficient evidence to indicate that panitumumab offers an extension to life of approximately 3 months compared with best supportive care alone. The Committee noted that panitumumab has a marketing authorisation for people with KRAS wild-type and EGFR-expressing metastatic colorectal cancer in whom both irinotecan- and oxaliplatin-containing chemotherapy has failed. The Committee agreed that this represents a small patient population. However, the Committee was aware that the Committee for Medicinal Products for Human Use recently recommended an extension of the marketing authorisation for panitumumab in combination therapy for KRAS wild-type metastatic colorectal cancer to first-line and second-line settings. Therefore it is expected that in the near future panitumumab will be licensed for the treatment of metastatic colorectal cancer in a patient population of similar size to that estimated for cetuximab. The Committee noted the most plausible ICER for panitumumab monotherapy lies between £110,000 and £150,000 per QALY gained. Therefore, the Committee concluded that, even if panitumumab monotherapy met all the criteria for a life-extending, end-of-life treatment, the additional weight that would need to be assigned to the QALY benefits would be too great to justify it as an appropriate use of limited NHS resources.
The Committee noted that testing tumour characteristics, such as the KRAS mutation, allowed clinicians to identify people who were more likely to respond to treatment with cetuximab or panitinumab, and agreed that this was an innovation in the treatment of metastatic colorectal cancer. The Committee also heard from the clinical specialists that in the future, the identification of further KRAS andalso BRAF mutations will allow even better identification of people who are likely to benefit from therapy. The Committee considered whether any of the technologies in this appraisal could be considered innovative. It concluded that it had not been presented with a case, substantiated by data, that the treatments add demonstrable and distinctive benefits of a substantial nature that had not already been adequately captured in the QALY measure.
# Summary of Appraisal Committee's key conclusions
TA242
Appraisal title: Cetuximab (monotherapy or combination chemotherapy), bevacizumab (in combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology appraisal 150 and part review of technology appraisal guidance 118)
Section
Key conclusion
Cetuximab monotherapy or combination chemotherapy, bevacizumab in combination with non-oxaliplatin (fluoropyrimidine-based) chemotherapy, and panitumumab monotherapy are not recommended for the treatment of people with metastatic colorectal cancer that has progressed after first-line chemotherapy.
This is because:
It was not possible to confirm by how much bevacizumab in combination with non-oxaliplatin (fluoropyrimidine-based) chemotherapy would extend life when used as second-line therapy, and evidence from previous assessments of bevacizumab with other combination regimens or for first-line treatment does not allow a justification for a positive recommendation in this appraisal.
The ICERs for cetuximab monotherapy or combination chemotherapy and for panitumumab monotherapy were very high (£90,000, £88,000 and £110,000–£150,000 per QALY gained respectively) and therefore these technologies did not represent a cost-effective use of NHS resources.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee heard from the clinical specialists and patient experts that there are limited treatment options for people with metastatic colorectal cancer that has progressed after treatment with first-line chemotherapy.
For second-line therapy in people whose disease has progressed despite first-line treatment, NICE technology appraisal guidance 93 recommends monotherapy with irinotecan as an option for people who received FOLFOX as first-line treatment, and FOLFOX as an option for people who received FOLFIRI as first-line treatment.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee agreed that KRAS testing was an innovation in the treatment of metastatic colorectal cancer. The Committee was not presented with a case, substantiated by data, that the technologies under consideration add demonstrable and distinctive benefits of a substantial nature that have not already been adequately captured in the QALY measure.
What is the position of the treatment in the pathway of care for the condition?
The UK marketing authorisation for bevacizumab is in combination with fluoropyrimidine-based chemotherapy for the treatment of patients with metastatic carcinoma of the colon or rectum.
Cetuximab has a UK marketing authorisation for the treatment of patients with EGFR-expressing, KRAS wild-type metastatic colorectal cancer, in combination with irinotecan-based chemotherapy or FOLFOX (5-FU and folinic acid and oxaliplatin) or as a single agent in patients whose disease has failed to respond to oxaliplatin and irinotecan-based therapy, and who are intolerant to irinotecan.
Panitumumab has a UK marketing authorisation as a 'monotherapy for the treatment of patients with EGFR-expressing metastatic colorectal cancer with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens'.
Adverse reactions
The Committee did not discuss specific issues around the adverse reactions to the technologies appraised but it was aware of the special warnings and precautions for use outlined in the SPCs for bevacizumab, cetuximab and panitumumab.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee noted the only evidence identified for the clinical effectiveness of bevacizumab as second-line treatment for metastatic colorectal cancer was one RCT (the E3200 trial) in which bevacizumab was given with oxaliplatin-containing chemotherapy, and two non-randomised observational studies using data from the BRiTE and ARIES patient registries. The Committee agreed that the evidence presented by the manufacturer could not be used to establish the overall survival gain with bevacizumab plus non-oxaliplatin chemotherapy as second- or third-line treatment for people with metastatic colorectal cancer that had not responded to first-line or second-line chemotherapy.
The only evidence for the clinical effectiveness of cetuximab was one RCT (the CO.17 trial) in people with KRAS wild-type metastatic colorectal cancer that had progressed after first-line chemotherapy. The Committee noted that the people in the CO.17 trial had previously received oxaliplatin- and irinotecan-based therapy, and that the trial had shown a median overall survival of 9.5 months for cetuximab plus best supportive care compared with 4.8 months for best supportive care alone.
The Committee noted that there were no head-to-head trials of cetuximab plus irinotecan compared with best supportive care in KRAS wild-type colorectal cancer. The Committee agreed that the results of the mixed treatment comparisons should be interpreted with caution, and concluded that the estimates of overall survival for cetuximab plus irinotecan were subject to a high degree of uncertainty.
The only evidence for the clinical effectiveness of panitumumab monotherapy came from one RCT (the Amgen trial) in people with KRAS wild-type metastatic colorectal cancer that had progressed after first-line chemotherapy. However, people in the trial had previously received both oxaliplatin- and irinotecan-based therapy, that is, panitumumab was given as third-line or subsequent therapy.
The Committee noted that although a benefit in progression-free survival of 5 weeks was associated with panitumumab monotherapy relative to best supportive care, no statistically significant effect on overall survival was observed and therefore the magnitude of this benefit was uncertain.
Relevance to general clinical practice in the NHS
The Committee did not discuss specific issues around the relevance to general clinical practice in the NHS.
Uncertainties generated by the evidence
The uncertainties were:
the overall survival gain with bevacizumab plus non-oxaliplatin chemotherapy in people with metastatic colorectal cancer who had previously received chemotherapy
the estimates of overall survival for cetuximab plus irinotecan based on the mixed treatment comparison
the magnitude of the survival benefit of panitumumab relative to best supportive care.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
None considered.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that there was sufficient evidence to show that cetuximab plus best supportive care gave greater benefit in terms of both progression-free survival and overall survival than best supportive care alone.
The Committee concluded that panitumumab provided a survival benefit relative to best supportive care, but that the magnitude of this benefit was uncertain.
Evidence for cost effectiveness
Availability and nature of evidence
Two economic models were available for this appraisal, one from the manufacturer of cetuximab and one from the Assessment Group.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The uncertainties were:
the mean time on cetuximab treatment
the overall survival estimates used in the economic models for panitumumab and cetuximab in combination with irinotecan, which were based on the mixed treatment comparison.
Incorporation of health-related quality-of-life benefits and utility values
The Committee noted that the utility estimates for each of the disease states were not consistent with the expectation that quality of life worsens with progression of disease. The Committee also noted that the utility estimates in the model (for example, 0.81 for progression-free disease for cetuximab plus best supportive care) were similar to those expected for people of the same age without metastatic colorectal cancer. The Committee concluded that the utility values in the manufacturer's model were highly uncertain.
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
None considered.
Are there specific groups of people for whom the technology is particularly cost effective?
None considered.
What are the key drivers of cost effectiveness?
The Committee noted that one of the main factors affecting the cost effectiveness of cetuximab was the assumption about the mean duration of treatment.
For panitumumab, the estimate of overall survival was the main factor found to substantially change the ICER.
Most likely cost-effectiveness estimate (given as an ICER)
The most plausible ICER for cetuximab plus best supportive care was £90,000 per QALY gained and for cetuximab plus irinotecan plus best supportive care the ICER was £88,000 per QALY gained, both compared with best supportive care.
It was not possible to specify a precise ICER for panitumumab plus best supportive care compared with best supportive care alone, but this would likely lie between £110,000 and £150,000 per QALY gained.
Additional factors taken into account
Patient access schemes (PPRS)
N/A
End-of-life considerations
The Committee agreed that the life expectancy of people with metastatic colorectal cancer treated with best supportive care in the second-line setting was less than 12 months.
The Committee concluded that bevacizumab plus non-oxaliplatin chemotherapy did not meet all of the criteria for a life-extending, end-of-life treatment. This was because there was no evidence to show by how much bevacizumab plus non-oxaliplatin chemotherapy given as second-line treatment extended survival and bevacizumab has a marketing authorisation for a number of indications and therefore does not fulfil the criterion of being indicated for a small patient group.
The Committee concluded that cetuximab did not meet all of the criteria for a life-extending, end-of-life treatment because the cumulative population covered by the indications in the marketing authorisation for cetuximab was likely to be over 10,000 patients and was not small.
The Committee noted that in the near future, panitumumab will be licensed for the treatment of metastatic colorectal cancer in a patient population of similar size to that for cetuximab. The Committee noted that the most plausible ICER for panitumumab monotherapy lies between £110,000 and £150,000 per QALY gained. Therefore, the Committee concluded that, even if all the criteria for a life-extending, end-of-life treatment were met for panitumumab monotherapy, the additional weight that would need to be assigned to the QALY benefits would be too great to justify it as an appropriate use of limited NHS resources.
Equalities considerations and social value judgements
The Committee heard that people with colorectal cancer in England are becoming increasingly worried about what they perceive to be unequal access to treatment with biological drugs, which are currently only provided to some patients through the Cancer Drugs Fund.
# Recommendations for further research
The Committee was aware that a phase II clinical trial (SPIRITT) comparing bevacizumab plus FOLFIRI with panitumumab plus FOLFIRI after first-line treatment is under way. The expected study completion date is August 2012. The Committee noted that the results of this trial should be considered in any future review decision for this appraisal.# Related NICE guidance
Published
Diagnosis and management of colorectal cancer. NICE clinical guideline 131 (2011)
Bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer. NICE technology appraisal guidance 212 (2010).
Cetuximab for the first-line treatment of metastatic colorectal cancer. NICE technology appraisal guidance 176 (2009).
Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. NICE technology appraisal guidance 118 (2007).
Irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer (review of technology appraisal 33). NICE technology appraisal guidance 93 (2005).
Guidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer. NICE technology appraisal guidance 61 (2003).# Review of guidance
The guidance on this technology will be considered for review by the Guidance Executive in January 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveJanuary 2012# Changes after publication
February 2014: minor maintenance
June 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE multiple technology appraisal process.
It updates and replaces NICE technology appraisal 150 (published June 2008). It also partially updates NICE technology appraisal guidance 118 (published in January 2007). This guidance updates and replaces recommendation 1.2 of TA118. The review and re-appraisal of cetuximab for the treatment of metastatic colorectal cancer that has progressed after first-line chemotherapy has resulted in a change in the guidance. Cetuximab is not recommended for the treatment of metastatic colorectal cancer that has progressed after any first-line chemotherapy (rather than specifically irinotecan-based chemotherapy).
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance ': 'This guidance updates and replaces NICE technology appraisal 150 (published in June 2008). It also updates and replaces recommendations in NICE technology appraisal guidance 118 (published in January 2007) on the use of cetuximab for the treatment of colorectal cancer that has progressed after first-line chemotherapy. For details see About this guidance.\n\nCetuximab monotherapy or combination chemotherapy is not recommended for the treatment of people with metastatic colorectal cancer that has progressed after first-line chemotherapy.\n\nBevacizumab in combination with non-oxaliplatin (fluoropyrimidine-based) chemotherapy is not recommended for the treatment of people with metastatic colorectal cancer that has progressed after first-line chemotherapy.\n\nPanitumumab monotherapy is not recommended for the treatment of people with metastatic colorectal cancer that has progressed after first-line chemotherapy.\n\nPeople currently receiving cetuximab monotherapy or combination chemotherapy, bevacizumab in combination with non-oxaliplatin chemotherapy, or panitumumab monotherapy for the treatment of metastatic colorectal cancer that has progressed after first-line chemotherapy should have the option to continue treatment until they and their clinician consider it appropriate to stop.', 'Clinical need and practice': "Colorectal cancer originates in the lower part of the digestive system, including the colon and rectum. In metastatic colorectal cancer, the tumour spreads beyond the local or regional lymph nodes to other parts of the body. Approximately 32,000 people were diagnosed with colorectal cancer in England and Wales in 2008. The prevalence of colorectal cancer increases with age, from 35 per 100,000 in people younger than 60 years, to 345 per 100,000 in people over 75 years. The median age of people at diagnosis is over 70 years.\n\nThe overall 5-year survival rate for colorectal cancer in England and Wales is approximately 50%; however, large differences in duration of survival exist according to the stage of disease at diagnosis. In 2007, over 93% of people in the UK diagnosed with Stage A on the modified Dukes' classification system (the earliest stage of the disease) survived for 5 years compared with less than 7% of people with metastatic disease.\n\nAt the time of diagnosis, an estimated 20–55% of people with colorectal cancer already have metastatic disease. In addition, of the people who have undergone surgery for early-stage colorectal cancer, approximately 50–60% will eventually develop metastatic disease, most commonly in the liver.\n\nAdvanced, or metastatic, colorectal cancer is cancer that has spread beyond the colon to other areas of the body. The management of metastatic colorectal cancer is mainly palliative, that is, to relieve symptoms, and combines specialist treatments (such as palliative surgery, chemotherapy and radiation) with control of symptoms and psychosocial support. However, approximately 8% of people with metastatic colorectal cancer have potentially resectable liver metastases and, in some, chemotherapy may make these liver metastases operable.\n\nThe aim of treatment is to improve both the length and quality of the patient's remaining life. People with metastatic disease in sufficiently good health (World Health Organization performance status 2 or better) are usually treated with first-line chemotherapy and then, if their cancer progresses, second-line chemotherapy. For other people, the harms from chemotherapy may outweigh the potential benefits. Therefore treatment depends on the person's individual circumstances.\n\nCharacteristics of the tumour that influence outcomes of treatment in people with metastatic colorectal cancer include the presence of: epidermal growth factor receptor (EGFR) and the 'wild-type' (non-mutated) form of the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene. Drugs that target EGFR are more effective against tumours expressing EGFR and a normal (wild-type) KRAS gene compared with those not expressing EGFR and with a mutated KRAS gene. Around 80% of people with metastatic colorectal cancer have EGFR-expressing disease and 30–50% have the KRAS wild-type gene.\n\nAs first-line treatment options for advanced colorectal cancer, NICE has recommended oxaliplatin in combination with 5-fluorouracil plus folinic acid (FOLFOX) and irinotecan in combination with 5-fluorouracil plus folinic acid (FOLFIRI) ('Irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer' (review of technology appraisal 33) [NICE technology appraisal guidance 93; TA93]). Other first-line treatment options recommended for metastatic colorectal cancer are the oral analogues of 5-fluorouracil; capecitabine or tegafur with uracil (in combination with folinic acid) ('Guidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer' [NICE technology appraisal guidance 61; TA61]). If metastatic disease is confined to the liver, and the patient has KRAS wild-type disease, the aim of first-line treatment is to make the metastases resectable surgically, and cetuximab may be given with FOLFOX or FOLFIRI ('Cetuximab for the first-line treatment of metastatic colorectal cancer' [NICE technology appraisal guidance 176; TA176]).\n\nFor second-line therapy in people whose disease has progressed despite first-line treatment, TA93 recommends monotherapy with irinotecan as an option for people who received FOLFOX as first-line treatment, and FOLFOX as an option for people who received FOLFIRI as first-line treatment.", 'The technologies': "Bevacizumab (Avastin, Roche Products) is a recombinant monoclonal antibody that inhibits angiogenesis by targeting the biological activity of human vascular endothelial growth factor, which stimulates formation of new blood vessels in the tumour. The UK marketing authorisation states that bevacizumab 'in combination with fluoropyrimidine-based chemotherapy is indicated for the treatment of patients with metastatic carcinoma of the colon or rectum'. Fluoropyrimidines are anti-metabolite drugs which include 5-fluorouracil (5-FU), folinic acid, capecitabine and tegafur.\n\nBevacizumab is contraindicated in people who have hypersensitivity to the active substance or to any of the excipients. The summary of product characteristics (SPC) lists the following as special warnings and precautions for use: gastrointestinal perforations, gastrointestinal fistulae, wound healing complications, hypertension, reversible posterior leukoencephalopathy syndrome, proteinuria, thromboembolism (arterial and venous), haemorrhage (including pulmonary haemorrhage and haemoptysis), congestive heart failure, neutropenia, hypersensitivity reactions (including infusion reactions), osteonecrosis of the jaw and eye disorders. For full details of side effects and contraindications, see the SPC.\n\nBevacizumab is administered by intravenous infusion. The recommended dosage is 5 or 10 mg/kg of body weight once every 2 weeks or 7.5 or 15 mg/kg of body weight once every 3 weeks. The price of a 100-mg vial is £242.66, and a 400-mg vial is £924.40 (excluding VAT; 'British national formulary' [BNF] edition 61). Costs may vary in different settings because of negotiated procurement discounts.\n\nCetuximab (Erbitux, Merck Serono) is a recombinant monoclonal antibody that blocks the human EGFR and inhibits the proliferation of cells that depend on activation of EGFR for growth. Cetuximab has a UK marketing authorisation for the treatment of patients with EGFR-expressing, KRAS wild-type metastatic colorectal cancer, in combination with irinotecan-based chemotherapy or FOLFOX (5-FU and folinic acid and oxaliplatin) or as a single agent in patients whose disease has failed to respond to oxaliplatin and irinotecan-based therapy, and who are intolerant to irinotecan.\n\nCetuximab is contraindicated in people with known severe (grade 3 or 4) hypersensitivity reactions to cetuximab. The SPC lists the following as special warnings and precautions for use: infusion-related reactions, respiratory disorders, skin reactions, electrolyte disturbances, neutropenia and cardiovascular disorders. For full details of side effects and contraindications, see the SPC.\n\nCetuximab is administered by intravenous infusion. The recommended dosage is an initial dose of 400 mg/m2 of body surface area followed by 250 mg/m2 once a week. The list price of a 20-ml vial (100-mg) is £178.10, and a 100-ml vial (500-mg) is £890.50 (excluding VAT; BNF edition 61). The manufacturer of cetuximab has agreed with the Department of Health that the price to the NHS will be £136.50 for a 20-ml vial and £682.50 for a 100-ml vial. Because the reduced prices are in the public domain and are available across the NHS, all calculations in the economic model are based on these reduced prices. Costs may vary in different settings because of negotiated procurement discounts.\n\nPanitumumab (Vectibix, Amgen) is a recombinant monoclonal antibody that blocks EGFR, inhibiting the growth of tumours expressing EGFR. It has a UK marketing authorisation as a 'monotherapy for the treatment of patients with EGFR-expressing metastatic colorectal cancer with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens'.\n\nPanitumumab is contraindicated in people with severe hypersensitivity to the active substance or to any of the excipients and in people with interstitial pneumonitis or pulmonary fibrosis. The SPC lists the following as special warnings and precautions for use: 'dermatologic reactions, pulmonary complications, electrolyte disturbances, infusion-related reactions, acute renal failure and keratitis'. For full details of side effects and contraindications, see the SPC.\n\nPanitumumab is administered by intravenous infusion. The recommended dosage is 6 mg/kg of body weight once every 14 days. The price of a 100-mg vial is £379.29, and a 400-mg vial is £1517.16 (excluding VAT; BNF edition 61). Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation ': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\nThe scope specified that this appraisal would evaluate the clinical and cost effectiveness of: cetuximab (monotherapy or in combination with chemotherapy); bevacizumab (in combination with non-oxaliplatin chemotherapy) and panitumumab monotherapy. The populations covered included people with EGFR-expressing and KRAS wild-type metastatic colorectal cancer that has progressed after first-line chemotherapy (cetuximab or panitumumab) and people with metastatic colorectal cancer that has progressed after first-line chemotherapy (bevacizumab). The comparators were chemotherapy with oxaliplatin or irinotecan. The interventions were compared with each other and with best supportive care. The relevant outcomes were overall survival, progression-free survival, response rate, adverse reactions to treatment, and health-related quality of life.\n\n# Clinical effectiveness\n\nThe Assessment Group completed a systematic review of the efficacy of the technologies as second- and third-line treatments for metastatic colorectal cancer that has progressed after first-line chemotherapy. For cetuximab and panitumumab, the population of interest was limited to people with KRAS wild-type disease. For the three therapies under consideration, only two randomised clinical trials (RCTs) met the inclusion criteria and were judged to be of good quality. In neither study did people have their KRAS mutation status determined at the beginning of the trial. However, both trials retrospectively analysed this and reported results for the subgroup of people with KRAS wild-type tumours.\n\n## Bevacizumab\n\nThe manufacturer identified one RCT (the E3200 trial) of bevacizumab as second-line treatment for metastatic colorectal cancer. The trial investigated the effectiveness of bevacizumab plus an oxaliplatin-containing chemotherapy regimen, which is outside the scope of this appraisal. People with metastatic colorectal cancer (n = 829) who had previously been treated with a fluoropyrimidine with or without irinotecan were randomised to receive bevacizumab plus FOLFOX4 (oxaliplatin plus 5-fluorouracil 400 mg, fluorouracil 600 mg and folinic acid), FOLFOX4 alone or bevacizumab alone. The primary endpoint was overall survival.\n\nMedian overall survival was 12.9 months in people randomised to bevacizumab plus FOLFOX4 (n = 286), 10.8 months in people randomised to FOLFOX4 alone (n = 291), and 10.2 months in people randomised to bevacizumab alone (n = 252). The incremental overall median survival for bevacizumab plus FOLFOX4 compared with FOLFOX4 was 2.1 months, with a hazard ratio (HR) of 0.75 (95% confidence interval [CI] not provided, p = 0.001). Median progression-free survival was 7.3 months in the bevacizumab plus FOLFOX4 arm, 4.7 months in the FOLFOX4 alone arm, and 2.7 months in the bevacizumab alone arm. The incremental median progression-free survival for bevacizumab plus FOLFOX4 compared with FOLFOX4 alone was 2.6 months (p < 0.0001). The bevacizumab alone arm of the study closed early after an interim analysis suggested inferior overall survival compared with the other arms.\n\nThe manufacturer identified three RCTs (Hurwitz et al. 2004, Kabbinavar et al. 2005, Saltz et al. 2008) that investigated the effectiveness of bevacizumab as first-line treatment for metastatic colorectal cancer. However, the scope for this appraisal specifies that bevacizumab should be considered as second-line and subsequent treatment. The manufacturer stated that, because no RCTs for metastatic colorectal cancer in the second-line setting studied bevacizumab in combination with chemotherapy regimens not containing oxaliplatin, these RCTs in the first-line setting only provide evidence to 'indicate that bevacizumab is safe and effective in combination with irinotecan in second-line metastatic colorectal cancer'. One study (Hurwitz et al. 2004) compared bevacizumab plus irinotecan, bolus 5-fluorouracil and folinic acid (n = 402) with placebo plus irinotecan, bolus 5-fluorouracil and folinic acid (n = 411). The primary endpoint was median overall survival, which was 20.3 months for people randomised to bevacizumab plus irinotecan, bolus 5-fluorouracil and folinic acid compared with 15.6 months for people randomised to placebo plus folinic acid (HR = 0.66, p < 0.001). The median progression-free survival was 10.6 months for people randomised to bevacizumab plus irinotecan, bolus 5-fluorouracil and folinic acid and 6.2 months for people randomised to placebo plus folinic acid (HR = 0.54, p < 0.001). The second RCT (Kabbinavar et al. 2005) evaluated bevacizumab plus bolus 5-fluorouracil and folinic acid (n = 105) compared with placebo plus bolus 5-fluorouracil and folinic acid (n = 104). Median overall survival was 16.6 months in people randomised to bevacizumab plus bolus 5-fluorouracil and folinic acid compared with 12.9 months in people randomised to placebo plus 5-fluorouracil and folinic acid (HR = 0.79, p = 0.16). The third RCT (Saltz et al. 2008) compared bevacizumab plus oxaliplatin-based chemotherapy (FOLFOX or capecitabine plus oxaliplatin [XELOX], n = 699) with oxaliplatin-based chemotherapy alone (FOLFOX or XELOX, n = 667). Progression-free survival (the primary endpoint) was significantly greater in people randomised to bevacizumab plus chemotherapy compared with chemotherapy alone (median progression-free survival 9.4 months versus 8.0 months; HR = 0.83, p = 0.002). There was no significant difference in overall median survival between the two arms (21.3 months versus 19.9 months for the bevacizumab plus chemotherapy arm and chemotherapy alone arm respectively; HR = 0.89, p = 0.77).\n\nThe manufacturer identified two observational cohort studies that investigated the effectiveness of bevacizumab as second-line treatment for metastatic colorectal cancer in people with progressed disease. One study, which used data from the 'Bevacizumab Regimens: Investigation of Treatment Effects and Safety' (BRiTE) registry compared overall survival in people treated with bevacizumab as first- and second-line therapy (n = 642), with people treated with bevacizumab as first-line therapy but with other chemotherapy treatments in the second-line setting (n = 531). Overall survival was significantly greater in people who received bevacizumab as a second-line treatment compared with those receiving other second-line chemotherapy regimens (median overall survival post progression 31.8 months compared with 19.9 months; HR = 0.48, p < 0.001). The other observational study used data from the ARIES registry and compared overall survival in people with metastatic colorectal cancer who received bevacizumab as first- and second-line treatment (n = 208) with people treated with bevacizumab in the second-line setting only (n = 255). Overall survival was significantly greater in people who received bevacizumab as first- and second-line treatment compared with those who received it in the second-line setting only (median overall survival post progression 21.7 months (95% CI 17.8 to 27.0) compared with 17.5 months (95% CI 15.9 to 21.5). The manufacturer noted that the data from the registries were not available by type of chemotherapy, and therefore specific information about the effect of bevacizumab in combination with non-oxaliplatin-based chemotherapy could not be provided.\n\nThe Assessment Group did not identify any trials that met the inclusion criteria for its review (that is, bevacizumab plus non-oxaliplatin-based chemotherapy for the treatment of people with metastatic colorectal cancer whose disease had progressed after first-line chemotherapy).\n\n## Cetuximab\n\nThe manufacturer and the Assessment Group identified one RCT (the CO.17 trial), which compared cetuximab plus best supportive care with best supportive care alone in people (n = 572) with metastatic colorectal cancer who had previously been treated with a fluoropyrimidine, irinotecan and oxaliplatin or who had contraindications to these treatments. This trial was mainly a trial of third-line and subsequent therapy, because 96−98% of people had received both irinotecan and oxaliplatin. Nearly half of the participants had received four or more chemotherapy regimens. The primary endpoint was overall survival.\n\nThe median overall survival in the whole trial population (irrespective of KRAS mutation status of the tumour) was 6.1 months with cetuximab plus best supportive care and 4.6 months with best supportive care alone, with an HR of 0.77 (95% CI 0.64 to 0.92; p = 0.005). Approximately 7% of people randomised to best supportive care alone were given cetuximab after crossover.\n\nA total of 394 (68.9%) tumour specimens were retrospectively examined for KRAS mutation status after completion of the trial (Karapetis et al. 2008). Limiting analyses to people with KRAS wild-type status, the median overall survival was 9.5 months for people randomised to cetuximab plus best supportive care compared with 4.8 months for people randomised to best supportive care alone (HR = 0.55, 95% CI 0.41 to 0.74; p < 0.001). In an analysis that adjusted for both randomisation and potential prognostic factors (age, Eastern Cooperative Oncology Group performance status, previous chemotherapy), the HR increased to 0.62 (95% CI 0.44 to 0.87; p = 0.006).\n\nTo compare cetuximab plus best supportive care with cetuximab plus irinotecan in people with KRAS wild-type status, the manufacturer presented a published retrospective observational analysis (De Roock et al. 2008, referred to as the De Roock analysis) that analysed data on Belgian participants combined from four studies (EVEREST n = 50, BOND n = 44, SALVAGE n = 17 and BABEL n = 2). Approximately one-quarter of people had been treated with cextuximab monotherapy, and three-quarters with cetuximab (at varying dosages) plus irinotecan. The phase II EVEREST trial investigated the effect of cetuximab dose escalation on EGFR expression in people with metastatic colorectal cancer whose disease had not responded to prior treatment with irinotecan. The BOND study was a randomised open-label multicentre phase II RCT of cetuximab plus irinotecan versus cetuximab monotherapy in people with metastatic EGFR-expressing colorectal adenocarcinoma. The SALVAGE study was an uncontrolled trial of monotherapy with cetuximab in people with metastatic colorectal cancer, whose tumours expressed EGFR and were refractory to irinotecan, oxaliplatin and fluoropyrimidines. The BABEL study was an uncontrolled trial of cetuximab monotherapy in people with KRAS wild-type metastatic colorectal cancer. The De Roock analysis provided data for a total of 113 people (67 with KRAS wild-type status, 46 with the KRAS mutation) with irinotecan refractory metastatic colorectal cancer who had been treated with cetuximab monotherapy. The Assessment Group excluded the De Roock analysis from its review because it judged the analysis to have a number of limitations: the people selected may not have been representative of people treated in UK clinical practice, and two of the studies (BABEL and SALVAGE) were single arm (that is, uncontrolled) studies. Only the BOND study compared cetuximab plus irinotecan with cetuximab monotherapy.\n\n## Panitumumab\n\nThe manufacturer and the Assessment Group identified one RCT (the 'Amgen' trial) that compared panitumumab plus best supportive care with best supportive care alone in 463 people with metastatic colorectal cancer that had progressed after standard first- and second-line chemotherapy (a fluoropyrimidine, irinotecan and oxaliplatin). The primary endpoint of the trial was progression-free survival. Overall survival was analysed as a secondary endpoint. No statistically significant difference was observed in overall survival in the whole population (irrespective of KRAS mutation status) (HR = 1.00, 95% CI 0.82 to 1.22).\n\nTumour samples from 427 (92%) people in the Amgen trial were retrospectively obtained for KRAS mutation status testing after the end of the trial. In the KRAS wild-type population, median progression-free survival was 12.3 weeks in people randomised to panitumumab plus best supportive care compared with 7.3 weeks in people randomised to best supportive care alone. When calculating overall survival in people randomised to the best supportive care arm, the manufacturer excluded people with wild-type KRAS who crossed over to receive panitumumab. Overall survival was estimated using two mutually exclusive time points: mean time to disease progression and mean time from progression to death. Survival estimates for best supportive care were based on people randomised to best supportive care with a KRAS mutation or wild-type KRAS for the time until disease progression (before any treatment crossover occurred), and people randomised to best supportive care with a KRAS mutation for the time from disease progression to death. Mean times to disease progression and from progression to death were estimated by fitting survival models to patient-level data from the clinical trial and then estimating the area under the best-fit curves and the mean survival for each distribution. The median overall survival from an intention-to-treat analysis in the KRAS wild-type population was 8.1 months for people randomised to panitumumab plus best supportive care compared with 7.6 months for people randomised to best supportive care alone. No statistically significant difference in median overall survival after disease progression between panitumumab and best supportive care was shown in this KRAS wild-type population (HR = 0.99; 95% CI 0.75 to 1.29).\n\nThere was significant crossover in the Amgen trial; of 219 people randomised to best supportive care alone, 166 (76%) crossed over after disease progression to receive treatment with panitumumab. Because panitumumab lengthened progression-free survival, and many people randomised to best supportive care also received panitumumab after progression, the estimates of effectiveness from intention-to-treat analyses (see section 4.2.11) were considered by the manufacturer to underestimate the effectiveness of panitumumab. Therefore, in an attempt to adjust for this bias, the manufacturer adjusted the overall survival results by including people with KRAS mutations randomised to best supportive care in the analysis, regardless of whether they crossed over to receive panitumumab treatment after disease progression. The manufacturer's rationale for this method was that the trial showed that people with a KRAS mutation did not benefit from treatment with panitumumab. Therefore people with a KRAS mutation in the best supportive care arm who crossed over to receive panitumumab after disease progression would also be less likely to benefit from it. The average survival gain adjusted for crossover was between 2.74 months (overall survival estimated by splitting response rates) and 3.13 months (overall survival estimated by aggregating survival across response rates) for panitumumab compared with best supportive care. The Assessment Group judged that the manufacturer's approach and assumptions to adjust for crossover were reasonable.\n\n## Mixed treatment comparisons\n\nThe Assessment Group and the manufacturers did not identify any RCTs that directly compared each of the technologies included in this appraisal. Both the Assessment Group and the manufacturer of cetuximab carried out a mixed treatment comparison using the Bucher approach to estimate the relative effectiveness of the technologies relevant to the decision problem. Without clinical evidence for the use of bevacizumab as specified by the scope, there were four treatments or comparators:\n\nbest supportive care\n\nmonotherapy with cetuximab plus best supportive care\n\nmonotherapy with panitumumab plus best supportive care, and\n\ncetuximab plus chemotherapy plus best supportive care. The manufacturers of panitumumab and bevacizumab did not submit a mixed treatment comparison because they did not consider it possible to conduct a robust mixed treatment comparison of the three technologies based on the evidence available.\n\n## Manufacturer's (Merck Serono) mixed treatment comparison\n\nTo compare the clinical effectiveness of cetuximab plus chemotherapy with panitumumab plus best supportive care and best supportive care alone, the manufacturer (Merck Serono) used data from the CO.17 trial and from the Amgen trial. Although the scope of this appraisal covers cetuximab plus chemotherapy, the only evidence available was for cetuximab plus irinotecan. The manufacturer used data from 80 people in a retrospective analysis of the De Roock analysis to compare cetuximab plus best supportive care with cetuximab plus irinotecan in the KRAS wild-type population. The manufacturer did not identify any relevant evidence for bevacizumab.\n\nThe resulting HR for overall survival for cetuximab plus irinotecan and best supportive care compared with best supportive care alone was 0.29 (95% CI 0.14 to 0.59). Following advice from clinical specialists, the manufacturer concluded that the parametric model it had fitted to the Kaplan–Meier curve for overall survival (Weibull function) did not match the original data. The manufacturer therefore obtained additional data from the retrospective analysis of the De Roock analysis for 364 people. The resulting HR for overall survival for cetuximab plus irinotecan compared with best supportive care changed to 0.32 (confidence interval not reported). The manufacturer used the 95% CI from the original retrospective analysis of the De Roock analysis (that is, 95% CI 0.14 to 0.59). The resulting HR for overall survival for cetuximab plus best supportive care compared with panitumumab plus best supportive care was 0.56 (95% CI 0.37 to 0.83).\n\nThe Assessment Group expressed concerns about the validity of the manufacturer's approach to calculating progression-free survival and overall survival hazard ratios from the mixed treatment comparison because:\n\nit combined randomised and non-randomised evidence, subjecting it to bias and confounding\n\nit did not assess whether the populations in the chosen studies were comparable\n\nfor calculating the overall survival HR for cetuximab plus irinotecan compared with best supportive care, the manufacturer used data from a non-comparative study to adjust the HR to fit the model, but the statistical fit of the model was determined by clinical specialists rather than statistical testing, and the manufacturer did not clarify how adjustments were made to fit the data to the model\n\nthe manufacturer used unadjusted HRs from the cetuximab CO.17 RCT instead of values adjusted for patient characteristics, which may have overestimated the effectiveness of cetuximab\n\nthe BOND study, which was included in the observational retrospective analysis that combined four studies (the De Roock analysis) did not account for crossover, and this could have led to an underestimation of overall survival gain for cetuximab plus best supportive care compared with cetuximab plus irinotecan.\n\n## Assessment Group's mixed treatment comparison\n\nThe Assessment Group also carried out a mixed treatment comparison for the four treatments: best supportive care, cetuximab monotherapy plus best supportive care, panitumumab monotherapy plus best supportive care, and cetuximab plus irinotecan and best supportive care. The Assessment Group used data from the two RCTs used by the manufacturer of cetuximab in its mixed treatment comparison: the CO.17 trial (cetuximab plus best supportive care compared with best supportive care alone) and the Amgen trial (panitumumab plus best supportive care compared with best supportive care alone). It also used data from the retrospective analysis of four studies (the De Roock analysis). The Assessment Group assumed that best supportive care was equivalent between the CO.17 trial and the Amgen trial. Unlike the manufacturer's analysis, the Assessment Group adjusted HRs in its mixed treatment comparison for the patient characteristics in the KRAS wild-type population. However, the HRs obtained from the indirect comparison were not adjusted using data from the retrospective analysis (De Roock analysis).\n\nResults of the mixed treatment comparison showed that patients who received cetuximab plus best supportive care would be expected to have significantly longer overall survival than those receiving panitumumab plus best supportive care (unadjusted HR 0.56, 95% CI 0.37 to 0.83; adjusted HR 0.63, 95% CI 0.41 to 0.97). The Assessment Group highlighted that the HR for overall survival for panitumumab from the Amgen trial may have underestimated the effectiveness of panitumumab relative to best supportive care because most people randomised to best supportive care also received treatment with panitumumab after their disease had progressed. The Assessment Group reported an overall survival estimate of 16.2 months for cetuximab plus irinotecan in an appendix to the assessment report.\n\n# Cost effectiveness\n\n## Manufacturer's submission\n\nAmgen and Roche Products did not submit health economic models. Roche Products submitted calculations outlining the treatment costs for bevacizumab plus FOLFIRI compared with cetuximab plus FOLFIRI. The treatment cost for cetuximab plus FOLFIRI was estimated to exceed that for bevacizumab plus FOLFIRI by £5408, with an incremental cost for KRAS testing of £462, additional drugs costs of £3357 and additional administration costs of £1589.\n\nMerck Serono provided a Markov model to make four comparisons:\n\ncetuximab plus best supportive care compared with best supportive care alone\n\ncetuximab plus irinotecan plus best supportive care compared with best supportive care alone\n\ncetuximab plus best supportive care compared with panitumumab plus best supportive care\n\ncetuximab plus irinotecan plus best supportive care compared with panitumumab plus best supportive care.\n\nThe population modelled by Merck Serono included people with EGFR-expressing KRAS wild-type metastatic colorectal cancer who had received second- or subsequent-line chemotherapy for metastatic disease. The model had a 10-year time horizon and a UK National Health Service (NHS) perspective. The cycle length was 1 week and a half-cycle correction was not applied. The model had three health states: progression-free disease, progressive disease and death. Merck Serono based the transitions between health states on parametric approximations of Kaplan–Meier estimates of progression-free survival and overall survival from the relevant arms of the RCTs (with time spent by a patient in progressive disease defined as the difference between the two).\n\nTo compare cetuximab plus best supportive care with best supportive care alone, Merck Serono estimated separate probabilities for time to disease progression and time to death for people in the progression-free disease and progressive disease health states using patient-level data. Merck Serono chose different functions on the basis of goodness-of-fit measures for each transition (log-normal for time to progression; log-logistic for death from the health state of pre-progression; Weibull for death from the health state of progressive disease).\n\nFor the comparison of cetuximab plus irinotecan and best supportive care with best supportive care alone, Merck Serono modelled progression-free survival and overall survival using a two-stage process. First, it simulated progression-free survival and overall survival for people treated with best supportive care alone using a Weibull curve and then validated this curve using data from the best supportive care arm of the CO.17 trial. The corresponding values for progression-free survival and overall survival for cetuximab plus irinotecan and best supportive care were then estimated by applying the overall survival HRs for cetuximab plus irinotecan and best supportive care with the HR for best supportive care being drawn from the mixed treatment comparison. Merck Serono obtained estimates of utility for each health state using the Health Utility Index (HUI) scale (a generic preference-based measure of quality of life) by reanalysing data by health state in the CO.17 trial. These utility values were then applied to cetuximab plus irinotecan and best supportive care and panitumumab plus best supportive care. The manufacturer used utility values of 0.809 for progression-free disease, 0.789 for progressive disease and 0.000 for death.\n\nThe following assumptions were made in the model: the mean time on treatment with cetuximab plus best supportive care is 2.6 months and the mean time for cetuximab plus irinotecan is 4.4 months; active treatment stops at set cut-off time points, that is, 13 weeks for cetuximab plus best supportive care and 24 weeks for cetuximab plus irinotecan plus best supportive care, even if a patient's disease has not progressed.\n\nMerck Serono produced a series of pairwise comparisons of cost effectiveness in people with KRAS wild-type metastatic colorectal cancer:\n\nCetuximab plus best supportive care compared with best supportive care alone produced a base-case incremental cost-effectiveness ratio (ICER) of £47,095 per quality-adjusted life year (QALY) gained.\n\nCetuximab plus irinotecan plus best supportive care compared with best supportive care alone produced a base-case ICER of £43,887 per QALY gained.\n\nCetuximab plus irinotecan plus best supportive care compared with panitumumab plus best supportive care produced a base-case ICER of £21,819 per QALY gained. When cetuximab plus best supportive care was compared with panitumumab plus best supportive care, panitumumab was associated with higher costs and fewer QALYs (–0.193 incremental QALYs and £2629 incremental costs). Merck Serono completed one-way sensitivity analyses on all the model parameters and the only factor found to significantly change the ICERs was varying the cost of cetuximab (which included changes to the price of the drug, its administration costs, and/or the duration of treatment).\n\nMerck Serono's probabilistic sensitivity analyses indicated that, compared with best supportive care alone, cetuximab plus best supportive care and cetuximab plus irinotecan had a 64.7% and a 68% chance respectively of being cost effective at £50,000 per QALY gained. Compared with panitumumab plus best supportive care, cetuximab plus best supportive care had a 100% chance of being cost effective at £15,000 per QALY gained. Cetuximab plus irinotecan compared with panitumumab plus best supportive care has a 73.8% chance of being cost effective at £30,000 per QALY gained and a 93% chance of being cost effective at £50,000 per QALY gained.\n\n## Assessment Group's report\n\nFrom a literature review the Assessment Group identified one cost-effectiveness analysis of bevacizumab in previously untreated metastatic colorectal cancer, which was not relevant to this appraisal. It also identified a study by Mittman et al. (2008) which was a trial-based cost-effectiveness analysis that used data from the cetuximab CO.17 trial. The Assessment Group also identified three studies (Annemans et al. 2007, Norum et al. 2006, Starling et al. 2007) which assessed the cost effectiveness of cetuximab plus irinotecan compared with best supportive care. The base-case ICER in the Annemans et al. study was €40,273 per life year gained (based on 12 weeks of treatment). The base-case ICER was €205,536 per life year gained in the Norum et al. study and £57,608 per QALY gained in the Starling et al. study.\n\nThe Assessment Group noted that the Merck Serono model did not attempt to compare cetuximab plus irinotecan plus best supportive care with cetuximab plus best supportive care. Moreover, Merck Serono assessed the cost effectiveness of cetuximab only as third-line treatment and did not consider it as second-line treatment, but the scope for this appraisal allows any of the technologies to be considered as second-line treatment. The Assessment Group questioned the validity of the utility values obtained from the CO.17 trial by Merck Serono because they exceeded the values produced by the health economic evaluation that accompanied the CO.17 trial (Mittman et al. 2008).\n\nThe Assessment Group provided an area under the curve model that compares cetuximab plus best supportive care with best supportive care alone, cetuximab plus irinotecan plus best supportive care with best supportive care alone, and panitumumab plus best supportive care with best supportive care alone in people with EGFR-expressing KRAS wild-type metastatic colorectal cancer who had received at least second-line chemotherapy for metastatic disease. The Assessment Group did not include bevacizumab in the economic analysis because no clinical effectiveness evidence was available for bevacizumab plus chemotherapy without oxaliplatin in people who had received previous chemotherapy. The model had a 10-year time horizon and a UK NHS perspective. The cycle length was 1 month and a half-cycle correction was applied.\n\nThe model had three health states: progression-free disease, progressive disease and death. The Assessment Group used an 'area under the curve' or 'cohort partition' method to determine the number of people in each health state at each cycle of the model, rather than using transition probabilities. The Assessment Group obtained estimates of utility from the Mittman et al. (2008) study that used individual patient-level data and HUI data from the CO.17 trial. The Assessment Group used utility values for progression-free disease of 0.81 for cetuximab plus best supportive care, 0.75 for best supportive care, 0.75 for cetuximab plus irinotecan, and 0.87 for panitumumab plus best supportive care; a utility value of 0.69 was used for progressive disease (for all treatments).\n\nThe Assessment Group's model differed from the Merck Serono model in the following ways for the comparison of cetuximab plus best supportive care versus best supportive care alone:\n\nthe estimates of mean time on cetuximab varied: Assessment Group 4.8 months, Merck Serono 2.6 months\n\nthe estimates of drug costs varied because of differences in estimates of treatment duration: Assessment Group £14,400, Merck Serono £8200\n\nthe estimates of drug administration costs varied because of differences in estimates of treatment duration: Assessment Group £5500, Merck Serono £2000\n\nthe estimates of utility were taken directly from Mittman et al. (2008) by the Assessment Group; reanalysed estimates from the CO.17 trial were used by Merck Serono\n\nthe Assessment Group model included an adjustment for crossover for the overall survival HR for panitumumab compared with best supportive care whereas the Merck Serono model did not.\n\nFor the comparison of cetuximab plus irinotecan versus best supportive care, the main differences between the Assessment Group's model and the Merck Serono model were the:\n\nestimates of mean time on cetuximab plus irinotecan varied: Assessment Group 8.8 months, Merck Serono 4.4 months\n\nestimates of drug costs varied because of differences in estimates of treatment duration: Assessment Group £32,000, Merck Serono £17,400\n\nestimates of drug administration costs varied because of differences in estimates of treatment duration: Assessment Group £12,700, Merck Serono £3800.\n\nThe Assessment Group produced a series of pairwise comparisons of cost effectiveness in people with KRAS wild-type metastatic colorectal cancer:\n\nCetuximab plus best supportive care compared with best supportive care alone produced a base-case ICER of £98,000 per QALY gained.\n\nCetuximab plus irinotecan plus best supportive care compared with best supportive care alone produced a base-case ICER of £88,000 per QALY gained.\n\nPanitumumab plus best supportive care compared with best supportive care alone produced a base-case ICER of £150,000 per QALY gained. The Assessment Group completed deterministic one-way sensitivity analyses on model parameters and the only factor found to substantially change the ICER was the estimate of overall survival. The ICER for cetuximab plus best supportive care compared with best supportive care alone was more than £70,000 per QALY gained in all scenarios, the ICER for cetuximab plus irinotecan compared with best supportive care was more than £55,000 per QALY gained, and the ICER for panitumumab plus best supportive care compared with best supportive care was more than £110,000 per QALY gained. When the unadjusted progression-free survival estimates from the Amgen trial were used, the ICER for panitumumab plus best supportive care compared with best supportive care was reduced to £109,000 per QALY gained. In an additional analysis conducted in response to comments received from the manufacturers during consultation on the assessment report, the overall survival estimate for best supportive care was increased from 6.8 months to 7.2 months. This gave an ICER of £119,000 per QALY gained for panitumumab plus best supportive care compared with best supportive care.\n\nThe Assessment Group's probabilistic sensitivity analyses indicated that below £60,000 per QALY gained, none of the drugs appraised is the most cost-effective treatment for second-line or subsequent chemotherapy of metastatic colorectal cancer. Above £90,000 per QALY gained, cetuximab plus irinotecan is likely to be the most cost-effective treatment compared with best supportive care. Cetuximab monotherapy or panitumumab are never the most cost-effective option when compared with best supportive care.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab in combination with non-oxaliplatin chemotherapy, cetuximab either in combination with chemotherapy or as monotherapy, and panitumumab monotherapy. The Committee did so having considered evidence on the nature of metastatic colorectal cancer and the value placed on the benefits of bevacizumab, cetuximab and panitumumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee heard from the clinical specialists and patient experts that there are limited treatment options for people with metastatic colorectal cancer that has progressed after treatment with first-line chemotherapy (progression being defined as radiological evidence of tumour growth or spread, and/or by clinical symptoms). The second-line treatment options that NICE recommends currently (in TA93) are irinotecan monotherapy and FOLFOX. Irinotecan monotherapy is offered to people who received FOLFOX as first-line treatment, and FOLFOX is offered to people who received FOLFIRI as first-line treatment. TA93 also specifies that people may receive treatment with either FOLFOX or irinotecan as second-line and subsequent-line therapy if they have received 5-fluorouracil and folinic acid or oral analogues as first-line treatment. The Committee heard from the clinical specialists that frail people and older adults were more likely to be offered as first-line therapy 5-fluorouracil and folinic acid over FOLFIRI or FOLFOX, with FOLFOX (or the same combination of oral analogues) being less toxic than FOLFIRI. The Committee also heard that as second-line therapy, clinicians prefer to offer combination chemotherapy (for example, FOLFOX) over irinotecan monotherapy (partly because of irinotecan's toxicity), but that clinicians consider offering irinotecan monotherapy as third-line therapy after second-line combination chemotherapy.\n\nThe Committee heard from the clinical specialists that EGFR testing was not routinely carried out in clinical practice for people with colorectal cancer because the results had not been found to correlate with response to specific chemotherapy regimens. The Committee further heard from the clinical specialists that KRAS testing is now routinely offered in the NHS in some parts of England and Wales, that several proprietary test kits are available, and that NHS pathology laboratories can carry out this testing at low cost. The Committee was also aware that Merck Serono offers KRAS testing for free, and that accepting Merck Serono's test did not prevent clinicians from prescribing treatments from other manufacturers. The Committee concluded that the KRAS testing required by the marketing authorisations for treatment with cetuximab and panitumumab would not be a barrier to treatment.\n\nThe Committee heard from the patient experts that people who need to have second- and third-line chemotherapy particularly value even very small increases in life expectancy because this extra time allows them to put their affairs in order and help family and friends. The Committee also heard from the patient experts that the opportunity to receive active treatment rather than palliative care alone is very important to people with metastatic colorectal cancer. In addition, the Committee heard that people with colorectal cancer in England are becoming increasingly worried about what they perceive to be unequal access to treatment with biological drugs, which are currently only provided to some people through the Cancer Drugs Fund.\n\n## Bevacizumab\n\nThe Committee discussed the clinical effectiveness of bevacizumab in people with metastatic colorectal cancer who have received first-line chemotherapy. The Committee discussed the results of the three RCTs (see section 4.2.4) presented in the Roche Products submission, which investigated the effectiveness of bevacizumab as first-line treatment for metastatic colorectal cancer. The Committee agreed that these trials demonstrated that bevacizumab is an effective first-line treatment for metastatic colorectal cancer, but recognised that the scope of this appraisal was to consider bevacizumab in the second- and third-line setting. The Committee understood that Roche Products, the regulatory authorities and the clinical specialists considered that if bevacizumab plus a non-oxaliplatin-containing regimen is effective in the first-line setting, the combination would also likely be effective in second- and third-line settings, despite not having been tested in these situations. The Committee heard that this assumption was the basis of the regulatory approval for bevacizumab as a second-line therapy. However, the Committee agreed that people receiving bevacizumab as second-line therapy would have more advanced disease than people receiving bevacizumab for first-line therapy. Therefore, the Committee concluded that people receiving bevacizumab as second-line therapy would likely have smaller gains in survival than people who have not previously received chemotherapy.\n\nThe Committee noted the results of two registry-based observational studies, BRiTE and ARIES. The Committee understood that Roche Products could not provide data from these registries specifically for bevacizumab in combination with non-oxaliplatin chemotherapy. In line with this, the manufacturer also informed the Committee that these registries were unlikely to inform the Committee's decision regarding the use of bevacizumab as second-line or subsequent therapy in combination with non-oxaliplatin chemotherapy. The Committee concluded that the observational evidence presented in the manufacturer's submission could not be used to establish the magnitude of the overall survival gain with bevacizumab plus non-oxaliplatin chemotherapy for people with metastatic colorectal cancer which had not responded to first-line chemotherapy.\n\nThe Committee then discussed the E3200 RCT presented in the Roche Products submission (see section 4.2.2), which investigated the effectiveness of bevacizumab plus an oxaliplatin-containing chemotherapy regimen as second-line treatment compared with placebo plus folinic acid for metastatic colorectal cancer. The Committee acknowledged that 'Bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer' (NICE technology appraisal guidance 212 [TA212]) has already evaluated the clinical and cost effectiveness of bevacizumab plus oxaliplatin-containing chemotherapy in metastatic colorectal cancer, and that the remit of the current appraisal is to appraise bevacizumab plus non-oxaliplatin chemotherapy. The Committee agreed that the results of the E3200 trial could not be used to establish the overall survival gain with bevacizumab plus non-oxaliplatin chemotherapy as second- or third-line treatment for people with metastatic colorectal cancer who had not responded to first-line or second-line chemotherapy. The Committee noted that this conclusion was supported by one of the clinical specialists, who pointed out that the effectiveness of biological drugs plus oxaliplatin differs from the effectiveness of biological drugs plus irinotecan. The Committee acknowledged that there is an ongoing RCT of bevacizumab plus FOLFIRI compared with panitumumab plus FOLFIRI as second-line treatment of metastatic colorectal cancer, which is due to finish in August 2012. However it agreed that it was not aware of any currently available evidence on which to base a decision about the clinical effectiveness of bevacizumab plus non-oxaliplatin chemotherapy in people with metastatic colorectal cancer who had previously received chemotherapy.\n\nThe Committee discussed the likely cost effectiveness of bevacizumab plus non-oxaliplatin chemotherapy compared with best supportive care and noted the Assessment Group's view that lack of relevant evidence on clinical effectiveness meant that it was not feasible to carry out a cost-effectiveness evaluation of bevacizumab. The Committee also heard from Roche Products that it had not submitted an economic model because it did not believe it would be possible to establish that bevacizumab plus non-oxaliplatin chemotherapy is cost effective as a second-line treatment for metastatic colorectal cancer. The Committee noted that previous NICE technology appraisal guidance (TA212 and 'Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer' [NICE technology appraisal guidance 118; TA118]) had not found bevacizumab to be a cost-effective first-line or second-line treatment for metastatic colorectal cancer. In view of its previous judgement that bevacizumab is likely to be less effective as second-line therapy than as first-line therapy, on balance, the Committee felt that it was unlikely that bevacizumab would be a cost-effective treatment for people with metastatic colorectal cancer who had received first-line therapy. The Committee therefore concluded that the available clinical and cost-effectiveness evidence does not justify a positive recommendation for bevacizumab plus non-oxaliplatin chemotherapy as second-line treatment for metastatic colorectal cancer.\n\n## Cetuximab\n\nThe Committee discussed the clinical effectiveness of cetuximab (monotherapy or combination chemotherapy) in people with KRAS wild-type metastatic colorectal cancer that has progressed after first-line chemotherapy. The Committee noted that the people in the CO.17 trial had previously received oxaliplatin- and irinotecan-based therapy, that is, cetuximab was used in the third-line or later setting. The trial had shown a median overall survival of 9.5 months for cetuximab plus best supportive care compared with 4.8 months for best supportive care alone. The Committee was aware that only 68.9% of people in the CO.17 trial were tested for KRAS mutation status, and was concerned that there may have been selection bias related to the KRAS mutation testing if those people tested were fundamentally different in a way which influenced their response to treatment. The Committee noted the Assessment Group's comment that the age of people in the trial, including people whose tumour displayed KRAS mutations and those not tested, averaged 63 years (range 28–88 years), which was on average 10 years younger than people with metastatic colorectal cancer typically seen in clinical practice in the NHS. The Committee heard from the clinical specialists that age at of the start of treatment was unlikely to affect clinical response. The Committee therefore agreed that although the trial population did not fully represent people seen in clinical practice in the NHS, the evidence of clinical effectiveness for cetuximab monotherapy was generalisable to UK clinical practice. The Committee concluded that there was sufficient evidence to show that cetuximab plus best supportive care gave greater benefit in terms of both progression-free survival and overall survival than best supportive care alone.\n\nThe Committee discussed the evidence available for the clinical effectiveness of cetuximab plus irinotecan chemotherapy. The Committee noted that there were no head-to-head trials of cetuximab plus irinotecan compared with best supportive care in KRAS wild-type colorectal cancer. The Committee therefore discussed the results of the manufacturer's mixed treatment comparison that compared cetuximab plus chemotherapy with panitumumab or best supportive care and cetuximab monotherapy with panitumumab in the KRAS wild-type population. The Committee noted the Assessment Group's concerns about the validity of the mixed treatment comparison (see section 4.2.17). The Assessment Group was particularly concerned about the reliance on the retrospective observational analysis (the De Roock analysis) for the effectiveness estimate for cetuximab plus irinotecan, which combined data from RCTs and non-RCTs (single-arm trials), not all of which included treatment with cetuximab plus irinotecan. The Committee therefore agreed that the results of the mixed treatment comparison should be interpreted with caution. The Committee concluded that the estimates of overall survival for cetuximab plus irinotecan were subject to a high degree of uncertainty.\n\nThe Committee discussed the economic model submitted by the manufacturer of cetuximab, and the Assessment Group's comments on this model. The Committee concluded that using best supportive care as one of the comparators in the model was appropriate. However, the Committee was concerned that the manufacturer had not submitted an economic comparison of cetuximab plus best supportive care versus cetuximab plus irinotecan plus best supportive care, despite having submitted estimates of clinical effectiveness, and had not given a reason for this. The Committee discussed two concerns about the total cost estimated by the manufacturer for cetuximab; that is, the administration costs and costs associated with duration of treatment. The Committee was aware that the Assessment Group model had used estimated administration costs for cetuximab that were two to three times higher than those estimated by the manufacturer. The Committee discussed its concerns about the assumptions in the manufacturer's model about the duration of treatment; particularly whether in clinical practice people would receive cetuximab for a fixed treatment period (as modelled) rather than until disease progresses (as specified in the SPC). The Committee heard from the clinical specialists that clinicians would offer people treatment with cetuximab monotherapy until their disease progressed, but would likely offer cetuximab plus irinotecan for a fixed period in view of the increased toxicity of combined treatment. The Committee therefore concluded that it did not accept the assumption in the manufacturer's model that a fixed treatment period for cetuximab represented UK clinical practice. The Committee also noted a comment made by Amgen during consultation that the NICE 'Guide to the methods of technology appraisal' states a preference for the use of the public list price for a technology and not the negotiated price to the NHS. The Committee noted that the lower NHS price for cetuximab was previously used in NICE technology appraisal 176 rather than the list price. It agreed that the most relevant price to be considered in this appraisal is the one that is nationally available and in the public domain, and therefore considered it appropriate to use the NHS price for cetuximab in the economic model.\n\nThe Committee discussed the utility estimates in the manufacturer's model, which were obtained from the CO.17 trial. The Committee was aware that using HUI deviated from the NICE reference case, which encourages the use of EQ-5D. However, it agreed that the HUI was a valid measure of utility and that values obtained from the trial population were likely to be generalisable to patients in the UK. The Committee noted that the utility estimates for each of the disease states were not consistent with the expectation that quality of life worsens with progression of disease. The Committee was aware of the Assessment Group's concern that the values of utility recalculated by the manufacturer from the CO.17 trial were higher for progression-free disease than those of Mittman et al. from the same trial. The Committee also noted that the utility estimates used in the model (for example, 0.81 for progression-free disease for cetuximab plus best supportive care) were similar to those expected for people of the same age without metastatic colorectal cancer. The Committee concluded that the utility values in the manufacturer's model were highly uncertain.\n\nThe Committee discussed the results of the manufacturer's sensitivity analyses and noted that the estimate of cost effectiveness was most sensitive to the estimate of overall drug costs, which was determined by the time on cetuximab treatment. The Committee heard from the manufacturer that the estimates of time on treatment in the model were based on clinical opinion rather than direct estimates from the CO.17 trial. The Committee agreed that the assumption of a fixed treatment period for cetuximab in the manufacturer's model did not represent UK clinical practice (see section 4.4.11).\n\nThe Committee considered the Assessment Group's economic model for cetuximab. The Committee heard that the utility estimates in the Assessment Group's model had been obtained from a published cost–utility study of the CO.17 trial (Mittman et al. 2008) and were in general lower than those used in the manufacturer's model. The Committee agreed that the utility values used by the manufacturer were implausibly high because they were similar to those of the general population of the same age without metastatic colorectal cancer. The Committee also noted that because the manufacturer did not provide an estimate of the average length of cetuximab treatment in the CO.17 trial, the Assessment Group contacted Dr Mittman to obtain this estimate after the assessment report had been submitted to the Committee. This estimate was provided to the Committee as an addendum, and is not given in this document because it is considered academic-in-confidence. The Committee agreed that this estimate of time on treatment was more appropriate because it was derived from trial data rather than from an assumption.\n\nThe Committee noted that one of the main factors affecting the cost effectiveness of cetuximab was the assumption about the duration of treatment. The Committee agreed that using the values provided as academic-in-confidence in the Assessment Group's analyses gave the most plausible ICER for cetuximab plus best supportive care of £90,000 per QALY gained and for cetuximab plus irinotecan plus best supportive care of £88,000 per QALY gained, both compared with best supportive care. The Committee was aware of another cost−utility analysis of the CO.17 trial (Mittman et al. 2008) that had estimated an ICER of £101,000 per QALY gained for cetuximab plus best supportive care compared with best supportive care. The Committee was also aware that the manufacturer, Merck Serono, noted in its comments during consultation that cetuximab 'is not cost effective under the usual threshold range for acceptability'.The Committee concluded that the most plausible ICERs for cetuximab monotherapy and cetuximab in combination chemotherapy did not represent a cost-effective use of NHS resources.\n\n## Panitumumab\n\nThe Committee discussed the clinical effectiveness of panitumumab monotherapy in people with KRAS wild-type metastatic colorectal cancer that has progressed after first-line chemotherapy. It noted that the only trial evidence available applied to people who had previously received both oxaliplatin- and irinotecan-based therapy, that is, in the third-line or subsequent setting (the Amgen trial). The Committee heard from the manufacturer that over 90% of people in the trial were assessed for the KRAS mutation and concluded that selection bias associated with testing was unlikely. The Committee noted that although a benefit in progression-free survival of 5 weeks was associated with panitumumab monotherapy relative to best supportive care, no statistically significant effect on overall survival was observed in the trial. The Committee heard from one of the clinical specialists that in trials of metastatic colorectal cancer, gains in progression-free survival cannot reliably translate to gains in overall survival. The Committee was aware that most people in the study who had been randomised to receive best supportive care crossed over to receive panitumumab. The Committee noted that one consultee proposed that analyses adjusting for crossover did not adjust for the adverse reactions related to panitumumab treatment. It heard the Assessment Group's view that the manufacturer's analyses to adjust for crossover reflected a reasonable approach. The Committee concluded that panitumumab provided a survival benefit relative to best supportive care, but that the magnitude of this benefit was uncertain.\n\nThe Committee discussed the results of the Assessment Group's economic analysis for panitumumab, which was based on the HRs for panitumumab from the Assessment Group's mixed treatment comparison, adjusted for crossover. The Committee also noted the analyses carried out by the Assessment Group after public consultation on the assessment report, which used unadjusted HRs from the Amgen trial directly. These analyses resulted in a decrease in the ICER from £150,000 to £109,000 per QALY gained when panitumumab plus best supportive care was compared with best supportive care alone. The Committee also noted that the results of the Assessment Group's one-way sensitivity analyses showed that increasing the mean overall survival estimate for panitumumab plus best supportive care from the base-case value of 6.8 months to 7.2 months (based on an increase of 2 standard errors) resulted in an ICER of £110,000 per QALY gained. The Committee concluded that it was not possible to specify a precise ICER for panitumumab plus best supportive care compared with best supportive care alone, but that the most plausible ICER was likely to be between £110,000 and £150,000 per QALY gained.\n\n## End-of-life considerations\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24 months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations. In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe Committee discussed whether the technologies appraised fulfil the criteria for consideration as life-extending, end-of-life treatments. For metastatic colorectal cancer that has progressed after first-line treatment, the Committee agreed that the technologies fulfil the first criterion related to life expectancy, because estimates of life expectancy from people randomised to best supportive care in the second-line setting were less than 12 months.\n\nFor bevacizumab, the Committee agreed that there was no evidence to show how much bevacizumab plus non-oxaliplatin chemotherapy given as second-line treatment extends survival. In addition, the Committee understood that it should take into account all populations which are covered by all indications of the marketing authorisation for a given technology when considering the size of the patient population. The Committee noted that bevacizumab has a marketing authorisation for a number of indications and therefore does not fulfil the criterion of being indicated for a small patient group. The Committee concluded that bevacizumab plus non-oxaliplatin chemotherapy does not meet all of the criteria for a life-extending, end-of-life treatment.\n\nFor cetuximab, the Committee acknowledged that cetuximab plus best supportive care prolonged life by a median of 4.7 months in the third-line or later setting relative to best supportive care alone and therefore met the second end-of-life criterion. The Committee was aware from the manufacturer's data that approximately 7600 people have EGFR-positive, KRAS wild-type metastatic colorectal cancer in England and Wales, and only a small proportion of these (approximately 260 to 390 people) would be fit enough for third or subsequent lines of treatment. However, the Committee noted that cetuximab has a marketing authorisation for people with any stage of EGFR-positive KRAS wild-type metastatic colorectal cancer, and also for people with locally advanced and recurrent and/or metastatic head and neck cancer, which has previously been estimated to be a population of about 3000 (NICE technology appraisal guidance 172 [TA172]). The Committee discussed the decisions from two previous NICE technology appraisal appeals and noted that the Appeal Panel recognised that the criterion in the supplementary advice for end-of-life treatments for small patient populations indicated that 'Sufficient regard should be given to recognition of the desirability of developing new treatments in smaller disease areas and that higher prices, and therefore reduced cost effectiveness, were more likely to be justified given the need to recoup costs of development of the product from more limited licences'. The Appeal Panel had concluded that it was appropriate, according to the supplementary advice, to add together the potential patient populations covered by the marketing authorisation for different indications rather than on the basis of actual or recommended use. The Committee therefore concluded that the true size of the cumulative population covered by the marketing authorisation for cetuximab was likely to be over 10,000 patients and was not small, and that cetuximab does not meet all of the criteria for a life-extending, end-of-life treatment.\n\nThe Committee considered whether panitumumab provides a life extension of about 3 months. It noted that the manufacturer estimated that the mean life extension (after adjusting for crossover) was between 2.7 and 3.2 months, and that the Assessment Group judged the method used to derive this estimate to be reasonable. The Committee also noted that the progression-free survival benefit for panitumumab was similar to that for cetuximab and therefore there was sufficient evidence to indicate that panitumumab offers an extension to life of approximately 3 months compared with best supportive care alone. The Committee noted that panitumumab has a marketing authorisation for people with KRAS wild-type and EGFR-expressing metastatic colorectal cancer in whom both irinotecan- and oxaliplatin-containing chemotherapy has failed. The Committee agreed that this represents a small patient population. However, the Committee was aware that the Committee for Medicinal Products for Human Use recently recommended an extension of the marketing authorisation for panitumumab in combination therapy for KRAS wild-type metastatic colorectal cancer to first-line and second-line settings. Therefore it is expected that in the near future panitumumab will be licensed for the treatment of metastatic colorectal cancer in a patient population of similar size to that estimated for cetuximab. The Committee noted the most plausible ICER for panitumumab monotherapy lies between £110,000 and £150,000 per QALY gained. Therefore, the Committee concluded that, even if panitumumab monotherapy met all the criteria for a life-extending, end-of-life treatment, the additional weight that would need to be assigned to the QALY benefits would be too great to justify it as an appropriate use of limited NHS resources.\n\nThe Committee noted that testing tumour characteristics, such as the KRAS mutation, allowed clinicians to identify people who were more likely to respond to treatment with cetuximab or panitinumab, and agreed that this was an innovation in the treatment of metastatic colorectal cancer. The Committee also heard from the clinical specialists that in the future, the identification of further KRAS andalso BRAF mutations will allow even better identification of people who are likely to benefit from therapy. The Committee considered whether any of the technologies in this appraisal could be considered innovative. It concluded that it had not been presented with a case, substantiated by data, that the treatments add demonstrable and distinctive benefits of a substantial nature that had not already been adequately captured in the QALY measure.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA242\n\nAppraisal title: Cetuximab (monotherapy or combination chemotherapy), bevacizumab (in combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology appraisal 150 and part review of technology appraisal guidance 118)\n\nSection\n\nKey conclusion\n\nCetuximab monotherapy or combination chemotherapy, bevacizumab in combination with non-oxaliplatin (fluoropyrimidine-based) chemotherapy, and panitumumab monotherapy are not recommended for the treatment of people with metastatic colorectal cancer that has progressed after first-line chemotherapy.\n\nThis is because:\n\n–1.3\n\n\n\nIt was not possible to confirm by how much bevacizumab in combination with non-oxaliplatin (fluoropyrimidine-based) chemotherapy would extend life when used as second-line therapy, and evidence from previous assessments of bevacizumab with other combination regimens or for first-line treatment does not allow a justification for a positive recommendation in this appraisal.\n\n, 4.4.6, 4.4.7\n\nThe ICERs for cetuximab monotherapy or combination chemotherapy and for panitumumab monotherapy were very high (£90,000, £88,000 and £110,000–£150,000 per QALY gained respectively) and therefore these technologies did not represent a cost-effective use of NHS resources.\n\n4.4.17\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard from the clinical specialists and patient experts that there are limited treatment options for people with metastatic colorectal cancer that has progressed after treatment with first-line chemotherapy.\n\n\n\n\n\nFor second-line therapy in people whose disease has progressed despite first-line treatment, NICE technology appraisal guidance 93 recommends monotherapy with irinotecan as an option for people who received FOLFOX as first-line treatment, and FOLFOX as an option for people who received FOLFIRI as first-line treatment.\n\n, 4.4.2\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee agreed that KRAS testing was an innovation in the treatment of metastatic colorectal cancer. The Committee was not presented with a case, substantiated by data, that the technologies under consideration add demonstrable and distinctive benefits of a substantial nature that have not already been adequately captured in the QALY measure.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe UK marketing authorisation for bevacizumab is in combination with fluoropyrimidine-based chemotherapy for the treatment of patients with metastatic carcinoma of the colon or rectum.\n\n\n\nCetuximab has a UK marketing authorisation for the treatment of patients with EGFR-expressing, KRAS wild-type metastatic colorectal cancer, in combination with irinotecan-based chemotherapy or FOLFOX (5-FU and folinic acid and oxaliplatin) or as a single agent in patients whose disease has failed to respond to oxaliplatin and irinotecan-based therapy, and who are intolerant to irinotecan.\n\n\n\n\n\nPanitumumab has a UK marketing authorisation as a 'monotherapy for the treatment of patients with EGFR-expressing metastatic colorectal cancer with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens'.\n\n\n\nAdverse reactions\n\nThe Committee did not discuss specific issues around the adverse reactions to the technologies appraised but it was aware of the special warnings and precautions for use outlined in the SPCs for bevacizumab, cetuximab and panitumumab.\n\n, 3.5, 3.8\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee noted the only evidence identified for the clinical effectiveness of bevacizumab as second-line treatment for metastatic colorectal cancer was one RCT (the E3200 trial) in which bevacizumab was given with oxaliplatin-containing chemotherapy, and two non-randomised observational studies using data from the BRiTE and ARIES patient registries. The Committee agreed that the evidence presented by the manufacturer could not be used to establish the overall survival gain with bevacizumab plus non-oxaliplatin chemotherapy as second- or third-line treatment for people with metastatic colorectal cancer that had not responded to first-line or second-line chemotherapy.\n\n, 4.2.5, 4.4.5, 4.4.6\n\nThe only evidence for the clinical effectiveness of cetuximab was one RCT (the CO.17 trial) in people with KRAS wild-type metastatic colorectal cancer that had progressed after first-line chemotherapy. The Committee noted that the people in the CO.17 trial had previously received oxaliplatin- and irinotecan-based therapy, and that the trial had shown a median overall survival of 9.5 months for cetuximab plus best supportive care compared with 4.8 months for best supportive care alone.\n\n\n\nThe Committee noted that there were no head-to-head trials of cetuximab plus irinotecan compared with best supportive care in KRAS wild-type colorectal cancer. The Committee agreed that the results of the mixed treatment comparisons should be interpreted with caution, and concluded that the estimates of overall survival for cetuximab plus irinotecan were subject to a high degree of uncertainty.\n\n\n\nThe only evidence for the clinical effectiveness of panitumumab monotherapy came from one RCT (the Amgen trial) in people with KRAS wild-type metastatic colorectal cancer that had progressed after first-line chemotherapy. However, people in the trial had previously received both oxaliplatin- and irinotecan-based therapy, that is, panitumumab was given as third-line or subsequent therapy.\n\nThe Committee noted that although a benefit in progression-free survival of 5 weeks was associated with panitumumab monotherapy relative to best supportive care, no statistically significant effect on overall survival was observed and therefore the magnitude of this benefit was uncertain.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee did not discuss specific issues around the relevance to general clinical practice in the NHS.\n\n-\n\nUncertainties generated by the evidence\n\nThe uncertainties were:\n\n\n\nthe overall survival gain with bevacizumab plus non-oxaliplatin chemotherapy in people with metastatic colorectal cancer who had previously received chemotherapy\n\n\n\nthe estimates of overall survival for cetuximab plus irinotecan based on the mixed treatment comparison\n\n\n\nthe magnitude of the survival benefit of panitumumab relative to best supportive care.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNone considered.\n\n-\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that there was sufficient evidence to show that cetuximab plus best supportive care gave greater benefit in terms of both progression-free survival and overall survival than best supportive care alone.\n\n\n\nThe Committee concluded that panitumumab provided a survival benefit relative to best supportive care, but that the magnitude of this benefit was uncertain.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nTwo economic models were available for this appraisal, one from the manufacturer of cetuximab and one from the Assessment Group.\n\n, 4.3.11\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe uncertainties were:\n\n\n\nthe mean time on cetuximab treatment\n\n\n\nthe overall survival estimates used in the economic models for panitumumab and cetuximab in combination with irinotecan, which were based on the mixed treatment comparison.\n\n, 4.4.16\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nThe Committee noted that the utility estimates for each of the disease states were not consistent with the expectation that quality of life worsens with progression of disease. The Committee also noted that the utility estimates in the model (for example, 0.81 for progression-free disease for cetuximab plus best supportive care) were similar to those expected for people of the same age without metastatic colorectal cancer. The Committee concluded that the utility values in the manufacturer's model were highly uncertain.\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nNone considered.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNone considered.\n\n-\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee noted that one of the main factors affecting the cost effectiveness of cetuximab was the assumption about the mean duration of treatment.\n\n\n\nFor panitumumab, the estimate of overall survival was the main factor found to substantially change the ICER.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe most plausible ICER for cetuximab plus best supportive care was £90,000 per QALY gained and for cetuximab plus irinotecan plus best supportive care the ICER was £88,000 per QALY gained, both compared with best supportive care.\n\n\n\n\n\nIt was not possible to specify a precise ICER for panitumumab plus best supportive care compared with best supportive care alone, but this would likely lie between £110,000 and £150,000 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nN/A\n\n-\n\nEnd-of-life considerations\n\nThe Committee agreed that the life expectancy of people with metastatic colorectal cancer treated with best supportive care in the second-line setting was less than 12 months.\n\n\n\nThe Committee concluded that bevacizumab plus non-oxaliplatin chemotherapy did not meet all of the criteria for a life-extending, end-of-life treatment. This was because there was no evidence to show by how much bevacizumab plus non-oxaliplatin chemotherapy given as second-line treatment extended survival and bevacizumab has a marketing authorisation for a number of indications and therefore does not fulfil the criterion of being indicated for a small patient group.\n\n\n\n\n\nThe Committee concluded that cetuximab did not meet all of the criteria for a life-extending, end-of-life treatment because the cumulative population covered by the indications in the marketing authorisation for cetuximab was likely to be over 10,000 patients and was not small.\n\n\n\nThe Committee noted that in the near future, panitumumab will be licensed for the treatment of metastatic colorectal cancer in a patient population of similar size to that for cetuximab. The Committee noted that the most plausible ICER for panitumumab monotherapy lies between £110,000 and £150,000 per QALY gained. Therefore, the Committee concluded that, even if all the criteria for a life-extending, end-of-life treatment were met for panitumumab monotherapy, the additional weight that would need to be assigned to the QALY benefits would be too great to justify it as an appropriate use of limited NHS resources.\n\n\n\nEqualities considerations and social value judgements\n\nThe Committee heard that people with colorectal cancer in England are becoming increasingly worried about what they perceive to be unequal access to treatment with biological drugs, which are currently only provided to some patients through the Cancer Drugs Fund.\n\n", 'Recommendations for further research ': 'The Committee was aware that a phase II clinical trial (SPIRITT) comparing bevacizumab plus FOLFIRI with panitumumab plus FOLFIRI after first-line treatment is under way. The expected study completion date is August 2012. The Committee noted that the results of this trial should be considered in any future review decision for this appraisal.', 'Related NICE guidance': 'Published\n\nDiagnosis and management of colorectal cancer. NICE clinical guideline 131 (2011)\n\nBevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer. NICE technology appraisal guidance 212 (2010).\n\nCetuximab for the first-line treatment of metastatic colorectal cancer. NICE technology appraisal guidance 176 (2009).\n\nBevacizumab and cetuximab for the treatment of metastatic colorectal cancer. NICE technology appraisal guidance 118 (2007).\n\nIrinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer (review of technology appraisal 33). NICE technology appraisal guidance 93 (2005).\n\nGuidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer. NICE technology appraisal guidance 61 (2003).', 'Review of guidance': 'The guidance on this technology will be considered for review by the Guidance Executive in January 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveJanuary 2012', 'Changes after publication': 'February 2014: minor maintenance\n\nJune 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nIt updates and replaces NICE technology appraisal 150 (published June 2008). It also partially updates NICE technology appraisal guidance 118 (published in January 2007). This guidance updates and replaces recommendation 1.2 of TA118. The review and re-appraisal of cetuximab for the treatment of metastatic colorectal cancer that has progressed after first-line chemotherapy has resulted in a change in the guidance. Cetuximab is not recommended for the treatment of metastatic colorectal cancer that has progressed after any first-line chemotherapy (rather than specifically irinotecan-based chemotherapy).\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta242
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Evidence-based recommendations on cetuximab (Erbitux), bevacizumab (Avastin) and panitumumab (Vectibix) for treating metastatic colorectal cancer in adults.
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Rituximab for the first-line treatment of stage III-IV follicular lymphoma
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Rituximab for the first-line treatment of stage III-IV follicular lymphoma
Evidence-based recommendations on rituximab for treating follicular lymphoma in adults.
# Guidance
This guidance replaces NICE technology appraisal guidance 110 issued in September 2006. For details see 'About this guidance'.
Rituximab, in combination with:
cyclophosphamide, vincristine and prednisolone (CVP)
cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)
mitoxantrone, chlorambucil and prednisolone (MCP)
cyclophosphamide, doxorubicin, etoposide, prednisolone and interferon-α (CHVPi) or
chlorambucilis recommended as an option for the treatment of symptomatic stage III and IV follicular lymphoma in previously untreated people.# Clinical need and practice
Non-Hodgkin's lymphoma is a cancer of the lymphatic tissue, which causes enlargement of the lymph nodes and generalised symptoms. The lymphatic system produces, stores and delivers lymphocytes, which are cells that fight infection. Follicular lymphoma is a type of low-grade or indolent non-Hodgkin's lymphoma that develops slowly, and often without symptoms, for many years. It affects B-cell lymphocytes and is therefore classified as a B-cell non-Hodgkin's lymphoma. Patients with follicular lymphoma typically present with painless, swollen lymph nodes in the neck, armpit or groin. Systemic or 'B' symptoms are rare and include fever, fatigue, night sweats, and unexplained weight loss.
When a diagnosis of follicular lymphoma is confirmed, investigations are undertaken to find out which areas of the body are affected, the number of lymph nodes involved, and whether other organs are affected, such as the bone marrow or liver. It can be classified into four stages of disease (I–IV) that reflect both the number of sites involved and the presence of disease above or below the diaphragm. At most, 10–15% of follicular lymphomas are detected at an early stage; the majority of people present with advanced disease (stage III−IV). In 2008, the incidence of follicular lymphoma in England and Wales was 3.4 per 100,000 persons, equating to 1900 people. More than 70% of follicular lymphomas are diagnosed in people aged over 60 years.
Follicular lymphoma is characterised by a relapsing and remitting clinical course over several years, with each successive response to treatment becoming more difficult to achieve and of shorter duration. In the early 1990s, median survival was expected to be 8−10 years. However, in the past decade, longer median survival has been reported (for example, survival at 20 years has been reported to be as high as 44%). Advanced stage III−IV lymphomas eventually become resistant to chemotherapy and transform to high-grade or aggressive lymphomas, such as diffuse large B-cell lymphoma.
Advanced follicular lymphoma is not curable and so the aim of disease management is to both increase life expectancy and to increase health-related quality of life. A proportion of people with stage III−IV follicular lymphoma do not present with symptoms of disease and receive 'watchful waiting' until symptoms occur. Of the people who need systemic therapy, for the majority (90%) first-line therapy is rituximab and chemotherapy, with around two-thirds receiving the CVP regimen as the chemotherapy component of treatment. The next most frequent chemotherapy regimen used with rituximab is CHOP, which accounts for approximately 16% of chemotherapy regimens. People who have a lower performance status may receive chlorambucil as single-agent chemotherapy.
Maintenance treatment is given after response to first-line induction treatment. Rituximab for the first-line maintenance treatment of follicular non-Hodgkin's lymphoma (NICE technology appraisal guidance 226) recommends rituximab monotherapy as an option for maintenance treatment after first-line induction therapy with rituximab plus chemotherapy. After first-line induction therapy (with or without subsequent maintenance therapy), a person's disease eventually relapses, requiring further treatment. The treatment chosen for relapsed disease will depend on the first-line treatment regimen used, the duration of response to treatment and whether the disease has transformed to aggressive lymphoma.# The technology
Rituximab (MabThera, Roche Products) is a genetically engineered chimeric (mouse/human) monoclonal antibody that depletes B cells by targeting cells bearing the CD20 surface marker. Rituximab as a first-line treatment for follicular lymphoma was originally licensed in combination with CVP. The marketing authorisation was subsequently revised (January 2008) to allow the use of a wider range of chemotherapy regimens. The subject of this review of 'Rituximab for the treatment of follicular lymphoma' (NICE technology appraisal guidance 110) is the wider indication: rituximab for the treatment of previously untreated stage III−IV follicular lymphoma in combination with chemotherapy (not just CVP).
Rituximab has been associated with infusion-related reactions and infections, sometimes severe or life-threatening. Severe reactions are more common in people with high tumour burden, and the incidence and severity of infusion reactions decreases with successive infusions. It is contraindicated in people with active severe infections, and in people with severe heart failure or severe uncontrolled cardiac disease. For full details of side effects and contraindications, see the summary of product characteristics.
The recommended dose of rituximab in combination with chemotherapy for induction treatment of previously untreated patients with follicular lymphoma is 375 mg/m2 body surface area, per cycle, for up to eight cycles, administered on day 1 of the chemotherapy cycle. The cost of one 10-ml (100-mg) vial is £174.63 and one 50-ml (500-mg) vial is £873.15 (excluding VAT; British national formulary edition 61). For a person with a body surface area of 1.85 m2 and assuming vial wastage, the cost per infusion of rituximab induction treatment is £1222.41 (excluding VAT). Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
# Clinical effectiveness
The Assessment Group identified four randomised controlled trials that met the criteria for inclusion in the systematic review. The trials compared:
rituximab plus CVP with CVP alone (M39021)
rituximab plus CHOP with CHOP alone (GLSG-2000)
rituximab plus MCP with MCP alone (OSHO-39)
rituximab plus CHVPi with CHVPi alone (FL2000).
The M39021, GLSG-2000 and OSHO-39 trials used the licensed administration schedule for rituximab (375 mg/m2 per cycle for up to eight cycles), whereas the FL2000 trial used a different administration schedule that did not include rituximab in the first two cycles of CHVPi. The Assessment Group considered all four trials to be of good quality.
The four trials reported different efficacy outcomes but they all reported overall survival, which was defined as time from randomisation to the date of death by any cause. The OSHO-39 trial was the only trial to report progression-free survival defined as randomisation to disease progression or death from non-Hodgkin's lymphoma.
## Rituximab plus CVP versus CVP alone
The M39021 trial was an open-label multicentre trial that compared rituximab plus CVP with CVP alone. The trial recruited patients with stage III or IV follicular lymphoma (162 patients to rituximab plus CVP and 159 patients to CVP alone). The median age of patients was 52 years in the rituximab plus CVP group and 53 years in the CVP alone group. Most patients had an ECOG performance status of 0 to 1 and patients with an Eastern Cooperative Oncology Group (ECOG) performance status of more than 2 were excluded from the trial. The median follow-up was 53 months.
The primary outcome measure of the M39021 trial was time to treatment failure and secondary outcomes included overall survival, response rates (overall, complete and partial), response duration, time to next antilymphoma treatment and disease-free survival. The median time to treatment failure in the rituximab plus CVP group was 27 months compared with 7 months in the CVP alone group (p < 0.0001). Overall survival rate at 4 years was 83% in the rituximab plus CVP group and 77% in the CVP alone group (p < 0.0290). The median overall survival was not reached. The overall response rate was 81% in the rituximab plus CVP group and 57% in the CVP alone group (p < 0.0001). Complete response in the rituximab plus CVP group was 30% and in the CVP alone group was 8% (p < 0.001) and partial response was 51% in the rituximab plus CVP group compared with 49% in the CVP alone group (p value not reported).
## Rituximab plus CHOP versus CHOP alone
The GLSG-2000 trial was an open-label multicentre trial that compared rituximab plus CHOP with CHOP alone. The trial recruited patients with stage III and IV follicular lymphoma (279 patients to rituximab plus CHOP and 278 to CHOP alone). The median age of patients was 57 years for both treatment groups and most patients had an ECOG performance status of 0 to 1. The median follow-up was 56 months.
The primary outcome measure was time to treatment failure and secondary outcomes included overall survival, response rates (overall, complete and partial), response duration and time to next antilymphoma treatment. The median time to treatment failure was not reached in the rituximab plus CHOP group and was 35 months in the CHOP alone group (p < 0.0001). The overall survival rate at 5 years was 90% in the rituximab plus CHOP group and 84% in the CHOP alone group (p = 0.0493). The median overall survival was not reached. The overall response rate was 96% in the rituximab plus CHOP group and 91% in the CHOP alone group (p = 0.0046). Complete response in the rituximab plus CHOP group was 19% and 17% in the CHOP alone group (p value not reported). Partial response was 77% in the rituximab plus CHOP group compared with 74% in the CHOP alone group (p value not reported).
## Rituximab plus MCP versus MCP alone
The OSHO-39 trial was an open-label multicentre trial that compared rituximab plus MCP with MCP alone. The trial recruited patients with CD20-positive indolent non-Hodgkin's lymphoma, which included lymphoplasmacytic lymphoma and mantle cell lymphoma. The primary analysis population was defined as the population of patients with follicular lymphoma (105 patients to rituximab plus MCP and 96 patients to MCP alone). The median age of patients was 60 years in the rituximab plus MCP group and 57 years in the MCP alone group. Most patients had an ECOG performance status of 0 to 1, and patients with an ECOG performance status of more than 2 were excluded from the trial. The median follow-up was 49 months for the rituximab plus MCP group and 42 months for the MCP alone group.
The primary outcome measure of the OSHO-39 trial was overall response rate and secondary outcomes included progression-free survival, overall survival, response rates (overall, complete and partial), response duration, event-free survival and time to next antilymphoma treatment. The overall response rate was 92% in the rituximab plus MCP group and 75% in the MCP alone group (p < 0.0009). The overall survival rate at 4 years was 87% for the rituximab plus MCP group and 74% for the MCP alone group (p = 0.0096). The median overall survival was not reached. Complete response in the rituximab plus MCP group was 50% compared with 25% in the MCP alone group (p = 0.0004). Partial response in the rituximab plus MCP group was 43% and 50% in the MCP alone group (p value not reported). Median progression-free survival was not reached in the rituximab plus MCP group and was 28.8 months in the MCP alone group (p < 0.0001).
## Rituximab plus CHVPi versus CHVPi alone
The FL2000 trial was an open-label multicentre trial that compared rituximab plus CHVPi with CHVPi alone. The trial recruited patients with stage II–IV follicular lymphoma (175 patients to rituximab plus CHVPi and 183 patients to CHVPi alone). The median age of patients was 61 years. Most patients had an ECOG performance status of 0 to 1. The median follow-up was 60 months.
The primary outcome measure of the trial was event-free survival and secondary outcomes included overall survival, response rates (overall, complete and partial) and response duration. The outcomes were evaluated at 6 and 18 months; 18-month results are reported here. Event-free survival was not reached in the rituximab plus CHVPi group compared with 35 months in the CHVPi alone group (p = 0.0004). The overall survival rate at 5 years was 84% in the rituximab plus CHVPi group and 79% in the CHVPi alone group (not significant). The median overall survival was not reached. The overall response rate was 81% in the rituximab plus CHVPi group and 72% in the CHVPi alone group (p value not reported). Excluding unconfirmed complete responses, the complete response rate was 51% in the rituximab plus CHVPi group and 39% in the CHVPi alone group (p value not reported). Partial response was 30% in the rituximab plus CHVPi group and 33% in the CHVPi alone group (p value not reported).
## Adverse events
All four trials reported grade 3 and 4 adverse events. Although an increased incidence of leukocytopenia, neutropenia and granulocytopenia was observed in the trials in the rituximab plus chemotherapy arms, this was not associated with an increase in the rate of infection (infection is associated with leukocytopenia, neutropenia and granulocytopenia). However, considerable numbers of patients experienced grade 3 or 4 alopecia in both the rituximab plus CHOP and CHOP alone arms of the GLSG-2000 trial. This side effect is associated with the CHOP component of the treatment.
## Subgroup analyses
Rituximab plus chemotherapy compared with chemotherapy alone improved treatment outcomes for all subgroups analysed (Follicular Lymphoma International Prognostic Index score, International Prognostic Index score, age, quality of response to induction therapy and other prognostic factors). The four trials presented analyses of treatment outcomes according to FLIPI score and they showed that treatment outcomes were improved for most FLIPI groups. The GLSG-2000 trial found that time to treatment failure was prolonged in the rituximab plus CHOP group regardless of whether patients were younger or older than 60 years of age.
## Meta-analysis
Three exploratory meta-analyses were conducted by the Assessment Group to explore the overall response rate, complete response rate and partial response rate from the four trials. There were several problems with the validity of these analyses and specifically there were high levels of statistical heterogeneity. Therefore the Assessment Group decided that the response rates from the individual trials were a more robust estimate of the efficacy of the specific rituximab plus chemotherapy regimens.
# Cost effectiveness
The manufacturer submitted an economic model and the Assessment Group developed its own economic model and critiqued the economic model submitted by the manufacturer.
The Assessment Group identified three economic models from four published trials (Dundar et al. 2006, 2009; Hornberger et al. 2008; Ray et al. 2010) that met the criteria for inclusion in the systematic review of economic evaluations. One of these (Dundar et al. 2006) was the Evidence Review Group report prepared for NICE technology appraisal guidance 110 in which the addition of rituximab to CVP in first-line induction treatment was evaluated. The three identified economic models were similar and used a Markov approach. Three of the economic evaluations (Dundar et al. 2006, 2009 and Hornberger et al. 2008) only considered rituximab plus CVP, whereas the other study (Ray et al. 2010) evaluated the cost effectiveness of rituximab plus CVP, CHOP, MCP or CHVPi. The two UK economic evaluations (Dundar et al. 2006, 2009; Ray et al. 2010 ) produced broadly similar estimates of the incremental cost-effectiveness ratio (ICER) for rituximab plus CVP versus CVP alone (£8290 per quality-adjusted life year gained and £8613 per QALY gained respectively). The ICERs for the addition of rituximab to CHOP, MCP and CHVPi were £10,676, £7455 and £8498 per QALY gained respectively.
## Manufacturer's submission
The manufacturer of rituximab provided an economic model that evaluated the cost effectiveness of the addition of rituximab to CVP, CHOP, MCP and CHVPi for patients with advanced follicular lymphoma. The model was a Markov model that estimated the costs and benefits resulting from the first-line treatment of follicular lymphoma over the patient's lifetime. The population included in the economic analysis was patients with previously untreated follicular lymphoma for whom rituximab plus chemotherapy was suitable.
The model has four distinct health states: progression-free survival first-line, progression-free survival second-line, progressive disease, and death. The model has a starting age of 60 years and a follow-up period of 25 years. A half-cycle correction was applied to the model.
Efficacy data for first-line induction therapy was based on the individual clinical trials. For the comparison of rituximab plus CVP versus CVP alone, individual patient-level data were available. Therefore two analyses were presented for rituximab plus CVP versus CVP alone. The first analysis fitted separate curves to each arm using individual patient-level data, whereas the second analysis used the same method used in the other comparisons which was based on an extrapolation technique (exponential distribution estimated using ordinary least squares regression). After first-line therapy it was assumed that patients would receive either CHOP or rituximab plus CHOP as second-line treatment, which could be followed by rituximab maintenance for those responding to second-line treatment. Efficacy data for second-line treatment was taken from the EORTC 20981 trial that reported the effectiveness of rituximab in second-line treatment of follicular lymphoma in patients not previously treated with rituximab.
The utility values used in the model were derived from a study commissioned by the manufacturer. This study included 222 patients with follicular lymphoma and ECOG performance status 0 to 2. Utilities were elicited using the EQ-5D questionnaire. The following utility values were used in the model: PF1 = 0.88; PF2 = 0.79 and progressive disease = 0.62.
Drug costs used the planned dose from the trials assuming a body surface area of 1.85 m2. In the CVP, CHOP, MCP and CHVPi groups the monthly drug costs of chemotherapy alone were £72, £360, £182 and £413 respectively; when rituximab was added these costs increased to £1830, £2119, £1501 and £1626 respectively. Administration costs were taken from NHS reference costs and estimated to be £268 for rituximab plus chemotherapy and £186 for chemotherapy alone, based on an assumption that rituximab treatment was administered as a hospital day case. The economic model also includes costs associated with monitoring/surveillance and supportive care.
The base-case analysis showed that addition of rituximab to CVP compared with CVP alone resulted in an ICER of £1529 per QALY gained (incremental cost £1325 and incremental QALY 0.867) using patient-level data, and £5611 per QALY gained (incremental cost £2486 and incremental QALY 0.443) using ordinary least squares regression. The addition of rituximab to CHOP, MCP and CHVPi compared with CHOP, MCP and CHVPi alone resulted in ICERs of £5758 (incremental cost £6312 and incremental QALY 1.096), £4861 (incremental cost £6268 and incremental QALY 1.289), and £9251 (incremental cost £6247 and incremental QALY 0.675) per QALY gained respectively.
The Assessment Group reviewed the manufacturer's economic model and highlighted some inconsistencies, such as the derivation of the transition probability, calculation of post-progression survival and estimation of costs. It noted that the manufacturer used time-to-event data from clinical trials in which responders to first-line induction treatment received subsequent treatments, which may have over-estimated the effect of rituximab. The Assessment Group noted that the manufacturer had assumed that patients receive either CHOP or rituximab plus CHOP as second-line treatment, which it did not consider reflected the range of treatments used in clinical practice. The Assessment Group did not think that it was appropriate that the manufacturer used different utility values for patients in progression-free survival first-line and progression-free survival second-line.
## The Assessment Group's model
The Assessment Group developed an individual patient model that simulated 100,000 patients. The model assessed the cost effectiveness of the addition of rituximab to three chemotherapy regimens: CVP, CHOP and MCP in patients with previously untreated stage III–IV follicular lymphoma. The addition of rituximab to CHVPi was not assessed because the Assessment Group thought that there were limitations in the design of the FL2000 trial such as the administration schedule, which did not include rituximab in the first two cycles of CHVPi. Also, their clinical advisers suggested that the combination of CHVPi was not used frequently in UK clinical practice.
The Assessment Group's model has four health states: first-line treatment and progression-free survival, second-line treatment and progression-free survival, progressive disease and death. In the model, patients are separated into responders and non-responders according to the response rates after first- or second-line treatments. In a separate scenario analysis, patients responding to first-line induction treatment with rituximab receive rituximab as first-line maintenance treatment. The model uses a 25-year time horizon and costs and benefits are discounted at 3.5%.
For each of the therapies examined, the response rates from the applicable trials were used to classify patients into responders and non-responders. Individual patient data for time to progression from the M39021 trial were used in the model to develop progression-free survival curves for responders and non-responders. For the comparisons of CHOP alone with rituximab plus CHOP, and MCP alone with rituximab plus MCP, individual patient data were not available from the first-line induction trials. Furthermore, the Assessment Group considered that these trial data could be subject to confounding by the use of stem-cell transplantation or interferon as maintenance therapy in responders to treatment. The Assessment Group chose instead to use the data from the M39021 trial as a proxy to develop the progression-free survival curves.
The planned doses from the three main trials were used to calculate the drug acquisition costs. The planned number of cycles was also used in the economic model. The number of cycles a patient received was calculated from the progression-free survival curve to account for patients that withdrew as a result of disease progression before the end of planned treatment. Chemotherapies were assumed to be administered on a day-case basis. In addition to the administration costs, patients who received rituximab were assumed to incur additional pharmacy costs. The costs associated with transport were also included, assuming that 30% of patients required NHS transportation. In the CVP, CHOP and MCP groups the drug acquisition costs per cycle of chemotherapy alone were £60.48, £233.08 and £218.78 respectively, and with the addition of rituximab were £1282.89, £1455.49 and £1441.19 respectively.
The Assessment Group used the same report for the utility values in the economic model as the manufacturer (Pettengell et al. 2006). However, the Assessment Group used aggregated health states from an additional analysis, which were considered more appropriate than the disaggregated values in the main analysis (as used by the manufacturer) because the health-state utilities in the main analysis were calculated from the degree of response to therapy and not the number of lines of treatment. The utility values in first-line treatment and progression-free survival and second-line treatment and progression-free survival were assumed to be 0.805, and 0.7363 for patients in the progressive health state.
The economic model includes the impact of adverse events that occurred in the first-line induction setting in terms of management costs and impairment of quality of life.
The deterministic base-case cost-effectiveness analysis showed that the addition of rituximab to CVP, CHOP and MCP resulted in ICERs of £7720 (incremental cost £7389 and incremental QALY 0.96), £10,834 (incremental cost £5725 and incremental QALY 0.53) and £9316 (incremental cost £5267 and incremental QALY 0.57) per QALY gained respectively.
The Assessment Group carried out a probabilistic sensitivity analysis that showed that the ICERs for the addition of rituximab to CVP, CHOP and MCP were estimated to be £7735, £10,855 and £9313 per QALY gained respectively.
The Assessment Group explored a scenario in which first-line maintenance treatment was incorporated into the treatment pathway to reflect the recommendations made in the guidance on rituximab for maintenance treatment of follicular lymphoma (NICE technology appraisal guidance 226). Assuming that responders to rituximab plus chemotherapy receive first-line maintenance rituximab, the ICERs estimated by the Assessment Group for the addition of rituximab to CVP, CHOP and MCP were £14,959 (incremental cost £18,727 and incremental QALY 1.25), £21,687 (incremental cost £19,150 and incremental QALY 0.88) and £20,493 (incremental cost £17,976 and incremental QALY 0.88) per QALY gained respectively.
The Assessment Group performed a probabilistic sensitivity analysis for the addition of rituximab to CVP, CHOP and MCP, which assumed that responders to rituximab plus chemotherapy receive first-line maintenance rituximab and which resulted in ICERs of £15,017, £21,625 and £20,418 per QALY gained respectively.
The Assessment Group performed a range of univariate sensitivity analyses to assess the impact of main parameters and assumptions. The ICER was sensitive to the assumption about the time horizon, the choice of parametric distribution to model the effectiveness in first-line induction, the maximum time a patient can remain progression-free, and resistance to rituximab. For the base-case analysis, assuming a 25% reduction in efficacy of rituximab when used as second-line treatment in patients previously treated with rituximab increased the ICERs to £14,870, £26,939 and £21,253 per QALY gained, for the addition of rituximab to CVP, CHOP and MCP respectively.
# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rituximab in combination with chemotherapy, having considered evidence on the nature of advanced follicular lymphoma and the value placed on the benefits of rituximab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee considered current practice in the UK for the treatment of advanced follicular lymphoma. The clinical specialist explained that the goal of treatment is to maintain quality of life and to ensure that people are able to maintain employment and live independently for as long as possible. The availability of rituximab treatment was considered to have transformed clinical practice. The Committee heard from the clinical specialist that rituximab plus CVP (as recommended the original NICE technology appraisal guidance 110, now replaced by this guidance) is the most commonly used first-line treatment option. However, some patients, for example those with bulky disease, may be more appropriately treated with more aggressive regimens such as rituximab plus CHOP. The Committee understood that for first-line induction treatment rituximab plus CVP or rituximab plus CHOP are used to treat the majority of patients with advanced follicular lymphoma.
The Committee explored the use in clinical practice of first-line chemotherapy treatments other than CVP and CHOP. The clinical specialist explained that patients need different treatments depending on their overall health status with increasing age and therefore a range of treatment options is needed. Some people are not fit enough to receive rituximab plus CVP and clinicians might wish to offer other treatment options such as rituximab plus chlorambucil. The Committee heard that currently a patient can receive rituximab or chlorambucil but not a combination of rituximab plus chlorambucil, which might be considered inconsistent by some clinicians, although evidence of effectiveness for the combination is very limited. The Committee understood that being able to provide a range of treatments was valued by clinicians. It recognised that treatment with CVP or CHOP may not be suitable for all patients and that for these patients chlorambucil may have a role in treatment.
The Committee discussed patient experiences of rituximab treatment. The Committee heard from patient experts that they considered they had benefited from treatment with rituximab and that it had improved their quality of life, enabling them to look to the future. The patient experts also explained that the choice of treatment and availability of an effective treatment has a positive effect on patients' families in terms of the families' quality of life. The Committee recognised the importance of rituximab as an option for the treatment of follicular lymphoma.
The Committee discussed consultation comments that suggested that rituximab plus bendamustine should be considered as an option for the first-line treatment of follicular lymphoma. It heard from the manufacturer that at the time of rituximab's marketing authorisation no data were submitted for the combination of rituximab plus bendamustine, and that the manufacturer of bendamustine was submitting a separate marketing authorisation for bendamustine plus rituximab for the first-line treatment of indolent non-Hodgkin's lymphoma. A NICE technology appraisal of bendamustine plus rituximab as first-line treatment of indolent non-Hodgkin's lymphoma is planned in 2012. The Committee understood that the use of rituximab plus bendamustine for the first-line treatment of follicular lymphoma would be considered in this planned appraisal. Consequently, the consideration of rituximab plus bendamustine is not included in this current appraisal.
## Clinical effectiveness
The Committee considered the clinical effectiveness of rituximab plus CVP, CHOP, MCP and CHVPi for the treatment of advanced follicular lymphoma. The Committee noted that the evidence came from four good-quality randomised controlled trials. The Committee accepted that the results of the individual trials indicated that the addition of rituximab to CVP, CHOP, MCP and CHVPi improved clinical outcomes including overall survival and overall response compared with chemotherapy alone. The Committee noted the length of follow-up in the four trials was short compared with the natural course of follicular lymphoma but it agreed that this was common in trials involving follicular lymphoma. The Committee then discussed the adverse events reported in the trials and noted that the addition of rituximab to CVP, CHOP, MCP and CHVPi did not significantly increase adverse-event rates. The Committee concluded that in the clinical trials rituximab plus CVP, CHOP, MCP and CHVPi had been demonstrated to be more effective than CVP, CHOP, MCP and CHVPi alone for the treatment of advanced follicular lymphoma.
The Committee discussed whether the results of the clinical trials could be considered representative of the population in UK clinical practice. The Committee noted that the population in the four trials was younger than the median age of people with advanced follicular lymphoma in the UK. It discussed whether this would have had a favourable impact on the efficacy of rituximab in the trials. The Committee heard from the clinical specialist that even though the trials did enrol younger people, some rituximab plus chemotherapy combinations, such as rituximab plus CHOP, tended to be given to younger people because of the aggressive nature of the chemotherapy regimen. The Committee was aware of the subgroup analysis by age from one of the four trials that showed that time to treatment failure was prolonged in the rituximab plus CHOP group regardless of the age of the patient. The Committee was persuaded that the results reported in the trials could be considered as broadly representative of the outcomes of rituximab treatment in UK clinical practice.
The Committee considered the evidence of effectiveness for the combination of rituximab with chemotherapy regimens not included in the clinical trials. The Committee heard from the clinical specialist that the clinical trial data suggest that rituximab improves clinical outcomes when added to a range of chemotherapy regimens and that this would also be observed for the combination of rituximab with chemotherapy regimens not reflected in the clinical trial data. However, it was recognised that the data to support this were limited. The Committee noted comments from consultation that there are randomised studies comparing different rituximab chemotherapy regimens that have been published as abstracts. However, the Committee considered that these data include rituximab in all treatment groups and therefore do not provide direct evidence of the benefit of adding rituximab to chemotherapy. The Committee also understood that there is one uncontrolled study that investigated the efficacy of rituximab plus chlorambucil in 27 patients. The Committee heard from the manufacturer that the conclusions of the study suggested that a randomised controlled trial would be useful. However, the Committee recognised that it was unlikely that a randomised controlled trial would be conducted. The Committee considered that there was uncertainty as to the relative effect and absolute response rates of the addition of rituximab to chemotherapy regimens other than those studied in the clinical trials. However, on balance, the Committee was persuaded that on the basis of the evidence submitted and comments provided rituximab would provide an additional clinical benefit when added to chemotherapy.
## Cost effectiveness
The Committee considered the evidence of the cost effectiveness of rituximab plus CVP, CHOP, MCP and CHVPi compared with chemotherapy alone for the treatment of advanced follicular lymphoma. The Committee discussed the deterministic ICERs from the Assessment Group's model and noted that the Assessment Group had not included the combination of rituximab plus CHVPi in its economic model because there were issues with the design of the trial and the combination was not frequently used in UK clinical practice. It also noted that rituximab plus chemotherapy was compared with chemotherapy alone and not with other rituximab plus chemotherapy regimens and so comparisons could not be made between chemotherapy regimens. The Assessment Group calculated an ICER of £7720 per QALY gained for rituximab plus CVP, £10,800 per QALY gained for rituximab plus CHOP and £9320 per QALY gained for rituximab plus MCP (see section 4.2.16). The Committee also noted the ICERs presented by the manufacturer for rituximab plus CVP, CHOP, MCP and CHVPi, which ranged between £1530 and £9250 per QALY gained (see section 4.2.8). The Committee noted the Assessment Group's concerns about the manufacturer's model (see section 4.2.9) and considered the Assessment Group's calculations for rituximab plus CVP, CHOP and MCP. It agreed that the manufacturer's comparison of rituximab plus CHVPi versus CHVPi alone would need to inform the decision-making for the addition of rituximab to CHVPi. The Committee noted that the base-case ICERs were within an acceptable range of what would be considered cost effective. However, neither analysis included the use of rituximab first-line maintenance treatment, and both assumed that the efficacy of rituximab was maintained when used again as a second-line induction treatment after first-line rituximab. The Committee concluded that on the basis of current clinical practice these two factors needed to be considered when making the decision on the cost effectiveness of rituximab plus CVP, CHOP, MCP and CHVPi.
The Committee considered whether it was appropriate to assume that the effect of rituximab is maintained in patients whose follicular lymphoma has relapsed and whose disease is re-treated with rituximab. The Committee noted that the Assessment Group's and manufacturer's models assumed that there was no loss of efficacy of rituximab in patients who are re-treated with rituximab. The Committee also noted that the Assessment Group had performed a sensitivity analysis that explored the impact of reduced effectiveness of rituximab among previously treated patients and which showed that the ICER was sensitive to this assumption. The analyses by the Assessment Group suggested that if there was a 25% reduction in efficacy with re-treatment with rituximab then the ICERs increased from £7720–£10,800 to £14,900–£26,900 per QALY gained. The Committee heard from the clinical specialist that there was limited evidence to suggest whether or not there might be a loss of efficacy after re-treatment with rituximab. The Committee concluded that the efficacy of rituximab after re-treatment was a key uncertainty in the economic modelling.
The Committee discussed the role of rituximab maintenance treatment in clinical practice. It recognised that rituximab maintenance treatment after first-line induction therapy was recommended as a treatment option in the guidance on rituximab for maintenance treatment of follicular lymphoma (NICE technology appraisal guidance 226). The Committee therefore considered the Assessment Group's scenario analysis in which first-line maintenance treatment with rituximab was incorporated into the treatment pathway. The Committee was aware that the inclusion of rituximab first-line maintenance treatment increased the ICERs to £15,000–£21,600 per QALY gained and that in the Assessment Group's model it was suggested that rituximab first-line maintenance treatment is not cost effective. The Committee concluded that in view of the recommendations in NICE technology appraisal guidance 226 it was appropriate to consider the ICERs from the Assessment Group's scenario analysis and that in light of the differences between the estimates of cost effectiveness, NICE technology appraisal guidance 226 and this current appraisal should be considered for review together.
The Committee discussed the treatment pathway after first-line therapy used in the economic model. The Committee noted that the manufacturer assumed that after first-line treatment, patients would receive rituximab plus CHOP or CHOP alone. The Committee heard from the Assessment Group that the treatment pathways in its model also included CHOP, but after discussions with the clinical advisers the model had also been developed to include fludarabine-cyclophosphamide and stem-cell transplant. The advisers to the Assessment Group stated that subsequent treatment after first-line treatment would depend on what first-line treatment the patient had received and how soon the patient relapsed. The Committee also heard from the clinical specialist, who confirmed that the treatment pathways used in the Assessment Group's model reflect clinical practice in the UK. The Committee concluded that the treatment pathways used in the Assessment Group's model were appropriate.
The Committee discussed the estimates of the most plausible ICER. The Committee noted that in the base-case analyses the ICERs from the Assessment Group were within acceptable levels and suggested that rituximab plus CVP, CHOP or MCP are cost-effective options for the treatment of advanced follicular lymphoma. The Committee recognised that the Assessment Group had not included the combination of rituximab plus CHVPi in its model. The Committee accepted that using the manufacturer's estimates, and taking into account the Assessment Group's concerns, the ICER was still likely to be within acceptable levels. However, the Committee did not consider that the analyses fully reflect how rituximab is used in clinical practice and the ICERs increase when it is assumed that rituximab first-line maintenance treatment is provided. It considered that the efficacy of rituximab when used as a re-treatment is also uncertain, and if there is a loss of efficacy then this would further increase the ICER. However, the Committee was persuaded that this uncertainty was not such that it increased the ICERs to above the threshold range (£20,000–30,000) that would normally be considered cost effective. The Committee therefore concluded that rituximab plus CVP, CHOP, MCP or CHVPi is both clinically effective and cost effective for the treatment of symptomatic advanced follicular lymphoma in previously untreated people and is an appropriate use of NHS resources.
The Committee was mindful that in clinical practice chemotherapy regimens other than CVP, CHOP, MCP and CHVPi may be used. The Committee noted that the addition of rituximab to chemotherapy regimens other than CVP, CHOP, MCP and CHVPi had not been modelled by either the Assessment Group or the manufacturer. It agreed that recommending rituximab with any chemotherapy was not appropriate despite its conclusion on likely clinical effectiveness (see section 4.3.8); that would result in recommending combinations yet to be appraised (see section 4.3.5), and cost effectiveness cannot be assumed without evidence. However the Committee specifically discussed the addition of rituximab to chlorambucil, noting the consultation comments and evidence from clinical specialists that rituximab plus chlorambucil would be a useful option in older patients or patients with a lower performance status. It noted that this group may be disadvantaged by guidance only recommending rituximab with more aggressive chemotherapy regimens, as had been studied in the clinical trials. It requested that the Assessment Group provide informal cost-effectiveness advice and heard that, based on their base-case analysis, the ICER for rituximab plus chlorambucil would still be within the cost-effective range if the QALY gain for rituximab plus chlorambucil was half that for rituximab plus CHOP. The Committee was mindful of the limited clinical data and the absence of a formal cost-effectiveness analysis, but for the group of patients likely to receive rituximab plus chlorambucil in the NHS, the Committee concluded that rituximab plus chlorambucil was an appropriate use of NHS resources.
# Summary of Appraisal Committee's key conclusions
TA243
Appraisal title: Rituximab for the first-line treatment of stage III–IV follicular lymphoma (review of NICE technology appraisal guidance 110)
Section
Key conclusion
Rituximab, in combination with:
cyclophosphamide, vincristine and prednisolone (CVP)
cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)
mitoxantrone, chlorambucil and prednisolone (MCP)
cyclophosphamide, doxorubicin, etoposide, prednisolone and interferon-α (CHVPi) or
chlorambucil
is recommended as an option for the treatment of symptomatic stage III and IV follicular lymphoma in previously untreated patients.
The key drivers for this recommendation are:
The clinical evidence suggests that rituximab plus CVP, CHOP, MCP and CHVPi is more effective than CVP, CHOP, MCP and CHVPi alone for the treatment of advanced follicular lymphoma.
On the basis of the evidence submitted and comments provided, rituximab would provide an additional clinical benefit when added to chemotherapy.
The cost-effectiveness analyses for rituximab plus CVP, CHOP, MCP and CHVPi compared with CVP, CHOP, MCP and CHVPi alone gave incremental cost-effectiveness ratios (ICERs) in the cost-effective range.
Despite the limited clinical data and absence of a formal cost-effectiveness analysis for rituximab plus chlorambucil, the Committee concluded that rituximab plus chlorambucil was an appropriate use of NHS resources for the group of patients likely to receive rituximab plus chlorambucil.
Current practice
Clinical need of patients, including the availability of alternative treatments
A range of treatment options is needed because patients need different treatments depending on their overall health status with increasing age.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The availability of rituximab treatment was considered by the clinical specialist to have transformed clinical practice. Patient experts considered that they had benefited from treatment with rituximab and that it had improved their quality of life. The choice of treatment and availability of an effective treatment had a positive effect on patients' families in terms of the families' quality of life.
What is the position of the treatment in the pathway of care for the condition?
The appraisal considers a single position in the treatment pathway: rituximab in combination with chemotherapy for the treatment of previously untreated stage III or IV follicular lymphoma.
Adverse effects
The addition of rituximab to CVP, CHOP, MCP and CHVPi did not significantly increase adverse-event rates.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The evidence came from four good-quality randomised controlled trials.
Relevance to general clinical practice in the NHS
The results reported in the trials could be considered as broadly representative of the outcomes of rituximab treatment in UK clinical practice.
and 4.3.7
Uncertainties generated by the evidence
Rituximab may be combined with a number of chemotherapy regimens not included in the clinical trials. The Committee considered that there was uncertainty as to the relative effect and absolute response rates of the addition of rituximab to chemotherapy regimens other than those studied in the clinical trials. However, on balance, the Committee was persuaded that on the basis of the evidence submitted and comments provided rituximab would provide an additional clinical benefit when added to chemotherapy.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
There were no subgroups for which there was evidence of differential effectiveness.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that in the clinical trials rituximab plus CVP, CHOP, MCP and CHVPi had been demonstrated to be more effective than CVP, CHOP, MCP and CHVPi alone for the treatment of advanced follicular lymphoma.
Evidence for cost effectiveness
Availability and nature of evidence
The manufacturer's model evaluated the cost effectiveness of rituximab plus CVP, CHOP, MCP and CHVPi. The Assessment Group's model included rituximab plus CVP, CHOP and MCP but it did not include the combination of rituximab plus CHVPi because there were issues with the design of the trial and the combination was not frequently used in UK clinical practice.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted that neither the manufacturer nor the Assessment Group included the use of rituximab first-line maintenance treatment in their base-case analyses. They also assumed that the efficacy of rituximab was maintained when used again as second-line induction treatment after first-line rituximab. The Committee concluded that on the basis of current clinical practice these two factors needed to be considered when making the decision on the cost effectiveness of rituximab plus CVP, CHOP, MCP and CHVPi.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The health-related quality-of-life benefits were not a key driver of the recommendations in this appraisal.
Are there specific groups of people for whom the technology is particularly cost effective?
No subgroups were identified.
What are the key drivers of cost effectiveness?
The ICERs increased when it was assumed that rituximab was used as first-line maintenance treatment. They also increased if it was assumed that there was a reduction in efficacy when rituximab is used as a re-treatment.
Most likely cost-effectiveness estimate (given as an ICER)
The Assessment Group calculated an ICER of £7720 per quality-adjusted life year (QALY) gained for rituximab plus CVP, £10,800 per QALY gained for rituximab plus CHOP and £9320 per QALY gained for rituximab plus MCP. The Committee agreed that the manufacturer's comparison of rituximab plus CHVPi versus CHVPi alone would need to inform the decision-making for the addition of rituximab to CHVPi. The Committee did not accept that the analyses fully reflected how rituximab was used in clinical practice and the ICERs increased when it was assumed that rituximab first-line maintenance treatment was provided and if there was a loss of efficacy when rituximab was used as a re-treatment. However, the Committee was persuaded that this uncertainty was not such that it increased the ICERs to above the threshold range (£20,000–30,000) that would normally be considered cost effective. The Committee was mindful of the limited clinical data and the absence of a formal cost-effectiveness analysis, but for the group of patients likely to receive rituximab plus chlorambucil in the NHS, the Committee concluded that rituximab plus chlorambucil was an appropriate use of NHS resources.
Additional factors taken into account
Patient access schemes (PPRS)
The manufacturer did not submit a patient access scheme.
End-of-life considerations
The supplementary advice was not relevant to this appraisal.
Equalities considerations and social value judgements
No equalities issues were raised in the appraisal.
# Related NICE guidance
Rituximab for the first-line maintenance treatment of follicular non-Hodgkin's lymphoma. NICE technology appraisal guidance 226 (2011).
Rituximab for the treatment of relapsed or refractory stage III of IV follicular non-Hodgkin's lymphoma (review of NICE technology appraisal guidance 37). NICE technology appraisal guidance 137 (2008).
Improving outcomes in haematological cancers – the manual. NICE cancer service guidance (2003).# Review of guidance
The guidance on this technology will be considered for review with NICE technology appraisal 226 in May 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveJanuary 2012# Changes after publication
February 2014: implementation section updated to clarify that rituximab is recommended as an option for treating stage III-IV follicular lymphoma.
July 2012: minor maintenance
June 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE multiple technology appraisal process.
It updates and replaces NICE technology appraisal guidance 110 (published September 2006). The review and re-appraisal of rituximab for the first-line treatment of stage III–IV follicular lymphoma has resulted in a change in the guidance. Specifically, extending the recommendation to cover regimens using:
cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)
mitoxantrone, chlorambucil and prednisolone (MCP)
cyclophosphamide, doxorubicin, etoposide, prednisolone and interferon-α (CHVPi) or
chlorambucilas well as cyclophosphamide, vincristine and prednisolone.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': "This guidance replaces NICE technology appraisal guidance 110 issued in September 2006. For details see 'About this guidance'.\n\nRituximab, in combination with:\n\ncyclophosphamide, vincristine and prednisolone (CVP)\n\ncyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)\n\nmitoxantrone, chlorambucil and prednisolone (MCP)\n\ncyclophosphamide, doxorubicin, etoposide, prednisolone and interferon-α (CHVPi) or\n\nchlorambucilis recommended as an option for the treatment of symptomatic stage III and IV follicular lymphoma in previously untreated people.", 'Clinical need and practice': "Non-Hodgkin's lymphoma is a cancer of the lymphatic tissue, which causes enlargement of the lymph nodes and generalised symptoms. The lymphatic system produces, stores and delivers lymphocytes, which are cells that fight infection. Follicular lymphoma is a type of low-grade or indolent non-Hodgkin's lymphoma that develops slowly, and often without symptoms, for many years. It affects B-cell lymphocytes and is therefore classified as a B-cell non-Hodgkin's lymphoma. Patients with follicular lymphoma typically present with painless, swollen lymph nodes in the neck, armpit or groin. Systemic or 'B' symptoms are rare and include fever, fatigue, night sweats, and unexplained weight loss.\n\nWhen a diagnosis of follicular lymphoma is confirmed, investigations are undertaken to find out which areas of the body are affected, the number of lymph nodes involved, and whether other organs are affected, such as the bone marrow or liver. It can be classified into four stages of disease (I–IV) that reflect both the number of sites involved and the presence of disease above or below the diaphragm. At most, 10–15% of follicular lymphomas are detected at an early stage; the majority of people present with advanced disease (stage III−IV). In 2008, the incidence of follicular lymphoma in England and Wales was 3.4 per 100,000 persons, equating to 1900 people. More than 70% of follicular lymphomas are diagnosed in people aged over 60 years.\n\nFollicular lymphoma is characterised by a relapsing and remitting clinical course over several years, with each successive response to treatment becoming more difficult to achieve and of shorter duration. In the early 1990s, median survival was expected to be 8−10 years. However, in the past decade, longer median survival has been reported (for example, survival at 20 years has been reported to be as high as 44%). Advanced stage III−IV lymphomas eventually become resistant to chemotherapy and transform to high-grade or aggressive lymphomas, such as diffuse large B-cell lymphoma.\n\nAdvanced follicular lymphoma is not curable and so the aim of disease management is to both increase life expectancy and to increase health-related quality of life. A proportion of people with stage III−IV follicular lymphoma do not present with symptoms of disease and receive 'watchful waiting' until symptoms occur. Of the people who need systemic therapy, for the majority (90%) first-line therapy is rituximab and chemotherapy, with around two-thirds receiving the CVP regimen as the chemotherapy component of treatment. The next most frequent chemotherapy regimen used with rituximab is CHOP, which accounts for approximately 16% of chemotherapy regimens. People who have a lower performance status may receive chlorambucil as single-agent chemotherapy.\n\nMaintenance treatment is given after response to first-line induction treatment. Rituximab for the first-line maintenance treatment of follicular non-Hodgkin's lymphoma (NICE technology appraisal guidance 226) recommends rituximab monotherapy as an option for maintenance treatment after first-line induction therapy with rituximab plus chemotherapy. After first-line induction therapy (with or without subsequent maintenance therapy), a person's disease eventually relapses, requiring further treatment. The treatment chosen for relapsed disease will depend on the first-line treatment regimen used, the duration of response to treatment and whether the disease has transformed to aggressive lymphoma.", 'The technology': "Rituximab (MabThera, Roche Products) is a genetically engineered chimeric (mouse/human) monoclonal antibody that depletes B cells by targeting cells bearing the CD20 surface marker. Rituximab as a first-line treatment for follicular lymphoma was originally licensed in combination with CVP. The marketing authorisation was subsequently revised (January 2008) to allow the use of a wider range of chemotherapy regimens. The subject of this review of 'Rituximab for the treatment of follicular lymphoma' (NICE technology appraisal guidance 110) is the wider indication: rituximab for the treatment of previously untreated stage III−IV follicular lymphoma in combination with chemotherapy (not just CVP).\n\nRituximab has been associated with infusion-related reactions and infections, sometimes severe or life-threatening. Severe reactions are more common in people with high tumour burden, and the incidence and severity of infusion reactions decreases with successive infusions. It is contraindicated in people with active severe infections, and in people with severe heart failure or severe uncontrolled cardiac disease. For full details of side effects and contraindications, see the summary of product characteristics.\n\nThe recommended dose of rituximab in combination with chemotherapy for induction treatment of previously untreated patients with follicular lymphoma is 375 mg/m2 body surface area, per cycle, for up to eight cycles, administered on day 1 of the chemotherapy cycle. The cost of one 10-ml (100-mg) vial is £174.63 and one 50-ml (500-mg) vial is £873.15 (excluding VAT; British national formulary [BNF] edition 61). For a person with a body surface area of 1.85 m2 and assuming vial wastage, the cost per infusion of rituximab induction treatment is £1222.41 (excluding VAT). Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nThe Assessment Group identified four randomised controlled trials that met the criteria for inclusion in the systematic review. The trials compared:\n\nrituximab plus CVP with CVP alone (M39021)\n\nrituximab plus CHOP with CHOP alone (GLSG-2000)\n\nrituximab plus MCP with MCP alone (OSHO-39)\n\nrituximab plus CHVPi with CHVPi alone (FL2000).\n\nThe M39021, GLSG-2000 and OSHO-39 trials used the licensed administration schedule for rituximab (375 mg/m2 per cycle for up to eight cycles), whereas the FL2000 trial used a different administration schedule that did not include rituximab in the first two cycles of CHVPi. The Assessment Group considered all four trials to be of good quality.\n\nThe four trials reported different efficacy outcomes but they all reported overall survival, which was defined as time from randomisation to the date of death by any cause. The OSHO-39 trial was the only trial to report progression-free survival defined as randomisation to disease progression or death from non-Hodgkin's lymphoma.\n\n## Rituximab plus CVP versus CVP alone\n\nThe M39021 trial was an open-label multicentre trial that compared rituximab plus CVP with CVP alone. The trial recruited patients with stage III or IV follicular lymphoma (162 patients to rituximab plus CVP and 159 patients to CVP alone). The median age of patients was 52 years in the rituximab plus CVP group and 53 years in the CVP alone group. Most patients had an ECOG performance status of 0 to 1 and patients with an Eastern Cooperative Oncology Group (ECOG) performance status of more than 2 were excluded from the trial. The median follow-up was 53 months.\n\nThe primary outcome measure of the M39021 trial was time to treatment failure and secondary outcomes included overall survival, response rates (overall, complete and partial), response duration, time to next antilymphoma treatment and disease-free survival. The median time to treatment failure in the rituximab plus CVP group was 27 months compared with 7 months in the CVP alone group (p < 0.0001). Overall survival rate at 4 years was 83% in the rituximab plus CVP group and 77% in the CVP alone group (p < 0.0290). The median overall survival was not reached. The overall response rate was 81% in the rituximab plus CVP group and 57% in the CVP alone group (p < 0.0001). Complete response in the rituximab plus CVP group was 30% and in the CVP alone group was 8% (p < 0.001) and partial response was 51% in the rituximab plus CVP group compared with 49% in the CVP alone group (p value not reported).\n\n## Rituximab plus CHOP versus CHOP alone\n\nThe GLSG-2000 trial was an open-label multicentre trial that compared rituximab plus CHOP with CHOP alone. The trial recruited patients with stage III and IV follicular lymphoma (279 patients to rituximab plus CHOP and 278 to CHOP alone). The median age of patients was 57 years for both treatment groups and most patients had an ECOG performance status of 0 to 1. The median follow-up was 56 months.\n\nThe primary outcome measure was time to treatment failure and secondary outcomes included overall survival, response rates (overall, complete and partial), response duration and time to next antilymphoma treatment. The median time to treatment failure was not reached in the rituximab plus CHOP group and was 35 months in the CHOP alone group (p < 0.0001). The overall survival rate at 5 years was 90% in the rituximab plus CHOP group and 84% in the CHOP alone group (p = 0.0493). The median overall survival was not reached. The overall response rate was 96% in the rituximab plus CHOP group and 91% in the CHOP alone group (p = 0.0046). Complete response in the rituximab plus CHOP group was 19% and 17% in the CHOP alone group (p value not reported). Partial response was 77% in the rituximab plus CHOP group compared with 74% in the CHOP alone group (p value not reported).\n\n## Rituximab plus MCP versus MCP alone\n\nThe OSHO-39 trial was an open-label multicentre trial that compared rituximab plus MCP with MCP alone. The trial recruited patients with CD20-positive indolent non-Hodgkin's lymphoma, which included lymphoplasmacytic lymphoma and mantle cell lymphoma. The primary analysis population was defined as the population of patients with follicular lymphoma (105 patients to rituximab plus MCP and 96 patients to MCP alone). The median age of patients was 60 years in the rituximab plus MCP group and 57 years in the MCP alone group. Most patients had an ECOG performance status of 0 to 1, and patients with an ECOG performance status of more than 2 were excluded from the trial. The median follow-up was 49 months for the rituximab plus MCP group and 42 months for the MCP alone group.\n\nThe primary outcome measure of the OSHO-39 trial was overall response rate and secondary outcomes included progression-free survival, overall survival, response rates (overall, complete and partial), response duration, event-free survival and time to next antilymphoma treatment. The overall response rate was 92% in the rituximab plus MCP group and 75% in the MCP alone group (p < 0.0009). The overall survival rate at 4 years was 87% for the rituximab plus MCP group and 74% for the MCP alone group (p = 0.0096). The median overall survival was not reached. Complete response in the rituximab plus MCP group was 50% compared with 25% in the MCP alone group (p = 0.0004). Partial response in the rituximab plus MCP group was 43% and 50% in the MCP alone group (p value not reported). Median progression-free survival was not reached in the rituximab plus MCP group and was 28.8 months in the MCP alone group (p < 0.0001).\n\n## Rituximab plus CHVPi versus CHVPi alone\n\nThe FL2000 trial was an open-label multicentre trial that compared rituximab plus CHVPi with CHVPi alone. The trial recruited patients with stage II–IV follicular lymphoma (175 patients to rituximab plus CHVPi and 183 patients to CHVPi alone). The median age of patients was 61 years. Most patients had an ECOG performance status of 0 to 1. The median follow-up was 60 months.\n\nThe primary outcome measure of the trial was event-free survival and secondary outcomes included overall survival, response rates (overall, complete and partial) and response duration. The outcomes were evaluated at 6 and 18 months; 18-month results are reported here. Event-free survival was not reached in the rituximab plus CHVPi group compared with 35 months in the CHVPi alone group (p = 0.0004). The overall survival rate at 5 years was 84% in the rituximab plus CHVPi group and 79% in the CHVPi alone group (not significant). The median overall survival was not reached. The overall response rate was 81% in the rituximab plus CHVPi group and 72% in the CHVPi alone group (p value not reported). Excluding unconfirmed complete responses, the complete response rate was 51% in the rituximab plus CHVPi group and 39% in the CHVPi alone group (p value not reported). Partial response was 30% in the rituximab plus CHVPi group and 33% in the CHVPi alone group (p value not reported).\n\n## Adverse events\n\nAll four trials reported grade 3 and 4 adverse events. Although an increased incidence of leukocytopenia, neutropenia and granulocytopenia was observed in the trials in the rituximab plus chemotherapy arms, this was not associated with an increase in the rate of infection (infection is associated with leukocytopenia, neutropenia and granulocytopenia). However, considerable numbers of patients experienced grade 3 or 4 alopecia in both the rituximab plus CHOP and CHOP alone arms of the GLSG-2000 trial. This side effect is associated with the CHOP component of the treatment.\n\n## Subgroup analyses\n\nRituximab plus chemotherapy compared with chemotherapy alone improved treatment outcomes for all subgroups analysed (Follicular Lymphoma International Prognostic Index [FLIPI] score, International Prognostic Index score, age, quality of response to induction therapy and other prognostic factors). The four trials presented analyses of treatment outcomes according to FLIPI score and they showed that treatment outcomes were improved for most FLIPI groups. The GLSG-2000 trial found that time to treatment failure was prolonged in the rituximab plus CHOP group regardless of whether patients were younger or older than 60 years of age.\n\n## Meta-analysis\n\nThree exploratory meta-analyses were conducted by the Assessment Group to explore the overall response rate, complete response rate and partial response rate from the four trials. There were several problems with the validity of these analyses and specifically there were high levels of statistical heterogeneity. Therefore the Assessment Group decided that the response rates from the individual trials were a more robust estimate of the efficacy of the specific rituximab plus chemotherapy regimens.\n\n# Cost effectiveness\n\nThe manufacturer submitted an economic model and the Assessment Group developed its own economic model and critiqued the economic model submitted by the manufacturer.\n\nThe Assessment Group identified three economic models from four published trials (Dundar et al. 2006, 2009; Hornberger et al. 2008; Ray et al. 2010) that met the criteria for inclusion in the systematic review of economic evaluations. One of these (Dundar et al. 2006) was the Evidence Review Group report prepared for NICE technology appraisal guidance 110 in which the addition of rituximab to CVP in first-line induction treatment was evaluated. The three identified economic models were similar and used a Markov approach. Three of the economic evaluations (Dundar et al. 2006, 2009 and Hornberger et al. 2008) only considered rituximab plus CVP, whereas the other study (Ray et al. 2010) evaluated the cost effectiveness of rituximab plus CVP, CHOP, MCP or CHVPi. The two UK economic evaluations (Dundar et al. 2006, 2009; Ray et al. 2010 ) produced broadly similar estimates of the incremental cost-effectiveness ratio (ICER) for rituximab plus CVP versus CVP alone (£8290 per quality-adjusted life year [QALY] gained and £8613 per QALY gained respectively). The ICERs for the addition of rituximab to CHOP, MCP and CHVPi were £10,676, £7455 and £8498 per QALY gained respectively.\n\n## Manufacturer's submission\n\nThe manufacturer of rituximab provided an economic model that evaluated the cost effectiveness of the addition of rituximab to CVP, CHOP, MCP and CHVPi for patients with advanced follicular lymphoma. The model was a Markov model that estimated the costs and benefits resulting from the first-line treatment of follicular lymphoma over the patient's lifetime. The population included in the economic analysis was patients with previously untreated follicular lymphoma for whom rituximab plus chemotherapy was suitable.\n\nThe model has four distinct health states: progression-free survival first-line, progression-free survival second-line, progressive disease, and death. The model has a starting age of 60 years and a follow-up period of 25 years. A half-cycle correction was applied to the model.\n\nEfficacy data for first-line induction therapy was based on the individual clinical trials. For the comparison of rituximab plus CVP versus CVP alone, individual patient-level data were available. Therefore two analyses were presented for rituximab plus CVP versus CVP alone. The first analysis fitted separate curves to each arm using individual patient-level data, whereas the second analysis used the same method used in the other comparisons which was based on an extrapolation technique (exponential distribution estimated using ordinary least squares regression). After first-line therapy it was assumed that patients would receive either CHOP or rituximab plus CHOP as second-line treatment, which could be followed by rituximab maintenance for those responding to second-line treatment. Efficacy data for second-line treatment was taken from the EORTC 20981 trial that reported the effectiveness of rituximab in second-line treatment of follicular lymphoma in patients not previously treated with rituximab.\n\nThe utility values used in the model were derived from a study commissioned by the manufacturer. This study included 222 patients with follicular lymphoma and ECOG performance status 0 to 2. Utilities were elicited using the EQ-5D questionnaire. The following utility values were used in the model: PF1 = 0.88; PF2 = 0.79 and progressive disease = 0.62.\n\nDrug costs used the planned dose from the trials assuming a body surface area of 1.85 m2. In the CVP, CHOP, MCP and CHVPi groups the monthly drug costs of chemotherapy alone were £72, £360, £182 and £413 respectively; when rituximab was added these costs increased to £1830, £2119, £1501 and £1626 respectively. Administration costs were taken from NHS reference costs and estimated to be £268 for rituximab plus chemotherapy and £186 for chemotherapy alone, based on an assumption that rituximab treatment was administered as a hospital day case. The economic model also includes costs associated with monitoring/surveillance and supportive care.\n\nThe base-case analysis showed that addition of rituximab to CVP compared with CVP alone resulted in an ICER of £1529 per QALY gained (incremental cost £1325 and incremental QALY 0.867) using patient-level data, and £5611 per QALY gained (incremental cost £2486 and incremental QALY 0.443) using ordinary least squares regression. The addition of rituximab to CHOP, MCP and CHVPi compared with CHOP, MCP and CHVPi alone resulted in ICERs of £5758 (incremental cost £6312 and incremental QALY 1.096), £4861 (incremental cost £6268 and incremental QALY 1.289), and £9251 (incremental cost £6247 and incremental QALY 0.675) per QALY gained respectively.\n\nThe Assessment Group reviewed the manufacturer's economic model and highlighted some inconsistencies, such as the derivation of the transition probability, calculation of post-progression survival and estimation of costs. It noted that the manufacturer used time-to-event data from clinical trials in which responders to first-line induction treatment received subsequent treatments, which may have over-estimated the effect of rituximab. The Assessment Group noted that the manufacturer had assumed that patients receive either CHOP or rituximab plus CHOP as second-line treatment, which it did not consider reflected the range of treatments used in clinical practice. The Assessment Group did not think that it was appropriate that the manufacturer used different utility values for patients in progression-free survival first-line and progression-free survival second-line.\n\n## The Assessment Group's model\n\nThe Assessment Group developed an individual patient model that simulated 100,000 patients. The model assessed the cost effectiveness of the addition of rituximab to three chemotherapy regimens: CVP, CHOP and MCP in patients with previously untreated stage III–IV follicular lymphoma. The addition of rituximab to CHVPi was not assessed because the Assessment Group thought that there were limitations in the design of the FL2000 trial such as the administration schedule, which did not include rituximab in the first two cycles of CHVPi. Also, their clinical advisers suggested that the combination of CHVPi was not used frequently in UK clinical practice.\n\nThe Assessment Group's model has four health states: first-line treatment and progression-free survival, second-line treatment and progression-free survival, progressive disease and death. In the model, patients are separated into responders and non-responders according to the response rates after first- or second-line treatments. In a separate scenario analysis, patients responding to first-line induction treatment with rituximab receive rituximab as first-line maintenance treatment. The model uses a 25-year time horizon and costs and benefits are discounted at 3.5%.\n\nFor each of the therapies examined, the response rates from the applicable trials were used to classify patients into responders and non-responders. Individual patient data for time to progression from the M39021 trial were used in the model to develop progression-free survival curves for responders and non-responders. For the comparisons of CHOP alone with rituximab plus CHOP, and MCP alone with rituximab plus MCP, individual patient data were not available from the first-line induction trials. Furthermore, the Assessment Group considered that these trial data could be subject to confounding by the use of stem-cell transplantation or interferon as maintenance therapy in responders to treatment. The Assessment Group chose instead to use the data from the M39021 trial as a proxy to develop the progression-free survival curves.\n\nThe planned doses from the three main trials were used to calculate the drug acquisition costs. The planned number of cycles was also used in the economic model. The number of cycles a patient received was calculated from the progression-free survival curve to account for patients that withdrew as a result of disease progression before the end of planned treatment. Chemotherapies were assumed to be administered on a day-case basis. In addition to the administration costs, patients who received rituximab were assumed to incur additional pharmacy costs. The costs associated with transport were also included, assuming that 30% of patients required NHS transportation. In the CVP, CHOP and MCP groups the drug acquisition costs per cycle of chemotherapy alone were £60.48, £233.08 and £218.78 respectively, and with the addition of rituximab were £1282.89, £1455.49 and £1441.19 respectively.\n\nThe Assessment Group used the same report for the utility values in the economic model as the manufacturer (Pettengell et al. 2006). However, the Assessment Group used aggregated health states from an additional analysis, which were considered more appropriate than the disaggregated values in the main analysis (as used by the manufacturer) because the health-state utilities in the main analysis were calculated from the degree of response to therapy and not the number of lines of treatment. The utility values in first-line treatment and progression-free survival and second-line treatment and progression-free survival were assumed to be 0.805, and 0.7363 for patients in the progressive health state.\n\nThe economic model includes the impact of adverse events that occurred in the first-line induction setting in terms of management costs and impairment of quality of life.\n\nThe deterministic base-case cost-effectiveness analysis showed that the addition of rituximab to CVP, CHOP and MCP resulted in ICERs of £7720 (incremental cost £7389 and incremental QALY 0.96), £10,834 (incremental cost £5725 and incremental QALY 0.53) and £9316 (incremental cost £5267 and incremental QALY 0.57) per QALY gained respectively.\n\nThe Assessment Group carried out a probabilistic sensitivity analysis that showed that the ICERs for the addition of rituximab to CVP, CHOP and MCP were estimated to be £7735, £10,855 and £9313 per QALY gained respectively.\n\nThe Assessment Group explored a scenario in which first-line maintenance treatment was incorporated into the treatment pathway to reflect the recommendations made in the guidance on rituximab for maintenance treatment of follicular lymphoma (NICE technology appraisal guidance 226). Assuming that responders to rituximab plus chemotherapy receive first-line maintenance rituximab, the ICERs estimated by the Assessment Group for the addition of rituximab to CVP, CHOP and MCP were £14,959 (incremental cost £18,727 and incremental QALY 1.25), £21,687 (incremental cost £19,150 and incremental QALY 0.88) and £20,493 (incremental cost £17,976 and incremental QALY 0.88) per QALY gained respectively.\n\nThe Assessment Group performed a probabilistic sensitivity analysis for the addition of rituximab to CVP, CHOP and MCP, which assumed that responders to rituximab plus chemotherapy receive first-line maintenance rituximab and which resulted in ICERs of £15,017, £21,625 and £20,418 per QALY gained respectively.\n\nThe Assessment Group performed a range of univariate sensitivity analyses to assess the impact of main parameters and assumptions. The ICER was sensitive to the assumption about the time horizon, the choice of parametric distribution to model the effectiveness in first-line induction, the maximum time a patient can remain progression-free, and resistance to rituximab. For the base-case analysis, assuming a 25% reduction in efficacy of rituximab when used as second-line treatment in patients previously treated with rituximab increased the ICERs to £14,870, £26,939 and £21,253 per QALY gained, for the addition of rituximab to CVP, CHOP and MCP respectively.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rituximab in combination with chemotherapy, having considered evidence on the nature of advanced follicular lymphoma and the value placed on the benefits of rituximab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee considered current practice in the UK for the treatment of advanced follicular lymphoma. The clinical specialist explained that the goal of treatment is to maintain quality of life and to ensure that people are able to maintain employment and live independently for as long as possible. The availability of rituximab treatment was considered to have transformed clinical practice. The Committee heard from the clinical specialist that rituximab plus CVP (as recommended the original NICE technology appraisal guidance 110, now replaced by this guidance) is the most commonly used first-line treatment option. However, some patients, for example those with bulky disease, may be more appropriately treated with more aggressive regimens such as rituximab plus CHOP. The Committee understood that for first-line induction treatment rituximab plus CVP or rituximab plus CHOP are used to treat the majority of patients with advanced follicular lymphoma.\n\nThe Committee explored the use in clinical practice of first-line chemotherapy treatments other than CVP and CHOP. The clinical specialist explained that patients need different treatments depending on their overall health status with increasing age and therefore a range of treatment options is needed. Some people are not fit enough to receive rituximab plus CVP and clinicians might wish to offer other treatment options such as rituximab plus chlorambucil. The Committee heard that currently a patient can receive rituximab or chlorambucil but not a combination of rituximab plus chlorambucil, which might be considered inconsistent by some clinicians, although evidence of effectiveness for the combination is very limited. The Committee understood that being able to provide a range of treatments was valued by clinicians. It recognised that treatment with CVP or CHOP may not be suitable for all patients and that for these patients chlorambucil may have a role in treatment.\n\nThe Committee discussed patient experiences of rituximab treatment. The Committee heard from patient experts that they considered they had benefited from treatment with rituximab and that it had improved their quality of life, enabling them to look to the future. The patient experts also explained that the choice of treatment and availability of an effective treatment has a positive effect on patients' families in terms of the families' quality of life. The Committee recognised the importance of rituximab as an option for the treatment of follicular lymphoma.\n\nThe Committee discussed consultation comments that suggested that rituximab plus bendamustine should be considered as an option for the first-line treatment of follicular lymphoma. It heard from the manufacturer that at the time of rituximab's marketing authorisation no data were submitted for the combination of rituximab plus bendamustine, and that the manufacturer of bendamustine was submitting a separate marketing authorisation for bendamustine plus rituximab for the first-line treatment of indolent non-Hodgkin's lymphoma. A NICE technology appraisal of bendamustine plus rituximab as first-line treatment of indolent non-Hodgkin's lymphoma is planned in 2012. The Committee understood that the use of rituximab plus bendamustine for the first-line treatment of follicular lymphoma would be considered in this planned appraisal. Consequently, the consideration of rituximab plus bendamustine is not included in this current appraisal.\n\n## Clinical effectiveness\n\nThe Committee considered the clinical effectiveness of rituximab plus CVP, CHOP, MCP and CHVPi for the treatment of advanced follicular lymphoma. The Committee noted that the evidence came from four good-quality randomised controlled trials. The Committee accepted that the results of the individual trials indicated that the addition of rituximab to CVP, CHOP, MCP and CHVPi improved clinical outcomes including overall survival and overall response compared with chemotherapy alone. The Committee noted the length of follow-up in the four trials was short compared with the natural course of follicular lymphoma but it agreed that this was common in trials involving follicular lymphoma. The Committee then discussed the adverse events reported in the trials and noted that the addition of rituximab to CVP, CHOP, MCP and CHVPi did not significantly increase adverse-event rates. The Committee concluded that in the clinical trials rituximab plus CVP, CHOP, MCP and CHVPi had been demonstrated to be more effective than CVP, CHOP, MCP and CHVPi alone for the treatment of advanced follicular lymphoma.\n\nThe Committee discussed whether the results of the clinical trials could be considered representative of the population in UK clinical practice. The Committee noted that the population in the four trials was younger than the median age of people with advanced follicular lymphoma in the UK. It discussed whether this would have had a favourable impact on the efficacy of rituximab in the trials. The Committee heard from the clinical specialist that even though the trials did enrol younger people, some rituximab plus chemotherapy combinations, such as rituximab plus CHOP, tended to be given to younger people because of the aggressive nature of the chemotherapy regimen. The Committee was aware of the subgroup analysis by age from one of the four trials that showed that time to treatment failure was prolonged in the rituximab plus CHOP group regardless of the age of the patient. The Committee was persuaded that the results reported in the trials could be considered as broadly representative of the outcomes of rituximab treatment in UK clinical practice.\n\nThe Committee considered the evidence of effectiveness for the combination of rituximab with chemotherapy regimens not included in the clinical trials. The Committee heard from the clinical specialist that the clinical trial data suggest that rituximab improves clinical outcomes when added to a range of chemotherapy regimens and that this would also be observed for the combination of rituximab with chemotherapy regimens not reflected in the clinical trial data. However, it was recognised that the data to support this were limited. The Committee noted comments from consultation that there are randomised studies comparing different rituximab chemotherapy regimens that have been published as abstracts. However, the Committee considered that these data include rituximab in all treatment groups and therefore do not provide direct evidence of the benefit of adding rituximab to chemotherapy. The Committee also understood that there is one uncontrolled study that investigated the efficacy of rituximab plus chlorambucil in 27 patients. The Committee heard from the manufacturer that the conclusions of the study suggested that a randomised controlled trial would be useful. However, the Committee recognised that it was unlikely that a randomised controlled trial would be conducted. The Committee considered that there was uncertainty as to the relative effect and absolute response rates of the addition of rituximab to chemotherapy regimens other than those studied in the clinical trials. However, on balance, the Committee was persuaded that on the basis of the evidence submitted and comments provided rituximab would provide an additional clinical benefit when added to chemotherapy.\n\n## Cost effectiveness\n\nThe Committee considered the evidence of the cost effectiveness of rituximab plus CVP, CHOP, MCP and CHVPi compared with chemotherapy alone for the treatment of advanced follicular lymphoma. The Committee discussed the deterministic ICERs from the Assessment Group's model and noted that the Assessment Group had not included the combination of rituximab plus CHVPi in its economic model because there were issues with the design of the trial and the combination was not frequently used in UK clinical practice. It also noted that rituximab plus chemotherapy was compared with chemotherapy alone and not with other rituximab plus chemotherapy regimens and so comparisons could not be made between chemotherapy regimens. The Assessment Group calculated an ICER of £7720 per QALY gained for rituximab plus CVP, £10,800 per QALY gained for rituximab plus CHOP and £9320 per QALY gained for rituximab plus MCP (see section 4.2.16). The Committee also noted the ICERs presented by the manufacturer for rituximab plus CVP, CHOP, MCP and CHVPi, which ranged between £1530 and £9250 per QALY gained (see section 4.2.8). The Committee noted the Assessment Group's concerns about the manufacturer's model (see section 4.2.9) and considered the Assessment Group's calculations for rituximab plus CVP, CHOP and MCP. It agreed that the manufacturer's comparison of rituximab plus CHVPi versus CHVPi alone would need to inform the decision-making for the addition of rituximab to CHVPi. The Committee noted that the base-case ICERs were within an acceptable range of what would be considered cost effective. However, neither analysis included the use of rituximab first-line maintenance treatment, and both assumed that the efficacy of rituximab was maintained when used again as a second-line induction treatment after first-line rituximab. The Committee concluded that on the basis of current clinical practice these two factors needed to be considered when making the decision on the cost effectiveness of rituximab plus CVP, CHOP, MCP and CHVPi.\n\nThe Committee considered whether it was appropriate to assume that the effect of rituximab is maintained in patients whose follicular lymphoma has relapsed and whose disease is re-treated with rituximab. The Committee noted that the Assessment Group's and manufacturer's models assumed that there was no loss of efficacy of rituximab in patients who are re-treated with rituximab. The Committee also noted that the Assessment Group had performed a sensitivity analysis that explored the impact of reduced effectiveness of rituximab among previously treated patients and which showed that the ICER was sensitive to this assumption. The analyses by the Assessment Group suggested that if there was a 25% reduction in efficacy with re-treatment with rituximab then the ICERs increased from £7720–£10,800 to £14,900–£26,900 per QALY gained. The Committee heard from the clinical specialist that there was limited evidence to suggest whether or not there might be a loss of efficacy after re-treatment with rituximab. The Committee concluded that the efficacy of rituximab after re-treatment was a key uncertainty in the economic modelling.\n\nThe Committee discussed the role of rituximab maintenance treatment in clinical practice. It recognised that rituximab maintenance treatment after first-line induction therapy was recommended as a treatment option in the guidance on rituximab for maintenance treatment of follicular lymphoma (NICE technology appraisal guidance 226). The Committee therefore considered the Assessment Group's scenario analysis in which first-line maintenance treatment with rituximab was incorporated into the treatment pathway. The Committee was aware that the inclusion of rituximab first-line maintenance treatment increased the ICERs to £15,000–£21,600 per QALY gained and that in the Assessment Group's model it was suggested that rituximab first-line maintenance treatment is not cost effective. The Committee concluded that in view of the recommendations in NICE technology appraisal guidance 226 it was appropriate to consider the ICERs from the Assessment Group's scenario analysis and that in light of the differences between the estimates of cost effectiveness, NICE technology appraisal guidance 226 and this current appraisal should be considered for review together.\n\nThe Committee discussed the treatment pathway after first-line therapy used in the economic model. The Committee noted that the manufacturer assumed that after first-line treatment, patients would receive rituximab plus CHOP or CHOP alone. The Committee heard from the Assessment Group that the treatment pathways in its model also included CHOP, but after discussions with the clinical advisers the model had also been developed to include fludarabine-cyclophosphamide and stem-cell transplant. The advisers to the Assessment Group stated that subsequent treatment after first-line treatment would depend on what first-line treatment the patient had received and how soon the patient relapsed. The Committee also heard from the clinical specialist, who confirmed that the treatment pathways used in the Assessment Group's model reflect clinical practice in the UK. The Committee concluded that the treatment pathways used in the Assessment Group's model were appropriate.\n\nThe Committee discussed the estimates of the most plausible ICER. The Committee noted that in the base-case analyses the ICERs from the Assessment Group were within acceptable levels and suggested that rituximab plus CVP, CHOP or MCP are cost-effective options for the treatment of advanced follicular lymphoma. The Committee recognised that the Assessment Group had not included the combination of rituximab plus CHVPi in its model. The Committee accepted that using the manufacturer's estimates, and taking into account the Assessment Group's concerns, the ICER was still likely to be within acceptable levels. However, the Committee did not consider that the analyses fully reflect how rituximab is used in clinical practice and the ICERs increase when it is assumed that rituximab first-line maintenance treatment is provided. It considered that the efficacy of rituximab when used as a re-treatment is also uncertain, and if there is a loss of efficacy then this would further increase the ICER. However, the Committee was persuaded that this uncertainty was not such that it increased the ICERs to above the threshold range (£20,000–30,000) that would normally be considered cost effective. The Committee therefore concluded that rituximab plus CVP, CHOP, MCP or CHVPi is both clinically effective and cost effective for the treatment of symptomatic advanced follicular lymphoma in previously untreated people and is an appropriate use of NHS resources.\n\nThe Committee was mindful that in clinical practice chemotherapy regimens other than CVP, CHOP, MCP and CHVPi may be used. The Committee noted that the addition of rituximab to chemotherapy regimens other than CVP, CHOP, MCP and CHVPi had not been modelled by either the Assessment Group or the manufacturer. It agreed that recommending rituximab with any chemotherapy was not appropriate despite its conclusion on likely clinical effectiveness (see section 4.3.8); that would result in recommending combinations yet to be appraised (see section 4.3.5), and cost effectiveness cannot be assumed without evidence. However the Committee specifically discussed the addition of rituximab to chlorambucil, noting the consultation comments and evidence from clinical specialists that rituximab plus chlorambucil would be a useful option in older patients or patients with a lower performance status. It noted that this group may be disadvantaged by guidance only recommending rituximab with more aggressive chemotherapy regimens, as had been studied in the clinical trials. It requested that the Assessment Group provide informal cost-effectiveness advice and heard that, based on their base-case analysis, the ICER for rituximab plus chlorambucil would still be within the cost-effective range if the QALY gain for rituximab plus chlorambucil was half that for rituximab plus CHOP. The Committee was mindful of the limited clinical data and the absence of a formal cost-effectiveness analysis, but for the group of patients likely to receive rituximab plus chlorambucil in the NHS, the Committee concluded that rituximab plus chlorambucil was an appropriate use of NHS resources.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA243\n\nAppraisal title: Rituximab for the first-line treatment of stage III–IV follicular lymphoma (review of NICE technology appraisal guidance 110)\n\nSection\n\nKey conclusion\n\nRituximab, in combination with:\n\ncyclophosphamide, vincristine and prednisolone (CVP)\n\ncyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)\n\nmitoxantrone, chlorambucil and prednisolone (MCP)\n\ncyclophosphamide, doxorubicin, etoposide, prednisolone and interferon-α (CHVPi) or\n\nchlorambucil\n\nis recommended as an option for the treatment of symptomatic stage III and IV follicular lymphoma in previously untreated patients.\n\n\n\n\n\nThe key drivers for this recommendation are:\n\nThe clinical evidence suggests that rituximab plus CVP, CHOP, MCP and CHVPi is more effective than CVP, CHOP, MCP and CHVPi alone for the treatment of advanced follicular lymphoma.\n\n\n\nOn the basis of the evidence submitted and comments provided, rituximab would provide an additional clinical benefit when added to chemotherapy.\n\n\n\nThe cost-effectiveness analyses for rituximab plus CVP, CHOP, MCP and CHVPi compared with CVP, CHOP, MCP and CHVPi alone gave incremental cost-effectiveness ratios (ICERs) in the cost-effective range.\n\n\n\nDespite the limited clinical data and absence of a formal cost-effectiveness analysis for rituximab plus chlorambucil, the Committee concluded that rituximab plus chlorambucil was an appropriate use of NHS resources for the group of patients likely to receive rituximab plus chlorambucil.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nA range of treatment options is needed because patients need different treatments depending on their overall health status with increasing age.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe availability of rituximab treatment was considered by the clinical specialist to have transformed clinical practice. Patient experts considered that they had benefited from treatment with rituximab and that it had improved their quality of life. The choice of treatment and availability of an effective treatment had a positive effect on patients' families in terms of the families' quality of life.\n\n, 4.3.3, 4.3.4\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe appraisal considers a single position in the treatment pathway: rituximab in combination with chemotherapy for the treatment of previously untreated stage III or IV follicular lymphoma.\n\n\n\nAdverse effects\n\nThe addition of rituximab to CVP, CHOP, MCP and CHVPi did not significantly increase adverse-event rates.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe evidence came from four good-quality randomised controlled trials.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe results reported in the trials could be considered as broadly representative of the outcomes of rituximab treatment in UK clinical practice.\n\nand 4.3.7\n\nUncertainties generated by the evidence\n\nRituximab may be combined with a number of chemotherapy regimens not included in the clinical trials. The Committee considered that there was uncertainty as to the relative effect and absolute response rates of the addition of rituximab to chemotherapy regimens other than those studied in the clinical trials. However, on balance, the Committee was persuaded that on the basis of the evidence submitted and comments provided rituximab would provide an additional clinical benefit when added to chemotherapy.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThere were no subgroups for which there was evidence of differential effectiveness.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that in the clinical trials rituximab plus CVP, CHOP, MCP and CHVPi had been demonstrated to be more effective than CVP, CHOP, MCP and CHVPi alone for the treatment of advanced follicular lymphoma.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer's model evaluated the cost effectiveness of rituximab plus CVP, CHOP, MCP and CHVPi. The Assessment Group's model included rituximab plus CVP, CHOP and MCP but it did not include the combination of rituximab plus CHVPi because there were issues with the design of the trial and the combination was not frequently used in UK clinical practice.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that neither the manufacturer nor the Assessment Group included the use of rituximab first-line maintenance treatment in their base-case analyses. They also assumed that the efficacy of rituximab was maintained when used again as second-line induction treatment after first-line rituximab. The Committee concluded that on the basis of current clinical practice these two factors needed to be considered when making the decision on the cost effectiveness of rituximab plus CVP, CHOP, MCP and CHVPi.\n\n9\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe health-related quality-of-life benefits were not a key driver of the recommendations in this appraisal.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo subgroups were identified.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe ICERs increased when it was assumed that rituximab was used as first-line maintenance treatment. They also increased if it was assumed that there was a reduction in efficacy when rituximab is used as a re-treatment.\n\n, 4.3.11\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Assessment Group calculated an ICER of £7720 per quality-adjusted life year (QALY) gained for rituximab plus CVP, £10,800 per QALY gained for rituximab plus CHOP and £9320 per QALY gained for rituximab plus MCP. The Committee agreed that the manufacturer's comparison of rituximab plus CHVPi versus CHVPi alone would need to inform the decision-making for the addition of rituximab to CHVPi. The Committee did not accept that the analyses fully reflected how rituximab was used in clinical practice and the ICERs increased when it was assumed that rituximab first-line maintenance treatment was provided and if there was a loss of efficacy when rituximab was used as a re-treatment. However, the Committee was persuaded that this uncertainty was not such that it increased the ICERs to above the threshold range (£20,000–30,000) that would normally be considered cost effective. The Committee was mindful of the limited clinical data and the absence of a formal cost-effectiveness analysis, but for the group of patients likely to receive rituximab plus chlorambucil in the NHS, the Committee concluded that rituximab plus chlorambucil was an appropriate use of NHS resources.\n\n, 4.3.13, 4.3.14\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe manufacturer did not submit a patient access scheme.\n\n\n\nEnd-of-life considerations\n\nThe supplementary advice was not relevant to this appraisal.\n\n\n\nEqualities considerations and social value judgements\n\nNo equalities issues were raised in the appraisal.\n\n", 'Related NICE guidance': "Rituximab for the first-line maintenance treatment of follicular non-Hodgkin's lymphoma. NICE technology appraisal guidance 226 (2011).\n\nRituximab for the treatment of relapsed or refractory stage III of IV follicular non-Hodgkin's lymphoma (review of NICE technology appraisal guidance 37). NICE technology appraisal guidance 137 (2008).\n\nImproving outcomes in haematological cancers – the manual. NICE cancer service guidance (2003).", 'Review of guidance': 'The guidance on this technology will be considered for review with NICE technology appraisal 226 in May 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveJanuary 2012', 'Changes after publication': 'February 2014: implementation section updated to clarify that rituximab is recommended as an option for treating stage III-IV follicular lymphoma.\n\nJuly 2012: minor maintenance\n\nJune 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nIt updates and replaces NICE technology appraisal guidance 110 (published September 2006). The review and re-appraisal of rituximab for the first-line treatment of stage III–IV follicular lymphoma has resulted in a change in the guidance. Specifically, extending the recommendation to cover regimens using:\n\ncyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)\n\nmitoxantrone, chlorambucil and prednisolone (MCP)\n\ncyclophosphamide, doxorubicin, etoposide, prednisolone and interferon-α (CHVPi) or\n\nchlorambucilas well as cyclophosphamide, vincristine and prednisolone.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta243
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Evidence-based recommendations on rituximab for treating follicular lymphoma in adults.
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89311b0ba6266578da3ce23a18cae9d436efde9c
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nice
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Breast reconstruction using lipomodelling after breast cancer treatment
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Breast reconstruction using lipomodelling after breast cancer treatment
# Guidance
Current evidence on the efficacy of breast reconstruction using lipomodelling after breast cancer treatment is adequate and the evidence raises no major safety concerns. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.
There is a theoretical concern about any possible influence of the procedure on recurrence of breast cancer in the long term, although there is no evidence of this in published reports. NICE therefore encourages long-term data collection on this procedure.
Patient selection should be carried out by a breast cancer multidisciplinary team.
Breast reconstruction using lipomodelling after breast cancer treatment should only be carried out by surgeons with specialist expertise and training in the procedure.# The procedure
# Indications and current treatments
Breast reconstruction following surgery for breast cancer may be done during the same operation or at a later date, and may involve prosthetic material (implant) alone, or autologous tissue (tissue from elsewhere in the body, usually the abdomen, buttocks or back), or a combination of the two.
# Outline of the procedure
Lipomodelling uses the patient's own fat cells to replace volume after breast reconstruction, or to fill defects in the breast following breast-conserving surgery. It can be used on its own or as an adjunct to other reconstruction techniques. The procedure aims to restore breast volume and contour without the morbidity of other reconstruction techniques. However, a degree of fat resorption is common in the first 6 months and there have been concerns that it may make future mammographic images more difficult to interpret.
With the patient under general or local anaesthesia, fat is harvested by aspiration with a syringe and cannula, commonly from the abdomen, outer thigh and/or flank. The fat is usually washed and centrifuged before being injected into the breast. Patients subsequently undergo repeat treatments (typically 2–4 sessions).
Commencement of lipomodelling treatment may be delayed for a variable period of time after treatment of breast cancer.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
In a case series of 734 procedures for breast reconstruction (880 procedures in total), the results of lipomodelling following conservative surgery were judged to be 'very good' in 50% of procedures, 'good' in 40% and 'moderately good' in 10% (based on clinical examination, photographs and patient opinion: absolute numbers not stated).
A case series of 820 patients, including 381 with asymmetry after mastectomy and breast reconstruction, reported that the majority of patients had a 'significant improvement in their breast size and/or shape postoperatively'. Long-term breast asymmetry was reported in 4% (34/820) of patients.
A case series of 69 patients (74 breasts) reported a 'good to very good' improvement in 87% (64/74) of breasts and a 'moderate' improvement in 14% (10/74) of breasts (assessment from photographs by 2 independent surgeons).
A non-randomised comparative study of 61 patients (62 breasts) treated by lipomodelling (n = 20) or standard treatment only (n = 42) (not described) reported improvement in mean aesthetic results from 2.7 at baseline to 4.3 and 3.1 points respectively at 3-month follow-up (p ≤ 0.032) (evaluated using a 5-point scale: 5 = very good).
The Specialist Advisers listed key efficacy outcomes as volume change, aesthetic assessment of breast shape, quality of life and body image assessments.
# Safety
The case series of 734 lipomodelling procedures for breast reconstruction reported that 10 years of oncological follow-up did not reveal any increased risk of local recurrence after mastectomy or after conservative treatment. In a case series of 137 patients who had a modified radical mastectomy, 96% were free from recurrence and 98% were free from distant metastasis at 5-year follow-up (absolute figures not stated).
The case series of 880 procedures reported 1 intraoperative pneumothorax (probably caused by the transfer cannula piercing the pleura), which resolved with the insertion of a pleural drain.
The case series of 880 procedures reported local infection in less than 1% of procedures (6/880); all resolved with treatment and had no impact on the final result. There was also an infection at a harvesting site in 1 case, which resolved with antibiotics.
The case series of 880 procedures reported a 3% rate of fat necrosis (absolute figures not stated). Liponecrotic cysts were reported in 7% (5/74) of breasts at 3-month follow-up in the case series of 69 patients and in 5% (2/43) in a case series of 37 patients.
The Specialist Advisers listed adverse events known from reports or experience as oil cysts, haematoma, calcification, donor and breast site deformity, complete resorption of fat, and uncertain findings on clinical surveillance and mammography. They raised the theoretical possibility of an increased rate of breast cancer recurrence and fat embolism.
# Other comments
The Committee noted that there have been concerns about possible interference as a result of the procedure with imaging of the breast for cancer surveillance. However, it was advised that this ought not to be an issue with current techniques for lipomodelling and with expert interpretation of subsequent images.
The Committee noted that the techniques used for lipomodelling continue to evolve.
The Committee noted that devices are being introduced which aim to concentrate adipose stem cells in the tissue that is being used for lipomodelling. Further information about the outcomes of this and other adaptations of the technique of lipomodelling is desirable for guiding their future use in clinical management.
The Committee noted that joint guidelines on lipomodelling are in development and these include a dataset for a proposed national audit.# Further information
For related NICE guidance see the NICE website.
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedures guidance process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Changes after publicationMay 2012: minor maintenance
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICENational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BTwww.nice.org.uknice@nice.org.uk0845 033 7780
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{'Guidance': 'Current evidence on the efficacy of breast reconstruction using lipomodelling after breast cancer treatment is adequate and the evidence raises no major safety concerns. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.\n\nThere is a theoretical concern about any possible influence of the procedure on recurrence of breast cancer in the long term, although there is no evidence of this in published reports. NICE therefore encourages long-term data collection on this procedure.\n\nPatient selection should be carried out by a breast cancer multidisciplinary team.\n\nBreast reconstruction using lipomodelling after breast cancer treatment should only be carried out by surgeons with specialist expertise and training in the procedure.', 'The procedure': "# Indications and current treatments\n\nBreast reconstruction following surgery for breast cancer may be done during the same operation or at a later date, and may involve prosthetic material (implant) alone, or autologous tissue (tissue from elsewhere in the body, usually the abdomen, buttocks or back), or a combination of the two.\n\n# Outline of the procedure\n\nLipomodelling uses the patient's own fat cells to replace volume after breast reconstruction, or to fill defects in the breast following breast-conserving surgery. It can be used on its own or as an adjunct to other reconstruction techniques. The procedure aims to restore breast volume and contour without the morbidity of other reconstruction techniques. However, a degree of fat resorption is common in the first 6 months and there have been concerns that it may make future mammographic images more difficult to interpret.\n\nWith the patient under general or local anaesthesia, fat is harvested by aspiration with a syringe and cannula, commonly from the abdomen, outer thigh and/or flank. The fat is usually washed and centrifuged before being injected into the breast. Patients subsequently undergo repeat treatments (typically 2–4 sessions).\n\nCommencement of lipomodelling treatment may be delayed for a variable period of time after treatment of breast cancer.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a case series of 734 procedures for breast reconstruction (880 procedures in total), the results of lipomodelling following conservative surgery were judged to be 'very good' in 50% of procedures, 'good' in 40% and 'moderately good' in 10% (based on clinical examination, photographs and patient opinion: absolute numbers not stated).\n\nA case series of 820 patients, including 381 with asymmetry after mastectomy and breast reconstruction, reported that the majority of patients had a 'significant improvement in their breast size and/or shape postoperatively'. Long-term breast asymmetry was reported in 4% (34/820) of patients.\n\nA case series of 69 patients (74 breasts) reported a 'good to very good' improvement in 87% (64/74) of breasts and a 'moderate' improvement in 14% (10/74) of breasts (assessment from photographs by 2 independent surgeons).\n\nA non-randomised comparative study of 61 patients (62 breasts) treated by lipomodelling (n = 20) or standard treatment only (n = 42) (not described) reported improvement in mean aesthetic results from 2.7 at baseline to 4.3 and 3.1 points respectively at 3-month follow-up (p ≤ 0.032) (evaluated using a 5-point scale: 5 = very good).\n\nThe Specialist Advisers listed key efficacy outcomes as volume change, aesthetic assessment of breast shape, quality of life and body image assessments.\n\n# Safety\n\nThe case series of 734 lipomodelling procedures for breast reconstruction reported that 10 years of oncological follow-up did not reveal any increased risk of local recurrence after mastectomy or after conservative treatment. In a case series of 137 patients who had a modified radical mastectomy, 96% were free from recurrence and 98% were free from distant metastasis at 5-year follow-up (absolute figures not stated).\n\nThe case series of 880 procedures reported 1 intraoperative pneumothorax (probably caused by the transfer cannula piercing the pleura), which resolved with the insertion of a pleural drain.\n\nThe case series of 880 procedures reported local infection in less than 1% of procedures (6/880); all resolved with treatment and had no impact on the final result. There was also an infection at a harvesting site in 1 case, which resolved with antibiotics.\n\nThe case series of 880 procedures reported a 3% rate of fat necrosis (absolute figures not stated). Liponecrotic cysts were reported in 7% (5/74) of breasts at 3-month follow-up in the case series of 69 patients and in 5% (2/43) in a case series of 37 patients.\n\nThe Specialist Advisers listed adverse events known from reports or experience as oil cysts, haematoma, calcification, donor and breast site deformity, complete resorption of fat, and uncertain findings on clinical surveillance and mammography. They raised the theoretical possibility of an increased rate of breast cancer recurrence and fat embolism.\n\n# Other comments\n\nThe Committee noted that there have been concerns about possible interference as a result of the procedure with imaging of the breast for cancer surveillance. However, it was advised that this ought not to be an issue with current techniques for lipomodelling and with expert interpretation of subsequent images.\n\nThe Committee noted that the techniques used for lipomodelling continue to evolve.\n\nThe Committee noted that devices are being introduced which aim to concentrate adipose stem cells in the tissue that is being used for lipomodelling. Further information about the outcomes of this and other adaptations of the technique of lipomodelling is desirable for guiding their future use in clinical management.\n\nThe Committee noted that joint guidelines on lipomodelling are in development and these include a dataset for a proposed national audit.", 'Further information': "For related NICE guidance see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges after publicationMay 2012: minor maintenance\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICENational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BTwww.nice.org.uknice@nice.org.uk0845 033 7780'}
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Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer
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Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer
Evidence-based recommendations on bevacizumab (Avastin) and cetuximab (Erbitux) for treating metastatic colorectal cancer in adults.
# Guidance
This guidance has been partially updated by NICE technology appraisal guidance 242 (TA242) Cetuximab (monotherapy or combination chemotherapy), bevacizumab (in combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology appraisal 150 and part review of technology appraisal guidance 118). See the guidance for more information.
Bevacizumab in combination with 5-fluorouracil plus folinic acid, with or without irinotecan, is not recommended for the first-line treatment of metastatic colorectal cancer.
This recommendation has been updated and replaced by NICE technology appraisal guidance 242.
People currently receiving bevacizumab or cetuximab should have the option to continue therapy until they and their consultants consider it appropriate to stop.# Clinical need and practice
Colorectal cancer is a malignant neoplasm arising from the lining (mucosa) of the large intestine (colon and rectum). Colorectal cancer is the third most common cancer in the UK, with approximately 30,000 new cases registered in England and Wales in 2002. This represents 12% of all new cancer cases in women and 14% of all new cancer cases in men. The incidence of colorectal cancer increases with age. In people between the ages of 45 and 49 years the incidence is 20 per 100,000. Amongst those over 75 years of age, the incidence is over 300 per 100,000 for men and 200 per 100,000 per year for women. The median age of patients at diagnosis is over 70 years. The overall 5-year survival rate for colorectal cancer in England and Wales is approximately 50%; however, large differences in survival exist according to the stage of disease at diagnosis.
Metastatic colorectal cancer, where the tumour has spread beyond the confines of the lymph nodes to other parts of the body, is generally defined as stage IV of the American Joint Committee on Cancer (AJCC) tumour node metastases (TNM) system or stage D of Dukes' classification.
The population of patients with metastatic colorectal cancer includes both those who present with metastatic disease and those who develop metastatic disease after surgery. Estimates of people presenting with metastatic colorectal cancer range from 20% to 55% of new cases. Out of those who have undergone surgery for colorectal cancer with apparently complete excision, approximately 50% will eventually develop advanced disease and distant metastases (typically presenting within 2 years of initial diagnosis). The 5-year survival rate for metastatic colorectal disease is 12%.
The management of metastatic colorectal cancer is mainly palliative and involves a combination of specialist treatments (such as palliative surgery, chemotherapy and radiation), symptom control and psychosocial support. The aim is to improve both the duration and quality of the individual's remaining life. Clinical outcomes such as overall survival, response and toxicity are important, but alternative outcomes such as progression-free survival, quality of life, convenience, acceptability and patient choice are also important.
The most frequent site of metastatic disease is the liver. In up to 50% of patients with metastatic disease, the liver may be the only site of spread. For these patients surgery provides the only chance of longer-term survival. Approximately 10% of patients with metastatic colorectal cancer present with potentially resectable liver metastases and for approximately 14% chemotherapy may render unresectable liver metastases operable.
Individuals with metastatic disease who are sufficiently fit (normally those with World Health Organization performance status 2 or better) are usually treated with active chemotherapy as first- or second-line therapy. First-line active chemotherapy options include infusional 5-fluorouracil plus folinic acid or leucovorin (calcium folinate) (5-FU/FA, 5-FU/LV), oxaliplatin plus infusional 5-FU/FA (FOLFOX), and irinotecan plus infusional 5-FU/FA (FOLFIRI). Oral analogues of 5-FU (capecitabine and tegafur with uracil) may also be used instead of infusional 5-FU. For those patients first receiving FOLFOX, irinotecan may be a second-line treatment option, whereas for patients first receiving FOLFIRI, FOLFOX may be a second-line treatment option (in accordance with its licensed indication). Patients receiving 5-FU/FA or oral therapy as first-line treatment may receive treatment with FOLFOX and irinotecan as second-line and subsequent therapies.
Survival estimates for patients with metastatic colorectal cancer receiving best supportive care are approximately 6 months. The use of infusional 5-FU/FA can increase survival to approximately 10−12 months, whereas combinations of FOLFIRI followed by FOLFOX, or FOLFOX followed by irinotecan, have been reported to increase survival to 20−21 months.# The technologies
# Bevacizumab
Bevacizumab (Avastin, Roche Products) is a recombinant humanised monoclonal IgG1 antibody that acts as an angiogenesis inhibitor. It targets the biological activity of human vascular endothelial growth factor, which stimulates new blood vessel formation in the tumour. Bevacizumab is licensed in the UK in combination with intravenous 5-FU/FA with or without irinotecan for first-line treatment of patients with metastatic carcinoma of the colon or rectum.
Bevacizumab is contraindicated in patients who are pregnant, have untreated central nervous system metastases, have hypersensitivity to the active substance or to any of the excipients, or have hypersensitivity to products derived from Chinese hamster ovary cell cultures or other recombinant human or humanised antibodies. The summary of product characteristics (SPC) lists the following complications that may be associated with bevacizumab treatment: gastrointestinal perforation, wound-healing problems, hypertension, proteinuria, arterial thromboembolism, haemorrhage and cardiomyopathy. For full details of side effects and contraindications, see the SPC.
Bevacizumab is administered as an intravenous infusion at a dose of 5 mg/kg body weight once every 14 days. Bevacizumab treatment is recommended until there is underlying disease progression. Bevacizumab is available in 100-mg and 400-mg vials at net prices of £242.66 and £924.40 respectively (excluding VAT; 'British national formulary' edition 51 ). If vial wastage is assumed, a 75-kg person would receive a single 400-mg vial of bevacizumab per dose, equating to a cost of £924.40. Patients in the key registration trial received an average of 18.2 doses, equating to an average total cost of drug acquisition of £16,824.08 per patient. Costs may vary in different settings because of negotiated procurement discounts.
# Cetuximab
Cetuximab (Erbitux, Merck Pharmaceuticals) is a recombinant monoclonal antibody that blocks the human epidermal growth factor receptor (EGFR) and thus inhibits the proliferation of cells that depend on EGFR activation for growth. Cetuximab is licensed in the UK in combination with irinotecan for the treatment of patients with EGFR-expressing metastatic colorectal cancer after failure of cytotoxic therapy that included irinotecan.
The UK marketing authorisation stipulates that before being treated with cetuximab patients should be tested to identify whether or not the tumour is expressing EGFR. This is currently done using the commercially available DakoCytomation kit, which uses immunohistochemistry to identify EGFR expression (£995.00 for a set of 35 tests ).
One common side effect of cetuximab therapy is the development of an acne-like rash. The SPC notes that if a patient experiences a grade 3 or 4 skin reaction cetuximab treatment must be interrupted, with treatment being resumed only if the reaction resolves to grade 2. In addition, the SPC lists infusion-related reactions and respiratory disorders that may be associated with treatment with cetuximab. For full details of side effects and contraindications, see the SPC.
Cetuximab is given as an intravenous infusion with an initial loading dose of 400 mg/m2 of body surface area and subsequent weekly doses of 250 mg/m2. Cetuximab treatment is recommended until there is underlying disease progression. Cetuximab is provided in 50-ml vials containing 2 mg cetuximab per ml. The net price for a 50-ml vial is £136.50 (excluding VAT; BNF 51). Assuming vial wastage, an average person with a body surface area of 1.75 m2 would receive seven vials per loading dose and five vials per maintenance dose, equating to a cost of £955.50 for the loading dose and £682.50 for each maintenance dose. Patients in the key registration trial received an average of 16.8 doses, equating to an average total drug acquisition cost of £11,739 per patient. Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
# Clinical effectiveness
## Bevacizumab
Three randomised controlled trials (RCTs) have investigated the effectiveness of bevacizumab as a first-line treatment for metastatic colorectal cancer.
One study (n = 813; median age 59 years) investigated the effect of irinotecan, bolus 5-FU and leucovorin (calcium folinate) (IFL) with and without the addition of bevacizumab.
The other two studies (one n = 71, median age 64 years; one n = 209, median age 71 years) investigated the effect of bolus 5-FU and leucovorin (5-FU/LV) with and without bevacizumab. For two of the studies the primary end point was overall survival, while in the smaller study that used 5-FU/LV as the comparator the primary end points were time to disease progression and best tumour response. In all three studies participants tended to have a good performance status (Eastern Cooperative Oncology Group status 0 or 1; unrestricted by disease or only restricted in strenuous physical activity), although in the larger study that used 5-FU/LV as a comparator, 7% had an ECOG status of 2 (ambulatory and capable of all self-care but unable to carry out any work activities).
Data taken from the manufacturer's submission are based on analyses carried out using data from the clinical trials database, which is subject to updates and revisions. Therefore in some instances the results presented here differ from the results in earlier published journal articles.
The addition of bevacizumab to IFL led to a statistically significant difference in median overall survival compared with IFL alone (20.3 months vs 15.6 months, respectively; hazard ratio 0.66, 95% confidence interval 0.54 to 0.81). In the studies that used 5-FU/LV as comparator there were no statistically significant differences in median overall survival. In the larger study the median overall survival in the bevacizumab-containing arm was 16.6 months compared with 13.2 months in the control arm (HR 0.77, 95% CI 0.56 to 1.05). In the smaller study the median overall survival in the bevacizumab-containing arm was 17.7 months compared with 13.6 months in the control arm (HR 0.52, 95% CI not reported; p = 0.07).
Progression-free survival (which was defined as time from randomisation until tumour progression or death) was measured in two of the studies. In both, there was a statistically significant difference in median progression-free survival. In the study comparing bevacizumab and IFL with IFL alone, the median progression-free survival was 10.6 months in the bevacizumab arm and 6.2 months in the control arm (HR 0.54, 95% CI 0.45 to 0.66). In the larger of the two studies comparing bevacizumab and 5-FU/LV with 5-FU/LV alone, the median progression-free survival was 9.2 months in the bevacizumab arm and 5.5 months in the control arm (HR 0.50, 95% CI 0.34 to 0.73). The smaller study that used 5-FU/LV as a comparator reported the median time to disease progression. There was a statistically significant difference favouring the bevacizumab arm over the control arm (9.0 months vs 5.2 months, respectively ).
All three studies measured tumour response rate (as partial or complete reduction in tumour size). In two studies, the differences in tumour response rate reached statistical significance. In the study with IFL as a comparator, the tumour response rate in the bevacizumab arm was 44.8% compared with 34.8% in the control arm (incremental difference 10.0%, 95% CI 3.3 to 16.7). In the smaller study that used 5-FU/LV as a comparator, the tumour response rate was 40.0% in the bevacizumab arm and 16.7% in the control arm (incremental difference 23.3%, 95% CI not reported; p = 0.029). In the larger study that used 5-FU/LV as a comparator, the difference in tumour response rate did not reach statistical significance (26.0% and 15.2% for treatment and control arms, respectively ).
In all the studies there was a higher incidence of grade 3 and 4 adverse events in the groups receiving bevacizumab compared with the control groups:
% vs 74.0%, respectively, with IFL as the comparator
% vs 54.3% in the smaller study with 5-FU/LV as the comparator
% vs 71% in the larger study with 5-FU/LV as the comparator. Higher incidences of grade 3 and 4 hypertension were also reported in the groups receiving bevacizumab compared with the control groups:
% vs 2.3%, respectively, with IFL as the comparator
% vs 0% in the smaller study with 5-FU/LV as the comparator
% vs 3% in the larger study with 5-FU/LV as the comparator. For other grade 3 and 4 toxicities there were no consistent patterns of effects. An increased incidence of diarrhoea was reported in the study that used IFL as the comparator (32.4% vs 24.7%), and there was an increased incidence of thrombotic events in the smaller study that used 5-FU/LV as the comparator (14.3% vs 2.9%).
## Cetuximab
The assessment group identified no studies that compared cetuximab with current standard treatments (which in the case of second- and subsequent-line treatment are FOLFOX and active/best supportive care , respectively). One RCT, the BOND study, was identified in which cetuximab combined with irinotecan was compared with cetuximab monotherapy (n = 329). In this study participants in the monotherapy arm could have irinotecan added to their treatment regimen upon disease progression. Three single-arm studies were also identified, of which two measured the effect of cetuximab monotherapy (one with 346 participants and one with 57 participants) and one measured the effect of cetuximab combined with irinotecan (n = 138). The primary outcome for all studies was tumour response rate. A median age of 56 years was reported in two of the trials and a median age of 59 years in the other two. In all four studies the populations tended to have good performance status (ECOG 0 to 1 or Karnofsky 80 to 100).
In the RCT there was no statistically significant difference in median overall survival between treatment groups. The median overall survival was 8.6 months in the cetuximab plus irinotecan arm and 6.9 months in the cetuximab monotherapy arm (HR 0.91, 95% CI 0.68 to 1.21). In the single-arm studies of cetuximab monotherapy, the median survival duration was 6.6 months (95% CI 5.6 to 7.6) in the larger and 6.4 months (95% CI 4.1 to 10.8) in the smaller study. In the single-arm study of cetuximab plus irinotecan, median overall survival duration was 8.4 months (95% CI 7.2 to 10.3).
In the RCT there was a statistically significant difference in median time to progression between treatment groups. The median time to progression was 4.1 months in the cetuximab combined with irinotecan arm and 1.5 months in the cetuximab monotherapy arm (HR 0.54, 95% CI 0.42 to 0.71). Median time to progression was reported in two of the single-arm studies: 1.4 months (95% CI 1.3 to 2.8) in the larger cetuximab monotherapy study and 2.9 months (95% CI 2.6 to 4.1) for cetuximab combined with irinotecan.
All four cetuximab studies measured tumour response rate. In the RCT there was a statistically significant difference between treatment groups. The tumour response rate was 22.9% in the cetuximab combined with irinotecan arm and 10.8% in the cetuximab monotherapy arm (incremental difference 12.1%, 95% CI 4.1 to 20.2). The rates of response in the single-arm studies were 8.8% (95% CI 2.9 to 19.3) and 12.0% (95% CI 8.4 to 15.4) in the two cetuximab monotherapy studies and 15.2% (95% CI 9.7 to 22.3) in the study that combined cetuximab with irinotecan. The Institute also received data, following completion of the assessment report, from three additional single-arm studies of cetuximab. In two of these studies all patients had received two prior chemotherapy regimens. Results from these studies confirmed the effect seen in other studies of cetuximab.
Data from the manufacturer's submission suggest that the response to cetuximab may be associated with an acne-like rash. Post hoc analyses of pooled data from the two studies in which patients received cetuximab combined with irinotecan (combined total of 339 patients) show 153 patients had stable disease at 6 weeks, of whom 50% had an acne-like rash of grade 2 or above (n = 76). Of these, 26% (n = 20) went on to have a partial response compared with 13% (n = 10) of those without an acne-like rash of grade 2 or above (p = 0.043).
Data from the RCT show that patients in the cetuximab plus irinotecan arm with an acne-like rash of grade 2 or above had an overall survival of 10.8 months compared with 5.8 months for those with either no rash or a grade 1 rash. In the single-arm study of cetuximab plus irinotecan, patients who had a grade 3 acne-like rash had a median survival of 13.1 months, compared with 10.6 months for those with a grade 2 rash, 6.2 months for those with a grade 1 rash and 4.3 months for those with no rash (p = 0.0008, grade 0 vs grade 1−3).
In the RCT the incidence of some adverse events was higher in patients receiving cetuximab plus irinotecan compared with those receiving cetuximab alone: grade 3 and 4 adverse events (65.1% vs 43.5%); diarrhoea (21.2% vs 1.7%); neutropenia (9.4% vs 0%); grade 3 or 4 acne-like rash (9.4% vs 5.2%).
# Cost effectiveness
No published economic analyses of either bevacizumab or cetuximab were identified. The manufacturers of bevacizumab and cetuximab both submitted cost-effectiveness models, and the assessment group developed two models for each drug.
## Bevacizumab – manufacturer's models
The manufacturer submitted two simple-state transition models with three health states: pre-progression, post-progression and death. Each model was based on data from a different bevacizumab study. The first was based on the study that compared bevacizumab plus IFL with IFL, while the second was based on the larger of the two studies that compared bevacizumab plus 5-FU/LV with 5-FU/LV. In both models the analysis was carried out from the perspective of the NHS. Data on progression-free survival for the treatment and control arms were taken from trial data, and an equal risk of death was applied following progression irrespective of treatment group. The models assumed equivalent utility scores for both the intervention and control groups, with a utility of 0.80 given to the pre-progression health state and 0.50 to the post-progression health state. Utility decrements associated with adverse events were not included. Pre-progression costs were calculated from the trials, augmented with data from other published sources. For post-progression costs an assumption of £2000 a month was used, applied equally to both arms.
With discounting of 6% for costs and 1.5% for benefits, the cost per quality-adjusted life year (QALY) gained was £88,364 for bevacizumab combined with IFL compared with IFL alone. With the same discounts, the cost per QALY gained for bevacizumab combined with 5-FU/LV was £56,628 compared with 5-FU/LV alone. One-way sensitivity analyses resulted in estimates of cost per QALY gained of between £82,577 and £106,770 for bevacizumab combined with IFL, and between £39,136 and £69,439 for bevacizumab combined with 5-FU/LV. Probabilistic sensitivity analyses suggest that the likelihood of cost effectiveness at a willingness-to-pay of £30,000 per QALY is 0.16 for bevacizumab combined with IFL, and 0.24 for bevacizumab combined with 5-FU/LV.
## Bevacizumab – assessment group models
The methods used for the models produced by the assessment group were similar to those used in the NICE appraisal of irinotecan, oxaliplatin and raltitrexed (NICE technology appraisal 93). The assessment group presented two models based on the same trials as used in the manufacturer's models. The models were simple-state transition models with costs and effects calculated from the perspective of the NHS. Unlike the manufacturer's models the outcome data were based on published overall survival curves from the two studies. The utility value for pre-progression was the same as was used in the manufacturer's models (0.80), whereas that for post-progression was slightly higher (0.60). Data on second-line and subsequent therapies were taken from a study that investigated the optimal sequence of FOLFOX and FOLFIRI as first- and second-line therapies, and were applied equally to treatment and control groups. Costs were calculated from study data and augmented from a range of sources including published literature and personal communications. Discounting was not used because the distribution of costs incurred over time was unknown and was not considered relevant by the assessment group because of the short time horizon in the model.
The base-case costs per QALY gained for the assessment group models were £62,857 for bevacizumab combined with IFL and £88,436 for bevacizumab combined with 5-FU/LV, compared with IFL or 5-FU/LV alone, respectively. One-way sensitivity analyses of the base case produced a cost per QALY gained of £60,430–£76,831 for bevacizumab combined with IFL, and £51,355 and higher for bevacizumab combined with 5-FU/LV. Probabilistic sensitivity analyses suggest that, with a willingness-to-pay threshold of £30,000, the likelihood of bevacizumab being cost effective is zero.
The differences in the cost per QALY gained between the assessment group's model and the manufacturer's model are likely to have been caused by the difference in the methods used to calculate survival. The manufacturer's model resulted in more favourable estimates of the cost per QALY than did the assessment group's model when the comparator was 5‑FU/LV because the difference in progression-free survival was greater than the difference in mean overall survival. Conversely, the assessment group's model resulted in more favourable cost per QALY estimates when the comparator was IFL, because the difference in overall survival was greater than the difference in progression-free survival.
## Cetuximab – manufacturer's model
The manufacturer's model for cetuximab used survival modelling to estimate the lifetime costs and benefits for patients receiving cetuximab combined with irinotecan compared with ASC/BSC. Two sets of analyses were presented. The first was based directly on survival data from the RCT, whereas in the second analysis adjustments were made to the survival data to reflect a proposed continuation rule. Under the continuation rule patients would only continue to receive cetuximab beyond 6 weeks if there were either a partial or complete tumour response or an acne-like rash of grade 2 or above.
The duration of survival of patients receiving cetuximab combined with irinotecan was extrapolated from data in the RCT. The survival of patients receiving ASC/BSC was calculated from the survival of the patients in the cetuximab monotherapy arm of the RCT. The data from the monotherapy arm were adjusted to remove the impact of cetuximab using an HR taken from an RCT of second-line irinotecan compared with ASC/BSC. Therefore the model assumes that the relative hazard of overall survival between cetuximab monotherapy and ASC/BSC as second-line and subsequent treatment is exactly equivalent to the relative survival hazard between irinotecan and ASC/BSC as second-line treatment. The modelling was carried out from the perspective of the NHS, with costs and resource data taken from the RCT comparing cetuximab monotherapy with cetuximab plus irinotecan and augmented from the published literature. Outcomes were presented as life years gained, with sensitivity analyses to examine the impact of quality of life using alternative utilities for metastatic colorectal cancer of 0.95 and 0.71, both constant over the lifetime and based on published data. Additional data were presented using a utility of 0.73, constant over the lifetime, based on data collected as part of a single-arm study that investigated the effectiveness of cetuximab as a second- and subsequent-line treatment for patients with metastatic colorectal cancer (MABEL). Costs and benefits were discounted at an annual rate of 3.5%.
The base-case analysis suggests a cost per life year gained of £33,263 if the continuation rule were applied. One-way sensitivity analyses with the application of the continuation rule result in cost per QALY estimates of £35,014 with a utility value of 0.95 and £45,566 with a utility value of 0.73. Without the continuation rule, cost per QALY estimates are £45,237 and £58,870 respectively. Cost-effectiveness acceptability curves suggest that at a willingness-to-pay threshold of £30,000 per life year gained the likelihood of cost effectiveness is 0.10.
## Cetuximab assessment group models
In the absence of direct comparisons of cetuximab plus irinotecan with ASC/BSC or FOLFOX, the assessment group developed two models. The first was a threshold analysis considering the incremental benefit that cetuximab combined with irinotecan would have to provide over ASC/BSC in order to be considered cost effective. The second model was an indirect comparison of data from the arm receiving cetuximab and irinotecan in the RCT with data from other published studies of second-line ASC/BSC.
In both models overall survival for patients receiving cetuximab was estimated from patient-level data in the RCT. In the threshold analysis, the survival of patients receiving ASC/BSC was held as an unknown variable, whereas in the indirect comparisons different values for overall survival, ranging from 6 to 9 months, were taken from three published studies. Health-related quality of life was estimated in the same way as in the bevacizumab model, applying a utility of 0.80 to pre-progression disease states and 0.60 to post-progression states. For the cetuximab arm, measures of the duration of pre-progression survival as a proportion of overall survival were estimated using data from the RCT. For the comparator arm, they were derived from a trial that compared tipifarnib (a farnesyl transferase inhibitor) with BSC in refractory advanced colorectal cancer. In this study the duration of pre-progression survival was approximately 37% of overall survival. Resource use and costs were taken from the RCT as reported in the manufacturer's submission and augmented from the published literature and personal communication with clinical experts. Discounting was not used in the model because the distribution of costs incurred over time was unknown and was not considered relevant by the assessment group because of the short time horizon in the model.
The base-case threshold analysis suggests it is not possible for cetuximab combined with irinotecan to have a cost per QALY gained of less than £20,000, irrespective of the application of the continuation rule. When the proposed continuation rule is applied, cetuximab plus irinotecan must provide 0.65 additional life years (7.8 months) compared with ASC/BSC in order to achieve a cost per QALY gained of £30,000. This would imply that survival for patients receiving ASC/BSC would have to be 0.14 life years (1.7 months) or less. It was not possible to achieve a cost per QALY gained of less than £30,000 without the continuation rule. A sensitivity analysis using utility values from the MABEL study suggested that with the continuation rule applied cetuximab plus irinotecan must provide 0.60 additional life years (7.2 months) compared with ASC/BSC in order to achieve a cost per QALY gained of £30,000. Indirect comparisons are associated with a high level of uncertainty, but they yielded estimates of the cost per QALY gained that ranged from £77,210 to £370,044.
# Consideration of the evidence
The Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab and cetuximab for metastatic colorectal cancer, having considered evidence on the nature of the condition and the value placed on the benefits of bevacizumab and cetuximab by people with metastatic colorectal cancer, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources.
The Committee heard from clinical specialists that it is accepted that multiple chemotherapy treatments lead to incremental gains in survival if patients are sufficiently fit to receive therapy. The Committee further heard from clinical specialists that treatment regimens frequently involve combination therapy of 5-FU/FA either with irinotecan or with oxaliplatin as first-line therapies, followed, where patients are sufficiently fit, by irinotecan as a second-line therapy where oxaliplatin has been given and by oxaliplatin plus 5-FU/FA as a second-line therapy where irinotecan has been given. The experts suggested that it would be of merit to add further options and lines of therapy to this sequence.
## Bevacizumab
The Committee reviewed the clinical effectiveness evidence from the bevacizumab studies and noted that the age of the population in the largest study was lower than the age of patients normally receiving chemotherapy in England and Wales. However, clinical specialists agreed that fitness, rather than age, is the primary factor when considering whether chemotherapy is appropriate. The Committee therefore agreed that the patients included in the bevacizumab trials could be considered to reflect a population of relatively fit patients with metastatic colorectal cancer in England and Wales.
The Committee noted that all bevacizumab studies demonstrated statistically significant gains in progression-free survival and that some studies also demonstrated statistically significant gains in overall survival and tumour response rate. However, the Committee noted that the comparators in the studies cannot be considered current standard practice in the NHS in England and Wales because the 5-FU treatment schedules involved administration by bolus rather than administration by infusion. It heard from clinical specialists that the benefits associated with bevacizumab in combination with bolus 5-FU are expected to be seen in infusional regimens because the two drugs have different mechanisms of action and their effects are therefore likely to be independent. This was also said to be supported by interim results from ongoing clinical studies. The Committee was therefore persuaded that the results seen in the studies could be considered generalisable to NHS practice in England and Wales.
The Committee then considered the estimates of cost effectiveness of bevacizumab. It noted that the models from the manufacturer and from the assessment group were similar in their methods and data sources; the models differed chiefly in their use of progression-free survival and overall survival, respectively, as the primary outcome data. The Committee noted that this difference resulted in different estimates of cost effectiveness from the manufacturer and the assessment group. However, the Committee considered that neither source resulted in a cost-effectiveness estimate that was compatible with the best use of NHS resources. The Committee noted that a proposal from the manufacturer for a registry programme could not be taken into further consideration because the Committee had been informed of imminent additional license extensions for bevacizumab, which would need to be taken into account of in any such scheme. It concluded that bevacizumab in combination with 5-FU/FA, with or without irinotecan as a first-line treatment for metastatic colorectal cancer would not be a cost-effective use of NHS resources.
## Cetuximab
The Committee considered the clinical effectiveness evidence from the cetuximab studies. The Committee understood that cetuximab plus irinotecan could be given in its current licensed indication either as a second-line treatment following failure of an irinotecan-containing regimen or as a subsequent-line treatment following failure of both irinotecan- and oxaliplatin-containing regimens. The Committee recognised that in both cases, some patients may still have a high performance status, meaning that further chemotherapy regimens could be considered appropriate.
The Committee was concerned that there were no studies that compared cetuximab with current standard care either in second- or subsequent-line therapy, or with any therapy not including cetuximab. The Committee noted that there were currently no clinical studies available comparing cetuximab with FOLFOX, and therefore the relative clinical effectiveness of cetuximab as a second-line treatment could not as yet be determined. The Committee heard testimonies from clinical specialists that subsequent to second-line treatment progression-free survival and tumour response would be negligible if further active treatment was not available. Therefore the results seen in the single-arm cetuximab studies for these outcomes could be interpreted as an effect of the drug. It also heard that clinical specialists believed that cetuximab, in this situation, where no other active treatment was available, could prolong survival for a number of months if the disease responded to the drug. The Committee was therefore persuaded that cetuximab in this situation demonstrated some evidence of effectiveness. However, the relative effectiveness against current standard care remains uncertain.
The Committee heard from patient experts and clinical specialists about the impact of the acne-like rash associated with treatment on patients' quality of life. They heard from patient experts that, for some patients, the side effects of the drugs were tolerated willingly because of the perceived benefit, whereas for others the side-effect profile may be more of a consideration. The Committee heard from clinical specialists that the acne-like rash was generally well managed with antibiotics, treatment breaks or dose reduction. The Committee was therefore satisfied that the side-effect profile of cetuximab should not be a determining factor in its deliberations.
The Committee noted the contradiction that although the UK marketing authorisation stipulates that patients need to be tested for the presence of EGFR, a positive test for the presence of EGFR did not predict response to treatment. The Committee heard from clinical specialists that there is increasing knowledge of the mechanism of action of cetuximab and that it is now thought that the antibody identified through EGFR testing is different from the one targeted by cetuximab. The Committee noted the difficulties in identifying patients who were likely to respond to cetuximab, but was fully aware that decisions about its use in the NHS would have to be based on the current marketing authorisation.
The Committee considered the continuation rule proposed by the manufacturer. The Committee expressed concern about conflicts with the SPC, but it agreed that this would only be an issue for the small proportion of patients who experience grade 3 and 4 acne rash. Although it acknowledged that there was some evidence to suggest that the presence of a rash may predict response to cetuximab, the Committee had reservations about using it to decide whether to continue or discontinue treatment because no studies have so far tested prospectively this continuation rule.
The Committee considered the cost-effectiveness evidence for cetuximab. It noted that the economic modelling from both the manufacturer and the assessment group had been completed using effectiveness data from the RCT of cetuximab where approximately 80% of patients received cetuximab plus irinotecan as a third-line or subsequent therapy. It was also aware that the comparator used in both models was ASC/BSC, which meant the modelled scenario and corresponding estimates of cost effectiveness more closely resembled third-line or subsequent use of cetuximab rather than second-line use.
The Committee discussed the uncertainties around the estimates of utility for patients with metastatic colorectal cancer. The manufacturer had provided estimates between 0.95 and 0.71, both constant over the lifetime of the patient. The Committee considered that the utility for a patient with metastatic colorectal cancer was more likely to reflect the lower end of this range, based on additional data submitted by the manufacturer from the MABEL study. The Committee concluded that, using the most realistic utility estimates, the cost-effectiveness estimates provided by both the manufacturer and the assessment group were not compatible with the best use of NHS resources. The Committee also noted that these estimates were associated with a high level of uncertainty because they were based on indirect comparisons.
The Committee therefore considered threshold analyses completed by the assessment group, where the survival in the comparator arm was held as unknown. The base-case threshold analysis suggested that, with the application of the continuation rule, a cost per QALY gained of £30,000 could only be achieved if survival with ASC/BSC is less than 2 months. A sensitivity analysis adjusting the assumptions to reflect utility values from the MABEL study did not materially alter the results. The Committee noted that the manufacturer had provided an estimate of mean survival of 5.6 months for patients receiving ASC/BSC in their economic model, while studies of ASC/BSC identified in the assessment report provided estimates of median survival ranging from 6 to 9 months. The Committee therefore considered that an estimate of mean survival while receiving ASC/BSC of approximately 2 months was an unrealistic underestimate. Considering all the available evidence on clinical and cost effectiveness, the Committee therefore concluded that cetuximab, either as a second-line or a subsequent-line treatment for metastatic colorectal cancer would not be a cost-effective use of NHS resources.# Recommendations for further research
The Committee noted the following ongoing clinical trials related to this guidance.
NCT00063141 is an RCT comparing cetuximab combined with irinotecan with irinotecan alone as second-line treatment in patients with metastatic colorectal cancer.
NCT00079066 is an RCT comparing cetuximab combined with best supportive care with best supportive care alone in patients with metastatic colorectal cancer.
The Committee was aware of other ongoing clinical trials with bevacizumab and cetuximab as part of different treatment regimens.
The TREE-2 trial is a randomised multicentre study comparing three regimens of oxaliplatin plus bolus, infusional or oral 5-FU with bevacizumab to evaluate safety and tolerability in the first-line treatment of patients with advanced colorectal cancer.
The NO16966C trial is a randomised phase III study of intermittent oral capecitabine in combination with intravenous oxaliplatin (CAPOX) with or without bevacizumab for the first-line treatment of patients with advanced colorectal cancer.
The CONcePT trial aims to develop an optimised schedule of administration of FOLFOX plus bevacizumab in the first-line treatment of patients with advanced colorectal cancer.
The E3200 trial is a phase III RCT of oxaliplatin, 5-FU and leucovorin with or without bevacizumab, versus bevacizumab alone in patients previously treated for advanced or metastatic colorectal cancer. Preliminary data have been presented. The bevacizumab monotherapy arm was prematurely halted because of lack of efficacy.
The first-line use of cetuximab in combination with standard chemotherapy regimens is being investigated in a number of studies. One example is the COIN study (NCT00182715), which aims to determine whether the addition of cetuximab to continuous oxaliplatin and 5-FU improves overall survival when compared with either continuous oxaliplatin and 5-FU on its own, or intermittent oxaliplatin and fluoropyrimidine chemotherapy. Other examples include NCT00145314 (5-FU/FA + oxaliplatin), NCT00286130 (FOLFIRI, FOLFOX) and NCT00215722 (capecitabine and oxaliplatin).
EXPLORE is an RCT comparing cetuximab combined with FOLFOX with FOLFOX alone as second-line treatment in patients with metastatic colorectal cancer. Recruitment to the trial was halted prematurely when the number of participants reached 102. Preliminary results were presented at the annual conference of the American Society for Clinical Oncology in 2005 for progression-free survival and response rate.
The Committee recommends research to investigate the predictive value of EGFR testing and the correlation of baseline and on-treatment markers with tumour response and survival.
Additionally, the Committee recommends studies to investigate the impact of bevacizumab and cetuximab treatment on health-related quality of life.# Related guidance
NICE has issued the following related guidance.
Irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer. NICE technology appraisal guidance 93 (2005).
Improving outcomes in colorectal cancers: manual update. NICE cancer service guidance (2004).
Guidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer. NICE technology appraisal guidance 61 (2003).# Review of guidance
The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.
The guidance on this technology was considered for review in January 2010. Details are on the NICE website.
Andrew DillonChief ExecutiveJanuary 2007# Changes after publication
March 2014: minor maintenance
March 2012: minor maintenance
January 2012: This guidance has been partially updated by NICE technology appraisal guidance 242 (TA242) Cetuximab (monotherapy or combination chemotherapy), bevacizumab (in combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology appraisal 150 and part review of technology appraisal guidance 118). See the guidance for more information.# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE multiple technology appraisal process.
The recommendations from this guideline have been incorporated into a NICE Pathway. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence . All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'This guidance has been partially updated by NICE technology appraisal guidance 242 (TA242) Cetuximab (monotherapy or combination chemotherapy), bevacizumab (in combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology appraisal 150 and part review of technology appraisal guidance 118). See the guidance for more information.\n\nBevacizumab in combination with 5-fluorouracil plus folinic acid, with or without irinotecan, is not recommended for the first-line treatment of metastatic colorectal cancer.\n\nThis recommendation has been updated and replaced by NICE technology appraisal guidance 242.\n\nPeople currently receiving bevacizumab or cetuximab should have the option to continue therapy until they and their consultants consider it appropriate to stop.', 'Clinical need and practice': "Colorectal cancer is a malignant neoplasm arising from the lining (mucosa) of the large intestine (colon and rectum). Colorectal cancer is the third most common cancer in the UK, with approximately 30,000 new cases registered in England and Wales in 2002. This represents 12% of all new cancer cases in women and 14% of all new cancer cases in men. The incidence of colorectal cancer increases with age. In people between the ages of 45 and 49\xa0years the incidence is 20 per 100,000. Amongst those over 75\xa0years of age, the incidence is over 300 per 100,000 for men and 200 per 100,000 per year for women. The median age of patients at diagnosis is over 70\xa0years. The overall 5-year survival rate for colorectal cancer in England and Wales is approximately 50%; however, large differences in survival exist according to the stage of disease at diagnosis.\n\nMetastatic colorectal cancer, where the tumour has spread beyond the confines of the lymph nodes to other parts of the body, is generally defined as stage IV of the American Joint Committee on Cancer (AJCC) tumour node metastases (TNM) system or stage D of Dukes' classification.\n\nThe population of patients with metastatic colorectal cancer includes both those who present with metastatic disease and those who develop metastatic disease after surgery. Estimates of people presenting with metastatic colorectal cancer range from 20% to 55% of new cases. Out of those who have undergone surgery for colorectal cancer with apparently complete excision, approximately 50% will eventually develop advanced disease and distant metastases (typically presenting within 2\xa0years of initial diagnosis). The 5-year survival rate for metastatic colorectal disease is 12%.\n\nThe management of metastatic colorectal cancer is mainly palliative and involves a combination of specialist treatments (such as palliative surgery, chemotherapy and radiation), symptom control and psychosocial support. The aim is to improve both the duration and quality of the individual's remaining life. Clinical outcomes such as overall survival, response and toxicity are important, but alternative outcomes such as progression-free survival, quality of life, convenience, acceptability and patient choice are also important.\n\nThe most frequent site of metastatic disease is the liver. In up to 50% of patients with metastatic disease, the liver may be the only site of spread. For these patients surgery provides the only chance of longer-term survival. Approximately 10% of patients with metastatic colorectal cancer present with potentially resectable liver metastases and for approximately 14% chemotherapy may render unresectable liver metastases operable.\n\nIndividuals with metastatic disease who are sufficiently fit (normally those with World Health Organization performance status 2 or better) are usually treated with active chemotherapy as first- or second-line therapy. First-line active chemotherapy options include infusional 5-fluorouracil plus folinic acid or leucovorin (calcium folinate) (5-FU/FA, 5-FU/LV), oxaliplatin plus infusional 5-FU/FA (FOLFOX), and irinotecan plus infusional 5-FU/FA (FOLFIRI). Oral analogues of 5-FU (capecitabine and tegafur with uracil) may also be used instead of infusional 5-FU. For those patients first receiving FOLFOX, irinotecan may be a second-line treatment option, whereas for patients first receiving FOLFIRI, FOLFOX may be a second-line treatment option (in accordance with its licensed indication). Patients receiving 5-FU/FA or oral therapy as first-line treatment may receive treatment with FOLFOX and irinotecan as second-line and subsequent therapies.\n\nSurvival estimates for patients with metastatic colorectal cancer receiving best supportive care are approximately 6\xa0months. The use of infusional 5-FU/FA can increase survival to approximately 10−12\xa0months, whereas combinations of FOLFIRI followed by FOLFOX, or FOLFOX followed by irinotecan, have been reported to increase survival to 20−21\xa0months.", 'The technologies': "# Bevacizumab\n\nBevacizumab (Avastin, Roche Products) is a recombinant humanised monoclonal IgG1 antibody that acts as an angiogenesis inhibitor. It targets the biological activity of human vascular endothelial growth factor, which stimulates new blood vessel formation in the tumour. Bevacizumab is licensed in the UK in combination with intravenous 5-FU/FA with or without irinotecan for first-line treatment of patients with metastatic carcinoma of the colon or rectum.\n\nBevacizumab is contraindicated in patients who are pregnant, have untreated central nervous system metastases, have hypersensitivity to the active substance or to any of the excipients, or have hypersensitivity to products derived from Chinese hamster ovary cell cultures or other recombinant human or humanised antibodies. The summary of product characteristics (SPC) lists the following complications that may be associated with bevacizumab treatment: gastrointestinal perforation, wound-healing problems, hypertension, proteinuria, arterial thromboembolism, haemorrhage and cardiomyopathy. For full details of side effects and contraindications, see the SPC.\n\nBevacizumab is administered as an intravenous infusion at a dose of 5\xa0mg/kg body weight once every 14\xa0days. Bevacizumab treatment is recommended until there is underlying disease progression. Bevacizumab is available in 100-mg and 400-mg vials at net prices of £242.66 and £924.40 respectively (excluding VAT; 'British national formulary' edition 51 [BNF 51]). If vial wastage is assumed, a 75-kg person would receive a single 400-mg vial of bevacizumab per dose, equating to a cost of £924.40. Patients in the key registration trial received an average of 18.2 doses, equating to an average total cost of drug acquisition of £16,824.08 per patient. Costs may vary in different settings because of negotiated procurement discounts.\n\n# Cetuximab\n\nCetuximab (Erbitux, Merck Pharmaceuticals) is a recombinant monoclonal antibody that blocks the human epidermal growth factor receptor (EGFR) and thus inhibits the proliferation of cells that depend on EGFR activation for growth. Cetuximab is licensed in the UK in combination with irinotecan for the treatment of patients with EGFR-expressing metastatic colorectal cancer after failure of cytotoxic therapy that included irinotecan.\n\nThe UK marketing authorisation stipulates that before being treated with cetuximab patients should be tested to identify whether or not the tumour is expressing EGFR. This is currently done using the commercially available DakoCytomation kit, which uses immunohistochemistry to identify EGFR expression (£995.00 for a set of 35 tests [information supplied by manufacturer]).\n\nOne common side effect of cetuximab therapy is the development of an acne-like rash. The SPC notes that if a patient experiences a grade 3 or 4 skin reaction cetuximab treatment must be interrupted, with treatment being resumed only if the reaction resolves to grade 2. In addition, the SPC lists infusion-related reactions and respiratory disorders that may be associated with treatment with cetuximab. For full details of side effects and contraindications, see the SPC.\n\nCetuximab is given as an intravenous infusion with an initial loading dose of 400\xa0mg/m2 of body surface area and subsequent weekly doses of 250\xa0mg/m2. Cetuximab treatment is recommended until there is underlying disease progression. Cetuximab is provided in 50-ml vials containing 2\xa0mg cetuximab per ml. The net price for a 50-ml vial is £136.50 (excluding VAT; BNF 51). Assuming vial wastage, an average person with a body surface area of 1.75\xa0m2 would receive seven vials per loading dose and five vials per maintenance dose, equating to a cost of £955.50 for the loading dose and £682.50 for each maintenance dose. Patients in the key registration trial received an average of 16.8 doses, equating to an average total drug acquisition cost of £11,739 per patient. Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\n## Bevacizumab\n\nThree randomised controlled trials (RCTs) have investigated the effectiveness of bevacizumab as a first-line treatment for metastatic colorectal cancer.\n\nOne study (n\xa0=\xa0813; median age 59\xa0years) investigated the effect of irinotecan, bolus 5-FU and leucovorin (calcium folinate) (IFL) with and without the addition of bevacizumab.\n\nThe other two studies (one n\xa0=\xa071, median age 64\xa0years; one n\xa0=\xa0209, median age 71\xa0years) investigated the effect of bolus 5-FU and leucovorin (5-FU/LV) with and without bevacizumab. For two of the studies the primary end point was overall survival, while in the smaller study that used 5-FU/LV as the comparator the primary end points were time to disease progression and best tumour response. In all three studies participants tended to have a good performance status (Eastern Cooperative Oncology Group [ECOG] status 0 or 1; unrestricted by disease or only restricted in strenuous physical activity), although in the larger study that used 5-FU/LV as a comparator, 7% had an ECOG status of 2 (ambulatory and capable of all self-care but unable to carry out any work activities).\n\nData taken from the manufacturer's submission are based on analyses carried out using data from the clinical trials database, which is subject to updates and revisions. Therefore in some instances the results presented here differ from the results in earlier published journal articles.\n\nThe addition of bevacizumab to IFL led to a statistically significant difference in median overall survival compared with IFL alone (20.3\xa0months vs 15.6\xa0months, respectively; hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54 to 0.81). In the studies that used 5-FU/LV as comparator there were no statistically significant differences in median overall survival. In the larger study the median overall survival in the bevacizumab-containing arm was 16.6\xa0months compared with 13.2\xa0months in the control arm (HR\xa00.77, 95%\xa0CI 0.56 to 1.05). In the smaller study the median overall survival in the bevacizumab-containing arm was 17.7\xa0months compared with 13.6\xa0months in the control arm (HR\xa00.52, 95%\xa0CI not reported; p\xa0=\xa00.07).\n\nProgression-free survival (which was defined as time from randomisation until tumour progression or death) was measured in two of the studies. In both, there was a statistically significant difference in median progression-free survival. In the study comparing bevacizumab and IFL with IFL alone, the median progression-free survival was 10.6\xa0months in the bevacizumab arm and 6.2\xa0months in the control arm (HR\xa00.54, 95%\xa0CI 0.45 to 0.66). In the larger of the two studies comparing bevacizumab and 5-FU/LV with 5-FU/LV alone, the median progression-free survival was 9.2\xa0months in the bevacizumab arm and 5.5\xa0months in the control arm (HR\xa00.50, 95%\xa0CI 0.34 to 0.73). The smaller study that used 5-FU/LV as a comparator reported the median time to disease progression. There was a statistically significant difference favouring the bevacizumab arm over the control arm (9.0\xa0months vs 5.2\xa0months, respectively [HR\xa00.44, 95%\xa0CI not reported; p=0.005]).\n\nAll three studies measured tumour response rate (as partial or complete reduction in tumour size). In two studies, the differences in tumour response rate reached statistical significance. In the study with IFL as a comparator, the tumour response rate in the bevacizumab arm was 44.8% compared with 34.8% in the control arm (incremental difference 10.0%, 95%\xa0CI 3.3 to 16.7). In the smaller study that used 5-FU/LV as a comparator, the tumour response rate was 40.0% in the bevacizumab arm and 16.7% in the control arm (incremental difference 23.3%, 95%\xa0CI not reported; p\xa0=\xa00.029). In the larger study that used 5-FU/LV as a comparator, the difference in tumour response rate did not reach statistical significance (26.0% and 15.2% for treatment and control arms, respectively [incremental difference 10.8%, 95%\xa0CI not reported; p\xa0=\xa00.055]).\n\nIn all the studies there was a higher incidence of grade 3 and 4 adverse events in the groups receiving bevacizumab compared with the control groups:\n\n% vs 74.0%, respectively, with IFL as the comparator\n\n% vs 54.3% in the smaller study with 5-FU/LV as the comparator\n\n% vs 71% in the larger study with 5-FU/LV as the comparator. Higher incidences of grade 3 and 4 hypertension were also reported in the groups receiving bevacizumab compared with the control groups:\n\n% vs 2.3%, respectively, with IFL as the comparator\n\n% vs 0% in the smaller study with 5-FU/LV as the comparator\n\n% vs 3% in the larger study with 5-FU/LV as the comparator. For other grade 3 and 4 toxicities there were no consistent patterns of effects. An increased incidence of diarrhoea was reported in the study that used IFL as the comparator (32.4% vs 24.7%), and there was an increased incidence of thrombotic events in the smaller study that used 5-FU/LV as the comparator (14.3% vs 2.9%).\n\n## Cetuximab\n\nThe assessment group identified no studies that compared cetuximab with current standard treatments (which in the case of second- and subsequent-line treatment are FOLFOX and active/best supportive care [ASC/BSC], respectively). One RCT, the BOND study, was identified in which cetuximab combined with irinotecan was compared with cetuximab monotherapy (n\xa0=\xa0329). In this study participants in the monotherapy arm could have irinotecan added to their treatment regimen upon disease progression. Three single-arm studies were also identified, of which two measured the effect of cetuximab monotherapy (one with 346 participants and one with 57 participants) and one measured the effect of cetuximab combined with irinotecan (n\xa0=\xa0138). The primary outcome for all studies was tumour response rate. A median age of 56\xa0years was reported in two of the trials and a median age of 59\xa0years in the other two. In all four studies the populations tended to have good performance status (ECOG 0 to 1 or Karnofsky 80 to 100).\n\nIn the RCT there was no statistically significant difference in median overall survival between treatment groups. The median overall survival was 8.6\xa0months in the cetuximab plus irinotecan arm and 6.9\xa0months in the cetuximab monotherapy arm (HR\xa00.91, 95%\xa0CI 0.68 to 1.21). In the single-arm studies of cetuximab monotherapy, the median survival duration was 6.6\xa0months (95%\xa0CI 5.6 to 7.6) in the larger and 6.4\xa0months (95%\xa0CI 4.1 to 10.8) in the smaller study. In the single-arm study of cetuximab plus irinotecan, median overall survival duration was 8.4\xa0months (95%\xa0CI 7.2 to 10.3).\n\nIn the RCT there was a statistically significant difference in median time to progression between treatment groups. The median time to progression was 4.1\xa0months in the cetuximab combined with irinotecan arm and 1.5\xa0months in the cetuximab monotherapy arm (HR\xa00.54, 95%\xa0CI 0.42 to 0.71). Median time to progression was reported in two of the single-arm studies: 1.4\xa0months (95%\xa0CI 1.3 to 2.8) in the larger cetuximab monotherapy study and 2.9\xa0months (95%\xa0CI 2.6 to 4.1) for cetuximab combined with irinotecan.\n\nAll four cetuximab studies measured tumour response rate. In the RCT there was a statistically significant difference between treatment groups. The tumour response rate was 22.9% in the cetuximab combined with irinotecan arm and 10.8% in the cetuximab monotherapy arm (incremental difference 12.1%, 95%\xa0CI 4.1 to 20.2). The rates of response in the single-arm studies were 8.8% (95%\xa0CI 2.9 to 19.3) and 12.0% (95%\xa0CI 8.4 to 15.4) in the two cetuximab monotherapy studies and 15.2% (95%\xa0CI 9.7 to 22.3) in the study that combined cetuximab with irinotecan. The Institute also received data, following completion of the assessment report, from three additional single-arm studies of cetuximab. In two of these studies all patients had received two prior chemotherapy regimens. Results from these studies confirmed the effect seen in other studies of cetuximab.\n\nData from the manufacturer's submission suggest that the response to cetuximab may be associated with an acne-like rash. Post hoc analyses of pooled data from the two studies in which patients received cetuximab combined with irinotecan (combined total of\xa0339 patients) show 153 patients had stable disease at 6\xa0weeks, of whom 50% had an acne-like rash of grade 2 or above (n\xa0=\xa076). Of these, 26% (n\xa0=\xa020) went on to have a partial response compared with 13% (n\xa0=\xa010) of those without an acne-like rash of grade 2 or above (p\xa0=\xa00.043).\n\nData from the RCT show that patients in the cetuximab plus irinotecan arm with an acne-like rash of grade 2 or above had an overall survival of 10.8\xa0months compared with 5.8\xa0months for those with either no rash or a grade 1 rash. In the single-arm study of cetuximab plus irinotecan, patients who had a grade 3 acne-like rash had a median survival of 13.1\xa0months, compared with 10.6\xa0months for those with a grade 2 rash, 6.2\xa0months for those with a grade 1 rash and 4.3\xa0months for those with no rash (p\xa0=\xa00.0008, grade 0 vs grade 1−3).\n\nIn the RCT the incidence of some adverse events was higher in patients receiving cetuximab plus irinotecan compared with those receiving cetuximab alone: grade 3 and 4 adverse events (65.1% vs 43.5%); diarrhoea (21.2% vs 1.7%); neutropenia (9.4% vs 0%); grade 3 or 4 acne-like rash (9.4% vs 5.2%).\n\n# Cost effectiveness\n\nNo published economic analyses of either bevacizumab or cetuximab were identified. The manufacturers of bevacizumab and cetuximab both submitted cost-effectiveness models, and the assessment group developed two models for each drug.\n\n## Bevacizumab – manufacturer's models\n\nThe manufacturer submitted two simple-state transition models with three health states: pre-progression, post-progression and death. Each model was based on data from a different bevacizumab study. The first was based on the study that compared bevacizumab plus IFL with IFL, while the second was based on the larger of the two studies that compared bevacizumab plus 5-FU/LV with 5-FU/LV. In both models the analysis was carried out from the perspective of the NHS. Data on progression-free survival for the treatment and control arms were taken from trial data, and an equal risk of death was applied following progression irrespective of treatment group. The models assumed equivalent utility scores for both the intervention and control groups, with a utility of 0.80 given to the pre-progression health state and 0.50 to the post-progression health state. Utility decrements associated with adverse events were not included. Pre-progression costs were calculated from the trials, augmented with data from other published sources. For post-progression costs an assumption of £2000 a month was used, applied equally to both arms.\n\nWith discounting of 6% for costs and 1.5% for benefits, the cost per quality-adjusted life year (QALY) gained was £88,364 for bevacizumab combined with IFL compared with IFL alone. With the same discounts, the cost per QALY gained for bevacizumab combined with 5-FU/LV was £56,628 compared with 5-FU/LV alone. One-way sensitivity analyses resulted in estimates of cost per QALY gained of between £82,577 and £106,770 for bevacizumab combined with IFL, and between £39,136 and £69,439 for bevacizumab combined with 5-FU/LV. Probabilistic sensitivity analyses suggest that the likelihood of cost effectiveness at a willingness-to-pay of £30,000 per QALY is 0.16 for bevacizumab combined with IFL, and 0.24 for bevacizumab combined with 5-FU/LV.\n\n## Bevacizumab – assessment group models\n\nThe methods used for the models produced by the assessment group were similar to those used in the NICE appraisal of irinotecan, oxaliplatin and raltitrexed (NICE technology appraisal 93). The assessment group presented two models based on the same trials as used in the manufacturer's models. The models were simple-state transition models with costs and effects calculated from the perspective of the NHS. Unlike the manufacturer's models the outcome data were based on published overall survival curves from the two studies. The utility value for pre-progression was the same as was used in the manufacturer's models (0.80), whereas that for post-progression was slightly higher (0.60). Data on second-line and subsequent therapies were taken from a study that investigated the optimal sequence of FOLFOX and FOLFIRI as first- and second-line therapies, and were applied equally to treatment and control groups. Costs were calculated from study data and augmented from a range of sources including published literature and personal communications. Discounting was not used because the distribution of costs incurred over time was unknown and was not considered relevant by the assessment group because of the short time horizon in the model.\n\nThe base-case costs per QALY gained for the assessment group models were £62,857 for bevacizumab combined with IFL and £88,436 for bevacizumab combined with 5-FU/LV, compared with IFL or 5-FU/LV alone, respectively. One-way sensitivity analyses of the base case produced a cost per QALY gained of £60,430–£76,831 for bevacizumab combined with IFL, and £51,355 and higher for bevacizumab combined with 5-FU/LV. Probabilistic sensitivity analyses suggest that, with a willingness-to-pay threshold of £30,000, the likelihood of bevacizumab being cost effective is zero.\n\nThe differences in the cost per QALY gained between the assessment group's model and the manufacturer's model are likely to have been caused by the difference in the methods used to calculate survival. The manufacturer's model resulted in more favourable estimates of the cost per QALY than did the assessment group's model when the comparator was 5‑FU/LV because the difference in progression-free survival was greater than the difference in mean overall survival. Conversely, the assessment group's model resulted in more favourable cost per QALY estimates when the comparator was IFL, because the difference in overall survival was greater than the difference in progression-free survival.\n\n## Cetuximab – manufacturer's model\n\nThe manufacturer's model for cetuximab used survival modelling to estimate the lifetime costs and benefits for patients receiving cetuximab combined with irinotecan compared with ASC/BSC. Two sets of analyses were presented. The first was based directly on survival data from the RCT, whereas in the second analysis adjustments were made to the survival data to reflect a proposed continuation rule. Under the continuation rule patients would only continue to receive cetuximab beyond 6 weeks if there were either a partial or complete tumour response or an acne-like rash of grade 2 or above.\n\nThe duration of survival of patients receiving cetuximab combined with irinotecan was extrapolated from data in the RCT. The survival of patients receiving ASC/BSC was calculated from the survival of the patients in the cetuximab monotherapy arm of the RCT. The data from the monotherapy arm were adjusted to remove the impact of cetuximab using an HR taken from an RCT of second-line irinotecan compared with ASC/BSC. Therefore the model assumes that the relative hazard of overall survival between cetuximab monotherapy and ASC/BSC as second-line and subsequent treatment is exactly equivalent to the relative survival hazard between irinotecan and ASC/BSC as second-line treatment. The modelling was carried out from the perspective of the NHS, with costs and resource data taken from the RCT comparing cetuximab monotherapy with cetuximab plus irinotecan and augmented from the published literature. Outcomes were presented as life years gained, with sensitivity analyses to examine the impact of quality of life using alternative utilities for metastatic colorectal cancer of 0.95 and 0.71, both constant over the lifetime and based on published data. Additional data were presented using a utility of 0.73, constant over the lifetime, based on data collected as part of a single-arm study that investigated the effectiveness of cetuximab as a second- and subsequent-line treatment for patients with metastatic colorectal cancer (MABEL). Costs and benefits were discounted at an annual rate of 3.5%.\n\nThe base-case analysis suggests a cost per life year gained of £33,263 if the continuation rule were applied. One-way sensitivity analyses with the application of the continuation rule result in cost per QALY estimates of £35,014 with a utility value of 0.95 and £45,566 with a utility value of 0.73. Without the continuation rule, cost per QALY estimates are £45,237 and £58,870 respectively. Cost-effectiveness acceptability curves suggest that at a willingness-to-pay threshold of £30,000 per life year gained the likelihood of cost effectiveness is 0.10.\n\n## Cetuximab assessment group models\n\nIn the absence of direct comparisons of cetuximab plus irinotecan with ASC/BSC or FOLFOX, the assessment group developed two models. The first was a threshold analysis considering the incremental benefit that cetuximab combined with irinotecan would have to provide over ASC/BSC in order to be considered cost effective. The second model was an indirect comparison of data from the arm receiving cetuximab and irinotecan in the RCT with data from other published studies of second-line ASC/BSC.\n\nIn both models overall survival for patients receiving cetuximab was estimated from patient-level data in the RCT. In the threshold analysis, the survival of patients receiving ASC/BSC was held as an unknown variable, whereas in the indirect comparisons different values for overall survival, ranging from 6 to 9\xa0months, were taken from three published studies. Health-related quality of life was estimated in the same way as in the bevacizumab model, applying a utility of 0.80 to pre-progression disease states and 0.60 to post-progression states. For the cetuximab arm, measures of the duration of pre-progression survival as a proportion of overall survival were estimated using data from the RCT. For the comparator arm, they were derived from a trial that compared tipifarnib (a farnesyl transferase inhibitor) with BSC in refractory advanced colorectal cancer. In this study the duration of pre-progression survival was approximately 37% of overall survival. Resource use and costs were taken from the RCT as reported in the manufacturer's submission and augmented from the published literature and personal communication with clinical experts. Discounting was not used in the model because the distribution of costs incurred over time was unknown and was not considered relevant by the assessment group because of the short time horizon in the model.\n\nThe base-case threshold analysis suggests it is not possible for cetuximab combined with irinotecan to have a cost per QALY gained of less than £20,000, irrespective of the application of the continuation rule. When the proposed continuation rule is applied, cetuximab plus irinotecan must provide 0.65 additional life years (7.8\xa0months) compared with ASC/BSC in order to achieve a cost per QALY gained of £30,000. This would imply that survival for patients receiving ASC/BSC would have to be 0.14 life years (1.7\xa0months) or less. It was not possible to achieve a cost per QALY gained of less than £30,000 without the continuation rule. A sensitivity analysis using utility values from the MABEL study suggested that with the continuation rule applied cetuximab plus irinotecan must provide 0.60 additional life years (7.2\xa0months) compared with ASC/BSC in order to achieve a cost per QALY gained of £30,000. Indirect comparisons are associated with a high level of uncertainty, but they yielded estimates of the cost per QALY gained that ranged from £77,210 to £370,044.\n\n# Consideration of the evidence\n\nThe Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab and cetuximab for metastatic colorectal cancer, having considered evidence on the nature of the condition and the value placed on the benefits of bevacizumab and cetuximab by people with metastatic colorectal cancer, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee heard from clinical specialists that it is accepted that multiple chemotherapy treatments lead to incremental gains in survival if patients are sufficiently fit to receive therapy. The Committee further heard from clinical specialists that treatment regimens frequently involve combination therapy of 5-FU/FA either with irinotecan or with oxaliplatin as first-line therapies, followed, where patients are sufficiently fit, by irinotecan as a second-line therapy where oxaliplatin has been given and by oxaliplatin plus 5-FU/FA as a second-line therapy where irinotecan has been given. The experts suggested that it would be of merit to add further options and lines of therapy to this sequence.\n\n## Bevacizumab\n\nThe Committee reviewed the clinical effectiveness evidence from the bevacizumab studies and noted that the age of the population in the largest study was lower than the age of patients normally receiving chemotherapy in England and Wales. However, clinical specialists agreed that fitness, rather than age, is the primary factor when considering whether chemotherapy is appropriate. The Committee therefore agreed that the patients included in the bevacizumab trials could be considered to reflect a population of relatively fit patients with metastatic colorectal cancer in England and Wales.\n\nThe Committee noted that all bevacizumab studies demonstrated statistically significant gains in progression-free survival and that some studies also demonstrated statistically significant gains in overall survival and tumour response rate. However, the Committee noted that the comparators in the studies cannot be considered current standard practice in the NHS in England and Wales because the 5-FU treatment schedules involved administration by bolus rather than administration by infusion. It heard from clinical specialists that the benefits associated with bevacizumab in combination with bolus 5-FU are expected to be seen in infusional regimens because the two drugs have different mechanisms of action and their effects are therefore likely to be independent. This was also said to be supported by interim results from ongoing clinical studies. The Committee was therefore persuaded that the results seen in the studies could be considered generalisable to NHS practice in England and Wales.\n\nThe Committee then considered the estimates of cost effectiveness of bevacizumab. It noted that the models from the manufacturer and from the assessment group were similar in their methods and data sources; the models differed chiefly in their use of progression-free survival and overall survival, respectively, as the primary outcome data. The Committee noted that this difference resulted in different estimates of cost effectiveness from the manufacturer and the assessment group. However, the Committee considered that neither source resulted in a cost-effectiveness estimate that was compatible with the best use of NHS resources. The Committee noted that a proposal from the manufacturer for a registry programme could not be taken into further consideration because the Committee had been informed of imminent additional license extensions for bevacizumab, which would need to be taken into account of in any such scheme. It concluded that bevacizumab in combination with 5-FU/FA, with or without irinotecan as a first-line treatment for metastatic colorectal cancer would not be a cost-effective use of NHS resources.\n\n## Cetuximab\n\nThe Committee considered the clinical effectiveness evidence from the cetuximab studies. The Committee understood that cetuximab plus irinotecan could be given in its current licensed indication either as a second-line treatment following failure of an irinotecan-containing regimen or as a subsequent-line treatment following failure of both irinotecan- and oxaliplatin-containing regimens. The Committee recognised that in both cases, some patients may still have a high performance status, meaning that further chemotherapy regimens could be considered appropriate.\n\nThe Committee was concerned that there were no studies that compared cetuximab with current standard care either in second- or subsequent-line therapy, or with any therapy not including cetuximab. The Committee noted that there were currently no clinical studies available comparing cetuximab with FOLFOX, and therefore the relative clinical effectiveness of cetuximab as a second-line treatment could not as yet be determined. The Committee heard testimonies from clinical specialists that subsequent to second-line treatment progression-free survival and tumour response would be negligible if further active treatment was not available. Therefore the results seen in the single-arm cetuximab studies for these outcomes could be interpreted as an effect of the drug. It also heard that clinical specialists believed that cetuximab, in this situation, where no other active treatment was available, could prolong survival for a number of months if the disease responded to the drug. The Committee was therefore persuaded that cetuximab in this situation demonstrated some evidence of effectiveness. However, the relative effectiveness against current standard care remains uncertain.\n\nThe Committee heard from patient experts and clinical specialists about the impact of the acne-like rash associated with treatment on patients' quality of life. They heard from patient experts that, for some patients, the side effects of the drugs were tolerated willingly because of the perceived benefit, whereas for others the side-effect profile may be more of a consideration. The Committee heard from clinical specialists that the acne-like rash was generally well managed with antibiotics, treatment breaks or dose reduction. The Committee was therefore satisfied that the side-effect profile of cetuximab should not be a determining factor in its deliberations.\n\nThe Committee noted the contradiction that although the UK marketing authorisation stipulates that patients need to be tested for the presence of EGFR, a positive test for the presence of EGFR did not predict response to treatment. The Committee heard from clinical specialists that there is increasing knowledge of the mechanism of action of cetuximab and that it is now thought that the antibody identified through EGFR testing is different from the one targeted by cetuximab. The Committee noted the difficulties in identifying patients who were likely to respond to cetuximab, but was fully aware that decisions about its use in the NHS would have to be based on the current marketing authorisation.\n\nThe Committee considered the continuation rule proposed by the manufacturer. The Committee expressed concern about conflicts with the SPC, but it agreed that this would only be an issue for the small proportion of patients who experience grade 3 and 4 acne rash. Although it acknowledged that there was some evidence to suggest that the presence of a rash may predict response to cetuximab, the Committee had reservations about using it to decide whether to continue or discontinue treatment because no studies have so far tested prospectively this continuation rule.\n\nThe Committee considered the cost-effectiveness evidence for cetuximab. It noted that the economic modelling from both the manufacturer and the assessment group had been completed using effectiveness data from the RCT of cetuximab where approximately 80% of patients received cetuximab plus irinotecan as a third-line or subsequent therapy. It was also aware that the comparator used in both models was ASC/BSC, which meant the modelled scenario and corresponding estimates of cost effectiveness more closely resembled third-line or subsequent use of cetuximab rather than second-line use.\n\nThe Committee discussed the uncertainties around the estimates of utility for patients with metastatic colorectal cancer. The manufacturer had provided estimates between 0.95 and 0.71, both constant over the lifetime of the patient. The Committee considered that the utility for a patient with metastatic colorectal cancer was more likely to reflect the lower end of this range, based on additional data submitted by the manufacturer from the MABEL study. The Committee concluded that, using the most realistic utility estimates, the cost-effectiveness estimates provided by both the manufacturer and the assessment group were not compatible with the best use of NHS resources. The Committee also noted that these estimates were associated with a high level of uncertainty because they were based on indirect comparisons.\n\nThe Committee therefore considered threshold analyses completed by the assessment group, where the survival in the comparator arm was held as unknown. The base-case threshold analysis suggested that, with the application of the continuation rule, a cost per QALY gained of £30,000 could only be achieved if survival with ASC/BSC is less than 2\xa0months. A sensitivity analysis adjusting the assumptions to reflect utility values from the MABEL study did not materially alter the results. The Committee noted that the manufacturer had provided an estimate of mean survival of 5.6\xa0months for patients receiving ASC/BSC in their economic model, while studies of ASC/BSC identified in the assessment report provided estimates of median survival ranging from 6 to 9 months. The Committee therefore considered that an estimate of mean survival while receiving ASC/BSC of approximately 2\xa0months was an unrealistic underestimate. Considering all the available evidence on clinical and cost effectiveness, the Committee therefore concluded that cetuximab, either as a second-line or a subsequent-line treatment for metastatic colorectal cancer would not be a cost-effective use of NHS resources.", 'Recommendations for further research': 'The Committee noted the following ongoing clinical trials related to this guidance.\n\nNCT00063141 is an RCT comparing cetuximab combined with irinotecan with irinotecan alone as second-line treatment in patients with metastatic colorectal cancer.\n\nNCT00079066 is an RCT comparing cetuximab combined with best supportive care with best supportive care alone in patients with metastatic colorectal cancer.\n\nThe Committee was aware of other ongoing clinical trials with bevacizumab and cetuximab as part of different treatment regimens.\n\nThe TREE-2 trial is a randomised multicentre study comparing three regimens of oxaliplatin plus bolus, infusional or oral 5-FU with bevacizumab to evaluate safety and tolerability in the first-line treatment of patients with advanced colorectal cancer.\n\nThe NO16966C trial is a randomised phase III study of intermittent oral capecitabine in combination with intravenous oxaliplatin (CAPOX) with or without bevacizumab for the first-line treatment of patients with advanced colorectal cancer.\n\nThe CONcePT trial aims to develop an optimised schedule of administration of FOLFOX plus bevacizumab in the first-line treatment of patients with advanced colorectal cancer.\n\nThe E3200 trial is a phase III RCT of oxaliplatin, 5-FU and leucovorin with or without bevacizumab, versus bevacizumab alone in patients previously treated for advanced or metastatic colorectal cancer. Preliminary data have been presented. The bevacizumab monotherapy arm was prematurely halted because of lack of efficacy.\n\nThe first-line use of cetuximab in combination with standard chemotherapy regimens is being investigated in a number of studies. One example is the COIN study (NCT00182715), which aims to determine whether the addition of cetuximab to continuous oxaliplatin and 5-FU improves overall survival when compared with either continuous oxaliplatin and 5-FU on its own, or intermittent oxaliplatin and fluoropyrimidine chemotherapy. Other examples include NCT00145314 (5-FU/FA + oxaliplatin), NCT00286130 (FOLFIRI, FOLFOX) and NCT00215722 (capecitabine and oxaliplatin).\n\nEXPLORE is an RCT comparing cetuximab combined with FOLFOX with FOLFOX alone as second-line treatment in patients with metastatic colorectal cancer. Recruitment to the trial was halted prematurely when the number of participants reached 102. Preliminary results were presented at the annual conference of the American Society for Clinical Oncology in 2005 for progression-free survival and response rate.\n\nThe Committee recommends research to investigate the predictive value of EGFR testing and the correlation of baseline and on-treatment markers with tumour response and survival.\n\nAdditionally, the Committee recommends studies to investigate the impact of bevacizumab and cetuximab treatment on health-related quality of life.', 'Related guidance': 'NICE has issued the following related guidance.\n\nIrinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer. NICE technology appraisal guidance 93 (2005).[Replaced by NICE clinical guideline 131]\n\nImproving outcomes in colorectal cancers: manual update. NICE cancer service guidance (2004).\n\nGuidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer. NICE technology appraisal guidance 61 (2003).', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.\n\nThe guidance on this technology was considered for review in January 2010. Details are on the NICE website.\n\nAndrew DillonChief ExecutiveJanuary 2007', 'Changes after publication': 'March 2014: minor maintenance\n\nMarch 2012: minor maintenance\n\nJanuary 2012: This guidance has been partially updated by NICE technology appraisal guidance 242 (TA242) Cetuximab (monotherapy or combination chemotherapy), bevacizumab (in combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology appraisal 150 and part review of technology appraisal guidance 118). See the guidance for more information.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nThe recommendations from this guideline have been incorporated into a NICE Pathway. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence [YEAR]. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta118
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Evidence-based recommendations on bevacizumab (Avastin) and cetuximab (Erbitux) for treating metastatic colorectal cancer in adults.
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9e7e7179c39e0ea4c79a660e9dd81f5e43c37f35
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nice
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Epiretinal brachytherapy for wet age-related macular degeneration
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Epiretinal brachytherapy for wet age-related macular degeneration
# Guidance
Current evidence on the efficacy of epiretinal brachytherapy for wet age-related macular degeneration (AMD) is inadequate and limited to small numbers of patients. With regard to safety, vitrectomy has well-recognised complications and there is a possibility of subsequent radiation retinopathy. Therefore this procedure should only be used in the context of research. Research studies should address whether epiretinal brachytherapy reduces the progression of wet AMD and whether it can reduce the number of injections of antivascular endothelial growth factor agents (anti-VEGF) required. Long-term outcomes should be reported.# The procedure
# Indications and current treatments
AMD is the most common cause of blindness in developed countries. A proportion of patients with AMD have wet AMD. Wet AMD is characterised by the abnormal growth of blood vessels in the choroid layer underneath the macular part of the retina. These vessels can threaten vision if they leak and cause scarring.
Current treatments for wet AMD include laser photocoagulation, photodynamic therapy and intravitreal injections of anti-VEGFs. Patients with advanced disease may benefit from optical aids such as magnifying glasses, eccentric viewing training and implantation of miniature lens systems.
# Outline of the procedure
Epiretinal brachytherapy for wet AMD aims to slow down the growth of blood vessels that cause wet AMD by administering beta radiation therapy targeted at the abnormal, leaking vessels.
The procedure is usually carried out with the patient under local anaesthesia, and is normally used in combination with an anti-VEGF agent. A vitrectomy is performed, and an intraocular epiretinal probe is placed in the vitreous cavity, over the fovea. Beta radiation is delivered by the probe. The radiation dose received by the patient is less than the dose received during a typical chest X-ray. The sclera is closed with an absorbable suture and the eye is patched. Prophylactic antibiotics and steroids are usually administered.
A number of different devices are available for this procedure.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview
# Efficacy
A case series of 34 patients treated by epiretinal brachytherapy (concomitant treatment not described) reported that 63% and 50% of patients receiving 24 Gy and 15 Gy of radiation respectively gained 1 or more letters of visual acuity at 12-month follow-up (absolute figures not given). In the same study, visual acuity improved by more than 15 letters in 21% and 0% of patients respectively (absolute figures not given).
A different case series of 34 patients treated by epiretinal brachytherapy plus anti-VEGF injections reported a gain of 8.9 letters in best-corrected visual acuity after the procedure; 38% (13/34) of patients demonstrated a clinically significant improvement of 3 lines or more at a median follow-up of 12 months. At 36-month follow-up, the mean change in visual acuity was a gain of 3.9 letters (n = 19); 21% (4/19) of patients had gained 15 letters or more.
The Specialist Advisers listed key efficacy outcomes as retention of visual acuity, number of anti-VEGF injections required, and time to recurrence of AMD.
# Safety
The case series of 34 patients treated by epiretinal brachytherapy plus anti-VEGF injections reported that 25% (6/24), 50% (12/24) and 54% (7/13) of phakic eye patients developed cataracts at follow-up periods of 12, 24 and 36 months.
The case series of 34 patients treated by epiretinal brachytherapy alone reported that there were no radiation-induced toxicity adverse events at 12-month follow-up. The other case series of 34 patients, treated by epiretinal brachytherapy plus intravitreal VEGF therapy, reported non-proliferative radiation retinopathy in 1 patient at 36-month follow-up. These changes were not considered to have an adverse effect on visual acuity.
Retinal tear was reported in 6% (2/34) and 3% (1/34) of patients in the 2 case series.
The case series of 34 patients treated by epiretinal brachytherapy plus anti-VEGF injections reported raised intraocular pressure in 6% (2/34) of patients (follow-up not stated).
The Specialist Advisers listed anecdotal or reported adverse events as cataract formation, retinal haemorrhage, retinal detachment, infective endopthalmitis, and radiation retinopathy. They considered theoretical adverse events to include radiation optic neuropathy and radiation-induced malignancy.
# Other comments
The Committee noted that a number of controlled clinical trials are currently in progress.# Further information
For related NICE guidance see www.nice.org.uk
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedures guidance process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Changes after publicationMay 2012: minor maintenance
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICENational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BTwww.nice.org.uknice@nice.org.uk0845 033 7780
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{'Guidance': 'Current evidence on the efficacy of epiretinal brachytherapy for wet age-related macular degeneration (AMD) is inadequate and limited to small numbers of patients. With regard to safety, vitrectomy has well-recognised complications and there is a possibility of subsequent radiation retinopathy. Therefore this procedure should only be used in the context of research. Research studies should address whether epiretinal brachytherapy reduces the progression of wet AMD and whether it can reduce the number of injections of antivascular endothelial growth factor agents (anti-VEGF) required. Long-term outcomes should be reported.', 'The procedure': '# Indications and current treatments\n\nAMD is the most common cause of blindness in developed countries. A proportion of patients with AMD have wet AMD. Wet AMD is characterised by the abnormal growth of blood vessels in the choroid layer underneath the macular part of the retina. These vessels can threaten vision if they leak and cause scarring.\n\nCurrent treatments for wet AMD include laser photocoagulation, photodynamic therapy and intravitreal injections of anti-VEGFs. Patients with advanced disease may benefit from optical aids such as magnifying glasses, eccentric viewing training and implantation of miniature lens systems.\n\n# Outline of the procedure\n\nEpiretinal brachytherapy for wet AMD aims to slow down the growth of blood vessels that cause wet AMD by administering beta radiation therapy targeted at the abnormal, leaking vessels.\n\nThe procedure is usually carried out with the patient under local anaesthesia, and is normally used in combination with an anti-VEGF agent. A vitrectomy is performed, and an intraocular epiretinal probe is placed in the vitreous cavity, over the fovea. Beta radiation is delivered by the probe. The radiation dose received by the patient is less than the dose received during a typical chest X-ray. The sclera is closed with an absorbable suture and the eye is patched. Prophylactic antibiotics and steroids are usually administered.\n\nA number of different devices are available for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview\n\n# Efficacy\n\nA case series of 34 patients treated by epiretinal brachytherapy (concomitant treatment not described) reported that 63% and 50% of patients receiving 24\xa0Gy and 15 Gy of radiation respectively gained 1 or more letters of visual acuity at 12-month follow-up (absolute figures not given). In the same study, visual acuity improved by more than 15 letters in 21% and 0% of patients respectively (absolute figures not given).\n\nA different case series of 34 patients treated by epiretinal brachytherapy plus anti-VEGF injections reported a gain of 8.9 letters in best-corrected visual acuity after the procedure; 38% (13/34) of patients demonstrated a clinically significant improvement of 3 lines or more at a median follow-up of 12\xa0months. At 36-month follow-up, the mean change in visual acuity was a gain of 3.9 letters (n\xa0=\xa019); 21% (4/19) of patients had gained 15 letters or more.\n\nThe Specialist Advisers listed key efficacy outcomes as retention of visual acuity, number of anti-VEGF injections required, and time to recurrence of AMD.\n\n# Safety\n\nThe case series of 34 patients treated by epiretinal brachytherapy plus anti-VEGF injections reported that 25% (6/24), 50% (12/24) and 54% (7/13) of phakic eye patients developed cataracts at follow-up periods of 12, 24 and 36\xa0months.\n\nThe case series of 34 patients treated by epiretinal brachytherapy alone reported that there were no radiation-induced toxicity adverse events at 12-month follow-up. The other case series of 34 patients, treated by epiretinal brachytherapy plus intravitreal VEGF therapy, reported non-proliferative radiation retinopathy in 1 patient at 36-month follow-up. These changes were not considered to have an adverse effect on visual acuity.\n\nRetinal tear was reported in 6% (2/34) and 3% (1/34) of patients in the 2 case series.\n\nThe case series of 34 patients treated by epiretinal brachytherapy plus anti-VEGF injections reported raised intraocular pressure in 6% (2/34) of patients (follow-up not stated).\n\nThe Specialist Advisers listed anecdotal or reported adverse events as cataract formation, retinal haemorrhage, retinal detachment, infective endopthalmitis, and radiation retinopathy. They considered theoretical adverse events to include radiation optic neuropathy and radiation-induced malignancy.\n\n# Other comments\n\nThe Committee noted that a number of controlled clinical trials are currently in progress.', 'Further information': "For related NICE guidance see www.nice.org.uk\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges after publicationMay 2012: minor maintenance\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICENational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BTwww.nice.org.uknice@nice.org.uk0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg415
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Tocilizumab for the treatment of systemic juvenile idiopathic arthritis
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Tocilizumab for the treatment of systemic juvenile idiopathic arthritis
Evidence-based recommendations on tocilizumab (RoActemra), for treating systemic juvenile idiopathic arthritis in people aged 2 and over.
# Guidance
Tocilizumab is recommended for the treatment of systemic juvenile idiopathic arthritis in children and young people aged 2 years and older whose disease has responded inadequately to non-steroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids and methotrexate if the manufacturer makes tocilizumab available with the discount agreed as part of the patient access scheme.
Tocilizumab is not recommended for the treatment of systemic juvenile idiopathic arthritis in children and young people aged 2 years and older whose disease continues to respond to methotrexate or who have not been treated with methotrexate.
Children and young people currently receiving tocilizumab for the treatment of systemic juvenile idiopathic arthritis who do not meet the criteria in 1.1 should have the option to continue treatment until it is considered appropriate to stop. This decision should be made jointly by the clinicians, and the child or young person and/or their parents or carers.# The technology
Tocilizumab (RoActemra, Roche Products) is a humanised monoclonal antibody that inhibits the cytokine interleukin-6 (IL-6). Reducing the activity of IL-6 can reduce inflammation in the joints, prevent long-term damage, and improve quality of life and function. Tocilizumab has a marketing authorisation for the treatment of active systemic juvenile idiopathic arthritis (JIA) 'in patients aged 2 years of age and older, who have responded inadequately to previous therapy with NSAIDs and systemic corticosteroids'. Tocilizumab can be given as monotherapy (in patients intolerant to methotrexate or if treatment with methotrexate is inappropriate) or in combination with methotrexate.
Upper respiratory tract infection, with typical symptoms such as cough, blocked nose, runny nose, sore throat and headache, is one of the most common side effects of tocilizumab. Other reported side effects include rash, urticaria, diarrhoea, epigastric discomfort and arthralgia. Infusion-related reactions that can be considered serious and life-threatening (such as angioedema) have also been reported. For full details of side effects and contraindications, see the summary of product characteristics.
Tocilizumab is administered as an intravenous infusion over 1 hour and treatment is repeated at 2-week intervals. The recommended dose is 8 mg/kg in patients weighing 30 kg or more, and 12 mg/kg in patients weighing less than 30 kg. The dose should be calculated based on the patient's body weight at each administration. A change in dose should only be based on a consistent change in the patient's body weight over time. The cost of 80 mg in a 4 ml vial is £102.40 (excluding VAT; 'British national formulary' edition 61). The average cost of treatment is £7987.20 per year for a 30 kg patient and £9984 per year for a 25 kg patient, assuming no wastage. The manufacturer of tocilizumab (Roche Products) has agreed a patient access scheme with the Department of Health which makes tocilizumab available with a discount applied to all invoices. The level of the discount is commercial-in-confidence (for further details see section 5.2). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this NICE technology appraisal guidance is published.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of tocilizumab and a review of this submission by the Evidence Review Group (ERG; appendix B).
The manufacturer submitted evidence for the two populations defined in the decision problem: population 1 – children and young people aged 2 years and older with systemic JIA that has not responded adequately to prior NSAIDs and systemic corticosteroids; and population 2 – children and young people aged 2 years and older with systemic JIA that has not responded adequately to prior NSAIDs, systemic corticosteroids and methotrexate. For population 1 the manufacturer compared tocilizumab with methotrexate. For population 2 the manufacturer carried out indirect comparisons of tocilizumab with tumour necrosis factor-alpha (TNF-alpha) inhibitors and anakinra.
In the manufacturer's submission, evidence of clinical effectiveness was based on one randomised controlled trial (TENDER). The TENDER trial is an ongoing three-part, 5-year, phase III study. Part one consisted of a 12-week international multicentre randomised double-blind placebo-controlled parallel two-group study to evaluate the efficacy and safety of tocilizumab in children with active systemic JIA. Part two is a 92-week single-group open-label extension and part three is a 3-year single-group open-label continuation of the study. The manufacturer stated that based on the inclusion criteria of the TENDER trial, all participants matched population 1 in the scope. The manufacturer also stated that 95% of TENDER trial participants who were either treated with methotrexate or had had methotrexate in the past matched population 2 in the scope because it was these participants whose disease could be regarded as having responded inadequately to methotrexate. Patients were included in the study if they had symptoms of active disease and the manufacturer stated that 'it follows that if patients have tried in the past or are currently administered methotrexate and continue to have persistent disease then they are inadequate responders'. An inadequate response to methotrexate was defined as patients being on a standard dose of methotrexate for a period of 3 months and still showing symptoms of active systemic JIA at baseline.
TENDER enrolled 112 participants (from 17 countries, including the UK) who were randomised 2:1 to tocilizumab (n = 75) or placebo (n = 37). Tocilizumab was administered every 2 weeks at a dose of 8 mg/kg for participants who weighed at least 30 kg (n = 37) and 12 mg/kg for those who weighed less than 30 kg (n = 38). Ages of patients in the trial ranged from 2 to 17 years, with an average age of 10 years. Patients had to have documented persistent disease activity (at least five active joints, or at least two active joints with fever above 38°C for any 5 out of 14 days of screening) for at least 6 months, and an inadequate response to NSAIDs and corticosteroids because of toxicity or lack of efficacy. An inadequate response to previous treatment was determined by the treating physician's clinical assessment. Before study entry, 78 out of 112 patients (70%) had been treated with methotrexate (36 entered the study on methotrexate that had been previously stopped then restarted; 42 were on their first course of methotrexate, which was ongoing). Approximately 26% (29) of patients were not on methotrexate at baseline but had received and stopped methotrexate previously. Five patients (approximately 5%) had never received methotrexate, and were considered methotrexate naive. Patients taking NSAIDs, corticosteroids and methotrexate were permitted to take part but had to enter the study on a stable dose of the medicines.
The primary outcome measures were the proportion of patients who had a JIA American College of Rheumatology (ACR) 30 response at 12 weeks and absence of fever (defined as no recorded temperature of 37.5°C or above in the preceding 7 days). A JIA ACR30 response is defined as an improvement of at least 30% from the baseline assessments in any three of six core outcome variables, with no more than one of the remaining variables deteriorating by more than 30%. The JIA core outcome variables are: physician global assessment of disease activity (100 mm visual analogue scale ); parent or patient global assessment of overall well-being (100 mm VAS); number of joints with active arthritis; number of joints with limitation of movement; erythrocyte sedimentation rate; and functional ability (using the Childhood Health Assessment Questionnaire , which measures eight everyday functional activities).
The secondary outcomes were: individual results for each JIA ACR core outcome variable at 12 weeks; JIA ACR 50/70/90 responses at 12 weeks (that is, an improvement of at least 50%, 70% or 90% respectively from the baseline assessments in any three of the six core outcome variables, and no more than one of the remaining variables worsening by more than 50%, 70% or 90%); corticosteroid reduction; fever; rash; pain; and laboratory outcomes (C-reactive protein ) levels, anaemia and haemoglobin levels, thrombocytosis and leucocytosis).
Efficacy endpoints were analysed using the intention-to-treat population. All patients were classified as either responders or non-responders. Patients who 'escaped' (patients whose disease did not respond to treatment who switched to an alternative treatment for the disease) or withdrew were classed as non-responders. There was an 'early escape' option to allow children with more severe disease at baseline an opportunity to escape and receive active open-label tocilizumab. Of the 112 patients enrolled, 21 received escape therapy, with 20 of those patients being initially randomised to the placebo arm. The main reasons for escape were fever for at least 3 consecutive days or a JIA ACR30 flare (a worsening of symptoms).
The results of the TENDER trial showed that for its primary endpoint (a JIA ACR30 response and absence of fever at week 12), 85.3% of the tocilizumab patients were classed as responders compared with 24.3% of the placebo patients, a statistically significant difference (p < 0.0001). Patients given tocilizumab had a greater chance of achieving JIA ACR30/50/70/90 responses at week 12 in comparison with the placebo patients. The differences in the proportions of tocilizumab patients and placebo patients at each JIA ACR response level were statistically significant (p < 0.0001). The proportion of responders showing an ACR30 response was higher in patients receiving tocilizumab 12 mg/kg (97.4%) compared with those receiving tocilizumab 8 mg/kg (83.8%). The efficacy of tocilizumab with respect to individual ACR core outcome variables was analysed as part of the secondary efficacy analyses; these results are marked by the manufacturer of tocilizumab as academic in confidence and therefore are not presented here.
The TENDER trial also included the Child Health Questionnaire (CHQ) as an instrument eliciting patient health-related quality of life. The CHQ assesses a child's physical, emotional and social wellbeing from the perspective of a parent or carer. The questionnaire was completed twice during the randomised period of the study: at baseline (visit 1) and at week 12 (visit 7).
The TENDER trial included data on adverse events. Infusion-related reactions were defined as all events occurring during or within 24 hours of an infusion. In the 12-week controlled phase, 4% of patients from the tocilizumab group experienced adverse events during infusion. One event (angioedema) was considered serious and life-threatening, and the patient stopped study treatment. In the 12-week controlled phase, 16% of patients in the tocilizumab group and 5.4% of patients in the placebo group experienced an adverse event within 24 hours of infusion. In the tocilizumab group, the adverse events included, but were not limited to, rash, urticaria, diarrhoea, epigastric discomfort, arthralgia and headache. One of these adverse events, urticaria, was considered serious. Clinically significant hypersensitivity reactions associated with tocilizumab that meant treatment was stopped were reported in 1 out of 112 patients (less than 1%) treated with tocilizumab during the controlled phase and up to and including the open-label clinical trial.
For the comparison of tocilizumab and methotrexate for population 1, the manufacturer used a post-hoc analysis to compare patients receiving tocilizumab with the 70% of patients in the placebo group who were receiving methotrexate. The manufacturer presented results that showed methotrexate had limited effect on the primary outcome in patients who were in the placebo group and those treated with tocilizumab. The manufacturer concluded that methotrexate as add-on therapy did not have a significant impact on the JIA ACR responses observed in the tocilizumab arms in the TENDER study. The manufacturer further presented results showing that the proportion of patients on tocilizumab who had an ACR30 response was 0.907, compared with 0.154 for those on methotrexate.
No head-to-head trials were available analysing the efficacy of tocilizumab compared with TNF-alpha inhibitors or anakinra for population 2. The manufacturer included data from two studies (Ruperto et al. 2007 and the ANAJIS study) in the indirect comparison analysis. The NCT00036374 trial compared the TNF-alpha inhibitor infliximab with placebo in patients with juvenile rheumatoid arthritis (systemic 16%, pauciarticular 23%, polyarticular 61%) described as having a suboptimal response to methotrexate. Participants were from North and South America and Europe, aged between 4 and 18 years, and were randomised to infliximab (62 patients) or placebo (60 patients). Patients received concomitant methotrexate alongside placebo or active treatment. The study was a randomised double-blind placebo-controlled trial, and the primary outcome was the proportion of patients who had a paediatric ACR30 response based on JIA core outcome variables at week 14.
The ANAJIS trial recruited children with systemic JIA and compared anakinra with placebo. This was a multicentre study with 24 participants (12 in each arm) aged 2–20 years, from North America and Europe. The study included patients whose systemic JIA had not responded to methotrexate or any of the disease-modifying anti-rheumatic drugs (DMARDs), and the protocol did not permit the administration of any DMARDs during the trial. The outcomes of the randomised controlled phase were reported after 1 month. The primary outcome was the paediatric ACR score, absence of fever and normalisation of CRP levels and erythrocyte sedimentation rate after 1 month.
The manufacturer undertook an indirect comparison of tocilizumab compared with anakinra. Data from the ANAJIS and the TENDER trials were used. The manufacturer used all patients in the TENDER trial, including those who were methotrexate naive, for the analysis. The relative risk for an outcome of a JIA ACR30 response for patients on tocilizumab compared with anakinra was 2.37 (95% CI 1.10 to 5.10), which was statistically significant. There were no significant differences in JIA ACR30 response and absence of fever between the anakinra and tocilizumab populations. The manufacturer also conducted an indirect comparison of tocilizumab and infliximab using the results from the NCT00036374 trial and the TENDER trial. The outcomes JIA ACR30, 50 and 70 responses were measured. Patients on tocilizumab had a statistically significantly greater chance of having these outcomes than those on infliximab. The relative risks were 2.87 (95% CI 1.49 to 5.55), 5.35 (95% CI 1.91 to 14.97) and 4.61 (95% CI 1.16 to 18.38) for JIA ACR30, 50 and 70 responses respectively.
The manufacturer used an adjustment factor derived from a study of etanercept by Prince et al. (2009). This was an observational study of 146 patients, of whom 27% had systemic JIA. The adjustment factor is the difference in the proportion of responders between the total population with JIA and the subpopulation with systemic JIA. This factor was used to correct for ACR response rates in the indirect comparison results that the manufacturer had derived from the NCT00036374 (infliximab) study (in which 16% of JIA patients had systemic JIA) and the TENDER trial. These resulting ACR response rates were assumed to represent the responses achieved with all of the TNF-alpha inhibitors.
The manufacturer originally submitted a Markov model to evaluate the cost effectiveness of tocilizumab as part of a sequence of treatments. In the tocilizumab versus methotrexate model, patients progressed to anakinra, etanercept and then adalimumab; in the tocilizumab versus anakinra model, patients progressed to etanercept, adalimumab and then abatacept.
In the manufacturer's original model the Markov chain had 22 states. The model clustered the states into five groups: four groups representing different lines of treatment and the fifth group containing death and uncontrolled disease. Each line of treatment consisted of five health states: ACR responses at the 30, 50, 70 and 90 levels and 'no ACR response'. A patient could move from a particular ACR response in a particular line only to 'no ACR response' in the next line or to death. From 'no ACR response' the patient could move only to one ACR response level within that line of treatment or to 'no ACR response' in the next line. The main assumption of the model was that there were no transitions between ACR response categories (that is, the patient could not move within a given line to a better or worse health state ). The analysis assumed that patients stayed in the same health state unless they changed treatment line. After 12 weeks of treatment, the cohort was put on the next treatment in the sequence. Only after being through all four lines did a patient move to the health state 'uncontrolled disease'. The probability of a response or non-response within a line of treatment depended on the treatment. The order in which the treatments were applied did not change these transitions. The probability of death was treatment independent and health-state independent. The probability of withdrawal was health-state independent, but was higher for methotrexate than for other treatment options (all other treatment options had the same probability as each other). All transitions stayed constant over time; that is, they were independent of age or disease duration. In each cycle, the proportion of patients in a given state was calculated. The distribution across states was used to calculate cycle-specific quality-adjusted life years (QALYs) and treatment costs, which were discounted and summed over the length of treatment. The manufacturer's original model had a time horizon of 16 years. This means that a patient in the model starting treatment aged 2 years turned 18 and could be considered an adult at the end of the simulation. The model allowed shorter and longer time durations for sensitivity analysis (up to 30 years). The discount rates applied were 3.5% for utilities and costs, and costs were considered from an NHS and personal social services perspective. A half-cycle correction was applied.
The initial CHAQ score at baseline for the cohort of patients used in the original economic model was equal to that observed in the TENDER trial. The change in the patient CHAQ score was determined by the level of ACR response after 12 weeks. Improvement in each health state as measured by relative ACR change led to an absolute change in the initial CHAQ score. For a given CHAQ score, a utility was assigned to calculate QALYs. The health-state costs varied with the health state and the treatment costs.
The data inputs for the manufacturer's original model included utility values. To derive utility values, the manufacturer had to map the CHAQ scores to utilities, using a mapping formula derived in adults with rheumatoid arthritis that mapped Health Assessment Questionnaire results onto EQ-5D utilities. The manufacturer recognised that the assumptions that CHAQ is equal to HAQ and that adult EQ-5D is equal to the health-related quality of life of a child are not evidence based, and acknowledged that this mapping method was only used for the analysis to derive QALYs for the economic model because of the lack of other available data.
Treatment costs in the original model were a composite of the cost of the medication and the cost of administering it. For some drugs, the necessary dosage depends on the body weight of the patient. The manufacturer based the unit costs on UK reference costs, literature and expert opinion. The health-state costs depended only on the ACR response level and were independent from any other health outcomes. The manufacturer stated that 'in all comparisons, the identified adverse events are of minor severity and short duration, and their management would have a minuscule cost impact'. Therefore, it can be assumed that they do not have a considerable bearing on the incremental costs of the two model arms.
In response to the preliminary recommendations in the appraisal consultation document, in which the Committee was minded not to recommend tocilizumab, the manufacturer submitted a revised cost-effectiveness Markov economic model. The economic model in the manufacturer's submission was modified such that health states are defined according to categories of CHAQ, rather than being based on ACR response categories in which an average CHAQ is applied. In the revised economic model the manufacturer adopted an approach in which CHAQ categories define health states. The health states were defined as 'controlled' 'mild', 'moderate' and 'severe'. A simulated patient distribution of CHAQ scores based on the TENDER trial was used to establish the proportion of patients that would fall into each CHAQ category at baseline. The manufacturer used ACR as a potential predictor of the CHAQ score. The manufacturer assigned the following utility values to the health states: 0.19, 0.55, 0.65 and 0.77 to 'severe', 'moderate', 'mild' and 'controlled' respectively.
In the revised economic model, incremental analyses were presented by the manufacturer that compared the sequences of tocilizumab followed by infliximab with infliximab followed by tocilizumab, and then compared tocilizumab followed by anakinra with anakinra followed by tocilizumab followed by anakinra.
When the manufacturer submitted its comments on the appraisal consultation document, it also submitted a patient access scheme, which is a discount on all invoices of tocilizumab. The manufacturer applied the discounted value of tocilizumab to the revised version of the economic model. This document only details the results for tocilizumab with the patient access scheme.
In the manufacturer's revised base-case analyses with the patient access scheme the ICER was £18,194 per QALY gained when tocilizumab followed by infliximab was compared with infliximab alone. When tocilizumab followed by anakinra was compared with anakinra alone, the ICER was £16,923 per QALY gained. The manufacturer conducted two separate incremental analyses for infliximab- and anakinra-containing sequences. In these sequences tocilizumab had been used either before or after infliximab or anakinra and compared with infliximab or anakinra alone respectively. The ICERs obtained when tocilizumab was used first followed by infliximab compared with infliximab alone was £18,194 per QALY gained. For infliximab followed by tocilizumab compared with infliximab alone, the ICER was £30,630 per QALY gained. In the anakinra-containing sequences the ICER was £16,923 per QALY gained when tocilizumab was used first followed by anakinra compared with anakinra alone. Anakinra followed by tocilizumab dominated anakinra alone.
The manufacturer also conducted a sensitivity analysis in the revised model that included:
The uncertainty around the adjustment factor derived from the etanercept study used to take account of the other juvenile idiopathic arthritis subgroups in the infliximab study. The base-case sensitivity analysis assuming an increase of the adjustment factor by 30% resulted in an ICER of £20,240 per QALY gained when the tocilizumab then infliximab strategy was compared with infliximab alone. The ICER was £16,923 per QALY gained when the tocilizumab then anakinra strategy was compared with anakinra alone. The respective ICERs when the adjustment factor was decreased by 30% were £16,407 and £16,923 per QALY gained.
A stopping rule for tocilizumab after treatment duration of 2 years. The base-case sensitivity analysis assuming treatment with tocilizumab was stopped after 2 years. This showed that the tocilizumab then infliximab strategy dominated infliximab alone, and the tocilizumab then anakinra strategy also dominated anakinra alone.
A decreased frequency of administration of tocilizumab from a 2-weekly regimen to a 4-weekly regimen after treatment duration of 6 months. The resulting ICERs for this base-case sensitivity analysis showed that the tocilizumab then infliximab strategy dominated infliximab alone, and the tocilizumab then anakinra strategy also dominated anakinra alone.
In response to the preliminary recommendations in the appraisal consultation document, in which the Committee was minded not to recommend tocilizumab, the manufacturer also submitted information on radiographic evidence of progression of joint damage for patients with systemic JIA receiving tocilizumab. The manufacturer stated that the radiographic results from the TENDER trial were not yet available but presented results from a case series (Inaba et al. ) that included seven children with a mean age of disease onset of 4.1 years and a mean age of start of treatment of 9.4 years. The mean follow-up of treatment was 56 months. There were radiographic improvements in 57% of joints, worsening in 13% and no change in 30%. The authors of this study noted limitations of the small sample size and radiographic deterioration in some joints, despite stabilisation of systemic inflammatory responses. The authors had concluded that further studies with a larger number of participants were needed. The manufacturer also presented data from a study from Japan (Kaneko et al. ), which included 46 patients with a mean age of 4 years who had systemic JIA receiving 8 mg/kg of tocilizumab every 2 weeks. The study noted that markers of systemic inflammation and numbers of tender/swollen joint counts were markedly improved following treatment with tocilizumab. However, progression of joint damage was observed in weight-bearing joints such as hip (85%) and knee (57%), along with growth disturbances and osteopenia. Radiographic progression was not seen in small joints.
In response to the preliminary recommendations in the appraisal consultation document, in which the Committee was minded not to recommend tocilizumab, the manufacturer also submitted long-term follow-up data, some of which were marked as academic in confidence and therefore are not presented here. Data from one trial in Japan (Yokota et al. ) in which 11 patients were given tocilizumab every 2 weeks and were followed up for 10–35 months showed that one patient withdrew because of duodenum perforation after 10 months. The authors suggested that this could be because of long-term steroid and NSAID use. The most serious adverse events were pneumonia in 2 patients.
The manufacturer also responded to the Committee's request for clarification on how the CHAQ responses were elicited from the 21 children in the TENDER trial under the age of 5 years. The manufacturer stated that the parents of the children filled in the CHAQ on their behalf.
The ERG noted that the TENDER trial compared tocilizumab plus standard care with placebo plus standard care. The ERG observed that the comparator in this study did not match that specified in the scope and decision problem. For population 1 (that is, children with systemic JIA that has not responded adequately to prior NSAIDs and systemic corticosteroids) the comparator in the scope is methotrexate. The manufacturer, in its submission, had used a post-hoc analysis to compare patients receiving tocilizumab with those patients in the placebo group also receiving methotrexate. The ERG noted that this was not methodologically acceptable because the trial participants were not originally randomised into those populations. In the TENDER trial, 5% of patients were methotrexate naive. The ERG considered that this population would represent population 1 in the decision problem, but the analyses were inadequate. The ERG thus considered that there was insufficient evidence for any comparison of tocilizumab with methotrexate.
For population 2 (children with systemic JIA that has not responded adequately to prior NSAIDs, corticosteroids and methotrexate) the manufacturer's original submission provided data for an indirect comparison of tocilizumab with anakinra, using data from the TENDER trial and a trial of anakinra versus placebo. The ERG considered that the 5% of participants in the TENDER trial who were methotrexate naive should be excluded from these analyses. The manufacturer's original submission only provided data for all participants in the TENDER trial. However, in response to the request for clarification, some data were provided in which methotrexate-naive patients were excluded. These data were not reported for the TENDER trial, but only for the indirect comparison with anakinra. When conducting analyses, the ERG used data for this population when possible. For the comparators, the ERG noted that the manufacturer had decided to broaden the inclusion criteria to include all subtypes of juvenile arthritis, not just systemic JIA. The manufacturer had taken this approach because of the lack of clinical evidence for systemic JIA. The ERG was concerned that this approach had been taken despite the manufacturer's clinical specialists stressing the differences between systemic JIA and other subtypes, and advising against comparing the evidence from different JIA populations.
The ERG also noted the assumption in the original economic model that patients move to a certain ACR response and stay in that state until they either withdraw (move to the next treatment line) or die. The ERG thought that, given the nature of the disease, this assumption was unlikely to be correct.
The ERG noted the lack of health-related quality-of-life data both in the TENDER trial and in the literature, and recognised that very large assumptions (such as assuming that the CHAQ score of a child is equal to the HAQ score of an adult and that adult EQ-5D is equivalent to the health-related quality of life of a child) were needed to assign a utility to each health state in the model. Because of the lack of data in the trial and the literature, the ERG considered the approach used by the manufacturer to be reasonable and acceptable.
The ERG noted the revised modelling approach taken by the manufacturer to address the requests of the Committee after the first Appraisal Committee meeting, regarding the issue of mutually exclusive health states. The ERG considered that by defining health states based on a CHAQ score, and using ACR scores to define the transitions, the revised manufacturer's model does adhere to common modelling practice. The ERG also noted the manufacturer's approach of linear extrapolation to assigning costs to health states. The ERG did not fully agree with the manufacturer that an individual patient simulation had been performed. However, the ERG was of the opinion that given the purpose of the model, it was an acceptable and practical approach to conduct further economic analyses.
The ERG questioned the cost estimates for health states in the original model as defined by expert opinion, because they present a cost for non-responders (£3300) that is more than six times higher than the cost for an ACR30 response (£500), whereas an ACR90 response is associated with only a 30% decrease in cost (to £350) compared with an ACR30 response. However, in the manufacturer's revised model the ERG considered the linear extrapolation approach to assigning costs to health states to be acceptable.
The ERG noted that the sequences of treatments had been reduced from four treatments in the original model to two treatments in the revised model. The ERG further noted that although there are significant problems in estimating the effect of treatments after first line, it would have been better to have considered all options of including up to four treatments. The ERG conducted exploratory analyses of the full incremental analyses that the manufacturer had presented with the patient access scheme. The ERG's analyses showed that infliximab followed by anakinra compared with infliximab alone resulted in an ICER of £15,819 per QALY gained. The tocilizumab then infliximab strategy compared with the infliximab then anakinra strategy produced an ICER of £22,018 per QALY gained. The tocilizumab then anakinra strategy compared with the tocilizumab then infliximab strategy resulted in an ICER of £67,714 per QALY gained.
Finally, the ERG noted that the revised economic model only allows comparison of two sequences; therefore a probabilistic sensitivity analysis could not be done across all options. The ERG also noted that the manufacturer did not provide the covariance matrix for the regression equation used to determine the correlations between coefficients. The ERG was unable to run a full probabilistic sensitivity analysis. The ERG ran the probabilistic sensitivity analysis twice, once for the infliximab then anakinra strategy compared with infliximab alone, and once for the tocilizumab then infliximab strategy compared with infliximab alone. The ERG noted in its exploratory analyses (which included the patient access scheme and the probabilistic sensitivity analysis) that the tocilizumab then infliximab strategy resulted in an ICER of £32,331 per QALY gained compared with the infliximab then anakinra strategy. The infliximab then anakinra strategy had an ICER of £22,350 per QALY gained compared with infliximab alone.
Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA238# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of tocilizumab, having considered evidence on the nature of systemic JIA and the value placed on the benefits of tocilizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee discussed the clinical pathway of care for systemic JIA. The Committee heard that there are currently no other treatments specifically licensed for systemic JIA, although it was noted that etanercept and adalimumab are licensed for polyarticular-course JIA, which would include some patients with systemic JIA. The Committee heard from the clinical specialists that in routine clinical practice in the UK, patients with systemic JIA are treated first with NSAIDs and systemic corticosteroids. If disease activity persists, or if it was severe initially, then methotrexate is used. If the child is intolerant of methotrexate or their condition does not adequately respond to an adequate trial of methotrexate, TNF-alpha inhibitors or anakinra are the next treatment options. It also heard that if there is an inadequate response to these biologicals, other treatment options include tocilizumab, steroid joint injections, high-dose intravenous immunoglobulin, oral ciclosporin, oral thalidomide, autologous stem cell rescue after marrow ablation, and cyclophosphamide.
The Committee considered the nature of the condition, and noted evidence submitted and presented by the patient experts and clinical specialists on the clinical symptoms associated with systemic JIA. The Committee heard that children with systemic JIA experience severe pain and fatigue, and considerable disability. This has a substantial impact on the child's family life, school life, and physical and emotional wellbeing. The condition also has an effect on the wider family, with siblings finding it distressing to see the child living with the condition, and parents and carers often have to stay at home and care for the child if they are unable to attend school. The Committee heard that it was extremely important to control symptoms as quickly as possible to prevent long-term disability in the child. The Committee heard that these children could be prescribed systemic corticosteroids over long periods of time. They could therefore experience increased morbidity and adverse effects that can lead to chronic conditions including infections, diabetes mellitus, cardiovascular complications and osteoporosis in later life, and risk of long-term joint damage and need for joint replacement. In addition, they may have visible side effects such as growth restriction and Cushing's syndrome. The Committee heard from the clinical specialists and patient experts how tocilizumab had made a dramatic difference to the majority of children who had been treated with it. The Committee heard from the patient expert how tocilizumab had made such a considerable difference to a child's symptoms that the child now had significantly less pain and better energy levels, could take part in everyday activities and sports, and could concentrate sufficiently to participate in school. The Committee also heard that a significant number of children taking tocilizumab had been able to reduce or completely stop using steroids and therefore the visible side effects of the corticosteroid treatment were no longer present.
The Committee heard there is variation in the use of tocilizumab in the UK, but tocilizumab is currently being used for patients whose condition does not respond to methotrexate, or following TNF-alpha inhibitors or anakinra. The Committee heard that the administration of anakinra involves daily subcutaneous injections, compared with an infusion of tocilizumab every 2 weeks. In addition, the Committee heard that, in many instances, although anakinra helps in the short term, its therapeutic effect may degrade whereas the therapeutic action of tocilizumab appeared to be sustained over time. The Committee heard that there was some concern about the unknown long-term effects of tocilizumab, especially in children whose treatment extends into adolescence or early adulthood. The Committee also heard that long-term studies would be needed to confirm that the therapeutic benefits of tocilizumab are sustained in the long term. However, the Committee heard that the magnitude of response to tocilizumab allowed some patients to stop taking the drug until they experienced a further relapse. The Committee also heard that depending on the response, there is the possibility of reducing the frequency of administration from once every 2 weeks to once every 4 weeks. The Committee heard that the peak age of onset of systemic JIA is around 18 months to 2 years, and this age group could potentially benefit most from using tocilizumab.
# Clinical effectiveness
The Committee considered the evidence for the effectiveness of tocilizumab and noted that the manufacturer derived data from the TENDER trial, part one of which was a 12-week randomised controlled trial that compared the efficacy of tocilizumab with placebo. The Committee heard from the clinical specialists that the population was largely generalisable to the UK, but that the mean age of approximately 10 years in the TENDER trial was older than the population they would treat with tocilizumab in routine clinical practice. The Committee concluded that the trial generally reflected the UK population of children with systemic JIA but agreed that the mean age in the trial was older than the population treated in the NHS.
The Committee then considered the evidence for patients whose systemic JIA had not responded to NSAIDs, systemic corticosteroids and methotrexate. The Committee noted that the manufacturer had indicated that in the TENDER trial an inadequate response to methotrexate was defined as patients still showing symptoms of active systemic JIA at baseline despite being on a standard dose of methotrexate for a period of 3 months. The Committee agreed that the 95% of patients in the TENDER trial who were either being treated with methotrexate or had previously been treated with methotrexate could be considered to have disease that had not adequately responded to methotrexate. The Committee therefore concluded that data for these patients should be considered in any comparison of tocilizumab with TNF-alpha inhibitors or anakinra.
The Committee considered the evidence presented for the two populations defined in the scope and the different views of the population definitions from the manufacturer and the ERG. For the population of patients whose systemic JIA had failed to respond to NSAIDs and systemic corticosteroids, the Committee noted that only 5% of the TENDER trial population were methotrexate naive. The Committee also noted that the manufacturer had used a post-hoc analysis to compare patients receiving tocilizumab with those patients in the placebo group receiving methotrexate and that this was not methodologically acceptable. The Committee noted that in practice some patients' systemic JIA would still be responding adequately to methotrexate but no data for these patients had been presented. The Committee therefore concluded that there was no evidence to allow them to further consider the clinical or cost effectiveness of tocilizumab compared with methotrexate.
The Committee considered the evidence on the clinical effectiveness of tocilizumab in the population who had experienced treatment failure with NSAIDs, systemic corticosteroids and methotrexate. It noted that there were statistically significant improvements in the primary efficacy endpoint (ACR30 response and no fever) and all secondary endpoints at 12 weeks. The Committee was satisfied with the results from the TENDER trial and concluded that tocilizumab was efficacious for the treatment of patients whose systemic JIA had not responded to NSAIDs, corticosteroids and methotrexate.
After requests made at the first Appraisal Committee meeting the Committee noted that radiographic data from the TENDER trial was still unavailable. It also noted that the radiographic progression data from clinical trials presented by the manufacturer were conflicting and the sample sizes of the trials were small, and therefore there was little certainty about the findings for radiographic progression. The Committee concluded that it was possible that patients receiving tocilizumab would experience a delay in the progression of joint damage.
The Committee next considered the manufacturer's indirect comparison of tocilizumab with TNF-alpha inhibitors and anakinra. The Committee noted that the manufacturer used data from the TENDER trial and the NCT00036374 trial to perform an indirect comparison between tocilizumab and infliximab, and used infliximab to represent the class effect of the TNF-alpha inhibitors. The Committee was aware that the NCT00036374 trial was not specifically for patients with systemic JIA and included patients with other subtypes of JIA. However, the Committee noted that patients on tocilizumab were significantly more likely to reach an ACR30 response than patients on infliximab. The Committee also noted the manufacturer presented evidence from the ANAJIS trial that compared anakinra with placebo. The primary outcome measured in the ANAJIS trial was a modified ACR30 response without fever, measured after 4 weeks. The Committee noted that the TENDER and ANAJIS trials were used for an indirect comparison analysis of tocilizumab with anakinra. The Committee also noted that the manufacturer used the whole population from the TENDER trial to represent tocilizumab, whereas the ERG used only the 95% of patients whose condition had not responded to methotrexate. The Committee noted that patients on tocilizumab were significantly more likely to reach an ACR30 response than patients on anakinra. The Committee also noted that there was no significant difference between tocilizumab and anakinra in terms of ACR30 response plus absence of fever. The Committee concluded from the indirect comparison data that tocilizumab was clinically effective compared with anakinra and infliximab.
# Cost effectiveness
The Committee considered the revised economic model submitted by the manufacturer that included the patient access scheme for cost-effectiveness analysis. The Committee heard how homogenous health states had been defined by CHAQ score and had been categorised as 'controlled', 'mild', 'moderate', and 'severe'. The Committee noted that health states were based on CHAQ scores and regression models had been used to predict expected CHAQ categories using ACR responses. The Committee also noted that there was the possibility that individuals could have the same ACR response and still be in different baseline CHAQ categories, The Committee heard from the ERG that using ACR to define response transitions adhered to common modelling practice. It further noted that the application of the regression model from the 12 week data from the TENDER trial to the baseline CHAQ score to predict 12 week CHAQ values had not been adequately explained. The Committee concluded that although the manufacturer had submitted a revised economic model that represented the natural history of systemic JIA and its response to treatment better than the original model, there were still concerns with some aspects of the model.
The Committee considered the utility values used in the revised economic model. The Committee noted that the manufacturer had identified limitations of the CHQ (which had been used in the TENDER trial to elicit patients' health-related quality of life) and therefore had instead used data from the CHAQ. The manufacturer had made the assumption that the CHAQ score of a child was equal to the HAQ score of an adult and that the adult EQ-5D was equal to the health-related quality of life of a child. The Committee expressed concern about the methods and assumptions that had been used by the manufacturer and considered the utility value of 0.19 assigned to the severe health state in the revised model to be implausible given that approximately two thirds of children entered the model in this state. The Committee heard from the ERG that as most children leave the severe health state after 12 weeks, this may only have a limitedeffect on the long-term model. The Committee concluded however that this would over-estimate the incremental QALY gain ascribed to tocilizumab.
The Committee considered the costs for tocilizumab used in the revised economic model. The Committee noted that the costs of treatment were a composite of cost of medication and cost of administering the medication. The Committee heard from the clinical specialists that the costs for the health states in the model were a reasonable reflection of clinical practice in the UK. The Committee concluded that the costs in the model were reasonable, however it noted that potential cost savings could result from reductions in orthopaedic surgery for future joint damage and in bone marrow transplant and stem cell procedures, and that these factors had not been taken into account in the revised model.
The Committee considered the starting age of 5 years in the manufacturer's revised economic model and noted the comment received from a consultee that this was too high. The Committee concluded that the start age in the model was a mean age of 5 years and therefore the spread would include children who were below 5 years of age.
The Committee considered the manufacturer's revised base-case results with the patient access scheme applied. The Committee noted that the anakinra treatment strategies had used the primary outcome of ACR30 response and no fever. The Committee noted that two distinct incremental analyses had been performed: an anakinra-containing strategy that evaluated the strategies of tocilizumab followed by anakinra and anakinra followed by tocilizumab, and how each compared to anakinra alone. The manufacturer had done the same analyses for tocilizumab and infliximab. The Committee heard from the ERG that the incremental analyses the manufacturer presented were not fully incremental. The ERG also noted that the manufacturer's analyses were only designed to compare two technologies with one. The Committee further heard from the ERG that a more rigorous analysis would have involved tocilizumab, infliximab and anakinra in the same sequence using tocilizumab in different places of the sequence. The Committee also noted that as well as not conducting a fully incremental analysis, the manufacturer had not conducted a revised probabilistic sensitivity analysis. The Committee therefore concluded that the manufacturer's cost-effectiveness estimates could not be considered robust.
The Committee reviewed the ERG's exploratory analyses of the revised model, which included the patient access scheme. The Committee noted the ERG's analysis for the strategy tocilizumab then infliximab, compared with infliximab alone. The Committee considered that this strategy was the most appropriate because tocilizumab is the only licensed technology for systemic JIA and because the strategy of tocilizumab then anakinra compared with anakinra was not considered to be cost effective. The Committee agreed that the ERG's deterministic sensitivity analysis results were preferable to the ERG's probabilistic sensitivity analysis because only a limited number of simulations of the data were run in the probabilistic analysis. Despite the considerable uncertainty around the ICERs, the most plausible ICERs for the strategy tocilizumab followed by infliximab compared with infliximab alone were within a range that would be considered an acceptable use of NHS resources. Given the other factors that had not been taken account of in the manufacturer's model (such as steroid sparing, a decrease in health-related quality of life of the parents or carers, reduction in future orthopaedic surgical operations, bone marrow transplantation and stem cell procedures), on balance, the Committee concluded that the resulting cost-effectiveness estimate would be at the lower end of this range.
The Committee considered the manufacturer's revised sensitivity analyses that included the patient access scheme. The Committee noted the manufacturer's results, and the uncertainty around the adjustment factor derived from the etanercept study used to take account of other types of JIA subgroups in the infliximab study. The Committee noted that an increase or decrease of the adjustment factor by 30% on the tocilizumab then infliximab strategy made only a small difference to the manufacturer's revised base-case ICER. The Committee concluded that the revised model was robust to the sensitivity analyses of the adjustment factor.
The Committee considered the manufacturer's revised scenario analyses including the patient access scheme that looked at the impact of decreasing the frequency of administration of tocilizumab from every 2 to every 4 weeks after a treatment period of 6 months and of stopping tocilizumab after 2 years of treatment. The Committee noted that both scenarios improved the cost effectiveness of tocilizumab further. The Committee had heard from the clinical specialists that in some instances tocilizumab would be stopped when patients were in complete remission or dose administrations decreased when there was a significant improvement in the patient's condition. The Committee was of the view that when these situations arise in clinical practice that clinicians could consider reducing the frequency of administration of tocilizumab or stop using tocilizumab. The Committee also highlighted the importance of registries in collecting further data on patients receiving tocilizumab so that specific information about long-term outcomes and treatment-related adverse events in systemic JIA can be collected.
In summary, because the Committee did not have any clinical evidence on the comparison of tocilizumab with methotrexate, it concluded that tocilizumab could not be recommended for the treatment of systemic JIA in children and young people aged 2 years and older whose disease continues to respond to methotrexate or who have not been treated with methotrexate. For the population of children whose systemic JIA has not responded adequately to methotrexate as well as NSAIDs and corticosteroids, the Committee accepted the manufacturer's revised model despite its reservations about some aspects of the cost-effectiveness evaluation. The Committee noted the patient access scheme proposed by the manufacturer is a simple discount and would not incur additional costs. Consequently, the Committee concluded that tocilizumab represents a cost-effective use of NHS resources and should be offered as an option for the treatment of systemic JIA in children and young people aged 2 years and older whose condition has inadequately responded to NSAIDs, corticosteroids and methotrexate.
# Summary of Appraisal Committee's key conclusions
TA238
Appraisal title: Tocilizumab for the treatment of systemic juvenile idiopathic arthritis
Section
Key conclusion
Tocilizumab is recommended as an option for the treatment of systemic juvenile idiopathic arthritis in children and young people aged 2 years and older whose disease has responded inadequately to non-steroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids and methotrexate if the manufacturer makes tocilizumab available with the discount agreed as part of the patient access scheme.
Because the Committee did not have any clinical evidence on the comparison of tocilizumab with methotrexate, it concluded that tocilizumab could not be recommended for the treatment of systemic JIA in children and young people aged 2 years and older whose disease continues to respond to methotrexate or who have not been treated with methotrexate.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee heard that children with systemic JIA experience severe pain and fatigue, and considerable disability. These children could be prescribed systemic corticosteroids over long periods of time. They could therefore experience increased morbidity and adverse effects that can lead to chronic conditions including infections, diabetes mellitus, cardiovascular complications and osteoporosis in later life, and risk of long-term joint damage and need for joint replacement. In addition, they may have visible side effects such as growth restriction and Cushing's syndrome. The Committee heard from the clinical specialists in the UK, patients with systemic JIA are treated first with NSAIDs and systemic corticosteroids. Methotrexate is then used if disease activity persists. If the child is intolerant of methotrexate or their condition does not adequately respond to an adequate trial of methotrexate, TNF alpha inhibitors or anakinra are the next treatment options to be used.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee heard from the patient expert how tocilizumab had made such a considerable difference to a child's symptoms that the child now had significantly less pain and better energy levels and could concentrate sufficiently to participate in school. The Committee also heard that a significant number of children taking tocilizumab had been able to reduce or completely stop using steroids and therefore the visible side effects of the corticosteroid treatment were no longer present.
What is the position of the treatment in the pathway of care for the condition?
The Committee heard that there are currently no other treatments specifically licensed for systemic JIA. The Committee heard from the clinical specialists that in routine clinical practice in the UK, patients with systemic JIA are treated first with NSAIDs and systemic corticosteroids.
The Committee heard there is variation in the use of tocilizumab in the UK, but tocilizumab is currently being used for patients whose condition does not respond to methotrexate, or following TNF alpha inhibitors or anakinra.
Adverse effects
Upper respiratory tract infection, with typical symptoms such as cough, blocked nose, runny nose, sore throat and headache, is one of the most common side effects of tocilizumab. Other reported side effects include rash, urticaria, diarrhoea, epigastric discomfort and arthralgia. Infusion-related reactions that can be considered serious and life-threatening (such as angioedema) have also been reported.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee considered the evidence for the effectiveness of tocilizumab and noted that the manufacturer derived data from the TENDER trial, part one of which was a 12-week randomised controlled trial that compared the efficacy of tocilizumab with placebo.
The Committee noted that the manufacturer used data from the TENDER trial and the NCT00036374 trial to perform an indirect comparison between tocilizumab and infliximab, and used infliximab to represent the class effect of the TNF-alpha inhibitors.
The Committee also noted the manufacturer presented evidence from the ANAJIS trial that compared anakinra with placebo.
For the population of patients whose systemic JIA had failed to respond to NSAIDs and systemic corticosteroids, the Committee noted that only 5% of the TENDER trial population were methotrexate naive.
Relevance to general clinical practice in the NHS
The Committee heard from the clinical specialists that the population was largely generalisable to the UK, but that the mean age of approximately 10 years in the TENDER trial was older than the population they would treat with tocilizumab in routine clinical practice.
Uncertainties generated by the evidence
The Committee also noted that the manufacturer had used a post-hoc analysis to compare patients receiving tocilizumab with those patients in the placebo group receiving methotrexate and that this was not methodologically acceptable. The Committee noted that in practice some patients' systemic JIA would still be responding adequately to methotrexate but no data for these patients had been presented. The Committee therefore concluded that there was no evidence to allow them to further consider the clinical or cost effectiveness of tocilizumab compared with methotrexate.
The Committee noted that the manufacturer used data from the TENDER trial and the NCT00036374 trial to perform an indirect comparison between tocilizumab and infliximab, and used infliximab to represent the class effect of the TNF-alpha inhibitors. The manufacturer used data from the TENDER trial and the ANAJIS trial to perform an indirect comparison between anakinra with placebo.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
No clinically relevant subgroups were identified for which there was differential effectiveness.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee considered the evidence on the clinical effectiveness of tocilizumab in the population who had experienced treatment failure with NSAIDs, systemic corticosteroids and methotrexate. It noted that there were statistically significant improvements in the primary efficacy endpoint (ACR30 response and no fever) and all secondary endpoints at 12 weeks when tocilizumab was compared with placebo.
The Committee noted the evidence and analyses conducted by the manufacturer from the TENDER, NCT0036374 and ANAJIS trials. The Committee noted that patients on tocilizumab were significantly more likely to reach an ACR30 response than patients on anakinra. The Committee also noted that there was no significant difference between tocilizumab and anakinra in terms of ACR30 response plus absence of fever. The Committee concluded from the indirect comparison data that tocilizumab was clinically effective compared with anakinra and infliximab.
Evidence for cost effectiveness
Availability and nature of evidence
The manufacturer provided a revised economic model in which CHAQ categories define health states. The health states were defined as 'controlled' 'mild', 'moderate' and 'severe'. A simulated patient distribution of CHAQ score based on the TENDER trial was used to establish the proportion of patients that would fall into each CHAQ category at baseline. The manufacturer used ACR as a potential predictor of the CHAQ score.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted that health states were based on CHAQ scores and regression models had been used to predict expected CHAQ categories using ACR responses.
The Committee further noted that the application of the regression model from the 12 week data from the TENDER trial to the baseline CHAQ score to predict 12 week CHAQ values had not been adequately explained. The Committee concluded that although the manufacturer had submitted a revised economic model that represented the natural history of systemic JIA and its response to treatment better than the original model, there were still concerns with some aspects of the model.
The Committee expressed concern about the methods and assumptions that had been used by the manufacturer and considered the utility value 0.19 assigned to the severe health state in the revised model to be implausible given that approximately two thirds of children entered the model in this state. The Committee heard from the ERG that as most children leave the severe health state after 12 weeks, this may only have a limited effect on the long-term model. The Committee concluded however that this would over-estimate the incremental QALY gain ascribed to tocilizumab.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The condition has an effect on the wider family, with siblings finding it distressing to see the child living with the condition, and parents and carers often have to stay at home and care for the child if they are unable to attend school. These have not been captured in the model.
The Committee noted that certain factors had not been taken into account of in the manufacturer's model such as steroid sparing, a decrease in health related quality of life of the parents and carers, reduction in future orthopaedic surgical operations, bone marrow transplantation and stem cell procedures.
Are there specific groups of people for whom the technology is particularly cost effective?
Children and young people aged 2 years and older whose disease has responded inadequately to NSAIDs systemic corticosteroids and methotrexate. This is cost effective only if the manufacturer makes tocilizumab available with the discount agreed as part of the patient access scheme.
What are the key drivers of cost effectiveness?
The starting age of treatment of systemic JIA.
The potential decrease of frequency of administration of tocilizumab from every 2 to every 4 weeks after a treatment period of 6 months and of stopping tocilizumab 2 years of treatment. The Committee noted that both scenarios were likely to improve the cost effectiveness of tocilizumab.
Most likely cost-effectiveness estimate (given as an ICER)
Despite the considerable uncertainty around the ICERs, the most plausible ICERs for the strategy tocilizumab followed by infliximab compared with infliximab alone in children and young people aged 2 years and older whose disease has responded inadequately to NSAIDs, systemic corticosteroids and methotrexate were within a range that would be considered an acceptable use of NHS resources. Given the other factors that had not been taken account of in the manufacturer's model (such as steroid sparing, a decrease in health-related quality of life of the parents or carers, reduction in future orthopaedic surgical operations, bone marrow transplantation and stem cell procedures), on balance, the Committee concluded that the resulting cost-effectiveness estimate would be at the lower end of this range.
Additional factors taken into account
Patient access schemes (PPRS)
A patient access scheme was submitted by the manufacturer. The level of discount is commercial in confidence
End-of-life considerations
The supplementary advice was not relevant to this appraisal.
Equalities considerations and social value judgements
No equalities issues were raised in this appraisal.
# Related NICE guidance
Guidance on the use of etanercept for the treatment of juvenile idiopathic arthritis.NICE technology appraisal guidance 35 (2002).# Review of guidance
The guidance on this technology will be considered for review in December 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveDecember 2011# Changes after publication
February 2014: minor maintenance
June 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Tocilizumab is recommended for the treatment of systemic juvenile idiopathic arthritis in children and young people aged 2 years and older whose disease has responded inadequately to non-steroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids and methotrexate if the manufacturer makes tocilizumab available with the discount agreed as part of the patient access scheme.\n\nTocilizumab is not recommended for the treatment of systemic juvenile idiopathic arthritis in children and young people aged 2 years and older whose disease continues to respond to methotrexate or who have not been treated with methotrexate.\n\nChildren and young people currently receiving tocilizumab for the treatment of systemic juvenile idiopathic arthritis who do not meet the criteria in 1.1 should have the option to continue treatment until it is considered appropriate to stop. This decision should be made jointly by the clinicians, and the child or young person and/or their parents or carers.', 'The technology ': "Tocilizumab (RoActemra, Roche Products) is a humanised monoclonal antibody that inhibits the cytokine interleukin-6 (IL-6). Reducing the activity of IL-6 can reduce inflammation in the joints, prevent long-term damage, and improve quality of life and function. Tocilizumab has a marketing authorisation for the treatment of active systemic juvenile idiopathic arthritis (JIA) 'in patients aged 2\xa0years of age and older, who have responded inadequately to previous therapy with NSAIDs and systemic corticosteroids'. Tocilizumab can be given as monotherapy (in patients intolerant to methotrexate or if treatment with methotrexate is inappropriate) or in combination with methotrexate.\n\nUpper respiratory tract infection, with typical symptoms such as cough, blocked nose, runny nose, sore throat and headache, is one of the most common side effects of tocilizumab. Other reported side effects include rash, urticaria, diarrhoea, epigastric discomfort and arthralgia. Infusion-related reactions that can be considered serious and life-threatening (such as angioedema) have also been reported. For full details of side effects and contraindications, see the summary of product characteristics.\n\nTocilizumab is administered as an intravenous infusion over 1 hour and treatment is repeated at 2-week intervals. The recommended dose is 8\xa0mg/kg in patients weighing 30\xa0kg or more, and 12\xa0mg/kg in patients weighing less than 30\xa0kg. The dose should be calculated based on the patient's body weight at each administration. A change in dose should only be based on a consistent change in the patient's body weight over time. The cost of 80\xa0mg in a 4\xa0ml vial is £102.40 (excluding VAT; 'British national formulary' [BNF] edition\xa061). The average cost of treatment is £7987.20 per year for a 30\xa0kg patient and £9984 per year for a 25\xa0kg patient, assuming no wastage. The manufacturer of tocilizumab (Roche Products) has agreed a patient access scheme with the Department of Health which makes tocilizumab available with a discount applied to all invoices. The level of the discount is commercial-in-confidence (for further details see section 5.2). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this NICE technology appraisal guidance is published.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of tocilizumab and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer submitted evidence for the two populations defined in the decision problem: population 1 – children and young people aged 2 years and older with systemic JIA that has not responded adequately to prior NSAIDs and systemic corticosteroids; and population 2 – children and young people aged 2 years and older with systemic JIA that has not responded adequately to prior NSAIDs, systemic corticosteroids and methotrexate. For population 1 the manufacturer compared tocilizumab with methotrexate. For population 2 the manufacturer carried out indirect comparisons of tocilizumab with tumour necrosis factor-alpha (TNF-alpha) inhibitors and anakinra.\n\nIn the manufacturer's submission, evidence of clinical effectiveness was based on one randomised controlled trial (TENDER). The TENDER trial is an ongoing three-part, 5-year, phase III study. Part one consisted of a 12-week international multicentre randomised double-blind placebo-controlled parallel two-group study to evaluate the efficacy and safety of tocilizumab in children with active systemic JIA. Part two is a 92-week single-group open-label extension and part three is a 3-year single-group open-label continuation of the study. The manufacturer stated that based on the inclusion criteria of the TENDER trial, all participants matched population 1 in the scope. The manufacturer also stated that 95% of TENDER trial participants who were either treated with methotrexate or had had methotrexate in the past matched population 2 in the scope because it was these participants whose disease could be regarded as having responded inadequately to methotrexate. Patients were included in the study if they had symptoms of active disease and the manufacturer stated that 'it follows that if patients have tried in the past or are currently administered methotrexate and continue to have persistent disease then they are inadequate responders'. An inadequate response to methotrexate was defined as patients being on a standard dose of methotrexate for a period of 3\xa0months and still showing symptoms of active systemic JIA at baseline.\n\nTENDER enrolled 112 participants (from 17 countries, including the UK) who were randomised 2:1 to tocilizumab (n\xa0=\xa075) or placebo (n\xa0=\xa037). Tocilizumab was administered every 2 weeks at a dose of 8\xa0mg/kg for participants who weighed at least 30\xa0kg (n\xa0=\xa037) and 12\xa0mg/kg for those who weighed less than 30\xa0kg (n\xa0=\xa038). Ages of patients in the trial ranged from 2 to 17 years, with an average age of 10 years. Patients had to have documented persistent disease activity (at least five active joints, or at least two active joints with fever above 38°C for any 5 out of 14 days of screening) for at least 6 months, and an inadequate response to NSAIDs and corticosteroids because of toxicity or lack of efficacy. An inadequate response to previous treatment was determined by the treating physician's clinical assessment. Before study entry, 78\xa0out of 112 patients (70%) had been treated with methotrexate (36 entered the study on methotrexate that had been previously stopped then restarted; 42 were on their first course of methotrexate, which was ongoing). Approximately 26% (29) of patients were not on methotrexate at baseline but had received and stopped methotrexate previously. Five patients (approximately 5%) had never received methotrexate, and were considered methotrexate naive. Patients taking NSAIDs, corticosteroids and methotrexate were permitted to take part but had to enter the study on a stable dose of the medicines.\n\nThe primary outcome measures were the proportion of patients who had a JIA American College of Rheumatology (ACR) 30 response at 12\xa0weeks and absence of fever (defined as no recorded temperature of 37.5°C or above in the preceding 7 days). A JIA ACR30 response is defined as an improvement of at least 30% from the baseline assessments in any three of six core outcome variables, with no more than one of the remaining variables deteriorating by more than 30%. The JIA core outcome variables are: physician global assessment of disease activity (100\xa0mm visual analogue scale [VAS]); parent or patient global assessment of overall well-being (100\xa0mm VAS); number of joints with active arthritis; number of joints with limitation of movement; erythrocyte sedimentation rate; and functional ability (using the Childhood Health Assessment Questionnaire [CHAQ], which measures eight everyday functional activities).\n\nThe secondary outcomes were: individual results for each JIA ACR core outcome variable at 12 weeks; JIA ACR 50/70/90 responses at 12 weeks (that is, an improvement of at least 50%, 70% or 90% respectively from the baseline assessments in any three of the six core outcome variables, and no more than one of the remaining variables worsening by more than 50%, 70% or 90%); corticosteroid reduction; fever; rash; pain; and laboratory outcomes (C-reactive protein [CRP]) levels, anaemia and haemoglobin levels, thrombocytosis and leucocytosis).\n\nEfficacy endpoints were analysed using the intention-to-treat population. All patients were classified as either responders or non-responders. Patients who 'escaped' (patients whose disease did not respond to treatment who switched to an alternative treatment for the disease) or withdrew were classed as non-responders. There was an 'early escape' option to allow children with more severe disease at baseline an opportunity to escape and receive active open-label tocilizumab. Of the 112\xa0patients enrolled, 21\xa0received escape therapy, with 20 of those patients being initially randomised to the placebo arm. The main reasons for escape were fever for at least 3 consecutive days or a JIA ACR30 flare (a worsening of symptoms).\n\nThe results of the TENDER trial showed that for its primary endpoint (a JIA ACR30 response and absence of fever at week 12), 85.3% of the tocilizumab patients were classed as responders compared with 24.3% of the placebo patients, a statistically significant difference (p\xa0<\xa00.0001). Patients given tocilizumab had a greater chance of achieving JIA ACR30/50/70/90 responses at week 12 in comparison with the placebo patients. The differences in the proportions of tocilizumab patients and placebo patients at each JIA ACR response level were statistically significant (p\xa0<\xa00.0001). The proportion of responders showing an ACR30 response was higher in patients receiving tocilizumab 12 mg/kg (97.4%) compared with those receiving tocilizumab 8 mg/kg (83.8%). The efficacy of tocilizumab with respect to individual ACR core outcome variables was analysed as part of the secondary efficacy analyses; these results are marked by the manufacturer of tocilizumab as academic in confidence and therefore are not presented here.\n\nThe TENDER trial also included the Child Health Questionnaire (CHQ) as an instrument eliciting patient health-related quality of life. The CHQ assesses a child's physical, emotional and social wellbeing from the perspective of a parent or carer. The questionnaire was completed twice during the randomised period of the study: at baseline (visit 1) and at week 12 (visit 7).\n\nThe TENDER trial included data on adverse events. Infusion-related reactions were defined as all events occurring during or within 24\xa0hours of an infusion. In the 12-week controlled phase, 4% of patients from the tocilizumab group experienced adverse events during infusion. One event (angioedema) was considered serious and life-threatening, and the patient stopped study treatment. In the 12-week controlled phase, 16% of patients in the tocilizumab group and 5.4% of patients in the placebo group experienced an adverse event within 24 hours of infusion. In the tocilizumab group, the adverse events included, but were not limited to, rash, urticaria, diarrhoea, epigastric discomfort, arthralgia and headache. One of these adverse events, urticaria, was considered serious. Clinically significant hypersensitivity reactions associated with tocilizumab that meant treatment was stopped were reported in 1 out of 112\xa0patients (less than\xa01%) treated with tocilizumab during the controlled phase and up to and including the open-label clinical trial.\n\nFor the comparison of tocilizumab and methotrexate for population\xa01, the manufacturer used a post-hoc analysis to compare patients receiving tocilizumab with the 70% of patients in the placebo group who were receiving methotrexate. The manufacturer presented results that showed methotrexate had limited effect on the primary outcome in patients who were in the placebo group and those treated with tocilizumab. The manufacturer concluded that methotrexate as add-on therapy did not have a significant impact on the JIA ACR responses observed in the tocilizumab arms in the TENDER study. The manufacturer further presented results showing that the proportion of patients on tocilizumab who had an ACR30 response was 0.907, compared with 0.154 for those on methotrexate.\n\nNo head-to-head trials were available analysing the efficacy of tocilizumab compared with TNF-alpha inhibitors or anakinra for population 2. The manufacturer included data from two studies (Ruperto et al. 2007 [NCT00036374] and the ANAJIS [anakinra in patients with systemic-onset juvenile idiopathic arthritis] study) in the indirect comparison analysis. The NCT00036374 trial compared the TNF-alpha inhibitor infliximab with placebo in patients with juvenile rheumatoid arthritis (systemic 16%, pauciarticular 23%, polyarticular 61%) described as having a suboptimal response to methotrexate. Participants were from North and South America and Europe, aged between 4 and 18 years, and were randomised to infliximab (62 patients) or placebo (60 patients). Patients received concomitant methotrexate alongside placebo or active treatment. The study was a randomised double-blind placebo-controlled trial, and the primary outcome was the proportion of patients who had a paediatric ACR30 response based on JIA core outcome variables at week 14.\n\nThe ANAJIS trial recruited children with systemic JIA and compared anakinra with placebo. This was a multicentre study with 24 participants (12 in each arm) aged 2–20 years, from North America and Europe. The study included patients whose systemic JIA had not responded to methotrexate or any of the disease-modifying anti-rheumatic drugs (DMARDs), and the protocol did not permit the administration of any DMARDs during the trial. The outcomes of the randomised controlled phase were reported after 1\xa0month. The primary outcome was the paediatric ACR score, absence of fever and normalisation of CRP levels and erythrocyte sedimentation rate after 1\xa0month.\n\nThe manufacturer undertook an indirect comparison of tocilizumab compared with anakinra. Data from the ANAJIS and the TENDER trials were used. The manufacturer used all patients in the TENDER trial, including those who were methotrexate naive, for the analysis. The relative risk for an outcome of a JIA ACR30 response for patients on tocilizumab compared with anakinra was 2.37 (95% CI 1.10 to 5.10), which was statistically significant. There were no significant differences in JIA ACR30 response and absence of fever between the anakinra and tocilizumab populations. The manufacturer also conducted an indirect comparison of tocilizumab and infliximab using the results from the NCT00036374 trial and the TENDER trial. The outcomes JIA ACR30, 50 and 70 responses were measured. Patients on tocilizumab had a statistically significantly greater chance of having these outcomes than those on infliximab. The relative risks were 2.87 (95% CI 1.49 to 5.55), 5.35 (95% CI 1.91 to 14.97) and 4.61 (95% CI 1.16 to 18.38) for JIA ACR30, 50 and 70 responses respectively.\n\nThe manufacturer used an adjustment factor derived from a study of etanercept by Prince et al. (2009). This was an observational study of 146 patients, of whom 27% had systemic JIA. The adjustment factor is the difference in the proportion of responders between the total population with JIA and the subpopulation with systemic JIA. This factor was used to correct for ACR response rates in the indirect comparison results that the manufacturer had derived from the NCT00036374 (infliximab) study (in which 16% of JIA patients had systemic JIA) and the TENDER trial. These resulting ACR response rates were assumed to represent the responses achieved with all of the TNF-alpha inhibitors.\n\nThe manufacturer originally submitted a Markov model to evaluate the cost effectiveness of tocilizumab as part of a sequence of treatments. In the tocilizumab versus methotrexate model, patients progressed to anakinra, etanercept and then adalimumab; in the tocilizumab versus anakinra model, patients progressed to etanercept, adalimumab and then abatacept.\n\nIn the manufacturer's original model the Markov chain had 22\xa0states. The model clustered the states into five groups: four groups representing different lines of treatment and the fifth group containing death and uncontrolled disease. Each line of treatment consisted of five health states: ACR responses at the 30, 50, 70 and 90 levels and 'no ACR response'. A patient could move from a particular ACR response in a particular line only to 'no ACR response' in the next line or to death. From 'no ACR response' the patient could move only to one ACR response level within that line of treatment or to 'no ACR response' in the next line. The main assumption of the model was that there were no transitions between ACR response categories (that is, the patient could not move within a given line to a better or worse health state [say, from ACR50 to ACR70]). The analysis assumed that patients stayed in the same health state unless they changed treatment line. After 12\xa0weeks of treatment, the cohort was put on the next treatment in the sequence. Only after being through all four lines did a patient move to the health state 'uncontrolled disease'. The probability of a response or non-response within a line of treatment depended on the treatment. The order in which the treatments were applied did not change these transitions. The probability of death was treatment independent and health-state independent. The probability of withdrawal was health-state independent, but was higher for methotrexate than for other treatment options (all other treatment options had the same probability as each other). All transitions stayed constant over time; that is, they were independent of age or disease duration. In each cycle, the proportion of patients in a given state was calculated. The distribution across states was used to calculate cycle-specific quality-adjusted life years (QALYs) and treatment costs, which were discounted and summed over the length of treatment. The manufacturer's original model had a time horizon of 16\xa0years. This means that a patient in the model starting treatment aged 2 years turned 18 and could be considered an adult at the end of the simulation. The model allowed shorter and longer time durations for sensitivity analysis (up to 30 years). The discount rates applied were 3.5% for utilities and costs, and costs were considered from an NHS and personal social services perspective. A half-cycle correction was applied.\n\nThe initial CHAQ score at baseline for the cohort of patients used in the original economic model was equal to that observed in the TENDER trial. The change in the patient CHAQ score was determined by the level of ACR response after 12 weeks. Improvement in each health state as measured by relative ACR change led to an absolute change in the initial CHAQ score. For a given CHAQ score, a utility was assigned to calculate QALYs. The health-state costs varied with the health state and the treatment costs.\n\nThe data inputs for the manufacturer's original model included utility values. To derive utility values, the manufacturer had to map the CHAQ scores to utilities, using a mapping formula derived in adults with rheumatoid arthritis that mapped Health Assessment Questionnaire [HAQ] results onto EQ-5D utilities. The manufacturer recognised that the assumptions that CHAQ is equal to HAQ and that adult EQ-5D is equal to the health-related quality of life of a child are not evidence based, and acknowledged that this mapping method was only used for the analysis to derive QALYs for the economic model because of the lack of other available data.\n\nTreatment costs in the original model were a composite of the cost of the medication and the cost of administering it. For some drugs, the necessary dosage depends on the body weight of the patient. The manufacturer based the unit costs on UK reference costs, literature and expert opinion. The health-state costs depended only on the ACR response level and were independent from any other health outcomes. The manufacturer stated that 'in all comparisons, the identified adverse events are of minor severity and short duration, and their management would have a minuscule cost impact'. Therefore, it can be assumed that they do not have a considerable bearing on the incremental costs of the two model arms.\n\nIn response to the preliminary recommendations in the appraisal consultation document, in which the Committee was minded not to recommend tocilizumab, the manufacturer submitted a revised cost-effectiveness Markov economic model. The economic model in the manufacturer's submission was modified such that health states are defined according to categories of CHAQ, rather than being based on ACR response categories in which an average CHAQ is applied. In the revised economic model the manufacturer adopted an approach in which CHAQ categories define health states. The health states were defined as 'controlled' 'mild', 'moderate' and 'severe'. A simulated patient distribution of CHAQ scores based on the TENDER trial was used to establish the proportion of patients that would fall into each CHAQ category at baseline. The manufacturer used ACR as a potential predictor of the CHAQ score. The manufacturer assigned the following utility values to the health states: 0.19, 0.55, 0.65 and 0.77 to 'severe', 'moderate', 'mild' and 'controlled' respectively.\n\nIn the revised economic model, incremental analyses were presented by the manufacturer that compared the sequences of tocilizumab followed by infliximab with infliximab followed by tocilizumab, and then compared tocilizumab followed by anakinra with anakinra followed by tocilizumab followed by anakinra.\n\nWhen the manufacturer submitted its comments on the appraisal consultation document, it also submitted a patient access scheme, which is a discount on all invoices of tocilizumab. The manufacturer applied the discounted value of tocilizumab to the revised version of the economic model. This document only details the results for tocilizumab with the patient access scheme.\n\nIn the manufacturer's revised base-case analyses with the patient access scheme the ICER was £18,194 per QALY gained when tocilizumab followed by infliximab was compared with infliximab alone. When tocilizumab followed by anakinra was compared with anakinra alone, the ICER was £16,923 per QALY gained. The manufacturer conducted two separate incremental analyses for infliximab- and anakinra-containing sequences. In these sequences tocilizumab had been used either before or after infliximab or anakinra and compared with infliximab or anakinra alone respectively. The ICERs obtained when tocilizumab was used first followed by infliximab compared with infliximab alone was £18,194 per QALY gained. For infliximab followed by tocilizumab compared with infliximab alone, the ICER was £30,630 per QALY gained. In the anakinra-containing sequences the ICER was £16,923 per QALY gained when tocilizumab was used first followed by anakinra compared with anakinra alone. Anakinra followed by tocilizumab dominated anakinra alone.\n\nThe manufacturer also conducted a sensitivity analysis in the revised model that included:\n\nThe uncertainty around the adjustment factor derived from the etanercept study used to take account of the other juvenile idiopathic arthritis subgroups in the infliximab study. The base-case sensitivity analysis assuming an increase of the adjustment factor by 30% resulted in an ICER of £20,240 per QALY gained when the tocilizumab then infliximab strategy was compared with infliximab alone. The ICER was £16,923 per QALY gained when the tocilizumab then anakinra strategy was compared with anakinra alone. The respective ICERs when the adjustment factor was decreased by 30% were £16,407 and £16,923 per QALY gained.\n\nA stopping rule for tocilizumab after treatment duration of 2\xa0years. The base-case sensitivity analysis assuming treatment with tocilizumab was stopped after 2 years. This showed that the tocilizumab then infliximab strategy dominated infliximab alone, and the tocilizumab then anakinra strategy also dominated anakinra alone.\n\nA decreased frequency of administration of tocilizumab from a 2-weekly regimen to a 4-weekly regimen after treatment duration of 6 months. The resulting ICERs for this base-case sensitivity analysis showed that the tocilizumab then infliximab strategy dominated infliximab alone, and the tocilizumab then anakinra strategy also dominated anakinra alone.\n\nIn response to the preliminary recommendations in the appraisal consultation document, in which the Committee was minded not to recommend tocilizumab, the manufacturer also submitted information on radiographic evidence of progression of joint damage for patients with systemic JIA receiving tocilizumab. The manufacturer stated that the radiographic results from the TENDER trial were not yet available but presented results from a case series (Inaba et al. [2011 and 2007]) that included seven children with a mean age of disease onset of 4.1 years and a mean age of start of treatment of 9.4 years. The mean follow-up of treatment was 56 months. There were radiographic improvements in 57% of joints, worsening in 13% and no change in 30%. The authors of this study noted limitations of the small sample size and radiographic deterioration in some joints, despite stabilisation of systemic inflammatory responses. The authors had concluded that further studies with a larger number of participants were needed. The manufacturer also presented data from a study from Japan (Kaneko et al. ), which included 46\xa0patients with a mean age of 4 years who had systemic JIA receiving 8\xa0mg/kg of tocilizumab every 2 weeks. The study noted that markers of systemic inflammation and numbers of tender/swollen joint counts were markedly improved following treatment with tocilizumab. However, progression of joint damage was observed in weight-bearing joints such as hip (85%) and knee (57%), along with growth disturbances and osteopenia. Radiographic progression was not seen in small joints.\n\nIn response to the preliminary recommendations in the appraisal consultation document, in which the Committee was minded not to recommend tocilizumab, the manufacturer also submitted long-term follow-up data, some of which were marked as academic in confidence and therefore are not presented here. Data from one trial in Japan (Yokota et al. ) in which 11 patients were given tocilizumab every 2 weeks and were followed up for 10–35 months showed that one patient withdrew because of duodenum perforation after 10 months. The authors suggested that this could be because of long-term steroid and NSAID use. The most serious adverse events were pneumonia in 2 patients.\n\nThe manufacturer also responded to the Committee's request for clarification on how the CHAQ responses were elicited from the 21\xa0children in the TENDER trial under the age of 5 years. The manufacturer stated that the parents of the children filled in the CHAQ on their behalf.\n\nThe ERG noted that the TENDER trial compared tocilizumab plus standard care with placebo plus standard care. The ERG observed that the comparator in this study did not match that specified in the scope and decision problem. For population 1 (that is, children with systemic JIA that has not responded adequately to prior NSAIDs and systemic corticosteroids) the comparator in the scope is methotrexate. The manufacturer, in its submission, had used a post-hoc analysis to compare patients receiving tocilizumab with those patients in the placebo group also receiving methotrexate. The ERG noted that this was not methodologically acceptable because the trial participants were not originally randomised into those populations. In the TENDER trial, 5% of patients were methotrexate naive. The ERG considered that this population would represent population 1 in the decision problem, but the analyses were inadequate. The ERG thus considered that there was insufficient evidence for any comparison of tocilizumab with methotrexate.\n\nFor population 2 (children with systemic JIA that has not responded adequately to prior NSAIDs, corticosteroids and methotrexate) the manufacturer's original submission provided data for an indirect comparison of tocilizumab with anakinra, using data from the TENDER trial and a trial of anakinra versus placebo. The ERG considered that the 5% of participants in the TENDER trial who were methotrexate naive should be excluded from these analyses. The manufacturer's original submission only provided data for all participants in the TENDER trial. However, in response to the request for clarification, some data were provided in which methotrexate-naive patients were excluded. These data were not reported for the TENDER trial, but only for the indirect comparison with anakinra. When conducting analyses, the ERG used data for this population when possible. For the comparators, the ERG noted that the manufacturer had decided to broaden the inclusion criteria to include all subtypes of juvenile arthritis, not just systemic JIA. The manufacturer had taken this approach because of the lack of clinical evidence for systemic JIA. The ERG was concerned that this approach had been taken despite the manufacturer's clinical specialists stressing the differences between systemic JIA and other subtypes, and advising against comparing the evidence from different JIA populations.\n\nThe ERG also noted the assumption in the original economic model that patients move to a certain ACR response and stay in that state until they either withdraw (move to the next treatment line) or die. The ERG thought that, given the nature of the disease, this assumption was unlikely to be correct.\n\nThe ERG noted the lack of health-related quality-of-life data both in the TENDER trial and in the literature, and recognised that very large assumptions (such as assuming that the CHAQ score of a child is equal to the HAQ score of an adult and that adult EQ-5D is equivalent to the health-related quality of life of a child) were needed to assign a utility to each health state in the model. Because of the lack of data in the trial and the literature, the ERG considered the approach used by the manufacturer to be reasonable and acceptable.\n\nThe ERG noted the revised modelling approach taken by the manufacturer to address the requests of the Committee after the first Appraisal Committee meeting, regarding the issue of mutually exclusive health states. The ERG considered that by defining health states based on a CHAQ score, and using ACR scores to define the transitions, the revised manufacturer's model does adhere to common modelling practice. The ERG also noted the manufacturer's approach of linear extrapolation to assigning costs to health states. The ERG did not fully agree with the manufacturer that an individual patient simulation had been performed. However, the ERG was of the opinion that given the purpose of the model, it was an acceptable and practical approach to conduct further economic analyses.\n\nThe ERG questioned the cost estimates for health states in the original model as defined by expert opinion, because they present a cost for non-responders (£3300) that is more than six times higher than the cost for an ACR30 response (£500), whereas an ACR90 response is associated with only a 30% decrease in cost (to £350) compared with an ACR30 response. However, in the manufacturer's revised model the ERG considered the linear extrapolation approach to assigning costs to health states to be acceptable.\n\nThe ERG noted that the sequences of treatments had been reduced from four treatments in the original model to two treatments in the revised model. The ERG further noted that although there are significant problems in estimating the effect of treatments after first line, it would have been better to have considered all options of including up to four treatments. The ERG conducted exploratory analyses of the full incremental analyses that the manufacturer had presented with the patient access scheme. The ERG's analyses showed that infliximab followed by anakinra compared with infliximab alone resulted in an ICER of £15,819 per QALY gained. The tocilizumab then infliximab strategy compared with the infliximab then anakinra strategy produced an ICER of £22,018 per QALY gained. The tocilizumab then anakinra strategy compared with the tocilizumab then infliximab strategy resulted in an ICER of £67,714 per QALY gained.\n\nFinally, the ERG noted that the revised economic model only allows comparison of two sequences; therefore a probabilistic sensitivity analysis could not be done across all options. The ERG also noted that the manufacturer did not provide the covariance matrix for the regression equation used to determine the correlations between coefficients. The ERG was unable to run a full probabilistic sensitivity analysis. The ERG ran the probabilistic sensitivity analysis twice, once for the infliximab then anakinra strategy compared with infliximab alone, and once for the tocilizumab then infliximab strategy compared with infliximab alone. The ERG noted in its exploratory analyses (which included the patient access scheme and the probabilistic sensitivity analysis) that the tocilizumab then infliximab strategy resulted in an ICER of £32,331 per QALY gained compared with the infliximab then anakinra strategy. The infliximab then anakinra strategy had an ICER of £22,350 per QALY gained compared with infliximab alone.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA238", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of tocilizumab, having considered evidence on the nature of systemic JIA and the value placed on the benefits of tocilizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the clinical pathway of care for systemic JIA. The Committee heard that there are currently no other treatments specifically licensed for systemic JIA, although it was noted that etanercept and adalimumab are licensed for polyarticular-course JIA, which would include some patients with systemic JIA. The Committee heard from the clinical specialists that in routine clinical practice in the UK, patients with systemic JIA are treated first with NSAIDs and systemic corticosteroids. If disease activity persists, or if it was severe initially, then methotrexate is used. If the child is intolerant of methotrexate or their condition does not adequately respond to an adequate trial of methotrexate, TNF-alpha inhibitors or anakinra are the next treatment options. It also heard that if there is an inadequate response to these biologicals, other treatment options include tocilizumab, steroid joint injections, high-dose intravenous immunoglobulin, oral ciclosporin, oral thalidomide, autologous stem cell rescue after marrow ablation, and cyclophosphamide.\n\nThe Committee considered the nature of the condition, and noted evidence submitted and presented by the patient experts and clinical specialists on the clinical symptoms associated with systemic JIA. The Committee heard that children with systemic JIA experience severe pain and fatigue, and considerable disability. This has a substantial impact on the child's family life, school life, and physical and emotional wellbeing. The condition also has an effect on the wider family, with siblings finding it distressing to see the child living with the condition, and parents and carers often have to stay at home and care for the child if they are unable to attend school. The Committee heard that it was extremely important to control symptoms as quickly as possible to prevent long-term disability in the child. The Committee heard that these children could be prescribed systemic corticosteroids over long periods of time. They could therefore experience increased morbidity and adverse effects that can lead to chronic conditions including infections, diabetes mellitus, cardiovascular complications and osteoporosis in later life, and risk of long-term joint damage and need for joint replacement. In addition, they may have visible side effects such as growth restriction and Cushing's syndrome. The Committee heard from the clinical specialists and patient experts how tocilizumab had made a dramatic difference to the majority of children who had been treated with it. The Committee heard from the patient expert how tocilizumab had made such a considerable difference to a child's symptoms that the child now had significantly less pain and better energy levels, could take part in everyday activities and sports, and could concentrate sufficiently to participate in school. The Committee also heard that a significant number of children taking tocilizumab had been able to reduce or completely stop using steroids and therefore the visible side effects of the corticosteroid treatment were no longer present.\n\nThe Committee heard there is variation in the use of tocilizumab in the UK, but tocilizumab is currently being used for patients whose condition does not respond to methotrexate, or following TNF-alpha inhibitors or anakinra. The Committee heard that the administration of anakinra involves daily subcutaneous injections, compared with an infusion of tocilizumab every 2\xa0weeks. In addition, the Committee heard that, in many instances, although anakinra helps in the short term, its therapeutic effect may degrade whereas the therapeutic action of tocilizumab appeared to be sustained over time. The Committee heard that there was some concern about the unknown long-term effects of tocilizumab, especially in children whose treatment extends into adolescence or early adulthood. The Committee also heard that long-term studies would be needed to confirm that the therapeutic benefits of tocilizumab are sustained in the long term. However, the Committee heard that the magnitude of response to tocilizumab allowed some patients to stop taking the drug until they experienced a further relapse. The Committee also heard that depending on the response, there is the possibility of reducing the frequency of administration from once every 2 weeks to once every 4 weeks. The Committee heard that the peak age of onset of systemic JIA is around 18 months to 2\xa0years, and this age group could potentially benefit most from using tocilizumab.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence for the effectiveness of tocilizumab and noted that the manufacturer derived data from the TENDER trial, part one of which was a 12-week randomised controlled trial that compared the efficacy of tocilizumab with placebo. The Committee heard from the clinical specialists that the population was largely generalisable to the UK, but that the mean age of approximately 10\xa0years in the TENDER trial was older than the population they would treat with tocilizumab in routine clinical practice. The Committee concluded that the trial generally reflected the UK population of children with systemic JIA but agreed that the mean age in the trial was older than the population treated in the NHS.\n\nThe Committee then considered the evidence for patients whose systemic JIA had not responded to NSAIDs, systemic corticosteroids and methotrexate. The Committee noted that the manufacturer had indicated that in the TENDER trial an inadequate response to methotrexate was defined as patients still showing symptoms of active systemic JIA at baseline despite being on a standard dose of methotrexate for a period of 3 months. The Committee agreed that the 95% of patients in the TENDER trial who were either being treated with methotrexate or had previously been treated with methotrexate could be considered to have disease that had not adequately responded to methotrexate. The Committee therefore concluded that data for these patients should be considered in any comparison of tocilizumab with TNF-alpha inhibitors or anakinra.\n\nThe Committee considered the evidence presented for the two populations defined in the scope and the different views of the population definitions from the manufacturer and the ERG. For the population of patients whose systemic JIA had failed to respond to NSAIDs and systemic corticosteroids, the Committee noted that only 5% of the TENDER trial population were methotrexate naive. The Committee also noted that the manufacturer had used a post-hoc analysis to compare patients receiving tocilizumab with those patients in the placebo group receiving methotrexate and that this was not methodologically acceptable. The Committee noted that in practice some patients' systemic JIA would still be responding adequately to methotrexate but no data for these patients had been presented. The Committee therefore concluded that there was no evidence to allow them to further consider the clinical or cost effectiveness of tocilizumab compared with methotrexate.\n\nThe Committee considered the evidence on the clinical effectiveness of tocilizumab in the population who had experienced treatment failure with NSAIDs, systemic corticosteroids and methotrexate. It noted that there were statistically significant improvements in the primary efficacy endpoint (ACR30 response and no fever) and all secondary endpoints at 12 weeks. The Committee was satisfied with the results from the TENDER trial and concluded that tocilizumab was efficacious for the treatment of patients whose systemic JIA had not responded to NSAIDs, corticosteroids and methotrexate.\n\nAfter requests made at the first Appraisal Committee meeting the Committee noted that radiographic data from the TENDER trial was still unavailable. It also noted that the radiographic progression data from clinical trials presented by the manufacturer were conflicting and the sample sizes of the trials were small, and therefore there was little certainty about the findings for radiographic progression. The Committee concluded that it was possible that patients receiving tocilizumab would experience a delay in the progression of joint damage.\n\nThe Committee next considered the manufacturer's indirect comparison of tocilizumab with TNF-alpha inhibitors and anakinra. The Committee noted that the manufacturer used data from the TENDER trial and the NCT00036374 trial to perform an indirect comparison between tocilizumab and infliximab, and used infliximab to represent the class effect of the TNF-alpha inhibitors. The Committee was aware that the NCT00036374 trial was not specifically for patients with systemic JIA and included patients with other subtypes of JIA. However, the Committee noted that patients on tocilizumab were significantly more likely to reach an ACR30 response than patients on infliximab. The Committee also noted the manufacturer presented evidence from the ANAJIS trial that compared anakinra with placebo. The primary outcome measured in the ANAJIS trial was a modified ACR30 response without fever, measured after 4\xa0weeks. The Committee noted that the TENDER and ANAJIS trials were used for an indirect comparison analysis of tocilizumab with anakinra. The Committee also noted that the manufacturer used the whole population from the TENDER trial to represent tocilizumab, whereas the ERG used only the 95% of patients whose condition had not responded to methotrexate. The Committee noted that patients on tocilizumab were significantly more likely to reach an ACR30 response than patients on anakinra. The Committee also noted that there was no significant difference between tocilizumab and anakinra in terms of ACR30 response plus absence of fever. The Committee concluded from the indirect comparison data that tocilizumab was clinically effective compared with anakinra and infliximab.\n\n# Cost effectiveness\n\nThe Committee considered the revised economic model submitted by the manufacturer that included the patient access scheme for cost-effectiveness analysis. The Committee heard how homogenous health states had been defined by CHAQ score and had been categorised as 'controlled', 'mild', 'moderate', and 'severe'. The Committee noted that health states were based on CHAQ scores and regression models had been used to predict expected CHAQ categories using ACR responses. The Committee also noted that there was the possibility that individuals could have the same ACR response and still be in different baseline CHAQ categories, The Committee heard from the ERG that using ACR to define response transitions adhered to common modelling practice. It further noted that the application of the regression model from the 12 week data from the TENDER trial to the baseline CHAQ score to predict 12 week CHAQ values had not been adequately explained. The Committee concluded that although the manufacturer had submitted a revised economic model that represented the natural history of systemic JIA and its response to treatment better than the original model, there were still concerns with some aspects of the model.\n\nThe Committee considered the utility values used in the revised economic model. The Committee noted that the manufacturer had identified limitations of the CHQ (which had been used in the TENDER trial to elicit patients' health-related quality of life) and therefore had instead used data from the CHAQ. The manufacturer had made the assumption that the CHAQ score of a child was equal to the HAQ score of an adult and that the adult EQ-5D was equal to the health-related quality of life of a child. The Committee expressed concern about the methods and assumptions that had been used by the manufacturer and considered the utility value of 0.19 assigned to the severe health state in the revised model to be implausible given that approximately two thirds of children entered the model in this state. The Committee heard from the ERG that as most children leave the severe health state after 12 weeks, this may only have a limitedeffect on the long-term model. The Committee concluded however that this would over-estimate the incremental QALY gain ascribed to tocilizumab.\n\nThe Committee considered the costs for tocilizumab used in the revised economic model. The Committee noted that the costs of treatment were a composite of cost of medication and cost of administering the medication. The Committee heard from the clinical specialists that the costs for the health states in the model were a reasonable reflection of clinical practice in the UK. The Committee concluded that the costs in the model were reasonable, however it noted that potential cost savings could result from reductions in orthopaedic surgery for future joint damage and in bone marrow transplant and stem cell procedures, and that these factors had not been taken into account in the revised model.\n\nThe Committee considered the starting age of 5 years in the manufacturer's revised economic model and noted the comment received from a consultee that this was too high. The Committee concluded that the start age in the model was a mean age of 5\xa0years and therefore the spread would include children who were below 5\xa0years of age.\n\nThe Committee considered the manufacturer's revised base-case results with the patient access scheme applied. The Committee noted that the anakinra treatment strategies had used the primary outcome of ACR30 response and no fever. The Committee noted that two distinct incremental analyses had been performed: an anakinra-containing strategy that evaluated the strategies of tocilizumab followed by anakinra and anakinra followed by tocilizumab, and how each compared to anakinra alone. The manufacturer had done the same analyses for tocilizumab and infliximab. The Committee heard from the ERG that the incremental analyses the manufacturer presented were not fully incremental. The ERG also noted that the manufacturer's analyses were only designed to compare two technologies with one. The Committee further heard from the ERG that a more rigorous analysis would have involved tocilizumab, infliximab and anakinra in the same sequence using tocilizumab in different places of the sequence. The Committee also noted that as well as not conducting a fully incremental analysis, the manufacturer had not conducted a revised probabilistic sensitivity analysis. The Committee therefore concluded that the manufacturer's cost-effectiveness estimates could not be considered robust.\n\nThe Committee reviewed the ERG's exploratory analyses of the revised model, which included the patient access scheme. The Committee noted the ERG's analysis for the strategy tocilizumab then infliximab, compared with infliximab alone. The Committee considered that this strategy was the most appropriate because tocilizumab is the only licensed technology for systemic JIA and because the strategy of tocilizumab then anakinra compared with anakinra was not considered to be cost effective. The Committee agreed that the ERG's deterministic sensitivity analysis results were preferable to the ERG's probabilistic sensitivity analysis because only a limited number of simulations of the data were run in the probabilistic analysis. Despite the considerable uncertainty around the ICERs, the most plausible ICERs for the strategy tocilizumab followed by infliximab compared with infliximab alone were within a range that would be considered an acceptable use of NHS resources. Given the other factors that had not been taken account of in the manufacturer's model (such as steroid sparing, a decrease in health-related quality of life of the parents or carers, reduction in future orthopaedic surgical operations, bone marrow transplantation and stem cell procedures), on balance, the Committee concluded that the resulting cost-effectiveness estimate would be at the lower end of this range.\n\nThe Committee considered the manufacturer's revised sensitivity analyses that included the patient access scheme. The Committee noted the manufacturer's results, and the uncertainty around the adjustment factor derived from the etanercept study used to take account of other types of JIA subgroups in the infliximab study. The Committee noted that an increase or decrease of the adjustment factor by 30% on the tocilizumab then infliximab strategy made only a small difference to the manufacturer's revised base-case ICER. The Committee concluded that the revised model was robust to the sensitivity analyses of the adjustment factor.\n\nThe Committee considered the manufacturer's revised scenario analyses including the patient access scheme that looked at the impact of decreasing the frequency of administration of tocilizumab from every 2 to every 4 weeks after a treatment period of 6 months and of stopping tocilizumab after 2 years of treatment. The Committee noted that both scenarios improved the cost effectiveness of tocilizumab further. The Committee had heard from the clinical specialists that in some instances tocilizumab would be stopped when patients were in complete remission or dose administrations decreased when there was a significant improvement in the patient's condition. The Committee was of the view that when these situations arise in clinical practice that clinicians could consider reducing the frequency of administration of tocilizumab or stop using tocilizumab. The Committee also highlighted the importance of registries in collecting further data on patients receiving tocilizumab so that specific information about long-term outcomes and treatment-related adverse events in systemic JIA can be collected.\n\nIn summary, because the Committee did not have any clinical evidence on the comparison of tocilizumab with methotrexate, it concluded that tocilizumab could not be recommended for the treatment of systemic JIA in children and young people aged 2\xa0years and older whose disease continues to respond to methotrexate or who have not been treated with methotrexate. For the population of children whose systemic JIA has not responded adequately to methotrexate as well as NSAIDs and corticosteroids, the Committee accepted the manufacturer's revised model despite its reservations about some aspects of the cost-effectiveness evaluation. The Committee noted the patient access scheme proposed by the manufacturer is a simple discount and would not incur additional costs. Consequently, the Committee concluded that tocilizumab represents a cost-effective use of NHS resources and should be offered as an option for the treatment of systemic JIA in children and young people aged 2 years and older whose condition has inadequately responded to NSAIDs, corticosteroids and methotrexate.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA238\n\nAppraisal title: Tocilizumab for the treatment of systemic juvenile idiopathic arthritis\n\nSection\n\nKey conclusion\n\nTocilizumab is recommended as an option for the treatment of systemic juvenile idiopathic arthritis in children and young people aged 2 years and older whose disease has responded inadequately to non-steroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids and methotrexate if the manufacturer makes tocilizumab available with the discount agreed as part of the patient access scheme.\n\nBecause the Committee did not have any clinical evidence on the comparison of tocilizumab with methotrexate, it concluded that tocilizumab could not be recommended for the treatment of systemic JIA in children and young people aged 2\xa0years and older whose disease continues to respond to methotrexate or who have not been treated with methotrexate.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard that children with systemic JIA experience severe pain and fatigue, and considerable disability. These children could be prescribed systemic corticosteroids over long periods of time. They could therefore experience increased morbidity and adverse effects that can lead to chronic conditions including infections, diabetes mellitus, cardiovascular complications and osteoporosis in later life, and risk of long-term joint damage and need for joint replacement. In addition, they may have visible side effects such as growth restriction and Cushing's syndrome. The Committee heard from the clinical specialists in the UK, patients with systemic JIA are treated first with NSAIDs and systemic corticosteroids. Methotrexate is then used if disease activity persists. If the child is intolerant of methotrexate or their condition does not adequately respond to an adequate trial of methotrexate, TNF alpha inhibitors or anakinra are the next treatment options to be used.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee heard from the patient expert how tocilizumab had made such a considerable difference to a child's symptoms that the child now had significantly less pain and better energy levels and could concentrate sufficiently to participate in school. The Committee also heard that a significant number of children taking tocilizumab had been able to reduce or completely stop using steroids and therefore the visible side effects of the corticosteroid treatment were no longer present.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee heard that there are currently no other treatments specifically licensed for systemic JIA. The Committee heard from the clinical specialists that in routine clinical practice in the UK, patients with systemic JIA are treated first with NSAIDs and systemic corticosteroids.\n\nThe Committee heard there is variation in the use of tocilizumab in the UK, but tocilizumab is currently being used for patients whose condition does not respond to methotrexate, or following TNF alpha inhibitors or anakinra.\n\n\n\n\n\n\n\n\n\n\n\nAdverse effects\n\nUpper respiratory tract infection, with typical symptoms such as cough, blocked nose, runny nose, sore throat and headache, is one of the most common side effects of tocilizumab. Other reported side effects include rash, urticaria, diarrhoea, epigastric discomfort and arthralgia. Infusion-related reactions that can be considered serious and life-threatening (such as angioedema) have also been reported.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee considered the evidence for the effectiveness of tocilizumab and noted that the manufacturer derived data from the TENDER trial, part one of which was a 12-week randomised controlled trial that compared the efficacy of tocilizumab with placebo.\n\nThe Committee noted that the manufacturer used data from the TENDER trial and the NCT00036374 trial to perform an indirect comparison between tocilizumab and infliximab, and used infliximab to represent the class effect of the TNF-alpha inhibitors.\n\nThe Committee also noted the manufacturer presented evidence from the ANAJIS trial that compared anakinra with placebo.\n\nFor the population of patients whose systemic JIA had failed to respond to NSAIDs and systemic corticosteroids, the Committee noted that only 5% of the TENDER trial population were methotrexate naive.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee heard from the clinical specialists that the population was largely generalisable to the UK, but that the mean age of approximately 10\xa0years in the TENDER trial was older than the population they would treat with tocilizumab in routine clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee also noted that the manufacturer had used a post-hoc analysis to compare patients receiving tocilizumab with those patients in the placebo group receiving methotrexate and that this was not methodologically acceptable. The Committee noted that in practice some patients' systemic JIA would still be responding adequately to methotrexate but no data for these patients had been presented. The Committee therefore concluded that there was no evidence to allow them to further consider the clinical or cost effectiveness of tocilizumab compared with methotrexate.\n\nThe Committee noted that the manufacturer used data from the TENDER trial and the NCT00036374 trial to perform an indirect comparison between tocilizumab and infliximab, and used infliximab to represent the class effect of the TNF-alpha inhibitors. The manufacturer used data from the TENDER trial and the ANAJIS trial to perform an indirect comparison between anakinra with placebo.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo clinically relevant subgroups were identified for which there was differential effectiveness.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee considered the evidence on the clinical effectiveness of tocilizumab in the population who had experienced treatment failure with NSAIDs, systemic corticosteroids and methotrexate. It noted that there were statistically significant improvements in the primary efficacy endpoint (ACR30 response and no fever) and all secondary endpoints at 12 weeks when tocilizumab was compared with placebo.\n\nThe Committee noted the evidence and analyses conducted by the manufacturer from the TENDER, NCT0036374 and ANAJIS trials. The Committee noted that patients on tocilizumab were significantly more likely to reach an ACR30 response than patients on anakinra. The Committee also noted that there was no significant difference between tocilizumab and anakinra in terms of ACR30 response plus absence of fever. The Committee concluded from the indirect comparison data that tocilizumab was clinically effective compared with anakinra and infliximab.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer provided a revised economic model in which CHAQ categories define health states. The health states were defined as 'controlled' 'mild', 'moderate' and 'severe'. A simulated patient distribution of CHAQ score based on the TENDER trial was used to establish the proportion of patients that would fall into each CHAQ category at baseline. The manufacturer used ACR as a potential predictor of the CHAQ score.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that health states were based on CHAQ scores and regression models had been used to predict expected CHAQ categories using ACR responses.\n\nThe Committee further noted that the application of the regression model from the 12 week data from the TENDER trial to the baseline CHAQ score to predict 12 week CHAQ values had not been adequately explained. The Committee concluded that although the manufacturer had submitted a revised economic model that represented the natural history of systemic JIA and its response to treatment better than the original model, there were still concerns with some aspects of the model.\n\nThe Committee expressed concern about the methods and assumptions that had been used by the manufacturer and considered the utility value 0.19 assigned to the severe health state in the revised model to be implausible given that approximately two thirds of children entered the model in this state. The Committee heard from the ERG that as most children leave the severe health state after 12 weeks, this may only have a limited effect on the long-term model. The Committee concluded however that this would over-estimate the incremental QALY gain ascribed to tocilizumab.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe condition has an effect on the wider family, with siblings finding it distressing to see the child living with the condition, and parents and carers often have to stay at home and care for the child if they are unable to attend school. These have not been captured in the model.\n\nThe Committee noted that certain factors had not been taken into account of in the manufacturer's model such as steroid sparing, a decrease in health related quality of life of the parents and carers, reduction in future orthopaedic surgical operations, bone marrow transplantation and stem cell procedures.\n\n\n\n\n\n\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nChildren and young people aged 2 years and older whose disease has responded inadequately to NSAIDs systemic corticosteroids and methotrexate. This is cost effective only if the manufacturer makes tocilizumab available with the discount agreed as part of the patient access scheme.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe starting age of treatment of systemic JIA.\n\nThe potential decrease of frequency of administration of tocilizumab from every 2 to every 4 weeks after a treatment period of 6 months and of stopping tocilizumab 2 years of treatment. The Committee noted that both scenarios were likely to improve the cost effectiveness of tocilizumab.\n\n\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nDespite the considerable uncertainty around the ICERs, the most plausible ICERs for the strategy tocilizumab followed by infliximab compared with infliximab alone in children and young people aged 2 years and older whose disease has responded inadequately to NSAIDs, systemic corticosteroids and methotrexate were within a range that would be considered an acceptable use of NHS resources. Given the other factors that had not been taken account of in the manufacturer's model (such as steroid sparing, a decrease in health-related quality of life of the parents or carers, reduction in future orthopaedic surgical operations, bone marrow transplantation and stem cell procedures), on balance, the Committee concluded that the resulting cost-effectiveness estimate would be at the lower end of this range.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nA patient access scheme was submitted by the manufacturer. The level of discount is commercial in confidence\n\n\n\nEnd-of-life considerations\n\nThe supplementary advice was not relevant to this appraisal.\n\n\n\nEqualities considerations and social value judgements\n\nNo equalities issues were raised in this appraisal.\n\n", 'Related NICE guidance': 'Guidance on the use of etanercept for the treatment of juvenile idiopathic arthritis.NICE technology appraisal guidance 35 (2002).', 'Review of guidance': 'The guidance on this technology will be considered for review in December 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveDecember 2011', 'Changes after publication': 'February 2014: minor maintenance\n\nJune 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta238
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Evidence-based recommendations on tocilizumab (RoActemra), for treating systemic juvenile idiopathic arthritis in people aged 2 and over.
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69f37f5911462c66106cf5d24da8a8f3c4684104
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Fulvestrant for the treatment of locally advanced or metastatic breast cancer
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Fulvestrant for the treatment of locally advanced or metastatic breast cancer
Evidence-based recommendations on fulvestrant (Faslodex), for treating locally advanced or metastatic breast cancer in adults.
# Guidance
Fulvestrant is not recommended, within its licensed indication, as an alternative to aromatase inhibitors for the treatment of oestrogen-receptor-positive, locally advanced or metastatic breast cancer in postmenopausal women whose cancer has relapsed on or after adjuvant anti-oestrogen therapy, or who have disease progression on anti-oestrogen therapy.
Post-menopausal women currently receiving fulvestrant within its licensed indication as an alternative to aromatase inhibitors for the treatment of oestrogen-receptor-positive, locally advanced or metastatic breast cancer whose cancer has relapsed on or after adjuvant anti-oestrogen therapy, or who have disease progression on anti-oestrogen therapy, should have the option to continue treatment until they and their clinicians consider it appropriate to stop.# The technology
Fulvestrant (Faslodex, AstraZeneca) is an oestrogen antagonist belonging to a class of agents known as selective oestrogen receptor down-regulators (SERDs). Fulvestrant has a UK marketing authorisation for 'the treatment of postmenopausal women with oestrogen receptor positive, locally advanced or metastatic breast cancer for disease relapse on or after adjuvant anti-oestrogen therapy, or disease progression on therapy with an anti-oestrogen'. The recommended dose is 500 mg (administered as two intramuscular injections of 250 mg) every month, with an additional 500 mg dose given 2 weeks after the initial dose.
According to the summary of product characteristics, the most common side effects associated with fulvestrant are nausea, vomiting, diarrhoea, venous thromboembolism, anorexia, headache, asthenia, urinary-tract infections, hot flushes, back pain, rash, injection-site reactions and hypersensitivity reactions ('British national formulary' edition 61). For full details of side effects and contraindications, see the summary of product characteristics.
The current NHS list price of fulvestrant is £522.41 for 2 x 5 ml (250 mg) prefilled syringes (excluding VAT; BNF edition 61). The first month of treatment with fulvestrant 500 mg includes an additional loading dose administered 2 weeks after the initial dose, resulting in a cost of £1044.82 for the first month. In subsequent months, the cost of fulvestrant 500 mg is £522.41 per month. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of fulvestrant and a review of this submission by the Evidence Review Group (ERG; appendix B).
The manufacturer's submission presented clinical-effectiveness data derived from one phase III trial (CONFIRM), supported by results from two dose-ranging phase II trials (FINDER-1 and FINDER-2). Women were eligible for these three studies if they were postmenopausal and had oestrogen-receptor-positive breast cancer. Their cancer could have relapsed during or within 12 months of completing adjuvant hormone therapy (with an anti-oestrogen or an aromatase inhibitor) for early breast cancer; or it could have progressed on anti-oestrogen or aromatase inhibitor therapy for advanced breast cancer provided that this hormone therapy was started more than 12 months after completion of adjuvant hormone therapy (anti-oestrogen or aromatase inhibitor); or it could have progressed while they were on first-line hormone therapy (anti-oestrogen or aromatase inhibitor) for advanced breast cancer. All three trials excluded patients who had received two or more lines of previous hormone therapy for locally advanced or metastatic breast cancer.
The CONFIRM trial was an international multicentre double-blind parallel-group randomised controlled trial (RCT) that included 736 patients who had previously received an anti-oestrogen or an aromatase inhibitor for the adjuvant treatment of early breast cancer or as palliative therapy for advanced breast cancer. Patients were randomised on a 1:1 basis to receive either fulvestrant 500 mg or fulvestrant 250 mg. The mean age of the patients was 61 years. The baseline characteristics of the groups in the two arms of the trial were generally comparable, although more patients in the fulvestrant 250 mg arm (102 compared with 69) had received radiotherapy as treatment for advanced disease.
The primary outcome measure in the CONFIRM study was median time to progression (TTP). Median TTP was statistically significantly longer in the overall mixed population (that is, including both patients who had previously received an anti-oestrogen and patients who had previously received an aromatase inhibitor) for the fulvestrant 500 mg arm compared with the fulvestrant 250 mg arm (6.5 months compared with 5.5 months; hazard ratio 0.80; 95% confidence interval 0.68 to 0.94; p = 0.006). A pre-planned analysis was done for the subgroups of patients last treated with an anti-oestrogen (58%) or an aromatase inhibitor (42%). The median TTPs for the fulvestrant 500 mg and fulvestrant 250 mg arms were 8.6 months and 5.8 months respectively (HR 0.76; 95% CI 0.62 to 0.94; p = 0.013) for the population last treated with an anti-oestrogen, and 5.4 months and 4.1 months respectively for the population last treated with an aromatase inhibitor (HR 0.85; 95% CI 0.67 to 1.08; p = 0.195).
Secondary outcomes reported in the CONFIRM study included objective response rate, clinical benefit rate and overall survival. The results suggested no statistically significant differences between the fulvestrant 500 mg and 250 mg arms for these outcomes, although the median overall survival was greater in the fulvestrant 500 mg group (25.1 months compared with 22.8 months). Log-rank tests suggested a trend for improved overall survival in the fulvestrant 500 mg group (HR 0.84; 95% CI 0.69 to 1.03; p = 0.091). Overall survival data from the CONFIRM trial were not mature: 51% of patients had died at the time of primary data cut-off for TTP. The manufacturer stated that it plans to re-analyse the overall survival data when 75% of patients have died.
A total of 2443 adverse events were reported by 483 (66%) of the 735 patients in the safety analysis in the CONFIRM trial. A serious adverse event was reported for 54 patients (7%), including 11 patients (1%) who died. Seventeen patients (2%) discontinued fulvestrant treatment because of an adverse event. There were no notable differences in the incidence of adverse events between treatment groups. The most common adverse events were injection-site pain (11.6%), nausea (9.7%) and bone pain (9.4%).
The manufacturer also provided health-related quality of life data taken from the CONFIRM study for a total of 145 women who completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire at baseline. No significant differences were detected between the fulvestrant 500 mg and 250 mg study arms.
The FINDER-1 study was a multicentre parallel-group double-blind phase II RCT conducted in Japan. A total of 143 patients recruited from 40 centres were randomised on a 1:1:1 basis to receive fulvestrant 500 mg, fulvestrant 250 mg or fulvestrant 250 mg with a loading dose. The FINDER-2 study was a multicentre international double-blind phase II RCT conducted in seven European countries and Canada. A total of 144 patients were recruited from 34 centres and randomised on a 1:1:1 basis to receive fulvestrant 500 mg, fulvestrant 250 mg or fulvestrant 250 mg with a loading dose. The primary outcome in the FINDER-1 and FINDER-2 trials was objective response rate, with secondary outcomes including clinical benefit rate and TTP. The findings from these trials were broadly in favour of fulvestrant 500 mg compared with fulvestrant 250 mg.
The manufacturer conducted a network meta-analysis to compare overall survival and TTP for fulvestrant 500 mg with the comparators listed in the scope. Five RCTs that included three of the other comparators (anastrozole, letrozole and fulvestrant 250 mg) listed in the scope were identified in the systematic literature review, resulting in eight trials being included in the network meta-analysis. Data from the total population in the fulvestrant trials were included, with the FINDER-1 and FINDER-2 trials contributing only to the TTP network meta-analysis. The manufacturer stated that inclusion of the group from the CONFIRM trial who had received an aromatase inhibitor as their last treatment did not alter the results in favour of fulvestrant. The manufacturer did not include exemestane as a comparator in the base-case network meta-analysis because of a lack of any relevant trials in which 70% or more patients had documented hormone-receptor-positive advanced breast cancer in a population who had received an anti-oestrogen. Therefore a secondary scenario analysis, as part of the cost-effectiveness analysis comparing fulvestrant 500 mg with exemestane, was carried out by the manufacturer.
For the base-case network meta-analysis, data on two outcomes were collected: overall survival and TTP. Data from the eight included trials were pooled and extrapolated. Based on patient-level data from the CONFIRM trial, the Weibull distribution was identified as the best-fitting distribution to estimate overall survival. Because hazard ratios in the CONFIRM trial were constant over time (the shape parameters were very similar for both treatment groups), the relative treatment effects of the alternative treatments were applied to the baseline treatment (fulvestrant 250 mg) using a pooled hazard ratio for overall survival estimated from the network meta-analysis. For TTP, the log-normal distribution was identified by the manufacturer as the best-fitting distribution for data from the CONFIRM trial because it was inappropriate to assume that hazard ratios were constant over time. A simultaneous extrapolation and network meta-analysis of TTP curves for all comparator treatments were derived from the available RCTs. This was done by relating the TTP Kaplan-Meier curves of each of the comparators directly to the parameters of the log-normal survival curves. A fixed-effects model was used to simultaneously extrapolate Kaplan-Meier curves over time by means of log-normal curves, to synthesise and to indirectly compare the different treatments. The shape and scale parameters for the baseline treatment (fulvestrant 250 mg) were estimated and used as the anchor to obtain estimates for the shape and scale parameters of the other comparators. Pooled TTP curves for each treatment were produced and the corresponding area under the curve was calculated to obtain the mean TTP estimates for each treatment.
The results of the network meta-analysis presented by the manufacturer suggested that fulvestrant 500 mg was associated with longer overall survival compared with fulvestrant 250 mg, anastrozole and letrozole, but this finding was not statistically significant. The results of the TTP network meta-analysis suggested that fulvestrant 500 mg was associated with a statistically significantly longer TTP than fulvestrant 250 mg, whereas anastrozole was associated with a statistically significantly shorter TTP than fulvestrant 250 mg. There were no statistically significant differences in TTP between letrozole 2.5 mg and fulvestrant 250 mg.
The manufacturer developed an Excel-based cost–utility model, based on a time-in-state model structure. The model structure is similar to that of a Markov cohort model, with three possible health states: pre-progression, post-progression and death. However, instead of using transition probabilities to determine movement between health states, the model calculates the proportion of patients in each health state according to the estimated survival functions for TTP and overall survival. All patients are assumed to be in the pre-progression health state at model entry (baseline). The duration of second-line hormonal therapy is assumed to be the same as the amount of time spent in the pre-progression health state. The post-progression health state captures a series of subsequent therapies, including third-line hormonal therapy, up to three sequential lines of chemotherapy, and supportive palliative care. Patients can move to the state of death from either the pre-progression or the post-progression health state, which captures death from any cause. The model uses monthly cycles with a lifetime (13-year) time horizon.
The results of the base-case network meta-analysis of the clinical effectiveness data on TTP and overall survival were used to populate the economic model. For the base-case analysis, comparator treatments were fulvestrant 250 mg, anastrozole and letrozole. The manufacturer used the overall CONFIRM trial population (that is, a mixed population who had received either an anti-oestrogen or an aromatase inhibitor as their last treatment) in the analysis. The manufacturer reported that it was not feasible to analyse the proportion of patients with grade 3 or grade 4 adverse events because adverse events were not reported consistently across the trials included in the network meta-analysis. However, the manufacturer included serious adverse events in the model because sufficient data were available to conduct a network meta-analysis. The serious adverse event data used in the model included both treatment-related and treatment-independent events, because these were available for all relevant RCTs used to derive the estimates of TTP and overall survival in the base-case analysis.
Health-related quality of life data based on the FACT-B questionnaire were collected at baseline (pre-progression) from a subgroup of patients in the CONFIRM study. However, the model structure required utility values for the pre-progression and post-progression health states that were not collected in the CONFIRM study. Therefore the manufacturer used published pre-progression and post-progression utility values based on a systematic literature review of utility studies for metastatic or locally advanced breast cancer. The manufacturer considered that the study by Lloyd et al. (2006) provided the most appropriate utility values. In this study, utility values were taken from a relatively small sample of the general public in the UK using the standard gamble technique. The study provided utility values of 0.72 and 0.44 for the pre-progression and post-progression health states respectively. Death was assigned a utility value of zero. Disutilities associated with treatment-related adverse events were not included in the model.
Resource use and costs in the economic model included those related to each second-line hormonal treatment used during the pre-progression phase, subsequent treatments during the post-progression phase including third-line hormonal therapy, supportive palliative care and chemotherapy, and treatment-related adverse events. No treatment-related monitoring costs associated with fulvestrant 500 mg or its comparators were included in the model. An overall average cost per monthly cycle of £1084 per patient was applied to each treatment arm for the patients in the post-progression health state. For adverse events, the model assumed that each serious adverse event is associated with an average hospital stay of 5 days at a cost of £321.02 per day, which was then weighted by the proportion of serious adverse events estimated in the network meta-analysis for each hormonal treatment considered in the scope. The model assumed that one-third of patients received fulvestrant in primary care and two-thirds in hospital.
The manufacturer reported the results from the economic model for the two key clinical outcomes, TTP and overall survival. The mean TTP was 15.0 months for fulvestrant 500 mg compared with 10.8 months for fulvestrant 250 mg, 9.5 months for anastrozole and 9.9 months for letrozole. The mean overall survival was 33.4 months for fulvestrant 500 mg compared with 29.0 months for fulvestrant 250 mg, 28.5 months for anastrozole and 24.9 months for letrozole.
In the base-case incremental analysis, fulvestrant 500 mg was associated with the highest total quality-adjusted life years (QALYs) (1.487 QALYs), followed by fulvestrant 250 mg (1.256 QALYs), anastrozole (1.214 QALYs) and letrozole (1.105 QALYs). Based on an incremental analysis ranking of treatments, the base-case results demonstrated that anastrozole and fulvestrant 250 mg were extendedly dominated by (that is, were more expensive and less effective than) a combination of two other single-agent treatments, fulvestrant 500 mg and letrozole. The comparison of fulvestrant 500 mg with letrozole produced an incremental cost-effectiveness ratio (ICER) of £31,982 per QALY gained (representing incremental costs of £12,239 and incremental QALYs of 0.383). The manufacturer stated that no patients were assumed to be on an adjuvant switch hormone treatment strategy (that is, sequential treatment with an anti-oestrogen and an aromatase inhibitor).
The manufacturer conducted deterministic sensitivity analyses by varying key model input parameters. These showed that the key drivers of the cost-effectiveness results were the estimates of TTP and overall survival for all treatments and the utility values assigned to the pre-progression and post-progression health states. The widest range of ICERs was found for the comparison of fulvestrant 500 mg with letrozole, in which the ICERs ranged from £21,894 to £55,160 per QALY gained when the upper and lower 95% credibility limits for the scale and log shape of the log-normal distribution of TTP for letrozole were used.
The manufacturer also conducted six scenario analyses to assess the impact of key assumptions made in the base-case analysis. These scenarios included: expanding the patient population to allow the inclusion of exemestane in the network meta-analysis (by including trials in which at least 50% of patients had documented hormone-receptor-positive cancer and patients who had last been treated with an aromatase inhibitor ); using alternative proportions for the administration of fulvestrant in the primary care setting and in hospital; altering the cost of the post-progression health state by using an alternative mix of chemotherapies; altering the cost of the post-progression health state by eliminating treatment skipping (patients skip further hormonal treatment if the extent and duration of response to a previous hormonal treatment was insufficient); discounting costs and benefits at 0% and 6%; and altering the time horizon. In summary, exemestane, anastrozole and fulvestrant 250 mg were all extendedly dominated by a combination of fulvestrant 500 mg and letrozole. The comparison of fulvestrant 500 mg with letrozole gave a range of ICERs from £29,881 to £38,566 per QALY gained.
The results of the manufacturer's probabilistic sensitivity analysis showed that, at a threshold of £20,000 per QALY gained, there is a 2% probability of fulvestrant 500 mg being cost effective. This increased to 20% at a threshold of £30,000 per QALY gained.
# ERG comments on the manufacturer's submission
The ERG commented that the manufacturer's systematic review of clinical-effectiveness studies was methodologically appropriate and that all relevant studies meeting the inclusion criteria appeared to have been identified.
The ERG commented that the CONFIRM study was well designed and that the clinical outcomes reported in this RCT and the supporting phase II trials (FINDER-1 and FINDER-2) address all the relevant outcomes outlined in the scope. However, the ERG noted that fulvestrant is currently most commonly used in clinical practice in England and Wales after aromatase inhibitors and often after an anti-oestrogen as well, and therefore it is a third- or fourth-line hormonal therapy in the treatment pathway for advanced breast cancer. In the fulvestrant trials used as the basis for direct clinical evidence and in the manufacturer's submission, fulvestrant was used in the treatment pathway in the position currently occupied by aromatase inhibitors, as second-line treatment. Therefore, the ERG commented that the generalisability of the patient population and trial results to clinical practice may be questionable, because there is a difference between the indication in the marketing authorisation for fulvestrant and its use in treatment in England and Wales.The ERG also noted that no patients were recruited to CONFIRM from the UK.
The ERG highlighted that the marketing authorisation for fulvestrant 500 mg specifies that the patient has received previous anti-oestrogen therapy, although the ERG noted that it is not clear from the wording of the marketing authorisation that eligibility for treatment depends on the last therapy received. Therefore, the ERG requested that the manufacturer divide the TTP data from CONFIRM in two main ways. First, the patients were divided into two treatment groups: patients who had received an anti-oestrogen as their last treatment (58%) and patients who had received an aromatase inhibitor as their last treatment (42%). Second, the patients were split into three treatment groups: patients who had received an anti-oestrogen but not an aromatase inhibitor; patients who had received an aromatase inhibitor but not an anti-oestrogen; and patients who had received both an anti-oestrogen and an aromatase inhibitor. The second set of data was provided 'in confidence'. The ERG noted from the patients divided into two treatment groups that 65.5% of patients who had received an anti-oestrogen as their last treatment were receiving fulvestrant as a first-line treatment for locally advanced or metastatic breast cancer, whereas 66.8% of patients who had received an aromatase inhibitor as their last treatment received fulvestrant as a second-line therapy for advanced breast cancer. The ERG also demonstrated significant differences between the demography of these two groups: the proportion of patients treated with hormone therapy for advanced disease was 34% in the anti-oestrogen group compared with 67% in the aromatase inhibitor group; and the proportion who had received two previous hormone therapies was 4% in the anti-oestrogen group compared with 27% in the aromatase inhibitor group. The ERG therefore speculated that the apparent increased benefit for fulvestrant after an anti-oestrogen rather than after an aromatase inhibitor may be influenced by where in the treatment sequence most patients received fulvestrant, rather than by whether the last treatment before fulvestrant was an anti-oestrogen or an aromatase inhibitor.
The ERG considered that the manufacturer's base-case economic evaluation was well conducted and closely matched the NICE reference case. The main issue raised by the ERG related to the use of data from the network meta-analysis, which included patients from the CONFIRM trial who had been treated previously with an aromatase inhibitor. The ERG considered it more appropriate to base the model only on patients who had previously received anti-oestrogen therapy, particularly in view of the heterogeneity of the anti-oestrogen and aromatase inhibitor groups. The ERG considered that the advantage of this approach of reducing the heterogeneity of the compared populations outweighed the main disadvantage of reducing the statistical power of the CONFIRM trial.
In its critique of the network meta-analysis, the ERG noted that in the comparator treatment trials, none of the patients had received a prior aromatase inhibitor. In addition, the ERG noted key differences in the baseline characteristics of the populations in the trials included in the network meta-analysis. For example, the percentage of patients whose oestrogen receptor status was not known to be positive ranged from to 0% (CONFIRM, FINDER-1 and FINDER-2) to 33.1% (Buzdar 1996/98); the proportion of patients treated previously with chemotherapy ranged from 35.1% (Buzdar 1996/98) to 72.5% (FINDER-1); and the proportion of patients with visceral spread was variable, although the ERG noted that the proportion of patients with known visceral spread was high in the fulvestrant trials.
Overall, the ERG considered that the population in the CONFIRM trial was heterogeneous and that it was not meaningful to regard the group who had received an anti-oestrogen and the group who had received an aromatase inhibitor as similar. The ERG suggested that the network meta-analyses should include data only from patients who had received an anti-oestrogen as their last treatment from the CONFIRM, FINDER-1 and FINDER-2 trials. Therefore the ERG re-ran the analysis using only data from CONFIRM trial patients whose previous hormone therapy was an anti-oestrogen (n = 423). The results were comparable with those obtained when the whole population of the CONFIRM trial was included in the analysis. All hazard ratios for overall survival still favoured fulvestrant 500 mg over other treatments considered in the scope, although the results were not statistically significant.
For the TTP network meta-analysis, the ERG questioned the assumption that the CONFIRM trial results follow a log-normal distribution. A direct comparison of the Kaplan-Meier analysis of the trial results with the outputs of the manufacturer's log-normal model appeared to suggest a reasonable match between data (TTP) and model. However, the ERG noted some divergence after 18 months, which would affect the projection of survival curves beyond the observed data. Therefore, the ERG argued that because the log-normal parametric model used by the manufacturer did not adequately represent the data on which it was calibrated, it should not be used to calibrate TTP estimates for all comparators included in the network meta-analysis. The ERG observed that the results of the Kaplan-Meier analysis from the CONFIRM trial showed a higher number of progression events occurring around 90 days, followed by a 90-day period with relatively few new events. From 180 days onward, there was a clear indication of a linear relationship between time and the cumulative TTP hazard. Therefore the ERG proposed that a more accurate approach would be to split the estimation of TTP into two phases and to include only the anti-oestrogen-treated population from the CONFIRM trial. For the first part of the analysis (0–180 days), the ERG performed a network meta-analysis on the log-hazard ratios at 180 days. For the second part of the analysis (after 180 days), TTP was modelled using an exponential distribution, which has a constant hazard or linear cumulative hazard, based on a clear indication of a linear relationship between time and cumulative TTP hazard in the CONFIRM trial. The results of this analysis showed no statistically significant differences in TTP between the groups receiving fulvestrant 500 mg and those receiving other treatments for the first 180 days (a period thought to be driven by protocol activities and short-term events). However, after 180 days (the ERG stated that this period relates to long-term patient experience) fulvestrant 500 mg was associated with statistically significant improvements in TTP compared with anastrozole and letrozole.
For the overall survival network meta-analysis, the ERG commented that the parametric model used by the manufacturer to estimate overall survival in the network meta-analysis appeared to be a reasonable match with the available CONFIRM trial data. However, the ERG also noted that projections of overall survival beyond the period of observation may be substantially over- or under-estimated because of the complex changes in risk that are likely to apply at later times. Therefore, the ERG suggested that an alternative approach to projective modelling was to consider modelling post-progression patient experience directly on the basis of the trial data, and then to combine pre- and post-progression estimates to obtain the best estimate of overall survival. Examination of post-progression survival data by the ERG showed no statistically significant differences between fulvestrant 500 mg and fulvestrant 250 mg, suggesting that any overall survival gains associated with fulvestrant 500 mg were obtained only in the pre-progression phase (TTP). Therefore the ERG estimated a compatible set of survival estimates (TTP), post-progression survival and overall survival) for fulvestrant 250 mg, anastrozole and letrozole by calibrating a hazard ratio applied to the overall survival estimated for the fulvestrant 500 mg group, which generated a gain in overall survival equal to the corresponding gain in TTP. The ERG noted that although this is an approximation, it allows the timing of post-progression survival to be calculated without elaborate additional modelling. This approach appeared fully justified for anastrozole, because key clinical trials comparing anastrozole with fulvestrant 250 mg showed no statistically significant differences in TTP or overall survival. However, this approach was less clearly supported in the case of letrozole, because there are no trials that directly compare letrozole with fulvestrant.
The ERG noted several criticisms about the design of the manufacturer's economic model, which was based on separate parametric models of the time from randomisation to TTP and overall survival. The ERG commented that when different probability distributions are used to represent the two sets of data, or when the same function is used for both but does not satisfy proportional hazards criteria (that is, the risk of an event occurring on one treatment relative to another treatment is assumed not to change over time), it is possible for projected estimates of TTP to exceed the corresponding estimates of overall survival. Although the model corrected any negative post-progression survival estimates to zero, it did not compensate for any resulting overestimation of survival. Overall, the ERG concluded that the design of the manufacturer's economic model is unlikely to provide a robust basis for projecting survival beyond the observed data.
The ERG identified four issues in relation to the cost data used in the manufacturer's model. First, the manufacturer's model does not account for wastage of part-used dispensed packs at the time of disease progression. Second, the ERG questioned the use of the two expert opinions for pre-progression and post-progression health state costs, and instead proposed that such costs should be based on treatment pathways described in 'Advanced breast cancer: diagnosis and treatment' (NICE clinical guideline 81). Third, the manufacturer's model limits drug-related adverse events to serious adverse events only. Fourth, the manufacturer's approach of applying a single average cost for UK hospital admission is simplistic and inappropriate for costing adverse events associated with treatment complications in advanced breast cancer. The ERG calculated an alternative estimate of £3147 per admission, compared with the estimate in the manufacturer's model of £1605 per episode. Overall, the ERG stated that making these four modifications to the model increased the ICER in all cases but, because each change represents only a small element of the total cost, the increases were small.
Finally, the ERG noted an error in the utility values assigned to the pre-progression and post-progression health states in the manufacturer's economic model. Utility values were based on the age of the participants in the study by Lloyd et al. (2006), taken from a sample of the general UK population, and not on the age of breast cancer patients. The ERG proposed that, to ensure consistency with standard UK EQ-5D tariff scores, the mean age should be set to 47 years (the mean age of the original UK York study sample used). The ERG also accounted for the 'responder status' of patients (that is, whether or not their cancer responded to treatment) when estimating new utility values for both health states. In summary, using ERG estimated utility values of 0.7733 for the pre-progression state and 0.4964 for the post-progression state reduced the ICER for fulvestrant by £2700 per QALY gained compared with letrozole.
The ERG made eight separate modifications to explore the impact of the various issues described in the critique of the manufacturer's economic model. Seven modifications were made to the economic model logic or parameter values, and the eighth modification involved using effectiveness data from the anti-oestrogen subgroup in the CONFIRM trial instead of data from the whole trial population. The ERG presented detailed deterministic results separately for the manufacturer's base-case scenario using the whole CONFIRM population and for the anti-oestrogen subgroup.
In summary, based on the full CONFIRM trial population, the calculated deterministic cost-effectiveness results of the ERG's exploratory analyses showed that fulvestrant 250 mg was extendedly dominated by the other comparators,. The ICERs for anastrozole compared with letrozole and for fulvestrant 500 mg compared with anastrozole were both close to £30,000 per QALY gained. The ERG's preferred exploratory deterministic cost-effectiveness analysis based on the anti-oestrogen subgroup from CONFIRM and an updated network meta-analysis resulted in fulvestrant 250 mg being extendedly dominated by the other comparators. The ICER for anastrozole compared with letrozole was £1162 per QALY gained, and the ICER for fulvestrant 500 mg compared with anastrozole was £34,972 per QALY gained.
Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA239# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of fulvestrant, having considered evidence on the nature of locally advanced or metastatic breast cancer and the value placed on the benefits of fulvestrant by women with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee considered the views of the patient experts on their experience of fulvestrant as a treatment for locally advanced or metastatic breast cancer. It heard from one patient expert who is currently receiving fulvestrant and understood that patients value the availability of a further treatment option after aromatase inhibitors and anti-oestrogen therapies, both as a treatment and because it delays the need for chemotherapy. The Committee also heard from this patient expert that she found the disadvantages of having two injections and the associated side effects of fulvestrant were outweighed by the benefits of remaining fit and well on this therapy. The Committee recognised the importance of additional treatment options for post-menopausal women with locally advanced or metastatic breast cancer.
The Committee considered the licensed indication for fulvestrant. It noted that fulvestrant has a marketing authorisation 'for the treatment of postmenopausal women with oestrogen receptor positive, locally advanced or metastatic breast cancer for disease relapse on or after adjuvant anti-oestrogen therapy, or disease progression on therapy with an anti-oestrogen'. The Committee noted comments from the ERG that it is not clear from the wording of the marketing authorisation that eligibility for treatment depends on the last therapy received and may include women who have received more than one previous line of treatment for metastatic breast cancer. However, the manufacturer confirmed that fulvestrant has a marketing authorisation as a second-line treatment for metastatic breast cancer in postmenopausal women after adjuvant or first-line treatment of advanced disease with an anti-oestrogen therapy (for most patients this is usually tamoxifen). The Committee was aware that 42% of the patients in the CONFIRM trial had received an aromatase inhibitor as their last treatment before fulvestrant. It also heard from the manufacturer that the European Medicines Agency had regarded the results for the group that had received an aromatase inhibitor as being inconclusive and had rejected the manufacturer's request for an extension of the marketing authorisation for fulvestrant to include patients who have experienced treatment failure with an aromatase inhibitor. Therefore the Committee was aware of the restriction of the marketing authorisation to patients who had been treated previously with an anti-oestrogen, and the manufacturer's confirmation about the marketing authorisation, which places fulvestrant, within its licensed indication, as an alternative to aromatase inhibitors after anti-oestrogen treatment.
The Committee considered the likely position of fulvestrant in the treatment pathway for women with oestrogen-receptor-positive advanced breast cancer in the UK. The Committee also examined the recommendations on the use of hormone therapy in the NICE clinical guidelines 'Early and locally advanced breast cancer: diagnosis and treatment' (NICE clinical guideline 80) and 'Advanced breast cancer: diagnosis and treatment' (NICE clinical guideline 81). It observed that aromatase inhibitors were recommended either as the sole, or as a significant part of, adjuvant treatment for most postmenopausal women with oestrogen-receptor-positive early breast cancer. The Committee also understood that aromatase inhibitors were recommended for postmenopausal women with oestrogen-receptor-positive advanced breast cancer who had no history of hormone therapy or who had been treated previously with tamoxifen. It heard from the clinical specialist that clinical practice follows these guidelines, in that most postmenopausal women receive an aromatase inhibitor as adjuvant hormone therapy for early breast cancer or as first-line treatment if presenting with advanced breast cancer. The Committee understood that the use of tamoxifen in clinical practice in postmenopausal women as a sole adjuvant treatment or as a first-line treatment for new locally advanced or metastatic breast cancer is diminishing, apart from in a small group of women with early breast cancer who have a very poor prognosis and in the small proportion of women who are unable to tolerate any aromatase inhibitor. The manufacturer stated in its submission that the split is approximately 20:80 between treatment with aromatase inhibitors and treatment with anti-oestrogens for patients whose disease progresses on or after adjuvant therapy. However, the Committee heard from the clinical specialist that the proportion of patients receiving aromatase inhibitors is increasing because of changes in clinical practice and therefore aromatase inhibitors are now increasingly favoured over anti-oestrogens. The clinical specialist also indicated that there was not thought to be any significant clinical difference between the effectiveness of anastrozole and letrozole for treating advanced disease. The clinical specialist informed the Committee that exemestane or tamoxifen may be offered as a second-line treatment to women whose disease has failed to respond to an aromatase inhibitor given as either adjuvant therapy or first-line treatment for advanced disease, with the choice depending on a variety of factors, including an assessment of how well previous treatment had worked. The Committee heard from the clinical specialist that fulvestrant is currently considered to be a third-line or fourth-line treatment for postmenopausal women with metastatic breast cancer in UK clinical practice. It further heard that there is little or no clinical evidence about the optimal treatment sequence for advanced breast cancer beyond first-line treatment. The Committee considered that the most likely position of fulvestrant in UK clinical practice would remain as a third-line or fourth-line treatment after therapy with aromatase inhibitors and/or an anti-oestrogen therapy. The Committee again noted the difference between the manufacturer's submission and clinical practice, and that fulvestrant was restricted by its marketing authorisation to use after treatment with an anti-oestrogen. However, based on the manufacturer's confirmation about the marketing authorisation for fulvestrant (see section 4.3), the Committee considered that third-line or fourth-line use was not within the remit of this technology appraisal.
The Committee considered the relevant comparator treatments for fulvestrant within its licensed indication. It understood that the scope listed low-dose (250 mg) fulvestrant and aromatase inhibitors (anastrozole, exemestane and letrozole) as the relevant treatment comparators. It heard from the manufacturer that fulvestrant 250 mg has been replaced by fulvestrant 500 mg as the licensed dose. The Committee considered the remaining comparators. It noted that for the only positions in the treatment pathway for which evidence for fulvestrant was available, non-steroidal aromatase inhibitors such as anastrozole and letrozole are the most likely treatments to be used in clinical practice. It heard from the clinical specialist that, for women who are unable to tolerate non-steroidal aromatase inhibitors, exemestane would be the appropriate comparator if they have been treated previously with an anti-oestrogen. The Committee concluded that the aromatase inhibitors anastrozole, letrozole and exemestane are the most appropriate comparators for the appraisal of fulvestrant.
# Clinical effectiveness
The Committee considered the clinical-effectiveness data from the CONFIRM trial. It noted that the only comparator in CONFIRM was low-dose (250 mg) fulvestrant. Relative to this comparator, the Committee noted that fulvestrant 500 mg offered benefits in increasing the TTP, but that the difference between groups was statistically significant only for those patients whose last therapy was an anti-oestrogen, and not for patients whose last therapy was an aromatase inhibitor. However, the Committee was also aware that the CONFIRM trial was not powered to detect a statistically significant difference in TTP between fulvestrant 500 mg and fulvestrant 250 mg in the two patient subgroups. The Committee concluded that fulvestrant 500 mg offered some clinical benefit compared with fulvestrant 250 mg.
The Committee noted that the results of the network meta-analyses by the manufacturer showed no statistically significant differences in overall survival between fulvestrant, anastrozole and letrozole, although fulvestrant resulted in statistically significantly longer TTP compared with anastrozole (but not letrozole). In addition, the Committee observed that parametric survival models had been used to estimate TTP (log-normal distribution) and overall survival (Weibull distribution) for fulvestrant and other comparators included in the network meta-analysis. The Committee agreed with the issues identified by the ERG about the fit of the log-normal survival model used by the manufacturer to estimate TTP for fulvestrant and other comparators included in the network. It agreed that this resulted in a small number of patients with very long TTPs, which was likely to significantly influence the mean TTP. The Committee also noted that, although the parametric model the manufacturer used to estimate overall survival in the network meta-analysis appeared to be a reasonable match with the CONFIRM trial data, the projections of overall survival beyond the period of observation may have been substantially over- or under-estimated because of the complex changes in risk that were likely to apply at later times. Therefore, the Committee concluded that there was high uncertainty about the validity of the results of the network meta-analyses used to estimate TTP and overall survival.
The Committee considered the populations of the trials included in the network meta-analysis, which included aromatase inhibitors as comparators. It was aware that, although the marketing authorisation for fulvestrant 500 mg is for patients who have received previous anti-oestrogen treatment, the CONFIRM, FINDER-1 and FINDER-2 trial populations included some patients who had last received an aromatase inhibitor, whereas all other trials in the network included only patients who had previously received an anti-oestrogen. The Committee further noted differences in the previous anti-oestrogen and previous aromatase inhibitor groups relating to the position of fulvestrant as a first-line or second-line therapy. Data from CONFIRM showed that most (65.5%) patients receiving fulvestrant after an anti-oestrogen therapy received fulvestrant as a first-line treatment for metastatic breast cancer and the remainder (34.5%) received fulvestrant as a second-line treatment for metastatic breast cancer. Conversely, of the patients who received an aromatase inhibitor as their last treatment before fulvestrant, most (66.8%) received fulvestrant as a second-line treatment for advanced breast cancer. The Committee also noted the differences in demography in the anti-oestrogen and aromatase inhibitor populations and agreed with the ERG that these two groups were heterogeneous. Therefore the Committee agreed that only data from the subgroup in the CONFIRM trial who had received an anti-oestrogen as their last treatment before fulvestrant should be included in the network meta-analyses, in line with the marketing authorisation for fulvestrant.
The Committee considered the eligibility criteria for trials included in the network meta-analysis. It was aware that CONFIRM, FINDER-1 and FINDER-2 were the only trials with an entire patient population documented as having oestrogen-receptor-positive breast cancer. The Committee noted that the manufacturer had sought advice from key opinion leaders about setting firm criteria for the selection of trials for inclusion in the meta-analysis (for example, including only recent trials, or agreeing a stipulated percentage of patients with cancer of unknown oestrogen receptor status), but that no such criteria could be agreed. The main inclusion criterion was relaxed by the manufacturer to include trials for comparators with at least 70% of patients with documented oestrogen-receptor-positive status. The Committee was aware that, based on this criterion, exemestane was excluded as a comparator because of the lack of any relevant trials with at least 70% of patients with oestrogen-receptor-positive cancer. The Committee noted that the percentage of patients with oestrogen-receptor-negative cancer in the trials included in the network meta-analysis ranged from 0% to 33%. The Committee also highlighted sources of heterogeneity between the trials included in the network meta-analysis, including inclusion criteria, median duration of follow-up, amount of previous chemotherapy given, types of recurrent and metastatic disease and the wide timespan of the included trials, which were published between 1996 and 2010. The Committee noted that fulvestrant 500 mg was linked to other treatments in the network only through fulvestrant 250 mg, which was used as the baseline comparator in the manufacturer's network meta-analysis. The Committee further noted that the baseline characteristics of the patients enrolled in the CONFIRM, FINDER-1 and FINDER-2 trials may not be directly comparable with those of patients enrolled in earlier studies that compared fulvestrant 250 mg with anastrozole. The Committee also observed that the results of the network meta-analyses suggested better outcomes in terms of overall survival and TTP for letrozole 0.5 mg (which does not have a marketing authorisation for this indication) than for letrozole 2.5 mg (which does have a marketing authorisation for this indication) when compared with fulvestrant 500 mg. The Committee noted the results of two other trials (Dombernowsky et al. 1998; Gershanovich et al. 1998) that were excluded from the network meta-analyses (because they did not meet the oestrogen-receptor-positive status inclusion criterion) in which there was a trend suggesting clinical superiority of letrozole 2.5 mg over letrozole 0.5 mg. The Committee concluded that the results of the manufacturer's network meta-analysis were subject to bias from the selection of studies included in the network and this therefore increased the uncertainty about the outputs of this analysis.
The Committee again discussed the parametric survival models used to project TTP and overall survival by the manufacturer. It accepted the ERG's exploratory analyses that derived the best estimate of overall survival from modelling post-progression on the basis of trial data and combining pre-progression and post-progression estimates. Overall, the Committee concluded that the manufacturer did not provide sufficient commentary or analysis of uncertainty about the fit of alternative parametric survival models and concluded that the estimates of TTP and overall survival based on the ERG's exploratory analysis were more appropriate and were therefore preferred.
# Cost effectiveness
The Committee considered the manufacturer's economic model and the ERG's critique of the model. The Committee agreed with the ERG that because two different probability distributions were fitted to the two sets of data, it is possible for projected estimates of TTP to exceed the corresponding estimates of overall survival, which can lead to negative values for the number of patients alive in the post-progression state in the economic model. The Committee noted that, although the model corrected any negative post-progression survival estimates to zero, it did not compensate for any resulting overestimation of survival. The Committee concluded that the manufacturer's economic model is unlikely to provide a robust basis for projecting survival data beyond the observed data from the CONFIRM trial.
The Committee discussed the utility values applied to the pre-progression and post-progression health states by the manufacturer. The Committee agreed that, although the utility values (taken from Lloyd et al. 2006) were not generated in line with the NICE reference case, they probably represent the best published estimates available, although methodological uncertainty remains. However, it agreed that the utility values based on the age of the participants in the study by Lloyd et al. (2006) should have been adjusted to the mean age of patients used to estimate UK EQ-5D tariff scores. The Committee also agreed with the ERG that the 'responder status' of patients should have been incorporated in the estimation of utility values for the pre-progression and post-progression health states. The Committee concluded that the ERG's adjusted utility values used in its exploratory analysis were preferable to those used by the manufacturer.
The Committee discussed the validity of the cost inputs used in the manufacturer's economic model. The Committee agreed with the ERG in relation to uncertainty about some of the cost inputs used and that modifications to these parameters resulted in small increases in the ICERs. The Committee also noted that the list price of anastrozole reported in the manufacturer's submission may not be what the NHS usually pays. Therefore the Committee concluded that it is likely that the ICERs for fulvestrant compared with anastrozole would be underestimated.
The Committee noted that the key drivers of the cost-effectiveness results in the manufacturer's model were the estimates of TTP and overall survival for all treatments and the utility values assigned to the pre-progression and post-progression health states. The Committee highlighted the results of the manufacturer's probabilistic sensitivity analysis, which indicated that fulvestrant 500 mg had a low probability of being cost effective (2%) at a threshold of £20,000 per QALY gained. The Committee also considered that the ICERs generated using the manufacturer's model were not reliable because of problems with the design of the model and the inclusion of the mixed patient population from the CONFIRM trial. The Committee agreed that the ICERs generated by the ERG's exploratory analysis – which used different estimates of TTP and overall survival, included only the population from the CONFIRM trial whose last treatment had been an anti-oestrogen, revised cost inputs and adjusted the utility estimates – would be more reliable. However, the Committee noted that the ERG's exploratory analysis was based on the same trials in the network meta-analysis as those used in the manufacturer's network meta-analysis. The Committee considered that the network meta-analysis contained considerable uncertainty, which was unaccounted for in the ICERs. Overall, the Committee concluded that the ERG's ICER of £35,000 per QALY gained for fulvestrant 500 mg compared with anastrozole was more plausible than the manufacturer's base-case estimate but there remained considerable uncertainty about this estimate.
The Committee noted that no comparison with exemestane could be made in the manufacturer's base-case cost-effectiveness analysis because of a lack of any relevant trials in which 70% or more of patients had oestrogen-receptor-positive advanced breast cancer in a population who had received an anti-oestrogen. The Committee noted that, as a result, the cost effectiveness of fulvestrant compared with exemestane in this patient population remains unknown. The Committee further concluded that a cost-effectiveness analysis for a subgroup of patients with contraindications to non-steroidal aromatase inhibitors would be desirable, but because the comparator treatment in such an analysis would be exemestane, this could not be undertaken. The Committee concluded that it was unable to recommend fulvestrant as an alternative to exemestane in postmenopausal women with oestrogen-receptor-positive, locally advanced or metastatic breast cancer, or disease progression on therapy with an anti-oestrogen who have contraindications to non-steroidal aromatase inhibitors.
The Committee considered the small subgroup of women who are unable to tolerate treatment with any aromatase inhibitor. The Committee noted that there was no available evidence on the clinical and cost effectiveness of fulvestrant for this small subgroup, and concluded that it was unable to recommend fulvestrant for women unable to tolerate both non-steroidal and steroidal aromatase inhibitors. However, the Committee was aware of alternative funding arrangements available for providing treatment for women who are unable to tolerate an aromatase inhibitor, such as individual funding requests based on exceptionality.
The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all of the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.
In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.
The Committee discussed whether fulvestrant fulfilled the criteria for a life-extending, end-of-life treatment. The Committee agreed that, based on the results of the CONFIRM trial, fulvestrant is indicated for patients with a life expectancy of more than 24 months (the ERG's estimate of mean overall survival for patients taking fulvestrant 500 mg was 36.33 months compared with 32.31 months for those taking anastrozole and 30.90 months for those taking letrozole) and so the criterion of patients with a short life expectancy was not met. Therefore, the Committee agreed that it was not necessary for the criteria of extension to life of at least an additional 3 months and a small patient population to be established. The Committee concluded that fulvestrant did not fulfil the end-of-life criteria.
The Committee considered the most plausible ICER for fulvestrant compared with anastrozole, which it had agreed was likely to be at least £35,000 per QALY gained (see section 4.14). The Committee also noted the considerable uncertainty associated with this estimate because of the network meta-analysis. The Committee concluded that fulvestrant could not be considered a cost-effective use of NHS resources as an alternative to aromatase inhibitors for the treatment of oestrogen-receptor-positive, locally advanced or metastatic breast cancer in post-menopausal women whose cancer has relapsed on or after adjuvant anti-oestrogen therapy, or who have disease progression on anti-oestrogen therapy.
The Committee considered a potential equalities issue highlighted during consultation about the use of fulvestrant for patients unable to swallow oral aromatase inhibitor medication. The Committee was aware that women who are unable to swallow (for example, following a stroke) would be fed using an enteral tube, and that oral medication can also be given by this route. In addition, given that the recommendation did not differentiate between any groups of people, the Committee concluded that its recommendations did not limit access to the technology for any specific group compared with other groups.
# Summary of Appraisal Committee's key conclusions
TA239
Appraisal title: Fulvestrant for the treatment of locally advanced or metastatic breast cancer
Section
Key conclusion
Fulvestrant is not recommended, within its licensed indication, as an alternative to aromatase inhibitors for the treatment of oestrogen-receptor-positive, locally advanced or metastatic breast cancer in postmenopausal women whose cancer has relapsed on or after adjuvant anti-oestrogen therapy, or who have disease progression on anti-oestrogen therapy.
Reasons for recommendation:
Fulvestrant has a marketing authorisation for patients who have been treated previously with an anti-oestrogen (that is; second line as an alternative to aromatase inhibitors).
The CONFIRM trial population consisted of a mixture of patients who had last received either an anti-oestrogen or an aromatase inhibitor. The only comparator included in the CONFIRM trial was fulvestrant 250 mg.
There was high uncertainty about the validity of the manufacturer's network meta-analysis because of heterogeneity between the studies included, the selection of studies included and the parametric survival models used to project TTP and overall survival.
The most plausible ICER presented for fulvestrant 500 mg compared with anastrozole was £35,000 per QALY gained (based on the ERG's exploratory analysis). However, there remained considerable uncertainty about this estimate because it was based on the same trials in the network meta-analysis as those used in the manufacturer's network meta-analysis.
The Committee concluded that fulvestrant did not fulfil the end-of-life criteria as it is indicated for patients with a life expectancy of more than 24 months.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee heard from the patient expert about the value of having a further treatment option after aromatase inhibitors and anti-oestrogen therapies. The Committee recognised the importance of additional treatment options for post-menopausal women with locally advanced or metastatic breast cancer.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee noted that although fulvestrant 500 mg offered benefits in increasing the TTP compared with low-dose (250 mg) fulvestrant in the CONFIRM trial, this difference was statistically significant only for patients whose last therapy was an anti-oestrogen, and not for patients whose last therapy was an aromatase inhibitor. However, the Committee was also aware that the CONFIRM trial was not powered to detect a statistically significant difference in TTP between fulvestrant 500 mg and fulvestrant 250 mg in the two patient subgroups. The Committee noted that the results of the network meta-analyses by the manufacturer showed no statistically significant differences in overall survival between fulvestrant, anastrozole and letrozole, although fulvestrant resulted in statistically significantly longer TTP compared with anastrozole (but not letrozole). However, the Committee concluded there was high uncertainty about the validity of these results because of the parametric survival models used.
No specific claim for innovation was made.
What is the position of the treatment in the pathway of care for the condition?
The manufacturer confirmed that fulvestrant has a marketing authorisation as a second-line treatment for metastatic breast cancer in postmenopausal women after adjuvant or first-line treatment of advanced disease with an anti-oestrogen therapy (for most patients this is usually tamoxifen). The Committee was aware that the marketing authorisation places fulvestrant as an alternative to aromatase inhibitors after anti-oestrogen treatment.
The Committee considered that third-line or fourth-line use was not within the remit of this technology appraisal.
The Committee concluded that the aromatase inhibitors anastrozole, letrozole and exemestane are the most appropriate comparators for the appraisal of fulvestrant.
Adverse effects
The Committee heard from one patient expert who is currently receiving fulvestrant that the disadvantages of having two injections and the associated side effects of fulvestrant were outweighed by the benefits of remaining fit and well on this therapy.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee was aware that the only treatment comparator in the CONFIRM trial was low-dose (250 mg) fulvestrant.
The Committee noted that although the marketing authorisation for fulvestrant 500 mg is for patients who have received previous anti-oestrogen treatment, the CONFIRM trial population consisted of a mixture of patients who had last received either an anti-oestrogen or an aromatase inhibitor. The Committee noted heterogeneity between these two subgroups in terms of previous treatment and patient characteristics. The Committee therefore agreed that only data from the subgroup in the CONFIRM trial who had received an anti-oestrogen as their last treatment should be included in the network meta-analyses.
The Committee noted that fulvestrant 500 mg was linked to other treatments in the network only through fulvestrant 250 mg, which was used as the baseline comparator in the manufacturer's network meta-analysis. The Committee noted that the manufacturer had sought advice from key opinion leaders about setting firm criteria for the selection of trials for inclusion in the meta-analysis (for example, including only recent trials, or agreeing a certain percentage of patients with cancer of unknown oestrogen receptor status), but that no such criteria could be agreed. The main inclusion criterion was relaxed by the manufacturer to include trials for comparators with at least 70% of patients with documented oestrogen-receptor-positive status. The Committee was aware that, based on this criterion, exemestane was excluded as a comparator in the base-case cost-effectiveness analysis. The Committee also highlighted sources of heterogeneity between the trials included in the network meta-analysis. The Committee concluded that the results of the manufacturer's network meta-analysis were subject to bias from the selection of studies included in the network.
Relevance to general clinical practice in the NHS
The Committee was aware of the restriction to the marketing authorisation to patients who had been treated previously with an anti-oestrogen, which places fulvestrant as an alternative to aromatase inhibitors after anti-oestrogen treatment.
The Committee considered that third-line or fourth-line use was not within the remit of this technology appraisal.
Uncertainties generated by the evidence
The Committee concluded that there was high uncertainty about the validity of the results of the manufacturer's network meta-analysis because of heterogeneity between the studies selected and the parametric survival models used to project TTP and overall survival.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee noted that the CONFIRM trial population consisted of a mixture of patients who had last received either an anti-oestrogen or an aromatase inhibitor. The Committee noted heterogeneity between these two subgroups in terms of previous treatment and patient characteristics. The Committee therefore agreed that only data from the subgroup in the CONFIRM trial who had received an anti-oestrogen as their last treatment should be included in the network meta-analyses, in line with the marketing authorisation for fulvestrant.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee noted that the results of the network meta-analyses by the manufacturer showed no significant differences in overall survival between fulvestrant, anastrozole and letrozole, although fulvestrant resulted in significantly longer TTP compared with anastrozole (but not letrozole). However, the Committee concluded that, because of the issues identified by the ERG concerning the fit of the parametric survival models used by the manufacturer, there was high uncertainty about these results.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee agreed with the ERG that because two different probability distributions were fitted to the two sets of data, it is possible for projected estimates of TTP to exceed the corresponding estimates of overall survival, which can lead to negative values for the number of patients alive in the post-progression state in the economic model. The Committee concluded that the manufacturer's economic model is unlikely to provide a robust basis for projecting survival data beyond the observed data from the CONFIRM trial.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee discussed the validity of the cost inputs used in the manufacturer's economic model. The Committee agreed with the ERG in relation to the cost data used and that modifications to these parameters resulted in small increases in the ICERs for fulvestrant.
The Committee also considered that the ICERs generated using the manufacturer's model were not reliable because of problems with the design of the model and the inclusion of the mixed patient population from the CONFIRM trial.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee discussed the utility values applied to the pre-progression and post-progression health states by the manufacturer. The Committee agreed that, although the utility values were not generated in line with the NICE reference case, they probably represent the best published estimates available. However, the Committee agreed with the ERG that the utility values should have been adjusted for the age and 'responder status' of the patients.
No evidence of additional benefits (other than those already accounted for in the QALY) of treatment with fulvestrant was presented or identified.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee noted that no comparison with exemestane could be made in the manufacturer's base-case cost-effectiveness analysis because of a lack of any relevant trials in which 70% or more of patients had oestrogen-receptor-positive advanced breast cancer in a population that had an anti-oestrogen as their last treatment. The Committee noted that, as a result, the cost effectiveness of exemestane compared with fulvestrant in this patient population remains unknown. The Committee thought that a cost-effectiveness analysis for a subgroup of patients with contraindications to non-steroidal aromatase inhibitors would be desirable, but that such an analysis could not be undertaken. The Committee concluded that it was unable to recommend fulvestrant as an alternative to exemestane in postmenopausal women with oestrogen-receptor-positive, locally advanced or metastatic breast cancer, or disease progression on therapy with an anti-oestrogen who are contraindicated to non-steroidal aromatase inhibitors.
The Committee also noted that there was no available clinical and cost-effectiveness evidence on fulvestrant for the small subgroup of women who are unable to tolerate treatment with any aromatase inhibitor.
What are the key drivers of cost effectiveness?
The Committee noted that the key drivers of the cost-effectiveness results in the manufacturer's model were the estimates of TTP and overall survival for all treatments and the utility values assigned to the pre-progression and post-progression health states.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee agreed that the ICERs generated by the ERG's analysis – which used different estimates of TTP and overall survival, included only the population from the CONFIRM trial whose last treatment had been an anti-oestrogen, revised cost inputs and adjusted utility estimates – would be more reliable than the ICERs generated in the manufacturer's model. Therefore, the Committee concluded that the ICER of £35,000 per QALY gained for fulvestrant 500 mg compared with anastrozole was more plausible than the manufacturer's base-case estimate but there remained considerable uncertainty about this estimate.
Additional factors taken into account
Patient access schemes (PPRS)
No approved patient access scheme was submitted for the technology being appraised.
End-of-life considerations
The Committee concluded that fulvestrant did not fulfil the end-of-life criteria because, based on the results of the CONFIRM trial, fulvestrant is indicated for patients with a life expectancy of more than 24 months.
Equalities considerations and social value judgements
The Committee considered a potential equalities issue highlighted during consultation about the use of fulvestrant for patients unable to swallow oral aromatase inhibitor medication. The Committee was aware that women who are unable to swallow (for example, following a stroke) would be fed using an enteral tube, and that oral medication can also be given by this route. In addition, given that the recommendation did not differentiate between any groups of people, the Committee concluded that its recommendations did not limit access to the technology for any specific group compared with other groups.
# Related NICE guidance
# Published
Advanced breast cancer: diagnosis and treatment. NICE clinical guideline 81 (2009).
Early and locally advanced breast cancer: diagnosis and treatment. NICE clinical guideline 80 (2009).
Gemcitabine for the treatment of metastatic breast cancer. NICE technology appraisal guidance 116 (2007).
# Under development
NICE is developing the following guidance (details available from www.nice.org.uk)
Eribulin for the treatment of locally advanced or metastatic breast cancer. NICE technology appraisal guidance (publication date to be confirmed).# Review of guidance
The guidance on this technology will be considered for review in August 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveDecember 2011# Changes after publication
March 2014: minor maintenance
June 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Fulvestrant is not recommended, within its licensed indication, as an alternative to aromatase inhibitors for the treatment of oestrogen-receptor-positive, locally advanced or metastatic breast cancer in postmenopausal women whose cancer has relapsed on or after adjuvant anti-oestrogen therapy, or who have disease progression on anti-oestrogen therapy.\n\nPost-menopausal women currently receiving fulvestrant within its licensed indication as an alternative to aromatase inhibitors for the treatment of oestrogen-receptor-positive, locally advanced or metastatic breast cancer whose cancer has relapsed on or after adjuvant anti-oestrogen therapy, or who have disease progression on anti-oestrogen therapy, should have the option to continue treatment until they and their clinicians consider it appropriate to stop.', 'The technology ': "Fulvestrant (Faslodex, AstraZeneca) is an oestrogen antagonist belonging to a class of agents known as selective oestrogen receptor down-regulators (SERDs). Fulvestrant has a UK marketing authorisation for 'the treatment of postmenopausal women with oestrogen receptor positive, locally advanced or metastatic breast cancer for disease relapse on or after adjuvant anti-oestrogen therapy, or disease progression on therapy with an anti-oestrogen'. The recommended dose is 500\xa0mg (administered as two intramuscular injections of 250\xa0mg) every month, with an additional 500\xa0mg dose given 2\xa0weeks after the initial dose.\n\nAccording to the summary of product characteristics, the most common side effects associated with fulvestrant are nausea, vomiting, diarrhoea, venous thromboembolism, anorexia, headache, asthenia, urinary-tract infections, hot flushes, back pain, rash, injection-site reactions and hypersensitivity reactions ('British national formulary' [BNF] edition 61). For full details of side effects and contraindications, see the summary of product characteristics.\n\nThe current NHS list price of fulvestrant is £522.41 for 2\xa0x\xa05\xa0ml (250\xa0mg) prefilled syringes (excluding VAT; BNF edition 61). The first month of treatment with fulvestrant 500\xa0mg includes an additional loading dose administered 2\xa0weeks after the initial dose, resulting in a cost of £1044.82 for the first month. In subsequent months, the cost of fulvestrant 500\xa0mg is £522.41 per month. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of fulvestrant and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer's submission presented clinical-effectiveness data derived from one phase III trial (CONFIRM), supported by results from two dose-ranging phase II trials (FINDER-1 and FINDER-2). Women were eligible for these three studies if they were postmenopausal and had oestrogen-receptor-positive breast cancer. Their cancer could have relapsed during or within 12\xa0months of completing adjuvant hormone therapy (with an anti-oestrogen or an aromatase inhibitor) for early breast cancer; or it could have progressed on anti-oestrogen or aromatase inhibitor therapy for advanced breast cancer provided that this hormone therapy was started more than 12\xa0months after completion of adjuvant hormone therapy (anti-oestrogen or aromatase inhibitor); or it could have progressed while they were on first-line hormone therapy (anti-oestrogen or aromatase inhibitor) for advanced breast cancer. All three trials excluded patients who had received two or more lines of previous hormone therapy for locally advanced or metastatic breast cancer.\n\nThe CONFIRM trial was an international multicentre double-blind parallel-group randomised controlled trial (RCT) that included 736\xa0patients who had previously received an anti-oestrogen or an aromatase inhibitor for the adjuvant treatment of early breast cancer or as palliative therapy for advanced breast cancer. Patients were randomised on a 1:1 basis to receive either fulvestrant 500\xa0mg or fulvestrant 250\xa0mg. The mean age of the patients was 61\xa0years. The baseline characteristics of the groups in the two arms of the trial were generally comparable, although more patients in the fulvestrant 250\xa0mg arm (102 compared with 69) had received radiotherapy as treatment for advanced disease.\n\nThe primary outcome measure in the CONFIRM study was median time to progression (TTP). Median TTP was statistically significantly longer in the overall mixed population (that is, including both patients who had previously received an anti-oestrogen and patients who had previously received an aromatase inhibitor) for the fulvestrant 500\xa0mg arm compared with the fulvestrant 250\xa0mg arm (6.5\xa0months compared with 5.5\xa0months; hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.68 to 0.94; p\xa0=\xa00.006). A pre-planned analysis was done for the subgroups of patients last treated with an anti-oestrogen (58%) or an aromatase inhibitor (42%). The median TTPs for the fulvestrant 500\xa0mg and fulvestrant 250\xa0mg arms were 8.6\xa0months and 5.8\xa0months respectively (HR 0.76; 95% CI 0.62 to 0.94; p\xa0=\xa00.013) for the population last treated with an anti-oestrogen, and 5.4\xa0months and 4.1\xa0months respectively for the population last treated with an aromatase inhibitor (HR\xa00.85; 95% CI 0.67 to 1.08; p\xa0=\xa00.195).\n\nSecondary outcomes reported in the CONFIRM study included objective response rate, clinical benefit rate and overall survival. The results suggested no statistically significant differences between the fulvestrant 500\xa0mg and 250\xa0mg arms for these outcomes, although the median overall survival was greater in the fulvestrant 500\xa0mg group (25.1\xa0months compared with 22.8\xa0months). Log-rank tests suggested a trend for improved overall survival in the fulvestrant 500\xa0mg group (HR 0.84; 95% CI 0.69 to 1.03; p\xa0=\xa00.091). Overall survival data from the CONFIRM trial were not mature: 51% of patients had died at the time of primary data cut-off for TTP. The manufacturer stated that it plans to re-analyse the overall survival data when 75% of patients have died.\n\nA total of 2443 adverse events were reported by 483 (66%) of the 735 patients in the safety analysis in the CONFIRM trial. A serious adverse event was reported for 54 patients (7%), including 11 patients (1%) who died. Seventeen patients (2%) discontinued fulvestrant treatment because of an adverse event. There were no notable differences in the incidence of adverse events between treatment groups. The most common adverse events were injection-site pain (11.6%), nausea (9.7%) and bone pain (9.4%).\n\nThe manufacturer also provided health-related quality of life data taken from the CONFIRM study for a total of 145 women who completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire at baseline. No significant differences were detected between the fulvestrant 500\xa0mg and 250\xa0mg study arms.\n\nThe FINDER-1 study was a multicentre parallel-group double-blind phase II RCT conducted in Japan. A total of 143 patients recruited from 40 centres were randomised on a 1:1:1 basis to receive fulvestrant 500\xa0mg, fulvestrant 250\xa0mg or fulvestrant 250\xa0mg with a loading dose. The FINDER-2 study was a multicentre international double-blind phase II RCT conducted in seven European countries and Canada. A total of 144 patients were recruited from 34 centres and randomised on a 1:1:1 basis to receive fulvestrant 500\xa0mg, fulvestrant 250\xa0mg or fulvestrant 250\xa0mg with a loading dose. The primary outcome in the FINDER-1 and FINDER-2 trials was objective response rate, with secondary outcomes including clinical benefit rate and TTP. The findings from these trials were broadly in favour of fulvestrant 500\xa0mg compared with fulvestrant 250\xa0mg.\n\nThe manufacturer conducted a network meta-analysis to compare overall survival and TTP for fulvestrant 500\xa0mg with the comparators listed in the scope. Five RCTs that included three of the other comparators (anastrozole, letrozole and fulvestrant 250\xa0mg) listed in the scope were identified in the systematic literature review, resulting in eight trials being included in the network meta-analysis. Data from the total population in the fulvestrant trials were included, with the FINDER-1 and FINDER-2 trials contributing only to the TTP network meta-analysis. The manufacturer stated that inclusion of the group from the CONFIRM trial who had received an aromatase inhibitor as their last treatment did not alter the results in favour of fulvestrant. The manufacturer did not include exemestane as a comparator in the base-case network meta-analysis because of a lack of any relevant trials in which 70% or more patients had documented hormone-receptor-positive advanced breast cancer in a population who had received an anti-oestrogen. Therefore a secondary scenario analysis, as part of the cost-effectiveness analysis comparing fulvestrant 500\xa0mg with exemestane, was carried out by the manufacturer.\n\nFor the base-case network meta-analysis, data on two outcomes were collected: overall survival and TTP. Data from the eight included trials were pooled and extrapolated. Based on patient-level data from the CONFIRM trial, the Weibull distribution was identified as the best-fitting distribution to estimate overall survival. Because hazard ratios in the CONFIRM trial were constant over time (the shape parameters were very similar for both treatment groups), the relative treatment effects of the alternative treatments were applied to the baseline treatment (fulvestrant 250\xa0mg) using a pooled hazard ratio for overall survival estimated from the network meta-analysis. For TTP, the log-normal distribution was identified by the manufacturer as the best-fitting distribution for data from the CONFIRM trial because it was inappropriate to assume that hazard ratios were constant over time. A simultaneous extrapolation and network meta-analysis of TTP curves for all comparator treatments were derived from the available RCTs. This was done by relating the TTP Kaplan-Meier curves of each of the comparators directly to the parameters of the log-normal survival curves. A fixed-effects model was used to simultaneously extrapolate Kaplan-Meier curves over time by means of log-normal curves, to synthesise and to indirectly compare the different treatments. The shape and scale parameters for the baseline treatment (fulvestrant 250\xa0mg) were estimated and used as the anchor to obtain estimates for the shape and scale parameters of the other comparators. Pooled TTP curves for each treatment were produced and the corresponding area under the curve was calculated to obtain the mean TTP estimates for each treatment.\n\nThe results of the network meta-analysis presented by the manufacturer suggested that fulvestrant 500\xa0mg was associated with longer overall survival compared with fulvestrant 250\xa0mg, anastrozole and letrozole, but this finding was not statistically significant. The results of the TTP network meta-analysis suggested that fulvestrant 500\xa0mg was associated with a statistically significantly longer TTP than fulvestrant 250\xa0mg, whereas anastrozole was associated with a statistically significantly shorter TTP than fulvestrant 250\xa0mg. There were no statistically significant differences in TTP between letrozole 2.5\xa0mg and fulvestrant 250\xa0mg.\n\nThe manufacturer developed an Excel-based cost–utility model, based on a time-in-state model structure. The model structure is similar to that of a Markov cohort model, with three possible health states: pre-progression, post-progression and death. However, instead of using transition probabilities to determine movement between health states, the model calculates the proportion of patients in each health state according to the estimated survival functions for TTP and overall survival. All patients are assumed to be in the pre-progression health state at model entry (baseline). The duration of second-line hormonal therapy is assumed to be the same as the amount of time spent in the pre-progression health state. The post-progression health state captures a series of subsequent therapies, including third-line hormonal therapy, up to three sequential lines of chemotherapy, and supportive palliative care. Patients can move to the state of death from either the pre-progression or the post-progression health state, which captures death from any cause. The model uses monthly cycles with a lifetime (13-year) time horizon.\n\nThe results of the base-case network meta-analysis of the clinical effectiveness data on TTP and overall survival were used to populate the economic model. For the base-case analysis, comparator treatments were fulvestrant 250\xa0mg, anastrozole and letrozole. The manufacturer used the overall CONFIRM trial population (that is, a mixed population who had received either an anti-oestrogen or an aromatase inhibitor as their last treatment) in the analysis. The manufacturer reported that it was not feasible to analyse the proportion of patients with grade 3 or grade 4 adverse events because adverse events were not reported consistently across the trials included in the network meta-analysis. However, the manufacturer included serious adverse events in the model because sufficient data were available to conduct a network meta-analysis. The serious adverse event data used in the model included both treatment-related and treatment-independent events, because these were available for all relevant RCTs used to derive the estimates of TTP and overall survival in the base-case analysis.\n\nHealth-related quality of life data based on the FACT-B questionnaire were collected at baseline (pre-progression) from a subgroup of patients in the CONFIRM study. However, the model structure required utility values for the pre-progression and post-progression health states that were not collected in the CONFIRM study. Therefore the manufacturer used published pre-progression and post-progression utility values based on a systematic literature review of utility studies for metastatic or locally advanced breast cancer. The manufacturer considered that the study by Lloyd et al. (2006) provided the most appropriate utility values. In this study, utility values were taken from a relatively small sample of the general public in the UK using the standard gamble technique. The study provided utility values of 0.72 and 0.44 for the pre-progression and post-progression health states respectively. Death was assigned a utility value of zero. Disutilities associated with treatment-related adverse events were not included in the model.\n\nResource use and costs in the economic model included those related to each second-line hormonal treatment used during the pre-progression phase, subsequent treatments during the post-progression phase including third-line hormonal therapy, supportive palliative care and chemotherapy, and treatment-related adverse events. No treatment-related monitoring costs associated with fulvestrant 500\xa0mg or its comparators were included in the model. An overall average cost per monthly cycle of £1084 per patient was applied to each treatment arm for the patients in the post-progression health state. For adverse events, the model assumed that each serious adverse event is associated with an average hospital stay of 5\xa0days at a cost of £321.02 per day, which was then weighted by the proportion of serious adverse events estimated in the network meta-analysis for each hormonal treatment considered in the scope. The model assumed that one-third of patients received fulvestrant in primary care and two-thirds in hospital.\n\nThe manufacturer reported the results from the economic model for the two key clinical outcomes, TTP and overall survival. The mean TTP was 15.0\xa0months for fulvestrant 500\xa0mg compared with 10.8\xa0months for fulvestrant 250\xa0mg, 9.5\xa0months for anastrozole and 9.9\xa0months for letrozole. The mean overall survival was 33.4\xa0months for fulvestrant 500\xa0mg compared with 29.0\xa0months for fulvestrant 250\xa0mg, 28.5\xa0months for anastrozole and 24.9\xa0months for letrozole.\n\nIn the base-case incremental analysis, fulvestrant 500\xa0mg was associated with the highest total quality-adjusted life years (QALYs) (1.487\xa0QALYs), followed by fulvestrant 250\xa0mg (1.256\xa0QALYs), anastrozole (1.214\xa0QALYs) and letrozole (1.105\xa0QALYs). Based on an incremental analysis ranking of treatments, the base-case results demonstrated that anastrozole and fulvestrant 250\xa0mg were extendedly dominated by (that is, were more expensive and less effective than) a combination of two other single-agent treatments, fulvestrant 500\xa0mg and letrozole. The comparison of fulvestrant 500\xa0mg with letrozole produced an incremental cost-effectiveness ratio (ICER) of £31,982 per QALY gained (representing incremental costs of £12,239 and incremental QALYs of 0.383). The manufacturer stated that no patients were assumed to be on an adjuvant switch hormone treatment strategy (that is, sequential treatment with an anti-oestrogen and an aromatase inhibitor).\n\nThe manufacturer conducted deterministic sensitivity analyses by varying key model input parameters. These showed that the key drivers of the cost-effectiveness results were the estimates of TTP and overall survival for all treatments and the utility values assigned to the pre-progression and post-progression health states. The widest range of ICERs was found for the comparison of fulvestrant 500\xa0mg with letrozole, in which the ICERs ranged from £21,894 to £55,160 per QALY gained when the upper and lower 95% credibility limits for the scale and log shape of the log-normal distribution of TTP for letrozole were used.\n\nThe manufacturer also conducted six scenario analyses to assess the impact of key assumptions made in the base-case analysis. These scenarios included: expanding the patient population to allow the inclusion of exemestane in the network meta-analysis (by including trials in which at least 50% of patients had documented hormone-receptor-positive cancer and patients who had last been treated with an aromatase inhibitor [because there are no studies comparing fulvestrant with exemestane in patients treated with an anti-oestrogen]); using alternative proportions for the administration of fulvestrant in the primary care setting and in hospital; altering the cost of the post-progression health state by using an alternative mix of chemotherapies; altering the cost of the post-progression health state by eliminating treatment skipping (patients skip further hormonal treatment if the extent and duration of response to a previous hormonal treatment was insufficient); discounting costs and benefits at 0% and 6%; and altering the time horizon. In summary, exemestane, anastrozole and fulvestrant 250\xa0mg were all extendedly dominated by a combination of fulvestrant 500\xa0mg and letrozole. The comparison of fulvestrant 500\xa0mg with letrozole gave a range of ICERs from £29,881 to £38,566 per QALY gained.\n\nThe results of the manufacturer's probabilistic sensitivity analysis showed that, at a threshold of £20,000 per QALY gained, there is a 2% probability of fulvestrant 500\xa0mg being cost effective. This increased to 20% at a threshold of £30,000 per QALY gained.\n\n# ERG comments on the manufacturer's submission\n\nThe ERG commented that the manufacturer's systematic review of clinical-effectiveness studies was methodologically appropriate and that all relevant studies meeting the inclusion criteria appeared to have been identified.\n\nThe ERG commented that the CONFIRM study was well designed and that the clinical outcomes reported in this RCT and the supporting phase II trials (FINDER-1 and FINDER-2) address all the relevant outcomes outlined in the scope. However, the ERG noted that fulvestrant is currently most commonly used in clinical practice in England and Wales after aromatase inhibitors and often after an anti-oestrogen as well, and therefore it is a third- or fourth-line hormonal therapy in the treatment pathway for advanced breast cancer. In the fulvestrant trials used as the basis for direct clinical evidence and in the manufacturer's submission, fulvestrant was used in the treatment pathway in the position currently occupied by aromatase inhibitors, as second-line treatment. Therefore, the ERG commented that the generalisability of the patient population and trial results to clinical practice may be questionable, because there is a difference between the indication in the marketing authorisation for fulvestrant and its use in treatment in England and Wales.The ERG also noted that no patients were recruited to CONFIRM from the UK.\n\nThe ERG highlighted that the marketing authorisation for fulvestrant 500\xa0mg specifies that the patient has received previous anti-oestrogen therapy, although the ERG noted that it is not clear from the wording of the marketing authorisation that eligibility for treatment depends on the last therapy received. Therefore, the ERG requested that the manufacturer divide the TTP data from CONFIRM in two main ways. First, the patients were divided into two treatment groups: patients who had received an anti-oestrogen as their last treatment (58%) and patients who had received an aromatase inhibitor as their last treatment (42%). Second, the patients were split into three treatment groups: patients who had received an anti-oestrogen but not an aromatase inhibitor; patients who had received an aromatase inhibitor but not an anti-oestrogen; and patients who had received both an anti-oestrogen and an aromatase inhibitor. The second set of data was provided 'in confidence'. The ERG noted from the patients divided into two treatment groups that 65.5% of patients who had received an anti-oestrogen as their last treatment were receiving fulvestrant as a first-line treatment for locally advanced or metastatic breast cancer, whereas 66.8% of patients who had received an aromatase inhibitor as their last treatment received fulvestrant as a second-line therapy for advanced breast cancer. The ERG also demonstrated significant differences between the demography of these two groups: the proportion of patients treated with hormone therapy for advanced disease was 34% in the anti-oestrogen group compared with 67% in the aromatase inhibitor group; and the proportion who had received two previous hormone therapies was 4% in the anti-oestrogen group compared with 27% in the aromatase inhibitor group. The ERG therefore speculated that the apparent increased benefit for fulvestrant after an anti-oestrogen rather than after an aromatase inhibitor may be influenced by where in the treatment sequence most patients received fulvestrant, rather than by whether the last treatment before fulvestrant was an anti-oestrogen or an aromatase inhibitor.\n\nThe ERG considered that the manufacturer's base-case economic evaluation was well conducted and closely matched the NICE reference case. The main issue raised by the ERG related to the use of data from the network meta-analysis, which included patients from the CONFIRM trial who had been treated previously with an aromatase inhibitor. The ERG considered it more appropriate to base the model only on patients who had previously received anti-oestrogen therapy, particularly in view of the heterogeneity of the anti-oestrogen and aromatase inhibitor groups. The ERG considered that the advantage of this approach of reducing the heterogeneity of the compared populations outweighed the main disadvantage of reducing the statistical power of the CONFIRM trial.\n\nIn its critique of the network meta-analysis, the ERG noted that in the comparator treatment trials, none of the patients had received a prior aromatase inhibitor. In addition, the ERG noted key differences in the baseline characteristics of the populations in the trials included in the network meta-analysis. For example, the percentage of patients whose oestrogen receptor status was not known to be positive ranged from to 0% (CONFIRM, FINDER-1 and FINDER-2) to 33.1% (Buzdar 1996/98); the proportion of patients treated previously with chemotherapy ranged from 35.1% (Buzdar 1996/98) to 72.5% (FINDER-1); and the proportion of patients with visceral spread was variable, although the ERG noted that the proportion of patients with known visceral spread was high in the fulvestrant trials.\n\nOverall, the ERG considered that the population in the CONFIRM trial was heterogeneous and that it was not meaningful to regard the group who had received an anti-oestrogen and the group who had received an aromatase inhibitor as similar. The ERG suggested that the network meta-analyses should include data only from patients who had received an anti-oestrogen as their last treatment from the CONFIRM, FINDER-1 and FINDER-2 trials. Therefore the ERG re-ran the analysis using only data from CONFIRM trial patients whose previous hormone therapy was an anti-oestrogen (n\xa0=\xa0423). The results were comparable with those obtained when the whole population of the CONFIRM trial was included in the analysis. All hazard ratios for overall survival still favoured fulvestrant 500\xa0mg over other treatments considered in the scope, although the results were not statistically significant.\n\nFor the TTP network meta-analysis, the ERG questioned the assumption that the CONFIRM trial results follow a log-normal distribution. A direct comparison of the Kaplan-Meier analysis of the trial results with the outputs of the manufacturer's log-normal model appeared to suggest a reasonable match between data (TTP) and model. However, the ERG noted some divergence after 18\xa0months, which would affect the projection of survival curves beyond the observed data. Therefore, the ERG argued that because the log-normal parametric model used by the manufacturer did not adequately represent the data on which it was calibrated, it should not be used to calibrate TTP estimates for all comparators included in the network meta-analysis. The ERG observed that the results of the Kaplan-Meier analysis from the CONFIRM trial showed a higher number of progression events occurring around 90\xa0days, followed by a 90-day period with relatively few new events. From 180\xa0days onward, there was a clear indication of a linear relationship between time and the cumulative TTP hazard. Therefore the ERG proposed that a more accurate approach would be to split the estimation of TTP into two phases and to include only the anti-oestrogen-treated population from the CONFIRM trial. For the first part of the analysis (0–180\xa0days), the ERG performed a network meta-analysis on the log-hazard ratios at 180\xa0days. For the second part of the analysis (after 180\xa0days), TTP was modelled using an exponential distribution, which has a constant hazard or linear cumulative hazard, based on a clear indication of a linear relationship between time and cumulative TTP hazard in the CONFIRM trial. The results of this analysis showed no statistically significant differences in TTP between the groups receiving fulvestrant 500\xa0mg and those receiving other treatments for the first 180\xa0days (a period thought to be driven by protocol activities and short-term events). However, after 180\xa0days (the ERG stated that this period relates to long-term patient experience) fulvestrant 500\xa0mg was associated with statistically significant improvements in TTP compared with anastrozole and letrozole.\n\nFor the overall survival network meta-analysis, the ERG commented that the parametric model used by the manufacturer to estimate overall survival in the network meta-analysis appeared to be a reasonable match with the available CONFIRM trial data. However, the ERG also noted that projections of overall survival beyond the period of observation may be substantially over- or under-estimated because of the complex changes in risk that are likely to apply at later times. Therefore, the ERG suggested that an alternative approach to projective modelling was to consider modelling post-progression patient experience directly on the basis of the trial data, and then to combine pre- and post-progression estimates to obtain the best estimate of overall survival. Examination of post-progression survival data by the ERG showed no statistically significant differences between fulvestrant 500\xa0mg and fulvestrant 250\xa0mg, suggesting that any overall survival gains associated with fulvestrant 500\xa0mg were obtained only in the pre-progression phase (TTP). Therefore the ERG estimated a compatible set of survival estimates (TTP), post-progression survival and overall survival) for fulvestrant 250\xa0mg, anastrozole and letrozole by calibrating a hazard ratio applied to the overall survival estimated for the fulvestrant 500\xa0mg group, which generated a gain in overall survival equal to the corresponding gain in TTP. The ERG noted that although this is an approximation, it allows the timing of post-progression survival to be calculated without elaborate additional modelling. This approach appeared fully justified for anastrozole, because key clinical trials comparing anastrozole with fulvestrant 250\xa0mg showed no statistically significant differences in TTP or overall survival. However, this approach was less clearly supported in the case of letrozole, because there are no trials that directly compare letrozole with fulvestrant.\n\nThe ERG noted several criticisms about the design of the manufacturer's economic model, which was based on separate parametric models of the time from randomisation to TTP and overall survival. The ERG commented that when different probability distributions are used to represent the two sets of data, or when the same function is used for both but does not satisfy proportional hazards criteria (that is, the risk of an event occurring on one treatment relative to another treatment is assumed not to change over time), it is possible for projected estimates of TTP to exceed the corresponding estimates of overall survival. Although the model corrected any negative post-progression survival estimates to zero, it did not compensate for any resulting overestimation of survival. Overall, the ERG concluded that the design of the manufacturer's economic model is unlikely to provide a robust basis for projecting survival beyond the observed data.\n\nThe ERG identified four issues in relation to the cost data used in the manufacturer's model. First, the manufacturer's model does not account for wastage of part-used dispensed packs at the time of disease progression. Second, the ERG questioned the use of the two expert opinions for pre-progression and post-progression health state costs, and instead proposed that such costs should be based on treatment pathways described in 'Advanced breast cancer: diagnosis and treatment' (NICE clinical guideline 81). Third, the manufacturer's model limits drug-related adverse events to serious adverse events only. Fourth, the manufacturer's approach of applying a single average cost for UK hospital admission is simplistic and inappropriate for costing adverse events associated with treatment complications in advanced breast cancer. The ERG calculated an alternative estimate of £3147 per admission, compared with the estimate in the manufacturer's model of £1605 per episode. Overall, the ERG stated that making these four modifications to the model increased the ICER in all cases but, because each change represents only a small element of the total cost, the increases were small.\n\nFinally, the ERG noted an error in the utility values assigned to the pre-progression and post-progression health states in the manufacturer's economic model. Utility values were based on the age of the participants in the study by Lloyd et al. (2006), taken from a sample of the general UK population, and not on the age of breast cancer patients. The ERG proposed that, to ensure consistency with standard UK EQ-5D tariff scores, the mean age should be set to 47\xa0years (the mean age of the original UK York study sample used). The ERG also accounted for the 'responder status' of patients (that is, whether or not their cancer responded to treatment) when estimating new utility values for both health states. In summary, using ERG estimated utility values of 0.7733 for the pre-progression state and 0.4964 for the post-progression state reduced the ICER for fulvestrant by £2700 per QALY gained compared with letrozole.\n\nThe ERG made eight separate modifications to explore the impact of the various issues described in the critique of the manufacturer's economic model. Seven modifications were made to the economic model logic or parameter values, and the eighth modification involved using effectiveness data from the anti-oestrogen subgroup in the CONFIRM trial instead of data from the whole trial population. The ERG presented detailed deterministic results separately for the manufacturer's base-case scenario using the whole CONFIRM population and for the anti-oestrogen subgroup.\n\nIn summary, based on the full CONFIRM trial population, the calculated deterministic cost-effectiveness results of the ERG's exploratory analyses showed that fulvestrant 250 mg was extendedly dominated by the other comparators,. The ICERs for anastrozole compared with letrozole and for fulvestrant 500\xa0mg compared with anastrozole were both close to £30,000 per QALY gained. The ERG's preferred exploratory deterministic cost-effectiveness analysis based on the anti-oestrogen subgroup from CONFIRM and an updated network meta-analysis resulted in fulvestrant 250\xa0mg being extendedly dominated by the other comparators. The ICER for anastrozole compared with letrozole was £1162 per QALY gained, and the ICER for fulvestrant 500\xa0mg compared with anastrozole was £34,972 per QALY gained.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA239", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of fulvestrant, having considered evidence on the nature of locally advanced or metastatic breast cancer and the value placed on the benefits of fulvestrant by women with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee considered the views of the patient experts on their experience of fulvestrant as a treatment for locally advanced or metastatic breast cancer. It heard from one patient expert who is currently receiving fulvestrant and understood that patients value the availability of a further treatment option after aromatase inhibitors and anti-oestrogen therapies, both as a treatment and because it delays the need for chemotherapy. The Committee also heard from this patient expert that she found the disadvantages of having two injections and the associated side effects of fulvestrant were outweighed by the benefits of remaining fit and well on this therapy. The Committee recognised the importance of additional treatment options for post-menopausal women with locally advanced or metastatic breast cancer.\n\nThe Committee considered the licensed indication for fulvestrant. It noted that fulvestrant has a marketing authorisation 'for the treatment of postmenopausal women with oestrogen receptor positive, locally advanced or metastatic breast cancer for disease relapse on or after adjuvant anti-oestrogen therapy, or disease progression on therapy with an anti-oestrogen'. The Committee noted comments from the ERG that it is not clear from the wording of the marketing authorisation that eligibility for treatment depends on the last therapy received and may include women who have received more than one previous line of treatment for metastatic breast cancer. However, the manufacturer confirmed that fulvestrant has a marketing authorisation as a second-line treatment for metastatic breast cancer in postmenopausal women after adjuvant or first-line treatment of advanced disease with an anti-oestrogen therapy (for most patients this is usually tamoxifen). The Committee was aware that 42% of the patients in the CONFIRM trial had received an aromatase inhibitor as their last treatment before fulvestrant. It also heard from the manufacturer that the European Medicines Agency had regarded the results for the group that had received an aromatase inhibitor as being inconclusive and had rejected the manufacturer's request for an extension of the marketing authorisation for fulvestrant to include patients who have experienced treatment failure with an aromatase inhibitor. Therefore the Committee was aware of the restriction of the marketing authorisation to patients who had been treated previously with an anti-oestrogen, and the manufacturer's confirmation about the marketing authorisation, which places fulvestrant, within its licensed indication, as an alternative to aromatase inhibitors after anti-oestrogen treatment.\n\nThe Committee considered the likely position of fulvestrant in the treatment pathway for women with oestrogen-receptor-positive advanced breast cancer in the UK. The Committee also examined the recommendations on the use of hormone therapy in the NICE clinical guidelines 'Early and locally advanced breast cancer: diagnosis and treatment' (NICE clinical guideline 80) and 'Advanced breast cancer: diagnosis and treatment' (NICE clinical guideline 81). It observed that aromatase inhibitors were recommended either as the sole, or as a significant part of, adjuvant treatment for most postmenopausal women with oestrogen-receptor-positive early breast cancer. The Committee also understood that aromatase inhibitors were recommended for postmenopausal women with oestrogen-receptor-positive advanced breast cancer who had no history of hormone therapy or who had been treated previously with tamoxifen. It heard from the clinical specialist that clinical practice follows these guidelines, in that most postmenopausal women receive an aromatase inhibitor as adjuvant hormone therapy for early breast cancer or as first-line treatment if presenting with advanced breast cancer. The Committee understood that the use of tamoxifen in clinical practice in postmenopausal women as a sole adjuvant treatment or as a first-line treatment for new locally advanced or metastatic breast cancer is diminishing, apart from in a small group of women with early breast cancer who have a very poor prognosis and in the small proportion of women who are unable to tolerate any aromatase inhibitor. The manufacturer stated in its submission that the split is approximately 20:80 between treatment with aromatase inhibitors and treatment with anti-oestrogens for patients whose disease progresses on or after adjuvant therapy. However, the Committee heard from the clinical specialist that the proportion of patients receiving aromatase inhibitors is increasing because of changes in clinical practice and therefore aromatase inhibitors are now increasingly favoured over anti-oestrogens. The clinical specialist also indicated that there was not thought to be any significant clinical difference between the effectiveness of anastrozole and letrozole for treating advanced disease. The clinical specialist informed the Committee that exemestane or tamoxifen may be offered as a second-line treatment to women whose disease has failed to respond to an aromatase inhibitor given as either adjuvant therapy or first-line treatment for advanced disease, with the choice depending on a variety of factors, including an assessment of how well previous treatment had worked. The Committee heard from the clinical specialist that fulvestrant is currently considered to be a third-line or fourth-line treatment for postmenopausal women with metastatic breast cancer in UK clinical practice. It further heard that there is little or no clinical evidence about the optimal treatment sequence for advanced breast cancer beyond first-line treatment. The Committee considered that the most likely position of fulvestrant in UK clinical practice would remain as a third-line or fourth-line treatment after therapy with aromatase inhibitors and/or an anti-oestrogen therapy. The Committee again noted the difference between the manufacturer's submission and clinical practice, and that fulvestrant was restricted by its marketing authorisation to use after treatment with an anti-oestrogen. However, based on the manufacturer's confirmation about the marketing authorisation for fulvestrant (see section 4.3), the Committee considered that third-line or fourth-line use was not within the remit of this technology appraisal.\n\nThe Committee considered the relevant comparator treatments for fulvestrant within its licensed indication. It understood that the scope listed low-dose (250\xa0mg) fulvestrant and aromatase inhibitors (anastrozole, exemestane and letrozole) as the relevant treatment comparators. It heard from the manufacturer that fulvestrant 250\xa0mg has been replaced by fulvestrant 500\xa0mg as the licensed dose. The Committee considered the remaining comparators. It noted that for the only positions in the treatment pathway for which evidence for fulvestrant was available, non-steroidal aromatase inhibitors such as anastrozole and letrozole are the most likely treatments to be used in clinical practice. It heard from the clinical specialist that, for women who are unable to tolerate non-steroidal aromatase inhibitors, exemestane would be the appropriate comparator if they have been treated previously with an anti-oestrogen. The Committee concluded that the aromatase inhibitors anastrozole, letrozole and exemestane are the most appropriate comparators for the appraisal of fulvestrant.\n\n# Clinical effectiveness\n\nThe Committee considered the clinical-effectiveness data from the CONFIRM trial. It noted that the only comparator in CONFIRM was low-dose (250\xa0mg) fulvestrant. Relative to this comparator, the Committee noted that fulvestrant 500\xa0mg offered benefits in increasing the TTP, but that the difference between groups was statistically significant only for those patients whose last therapy was an anti-oestrogen, and not for patients whose last therapy was an aromatase inhibitor. However, the Committee was also aware that the CONFIRM trial was not powered to detect a statistically significant difference in TTP between fulvestrant 500\xa0mg and fulvestrant 250\xa0mg in the two patient subgroups. The Committee concluded that fulvestrant 500\xa0mg offered some clinical benefit compared with fulvestrant 250\xa0mg.\n\nThe Committee noted that the results of the network meta-analyses by the manufacturer showed no statistically significant differences in overall survival between fulvestrant, anastrozole and letrozole, although fulvestrant resulted in statistically significantly longer TTP compared with anastrozole (but not letrozole). In addition, the Committee observed that parametric survival models had been used to estimate TTP (log-normal distribution) and overall survival (Weibull distribution) for fulvestrant and other comparators included in the network meta-analysis. The Committee agreed with the issues identified by the ERG about the fit of the log-normal survival model used by the manufacturer to estimate TTP for fulvestrant and other comparators included in the network. It agreed that this resulted in a small number of patients with very long TTPs, which was likely to significantly influence the mean TTP. The Committee also noted that, although the parametric model the manufacturer used to estimate overall survival in the network meta-analysis appeared to be a reasonable match with the CONFIRM trial data, the projections of overall survival beyond the period of observation may have been substantially over- or under-estimated because of the complex changes in risk that were likely to apply at later times. Therefore, the Committee concluded that there was high uncertainty about the validity of the results of the network meta-analyses used to estimate TTP and overall survival.\n\nThe Committee considered the populations of the trials included in the network meta-analysis, which included aromatase inhibitors as comparators. It was aware that, although the marketing authorisation for fulvestrant 500\xa0mg is for patients who have received previous anti-oestrogen treatment, the CONFIRM, FINDER-1 and FINDER-2 trial populations included some patients who had last received an aromatase inhibitor, whereas all other trials in the network included only patients who had previously received an anti-oestrogen. The Committee further noted differences in the previous anti-oestrogen and previous aromatase inhibitor groups relating to the position of fulvestrant as a first-line or second-line therapy. Data from CONFIRM showed that most (65.5%) patients receiving fulvestrant after an anti-oestrogen therapy received fulvestrant as a first-line treatment for metastatic breast cancer and the remainder (34.5%) received fulvestrant as a second-line treatment for metastatic breast cancer. Conversely, of the patients who received an aromatase inhibitor as their last treatment before fulvestrant, most (66.8%) received fulvestrant as a second-line treatment for advanced breast cancer. The Committee also noted the differences in demography in the anti-oestrogen and aromatase inhibitor populations and agreed with the ERG that these two groups were heterogeneous. Therefore the Committee agreed that only data from the subgroup in the CONFIRM trial who had received an anti-oestrogen as their last treatment before fulvestrant should be included in the network meta-analyses, in line with the marketing authorisation for fulvestrant.\n\nThe Committee considered the eligibility criteria for trials included in the network meta-analysis. It was aware that CONFIRM, FINDER-1 and FINDER-2 were the only trials with an entire patient population documented as having oestrogen-receptor-positive breast cancer. The Committee noted that the manufacturer had sought advice from key opinion leaders about setting firm criteria for the selection of trials for inclusion in the meta-analysis (for example, including only recent trials, or agreeing a stipulated percentage of patients with cancer of unknown oestrogen receptor status), but that no such criteria could be agreed. The main inclusion criterion was relaxed by the manufacturer to include trials for comparators with at least 70% of patients with documented oestrogen-receptor-positive status. The Committee was aware that, based on this criterion, exemestane was excluded as a comparator because of the lack of any relevant trials with at least 70% of patients with oestrogen-receptor-positive cancer. The Committee noted that the percentage of patients with oestrogen-receptor-negative cancer in the trials included in the network meta-analysis ranged from 0% to 33%. The Committee also highlighted sources of heterogeneity between the trials included in the network meta-analysis, including inclusion criteria, median duration of follow-up, amount of previous chemotherapy given, types of recurrent and metastatic disease and the wide timespan of the included trials, which were published between 1996 and 2010. The Committee noted that fulvestrant 500\xa0mg was linked to other treatments in the network only through fulvestrant 250\xa0mg, which was used as the baseline comparator in the manufacturer's network meta-analysis. The Committee further noted that the baseline characteristics of the patients enrolled in the CONFIRM, FINDER-1 and FINDER-2 trials may not be directly comparable with those of patients enrolled in earlier studies that compared fulvestrant 250\xa0mg with anastrozole. The Committee also observed that the results of the network meta-analyses suggested better outcomes in terms of overall survival and TTP for letrozole 0.5\xa0mg (which does not have a marketing authorisation for this indication) than for letrozole 2.5\xa0mg (which does have a marketing authorisation for this indication) when compared with fulvestrant 500\xa0mg. The Committee noted the results of two other trials (Dombernowsky et al. 1998; Gershanovich et al. 1998) that were excluded from the network meta-analyses (because they did not meet the oestrogen-receptor-positive status inclusion criterion) in which there was a trend suggesting clinical superiority of letrozole 2.5\xa0mg over letrozole 0.5\xa0mg. The Committee concluded that the results of the manufacturer's network meta-analysis were subject to bias from the selection of studies included in the network and this therefore increased the uncertainty about the outputs of this analysis.\n\nThe Committee again discussed the parametric survival models used to project TTP and overall survival by the manufacturer. It accepted the ERG's exploratory analyses that derived the best estimate of overall survival from modelling post-progression on the basis of trial data and combining pre-progression and post-progression estimates. Overall, the Committee concluded that the manufacturer did not provide sufficient commentary or analysis of uncertainty about the fit of alternative parametric survival models and concluded that the estimates of TTP and overall survival based on the ERG's exploratory analysis were more appropriate and were therefore preferred.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's economic model and the ERG's critique of the model. The Committee agreed with the ERG that because two different probability distributions were fitted to the two sets of data, it is possible for projected estimates of TTP to exceed the corresponding estimates of overall survival, which can lead to negative values for the number of patients alive in the post-progression state in the economic model. The Committee noted that, although the model corrected any negative post-progression survival estimates to zero, it did not compensate for any resulting overestimation of survival. The Committee concluded that the manufacturer's economic model is unlikely to provide a robust basis for projecting survival data beyond the observed data from the CONFIRM trial.\n\nThe Committee discussed the utility values applied to the pre-progression and post-progression health states by the manufacturer. The Committee agreed that, although the utility values (taken from Lloyd et al. 2006) were not generated in line with the NICE reference case, they probably represent the best published estimates available, although methodological uncertainty remains. However, it agreed that the utility values based on the age of the participants in the study by Lloyd et al. (2006) should have been adjusted to the mean age of patients used to estimate UK EQ-5D tariff scores. The Committee also agreed with the ERG that the 'responder status' of patients should have been incorporated in the estimation of utility values for the pre-progression and post-progression health states. The Committee concluded that the ERG's adjusted utility values used in its exploratory analysis were preferable to those used by the manufacturer.\n\nThe Committee discussed the validity of the cost inputs used in the manufacturer's economic model. The Committee agreed with the ERG in relation to uncertainty about some of the cost inputs used and that modifications to these parameters resulted in small increases in the ICERs. The Committee also noted that the list price of anastrozole reported in the manufacturer's submission may not be what the NHS usually pays. Therefore the Committee concluded that it is likely that the ICERs for fulvestrant compared with anastrozole would be underestimated.\n\nThe Committee noted that the key drivers of the cost-effectiveness results in the manufacturer's model were the estimates of TTP and overall survival for all treatments and the utility values assigned to the pre-progression and post-progression health states. The Committee highlighted the results of the manufacturer's probabilistic sensitivity analysis, which indicated that fulvestrant 500\xa0mg had a low probability of being cost effective (2%) at a threshold of £20,000 per QALY gained. The Committee also considered that the ICERs generated using the manufacturer's model were not reliable because of problems with the design of the model and the inclusion of the mixed patient population from the CONFIRM trial. The Committee agreed that the ICERs generated by the ERG's exploratory analysis – which used different estimates of TTP and overall survival, included only the population from the CONFIRM trial whose last treatment had been an anti-oestrogen, revised cost inputs and adjusted the utility estimates – would be more reliable. However, the Committee noted that the ERG's exploratory analysis was based on the same trials in the network meta-analysis as those used in the manufacturer's network meta-analysis. The Committee considered that the network meta-analysis contained considerable uncertainty, which was unaccounted for in the ICERs. Overall, the Committee concluded that the ERG's ICER of £35,000 per QALY gained for fulvestrant 500\xa0mg compared with anastrozole was more plausible than the manufacturer's base-case estimate but there remained considerable uncertainty about this estimate.\n\nThe Committee noted that no comparison with exemestane could be made in the manufacturer's base-case cost-effectiveness analysis because of a lack of any relevant trials in which 70% or more of patients had oestrogen-receptor-positive advanced breast cancer in a population who had received an anti-oestrogen. The Committee noted that, as a result, the cost effectiveness of fulvestrant compared with exemestane in this patient population remains unknown. The Committee further concluded that a cost-effectiveness analysis for a subgroup of patients with contraindications to non-steroidal aromatase inhibitors would be desirable, but because the comparator treatment in such an analysis would be exemestane, this could not be undertaken. The Committee concluded that it was unable to recommend fulvestrant as an alternative to exemestane in postmenopausal women with oestrogen-receptor-positive, locally advanced or metastatic breast cancer, or disease progression on therapy with an anti-oestrogen who have contraindications to non-steroidal aromatase inhibitors.\n\nThe Committee considered the small subgroup of women who are unable to tolerate treatment with any aromatase inhibitor. The Committee noted that there was no available evidence on the clinical and cost effectiveness of fulvestrant for this small subgroup, and concluded that it was unable to recommend fulvestrant for women unable to tolerate both non-steroidal and steroidal aromatase inhibitors. However, the Committee was aware of alternative funding arrangements available for providing treatment for women who are unable to tolerate an aromatase inhibitor, such as individual funding requests based on exceptionality.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all of the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24 months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.\n\nIn addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe Committee discussed whether fulvestrant fulfilled the criteria for a life-extending, end-of-life treatment. The Committee agreed that, based on the results of the CONFIRM trial, fulvestrant is indicated for patients with a life expectancy of more than 24\xa0months (the ERG's estimate of mean overall survival for patients taking fulvestrant 500\xa0mg was 36.33\xa0months compared with 32.31\xa0months for those taking anastrozole and 30.90\xa0months for those taking letrozole) and so the criterion of patients with a short life expectancy was not met. Therefore, the Committee agreed that it was not necessary for the criteria of extension to life of at least an additional 3 months and a small patient population to be established. The Committee concluded that fulvestrant did not fulfil the end-of-life criteria.\n\nThe Committee considered the most plausible ICER for fulvestrant compared with anastrozole, which it had agreed was likely to be at least £35,000 per QALY gained (see section 4.14). The Committee also noted the considerable uncertainty associated with this estimate because of the network meta-analysis. The Committee concluded that fulvestrant could not be considered a cost-effective use of NHS resources as an alternative to aromatase inhibitors for the treatment of oestrogen-receptor-positive, locally advanced or metastatic breast cancer in post-menopausal women whose cancer has relapsed on or after adjuvant anti-oestrogen therapy, or who have disease progression on anti-oestrogen therapy.\n\nThe Committee considered a potential equalities issue highlighted during consultation about the use of fulvestrant for patients unable to swallow oral aromatase inhibitor medication. The Committee was aware that women who are unable to swallow (for example, following a stroke) would be fed using an enteral tube, and that oral medication can also be given by this route. In addition, given that the recommendation did not differentiate between any groups of people, the Committee concluded that its recommendations did not limit access to the technology for any specific group compared with other groups.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA239\n\nAppraisal title: Fulvestrant for the treatment of locally advanced or metastatic breast cancer\n\nSection\n\nKey conclusion\n\nFulvestrant is not recommended, within its licensed indication, as an alternative to aromatase inhibitors for the treatment of oestrogen-receptor-positive, locally advanced or metastatic breast cancer in postmenopausal women whose cancer has relapsed on or after adjuvant anti-oestrogen therapy, or who have disease progression on anti-oestrogen therapy.\n\nReasons for recommendation:\n\nFulvestrant has a marketing authorisation for patients who have been treated previously with an anti-oestrogen (that is; second line as an alternative to aromatase inhibitors).\n\nThe CONFIRM trial population consisted of a mixture of patients who had last received either an anti-oestrogen or an aromatase inhibitor. The only comparator included in the CONFIRM trial was fulvestrant 250\xa0mg.\n\nThere was high uncertainty about the validity of the manufacturer's network meta-analysis because of heterogeneity between the studies included, the selection of studies included and the parametric survival models used to project TTP and overall survival.\n\nThe most plausible ICER presented for fulvestrant 500\xa0mg compared with anastrozole was £35,000 per QALY gained (based on the ERG's exploratory analysis). However, there remained considerable uncertainty about this estimate because it was based on the same trials in the network meta-analysis as those used in the manufacturer's network meta-analysis.\n\nThe Committee concluded that fulvestrant did not fulfil the end-of-life criteria as it is indicated for patients with a life expectancy of more than 24\xa0months.\n\n\n\n\n\n\n\n\n\n\n\n,\n\n,\n\n,\n\n,\n\n,\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard from the patient expert about the value of having a further treatment option after aromatase inhibitors and anti-oestrogen therapies. The Committee recognised the importance of additional treatment options for post-menopausal women with locally advanced or metastatic breast cancer.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee noted that although fulvestrant 500\xa0mg offered benefits in increasing the TTP compared with low-dose (250\xa0mg) fulvestrant in the CONFIRM trial, this difference was statistically significant only for patients whose last therapy was an anti-oestrogen, and not for patients whose last therapy was an aromatase inhibitor. However, the Committee was also aware that the CONFIRM trial was not powered to detect a statistically significant difference in TTP between fulvestrant 500 mg and fulvestrant 250 mg in the two patient subgroups. The Committee noted that the results of the network meta-analyses by the manufacturer showed no statistically significant differences in overall survival between fulvestrant, anastrozole and letrozole, although fulvestrant resulted in statistically significantly longer TTP compared with anastrozole (but not letrozole). However, the Committee concluded there was high uncertainty about the validity of these results because of the parametric survival models used.\n\nNo specific claim for innovation was made.\n\n,\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe manufacturer confirmed that fulvestrant has a marketing authorisation as a second-line treatment for metastatic breast cancer in postmenopausal women after adjuvant or first-line treatment of advanced disease with an anti-oestrogen therapy (for most patients this is usually tamoxifen). The Committee was aware that the marketing authorisation places fulvestrant as an alternative to aromatase inhibitors after anti-oestrogen treatment.\n\nThe Committee considered that third-line or fourth-line use was not within the remit of this technology appraisal.\n\nThe Committee concluded that the aromatase inhibitors anastrozole, letrozole and exemestane are the most appropriate comparators for the appraisal of fulvestrant.\n\n,\n\n,\n\n\n\n\n\n\n\n\n\n\n\nAdverse effects\n\nThe Committee heard from one patient expert who is currently receiving fulvestrant that the disadvantages of having two injections and the associated side effects of fulvestrant were outweighed by the benefits of remaining fit and well on this therapy.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee was aware that the only treatment comparator in the CONFIRM trial was low-dose (250\xa0mg) fulvestrant.\n\nThe Committee noted that although the marketing authorisation for fulvestrant 500\xa0mg is for patients who have received previous anti-oestrogen treatment, the CONFIRM trial population consisted of a mixture of patients who had last received either an anti-oestrogen or an aromatase inhibitor. The Committee noted heterogeneity between these two subgroups in terms of previous treatment and patient characteristics. The Committee therefore agreed that only data from the subgroup in the CONFIRM trial who had received an anti-oestrogen as their last treatment should be included in the network meta-analyses.\n\nThe Committee noted that fulvestrant 500\xa0mg was linked to other treatments in the network only through fulvestrant 250\xa0mg, which was used as the baseline comparator in the manufacturer's network meta-analysis. The Committee noted that the manufacturer had sought advice from key opinion leaders about setting firm criteria for the selection of trials for inclusion in the meta-analysis (for example, including only recent trials, or agreeing a certain percentage of patients with cancer of unknown oestrogen receptor status), but that no such criteria could be agreed. The main inclusion criterion was relaxed by the manufacturer to include trials for comparators with at least 70% of patients with documented oestrogen-receptor-positive status. The Committee was aware that, based on this criterion, exemestane was excluded as a comparator in the base-case cost-effectiveness analysis. The Committee also highlighted sources of heterogeneity between the trials included in the network meta-analysis. The Committee concluded that the results of the manufacturer's network meta-analysis were subject to bias from the selection of studies included in the network.\n\n,\n\n,\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee was aware of the restriction to the marketing authorisation to patients who had been treated previously with an anti-oestrogen, which places fulvestrant as an alternative to aromatase inhibitors after anti-oestrogen treatment.\n\nThe Committee considered that third-line or fourth-line use was not within the remit of this technology appraisal.\n\n\n\n,\n\n\n\nUncertainties generated by the evidence\n\nThe Committee concluded that there was high uncertainty about the validity of the results of the manufacturer's network meta-analysis because of heterogeneity between the studies selected and the parametric survival models used to project TTP and overall survival.\n\n,\n\n,\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee noted that the CONFIRM trial population consisted of a mixture of patients who had last received either an anti-oestrogen or an aromatase inhibitor. The Committee noted heterogeneity between these two subgroups in terms of previous treatment and patient characteristics. The Committee therefore agreed that only data from the subgroup in the CONFIRM trial who had received an anti-oestrogen as their last treatment should be included in the network meta-analyses, in line with the marketing authorisation for fulvestrant.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee noted that the results of the network meta-analyses by the manufacturer showed no significant differences in overall survival between fulvestrant, anastrozole and letrozole, although fulvestrant resulted in significantly longer TTP compared with anastrozole (but not letrozole). However, the Committee concluded that, because of the issues identified by the ERG concerning the fit of the parametric survival models used by the manufacturer, there was high uncertainty about these results.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee agreed with the ERG that because two different probability distributions were fitted to the two sets of data, it is possible for projected estimates of TTP to exceed the corresponding estimates of overall survival, which can lead to negative values for the number of patients alive in the post-progression state in the economic model. The Committee concluded that the manufacturer's economic model is unlikely to provide a robust basis for projecting survival data beyond the observed data from the CONFIRM trial.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee discussed the validity of the cost inputs used in the manufacturer's economic model. The Committee agreed with the ERG in relation to the cost data used and that modifications to these parameters resulted in small increases in the ICERs for fulvestrant.\n\nThe Committee also considered that the ICERs generated using the manufacturer's model were not reliable because of problems with the design of the model and the inclusion of the mixed patient population from the CONFIRM trial.\n\n,\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee discussed the utility values applied to the pre-progression and post-progression health states by the manufacturer. The Committee agreed that, although the utility values were not generated in line with the NICE reference case, they probably represent the best published estimates available. However, the Committee agreed with the ERG that the utility values should have been adjusted for the age and 'responder status' of the patients.\n\nNo evidence of additional benefits (other than those already accounted for in the QALY) of treatment with fulvestrant was presented or identified.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee noted that no comparison with exemestane could be made in the manufacturer's base-case cost-effectiveness analysis because of a lack of any relevant trials in which 70% or more of patients had oestrogen-receptor-positive advanced breast cancer in a population that had an anti-oestrogen as their last treatment. The Committee noted that, as a result, the cost effectiveness of exemestane compared with fulvestrant in this patient population remains unknown. The Committee thought that a cost-effectiveness analysis for a subgroup of patients with contraindications to non-steroidal aromatase inhibitors would be desirable, but that such an analysis could not be undertaken. The Committee concluded that it was unable to recommend fulvestrant as an alternative to exemestane in postmenopausal women with oestrogen-receptor-positive, locally advanced or metastatic breast cancer, or disease progression on therapy with an anti-oestrogen who are contraindicated to non-steroidal aromatase inhibitors.\n\nThe Committee also noted that there was no available clinical and cost-effectiveness evidence on fulvestrant for the small subgroup of women who are unable to tolerate treatment with any aromatase inhibitor.\n\n,\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee noted that the key drivers of the cost-effectiveness results in the manufacturer's model were the estimates of TTP and overall survival for all treatments and the utility values assigned to the pre-progression and post-progression health states.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee agreed that the ICERs generated by the ERG's analysis – which used different estimates of TTP and overall survival, included only the population from the CONFIRM trial whose last treatment had been an anti-oestrogen, revised cost inputs and adjusted utility estimates – would be more reliable than the ICERs generated in the manufacturer's model. Therefore, the Committee concluded that the ICER of £35,000 per QALY gained for fulvestrant 500\xa0mg compared with anastrozole was more plausible than the manufacturer's base-case estimate but there remained considerable uncertainty about this estimate.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNo approved patient access scheme was submitted for the technology being appraised.\n\n\n\nEnd-of-life considerations\n\nThe Committee concluded that fulvestrant did not fulfil the end-of-life criteria because, based on the results of the CONFIRM trial, fulvestrant is indicated for patients with a life expectancy of more than 24\xa0months.\n\n\n\nEqualities considerations and social value judgements\n\nThe Committee considered a potential equalities issue highlighted during consultation about the use of fulvestrant for patients unable to swallow oral aromatase inhibitor medication. The Committee was aware that women who are unable to swallow (for example, following a stroke) would be fed using an enteral tube, and that oral medication can also be given by this route. In addition, given that the recommendation did not differentiate between any groups of people, the Committee concluded that its recommendations did not limit access to the technology for any specific group compared with other groups.\n\n", 'Related NICE guidance': '# Published\n\nAdvanced breast cancer: diagnosis and treatment. NICE clinical guideline\xa081 (2009).\n\nEarly and locally advanced breast cancer: diagnosis and treatment. NICE clinical guideline 80 (2009).\n\nGemcitabine for the treatment of metastatic breast cancer. NICE technology appraisal guidance 116 (2007).\n\n# Under development\n\nNICE is developing the following guidance (details available from www.nice.org.uk)\n\nEribulin for the treatment of locally advanced or metastatic breast cancer. NICE technology appraisal guidance (publication date to be confirmed).', 'Review of guidance': 'The guidance on this technology will be considered for review in August 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveDecember 2011', 'Changes after publication': 'March 2014: minor maintenance\n\nJune 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta239
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Evidence-based recommendations on fulvestrant (Faslodex), for treating locally advanced or metastatic breast cancer in adults.
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8adcef37b818ae5899015accc259cb533fd19d7b
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nice
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Service user experience in adult mental health: improving the experience of care for people using adult NHS mental health services
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Service user experience in adult mental health: improving the experience of care for people using adult NHS mental health services
This guideline covers the components of a good experience of service use. It aims to make sure that all adults using NHS mental health services have the best possible experience of care.
# Introduction
Over the past few years several documents and initiatives have highlighted the importance of the service user's experience and the need to focus on improving this experience where possible.
Lord Darzi's report High quality care for all (2008) highlighted the importance of the entire service user experience within the NHS, ensuring people are treated with compassion, dignity and respect within a clean, safe and well‑managed environment.
The development of the NHS Constitution (2009 to 2010) was one of several recommendations from Lord Darzi's report. The Constitution describes the purpose, principles and values of the NHS and illustrates what staff, service users and the public can expect from the service. Since the Health Act came into force in January 2010, service providers and commissioners of NHS care have had a legal obligation to take the Constitution into account in all their decisions and actions.
The King's Fund charitable foundation has developed a comprehensive policy resource – Seeing the person in the patient: the point of care review paper (2008). Some of the topics explored in the paper are used in the development of this guidance and quality standard.
National initiatives aimed at improving service users' experience of healthcare include NHS Choices, a comprehensive information service that helps people to manage their healthcare and provides service users and carers with information and choice about their care. Initiatives, such as patient advice and liaison services (PALS), have also been introduced.
Despite these initiatives, there is evidence to suggest that further work is needed to deliver the best possible experience for users of NHS services. The Government signalled in its White Paper, Equity and excellence: liberating the NHS (July 2010) that more emphasis needs to be placed on improving service users' experience of NHS care. This guidance on service user experience in adult mental health services is a direct referral from the Department of Health.
In 2005 the Department of Health published Delivering race equality in mental health care: an action plan for reform inside and outside services and the government's response to the independent inquiry into the death of David Bennett. The report contained recommendations about the delivery of mental healthcare to service users, in particular those from black and minority ethnic communities. The recommendations also address wider issues in mental health settings, such as the safe use of physical interventions.
High‑quality care should be clinically effective, safe and be provided in a way that ensures the service user has the best possible experience of care. This guidance on service user experience aims to ensure that users of mental health services have the best possible experience of care from the NHS.
NICE's quality standard on service user experience in adult mental health services has been developed alongside this guidance. NICE quality standards are a set of specific, concise statements and associated measures. They set out aspirational, but achievable, markers of high‑quality, cost‑effective care. Quality standards are derived from the best available evidence and address three dimensions of quality: clinical effectiveness, service user safety and service user experience.
NICE clinical guidelines are usually shaped around both clinical and economic evidence, and include recommendations concerned with ensuring a good service user experience, with the recognition that such advice should sit alongside evidence of clinical and cost effectiveness. The recommendations in the current guidance have been informed by research evidence, recommendations in previously published NICE clinical guidelines, national survey data and consensus processes that have identified the key elements that are important to service users and how these can be improved to ensure a good experience of care. The guidance draws on multiple evidence and data sources in developing the recommendations.# Guidance
The following guidance is based on the best available evidence. The full guidance gives details of the methods and the evidence used to develop the guidance.
In this guidance, families and carers include relatives, friends, non‑professional advocates and significant others who play a supporting role for the person using mental health services. If the service user agrees, families and carers should have the opportunity to be involved in decisions about treatment and care. Families and carers should also be given the information and support they need.
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Care and support across all points on the care pathway
## Relationships and communication
Work in partnership with people using mental health services and their families or carers. Offer help, treatment and care in an atmosphere of hope and optimism. Take time to build trusting, supportive, empathic and non‑judgemental relationships as an essential part of care.
When working with people using mental health services:
aim to foster their autonomy, promote active participation in treatment decisions and support self‑management
maintain continuity of individual therapeutic relationships wherever possible
-ffer access to a trained advocate.
When working with people using mental health services and their family or carers:
ensure that you are easily identifiable (for example, by wearing appropriate identification) and approachable
address service users using the name and title they prefer
clearly explain any clinical language and check that the service user understands what is being said
take into account communication needs, including those of people with learning disabilities, sight or hearing problems or language difficulties, and provide independent interpreters (that is, someone who does not have a relationship with the service user) or communication aids (such as using pictures, symbols, large print, Braille, different languages or sign language) if required.
When working with people using mental health services:
make sure that discussions take place in settings in which confidentiality, privacy and dignity are respected
be clear with service users about limits of confidentiality (that is, which health and social care professionals have access to information about their diagnosis and its treatment and in what circumstances this may be shared with others).
## Providing information
When working with people using mental health services:
ensure that comprehensive written information about the nature of, and treatments and services for, their mental health problems is available in an appropriate language or format including any relevant text from NICE's information for the public
ensure that comprehensive information about other support groups, such as third sector, including voluntary organisations, is made available.
Ensure that you are:
familiar with local and national sources (organisations and websites) of information and/or support for people using mental health services
able to discuss and advise how to access these resources
able to discuss and actively support service users to engage with these resources.
## Avoiding stigma and promoting social inclusion
When working with people using mental health services:
take into account that stigma and discrimination are often associated with using mental health services
be respectful of and sensitive to service users' gender, sexual orientation, socioeconomic status, age, background (including cultural, ethnic and religious background) and any disability
be aware of possible variations in the presentation of mental health problems in service users of different genders, ages, cultural, ethnic, religious or other diverse backgrounds.
Health and social care professionals working with people using mental health services should have competence in:
assessment skills and using explanatory models of illness for people from different cultural, ethnic, religious or other diverse backgrounds
explaining the possible causes of different mental health problems, and care, treatment and support options
addressing cultural, ethnic, religious or other differences in treatment expectations and adherence
addressing cultural, ethnic, religious or other beliefs about biological, social and familial influences on the possible causes of mental health problems
conflict management and conflict resolution.
Health and social care providers' boards should work with local authorities and all other local organisations with an interest in mental health (including social services, other hospitals, third sector, including voluntary, organisations, local press and media groups, and local employer organisations) to develop a strategy to combat the stigma in the community and in the NHS associated with mental health problems and using mental health services.
## Decisions, capacity and safeguarding
Health and social care professionals should ensure that they:
understand and can apply the principles of the Mental Capacity Act (2005) appropriately
are aware that mental capacity needs to be assessed for each decision separately
can assess mental capacity using the test in the Mental Capacity Act (2005)
understand how the Mental Health Act (1983; amended 1995 and 2007) and the Mental Capacity Act (2005) relate to each other in practice.
Develop advance statements and advance decisions with the person using mental health services if they wish to do so, especially if their illness is severe and they have been previously treated under the Mental Health Act (1983; amended 1995 and 2007). Document these in their care plans and ensure copies are held by the service user and in primary and secondary care records.
When a service user has impaired capacity, check their care record for advance statements and advance decisions before offering or starting treatment.
Consider service users for assessment according to local safeguarding procedures for vulnerable adults if there are concerns regarding exploitation or self‑care, or if they have been in contact with the criminal justice system.
## Involving families and carers
Discuss with the person using mental health services if and how they want their family or carers to be involved in their care. Such discussions should take place at intervals to take account of any changes in circumstances, and should not happen only once. As the involvement of families and carers can be quite complex, staff should receive training in the skills needed to negotiate and work with families and carers, and also in managing issues relating to information sharing and confidentiality.
If the person using mental health services wants their family or carers to be involved, encourage this involvement and:
negotiate between the service user and their family or carers about confidentiality and sharing of information on an ongoing basis
explain how families or carers can help support the service user and help with treatment plans
ensure that no services are withdrawn because of the family's or carers' involvement, unless this has been clearly agreed with the service user and their family or carers.
If the person using mental health services wants their family or carers to be involved, give the family or carers verbal and written information about:
the mental health problem(s) experienced by the service user and its treatment, including relevant text from NICE's information for the public
statutory and third sector, including voluntary, local support groups and services specifically for families and carers, and how to access these
their right to a formal carer's assessment of their own physical and mental health needs, and how to access this (see NICE's guideline on supporting adult carers).
If the service user does not want their family or carers to be involved in their care:
seek consent from the service user, and if they agree give the family or carers verbal and written information on the mental health problem(s) experienced by the service user and its treatments, including relevant text from NICE's information for the public
give the family or carers information about statutory and third sector, including voluntary, local support groups and services specifically for families or carers, and how to access these
tell the family or carers about their right to a formal carer's assessment of their own physical and mental health needs, and how to access this (see NICE's guideline on supporting adult carers)
bear in mind that service users may be ambivalent or negative towards their family for many different reasons, including as a result of the mental health problem or as a result of prior experience of violence or abuse.
Ensure that service users who are parents with caring responsibilities receive support to access the full range of mental health and social care services, including:
information about childcare to enable them to attend appointments, groups and therapy sessions
hospital care in local mother and baby units for women in the late stages of pregnancy and within a year of childbirth
a family room or space in inpatient units where their children can visit them.
## Engaging service users in improving care
When providing training about any aspect of mental health and social care:
involve people using mental health services in the planning and delivery of training
ensure that all training aims to improve the quality and experience of care for people using mental health services; evaluate training with this as an outcome.
Health and social care providers should consider employing service users to be involved in training teams of health and social care professionals and supporting staff (such as receptionists, administrators, secretaries and housekeeping staff) in 'person‑centred care'. Such training should be tailored to the needs of people who attend mental health services and should be evaluated using experience of care as an outcome. Service users themselves should be provided with training and supervision to undertake this role.
Managers of health and social care providers should consider employing service users to monitor the experience of using mental health services, especially inpatient services, for example by paying them to undertake exit interviews with service users who have recently left a service. Offer service users training to do this.
Service managers should routinely commission reports on the experience of care across non‑acute and acute care pathways, including the experience of being treated under the Mental Health Act (1983; amended 1995 and 2007). These reports should:
include data that allow direct comparisons of the experience of care according to gender, sexual orientation, socioeconomic status, age, background (including cultural, ethnic and religious background) and disability
include analyses of data from multiple sources, particularly data collected by service users monitoring service user experience and complaints
be routinely communicated to the health and social care providers' board.
# Access to care
When people are referred to mental health services, ensure that:
they are given or sent a copy of the referral letter when this is sent to mental health services
they are offered a face‑to‑face appointment with a professional in mental health services taking place within 3 weeks of referral
they are informed that they can change the date and time of the appointment if they wish
any change in appointment does not result in a delay of more than 2 weeks.
When people are sent an appointment letter for mental health services it should:
give the name and professional designation of the person who will assess them
include information about the service, including a website address where available, and different options about how to get there
explain the process of assessment using plain language
specify all the information needed for the assessment, including about current medication
address the likely anxiety and concern often experienced by people attending mental health services for assessment
explain that although they can be accompanied by a family member, carer or advocate if they wish for all or part of the time, it is preferable to see the person alone for some of the assessment
ask if they require anything to support their attendance (for example, an interpreter, hearing loop, wider access)
give a number to ring if they have problems getting to the appointment or wish to change it.
Mental health services should establish close working relationships with primary care services to ensure:
agreed processes for referral, consistent with 1.2.1, are in place, and
primary care professionals can provide information about local mental health and social care services to the people they refer.
Take into account the requirements of the Equality Act 2010 and make sure services are equally accessible to, and supportive of, all people using mental health services.
Local mental health services should work with primary care and local third sector, including voluntary, organisations to ensure that:
all people with mental health problems have equal access to services based on clinical need and irrespective of gender, sexual orientation, socioeconomic status, age, background (including cultural, ethnic and religious background) and any disability
services are culturally appropriate.
# Assessment
On arrival at mental health services for assessment, service users should be greeted and engaged by reception and other staff in a warm, friendly, empathic, respectful and professional manner, anticipating possible distress.
Before the assessment begins, the health or social care professional undertaking the assessment should ensure that the service user understands:
the process of assessment and how long the appointment will last
that the assessment will cover all aspects of their experiences and life
confidentiality and data protection as this applies to them
the basic approach of shared decision‑making (also see the NICE guideline on decision-making and mental capacity)
that although they can be accompanied by a family member, carer or advocate for all or part of the time, it is preferable to see the person alone for some of the assessment
that they can refuse permission for any other member of staff, such as a student, to be present.
When carrying out an assessment:
ensure there is enough time for the service user to describe and discuss their problems
allow enough time towards the end of the appointment for summarising the conclusions of the assessment and for discussion, with questions and answers
explain the use and meaning of any clinical terms used
explain and give written material in an accessible format about any diagnosis given
give information about different treatment options, including drug and psychological treatments, and their side effects, to promote discussion and shared understanding
-ffer support after the assessment, particularly if sensitive issues, such as childhood trauma, have been discussed.
If a service user is unhappy about the assessment and diagnosis, give them time to discuss this and offer them the opportunity for a second opinion.
Copy all written communications with other health or social care professionals to the service user at the address of their choice, unless the service user declines this.
Ensure that if a service user needs to wait before an assessment, this is for no longer than 20 minutes after the agreed appointment time; explain the reasons for any delay.
Ensure that waiting rooms are comfortable, clean and warm, and have areas of privacy, especially for those who are distressed or who request this, or are accompanied by children.
Inform service users of their right to a formal community care assessment (delivered through local authority social services), and how to access this.
Inform service users how to make complaints and how to do this safely without fear of retribution.
# Community care
When communicating with service users use diverse media, including letters, phone calls, emails or text messages, according to the service user's preference.
Develop care plans jointly with the service user, and:
include activities that promote social inclusion such as education, employment, volunteering and other occupations such as leisure activities and caring for dependants
provide support to help the service user realise the plan
give the service user an up‑to‑date written copy of the care plan, and agree a suitable time to review it.
Support service users to develop strategies, including risk‑ and self‑management plans, to promote and maintain independence and self‑efficacy, wherever possible. Incorporate these strategies into the care plan.
If they are eligible, give service users the option to have a personal budget or direct payment so they can choose and control their social care and support, with appropriate professional and peer support as needed.
For people who may be at risk of crisis, a crisis plan should be developed by the service user and their care coordinator, which should be respected and implemented, and incorporated into the care plan. The crisis plan should include:
possible early warning signs of a crisis and coping strategies
support available to help prevent hospitalisation
where the person would like to be admitted in the event of hospitalisation
the practical needs of the service user if they are admitted to hospital (for example, childcare or the care of other dependants, including pets)
details of advance statements and advance decisions (see recommendation 1.1.11)
whether and the degree to which families or carers are involved
information about 24‑hour access to services
named contacts.
Ensure that service users routinely have access to their care plan and care record, including electronic versions. Care records should contain a section in which the service user can document their views and preferences, and any differences of opinion with health and social care professionals.
Health and social care providers should ensure that service users:
can routinely receive care and treatment from a single multidisciplinary community team
are not passed from one team to another unnecessarily
do not undergo multiple assessments unnecessarily.
Ensure that service users have timely access to the psychological, psychosocial and pharmacological interventions recommended for their mental health problem in NICE guidance.
Mental health services should work with local third sector, including voluntary, black and minority ethnic and other minority groups to jointly ensure that culturally appropriate psychological and psychosocial treatments, consistent with NICE guidance and delivered by competent practitioners, are provided to service users from these groups.
Mental health and social care professionals inexperienced in working with service users from different cultural, ethnic, religious and other diverse backgrounds should seek advice, training and supervision from health and social care professionals who are experienced in working with these groups.
# Assessment and referral in a crisis
Immediately before assessing a service user who has been referred in crisis, find out if they have had experience of acute or non‑acute mental health services, and consult their crisis plan and advance statements or advance decisions if they have made them. Find out if they have an advocate and contact them if the service user wishes. Ask if the service user has a preference for a male or female health or social care professional to conduct the assessment, and comply with their wishes wherever possible.
When undertaking a crisis assessment:
address and engage service users in a supportive and respectful way
provide clear information about the process and its possible outcomes, addressing the individual needs of the service user, as set out in the section on assessment
take extra care to understand and emotionally support the service user in crisis, considering their level of distress and associated fear, especially if they have never been in contact with services before, or if their prior experience of services has been difficult and/or they have had compulsory treatment under the Mental Health Act (1983; amended 1995 and 2007).
Assessment in crisis should be undertaken by experienced health and social care professionals competent in crisis working, and should include an assessment of the service user's relationships, social and living circumstances and level of functioning, as well as their symptoms, behaviour, diagnosis and current treatment.
If assessment in the service user's home environment is not possible, or if they do not want an assessment at home, take full consideration of their preferences when selecting a place for assessment.
When a person is referred in crisis they should be seen by specialist mental health secondary care services within 4 hours of referral.
Health and social care providers should provide local 24‑hour helplines, staffed by mental health and social care professionals, and ensure that all GPs in the area know the telephone number.
Health and social care providers should ensure that crisis resolution and home treatment teams are accessible 24‑hours a day, 7 days a week, and available to service users in crisis regardless of their diagnosis.
To avoid admission, aim to:
explore with the service user what support systems they have, including family, carers and friends
support a service user in crisis in their home environment
make early plans to help the service user maintain their day‑to‑day activities, including work, education, voluntary work, and other occupations such as caring for dependants and leisure activities, wherever possible.
At the end of a crisis assessment, ensure that the decision to start home treatment depends not on the diagnosis, but on:
the level of distress
the severity of the problems
the vulnerability of the service user
issues of safety and support at home
the person's cooperation with treatment.
Consider the support and care needs of families or carers of service users in crisis. Where needs are identified, ensure they are met when it is safe and practicable to do so.
Health and social care providers should support direct self‑referral to mental health services as an alternative to accessing urgent assessment via the emergency department.
# Hospital care
When a service user enters hospital, greet them using the name and title they prefer, in an atmosphere of hope and optimism, with a clear focus on their emotional and psychological needs, and their preferences. Ensure that the service user feels safe and address any concerns about their safety.
Give verbal and written information to service users, and their families or carers where agreed by the service user, about:
the hospital and the ward in which the service user will stay
treatments, activities and services available
expected contact from health and social care professionals
rules of the ward (including substance misuse policy)
service users' rights, responsibilities and freedom to move around the ward and outside
meal times
visiting arrangements.
Make sure there is enough time for the service user to ask questions.
Undertake shared decision‑making routinely with service users in hospital, including, whenever possible, service users who are subject to the Mental Health Act (1983; amended 1995 and 2007). See the NICE guideline on decision-making and mental capacity.
Commence formal assessment and admission processes within 2 hours of arrival.
Shortly after service users arrive in hospital, show them around the ward and introduce them to the health and social care team as soon as possible and within the first 12 hours if the admission is at night. If possible, this should include the named healthcare professional who will be involved throughout the person's stay.
Offer service users in hospital:
daily one‑to‑one sessions lasting at least 1 hour with a healthcare professional known to the service user
regular (at least weekly) one‑to‑one sessions lasting at least 20 minutes with their consultant
an opportunity to meet with a specialist mental health pharmacist to discuss medication choices and any associated risks and benefits.
Ensure that the overall coordination and management of care takes place at a regular multidisciplinary meeting led by the consultant and team manager with full access to the service user's paper and/or electronic record. Service users and their advocates should be encouraged to participate in discussions about their care and treatment, especially those relating to the use of the Mental Health Act (1983; amended 1995 and 2007). However, these meetings should not be used to see service users or carers as an alternative to their daily meeting with a known healthcare professional or their weekly one‑to‑one meeting with their consultant.
Health and social care providers should ensure that service users in hospital have access to the pharmacological, psychological and psychosocial treatments recommended in NICE guidance provided by competent health or social care professionals. Psychological and psychosocial treatments may be provided by health and social care professionals who work with the service user in the community.
Ensure that service users in hospital have access to a wide range of meaningful and culturally appropriate occupations and activities 7 days per week, and not restricted to 9am to 5pm. These should include creative and leisure activities, exercise, self‑care and community access activities (where appropriate). Activities should be facilitated by appropriately trained health or social care professionals.
Ensure that service users have access to the internet and telephone during their stay in hospital.
All health and social care professionals who work in a hospital setting should be trained as a team to use the same patient‑centred approach to treatment and care.
Service users receiving community care before hospital admission should be routinely visited while in hospital by the health and social care professionals responsible for their community care.
Ensure that all service users in hospital have access to advocates who can regularly feed back to ward professionals any problems experienced by current service users on that ward. Advocates may be formal Independent Mental Health Advocate (IMHAs), or former inpatients who have been trained to be advocates for other service users not detained under the Mental Health Act (1983; amended 1995 and 2007).
Ensure that hospital menus include a choice of foods, and that these are acceptable to service users from a range of ethnic, cultural and religious backgrounds and with specific physical health problems. Consider including service users in planning menus.
# Discharge and transfer of care
Anticipate that withdrawal and ending of treatments or services, and transition from one service to another, may evoke strong emotions and reactions in people using mental health services. Ensure that:
such changes, especially discharge, are discussed and planned carefully beforehand with the service user and are structured and phased
the care plan supports effective collaboration with social care and other care providers during endings and transitions, and includes details of how to access services in times of crisis
when referring a service user for an assessment in other services (including for psychological treatment), they are supported during the referral period and arrangements for support are agreed beforehand with them.
Agree discharge plans with the service user and include contingency plans in the event of problems arising after discharge. Ensure that a 24‑hour helpline is available to service users so that they can discuss any problems arising after discharge.
Before discharge or transfer of care, discuss arrangements with any involved family or carers. Assess the service user's financial and home situation, including housing, before they are discharged from inpatient care.
Give service users clear information about all possible support options available to them after discharge or transfer of care.
When plans for discharge are initiated by the service, give service users at least 48 hours' notice of the date of their discharge from a ward.
When preparing a service user for discharge, give them information about the local patient advice and liaison service (PALS) and inform them they can be trained as an advocate or become involved in monitoring services if they choose.
# Assessment and treatment under the Mental Health Act
Detain service users under the Mental Health Act (1983; amended 1995 and 2007) only after all alternatives have been fully considered in conjunction with the service user if possible, and with the family or carer if the service user agrees. Alternatives may include:
medicines review
respite care
acute day facilities
home treatment
crisis houses.
Carry out an assessment for possible detention under the Mental Health Act (1983; amended 1995 and 2007) in a calm and considered way. Respond to the service user's needs and treat them with dignity and, whenever possible, respect their wishes.
Explain to service users, no matter how distressed, why the compulsory detention or treatment is being used. Repeat the explanation if the service user appears not to have understood or is pre‑occupied or confused. Ask if the service user would like a family member, carer or advocate with them.
When detaining a service user under the Mental Health Act (1983; amended 1995 and 2007) inform the receiving mental health service about the service user so they are expecting them and ready to welcome them to the service.
When detaining a service user under the Mental Health Act (1983; amended 1995 and 2007):
give them verbal and written information appropriate to the section of the Act used, including 'patient rights leaflets' detailing what is happening to them and why, and what their rights are
repeat this information if they appear not to have understood or are pre‑occupied or confused
give them, and their families or carers if they agree, information about the legal framework of the Mental Health Act (1983; amended 1995 and 2007)
ensure they have access to an Independent Mental Health Advocate (IMHA).
Inform service users detained under the Mental Health Act (1983; amended 1995 and 2007) of their right to appeal to a mental health tribunal and support them if they appeal; provide information about the structure and likely speed of the appeals process.
Inform the service user that if they are dissatisfied with their care and wish to make a complaint while under the Mental Health Act (1983; amended 1995 and 2007) they should, in the first instance, direct their complaint to the service detaining them. If they are dissatisfied with the service's response to their complaint, inform them they can complain to the Care Quality Commission and explain how to do this.
When a service user is admitted to a 'place of safety' ensure they are assessed for the Mental Health Act (1983; amended 1995 and 2007) as soon as possible, and certainly within 4 hours.
After application of the Mental Health Act (1983; amended 1995 and 2007) ensure that:
transition to the inpatient unit is smooth, efficient and comfortable
family and carers can travel with the service user if safe to do so
the police are involved only if the safety of the service user, family, carers, dependent children or health and social care professionals is an important consideration and cannot be managed by other means, such as involving more professionals.
## Control and restraint, and compulsory treatment
Control and restraint, and compulsory treatment including rapid tranquillisation, should be used as a last resort, only after all means of negotiation and persuasion have been tried, and only by healthcare professionals trained and competent to do this. Document the reasons for such actions.
When a service user is subject to control and restraint, or receives compulsory treatment including rapid tranquillisation under the Mental Health Act (1983; amended 1995 and 2007):
recognise that they may consider it a violation of their rights
use minimum force
try to involve healthcare professionals whom the service user trusts
make sure the service user is physically safe
explain reasons for the episode of compulsory treatment to the service user and involved family members or carers
-ffer to discuss episodes of compulsory treatment with the service user at the time of discharge and do so in a calm and simple manner
ensure training in restraint involves service users.
After any episode of control and restraint, or compulsory treatment including rapid tranquillisation:
explain the reasons for such action to the service user and offer them the opportunity to document their experience of it in their care record, and any disagreement with healthcare professionals
ensure that other service users on the ward who are distressed by these events are offered support and time to discuss their experience.# Research recommendations
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.
# Training in the use of the national quality standard and guidance on service user experience of care
For people using adult mental health services, what is the effect of training community mental health teams (CMHTs) and inpatient ward staff in the use of the national quality standard and underpinning guidance on service user experience, when compared with no training, on service users' experience of care?
## Why this is important
The primary purpose of NICE quality standards is to make it clear what quality care is by providing patients and the public, health and social care professionals, commissioners and service providers with definitions of high‑quality health and social care. However, little is known about the impact of training health and social care professionals in the use of quality standards.
This question should be answered using a cluster randomised trial of community mental health teams (CMHTs) and inpatient ward staff to evaluate the impact of training them in the use of the national quality standard and underpinning guidance on service user experience of care. Three types of intervention should be included in the design:
CMHTs and wards with no training
CMHTs and wards where training is delivered by a professional trainer
CMHTs and wards where training is delivered by a professional trainer and service user(s).
Satisfaction with care and other aspects of service user experience should be surveyed. Qualitative interviews with service users and providers should be used to increase the explanatory power of the study.
# Late access to services and compulsory and intensive treatment
For people using adult mental health services, what are the personal and demographic factors associated with late access to services and an increased likelihood of compulsory and intensive treatment, and what are the key themes that are associated with poor engagement? This should include an examination of factors that impact on access to services among younger people and older adults.
## Why this is important
Qualitative research and experience surveys suggest that service users experience many problems relating to compulsory treatment. However, little is known about the factors associated with accessing services late and the need for compulsory and intensive treatment.
This question should be answered by a case‑control study to identify service users from different ethnic groups who use inpatient and intensive treatment services in order to identify the personal and demographic factors associated with late access to services and an increased likelihood of compulsory and intensive treatment. In‑depth interviews with service users should be undertaken to identify key themes that are associated with poor engagement.
# Shared decision‑making
For people using adult mental health services, what are the key aspects of 'shared decision‑making' that they prefer, and does a training programme for health and social care professionals designed around these key aspects, when compared with no training, improve service users' experience of care? A study should be undertaken to evaluate the impact on treatment choice, the experience of care and treatment effectiveness of training service users to deal with health and social care professionals assertively.
## Why this is important
In healthcare, 'shared decision‑making' is the sharing of preferences and decisions by both the professional and the service user to reach a consensus regarding the preferred treatment options. However, the key aspects of shared decision‑making are unknown, although the principle of shared decision‑making is an important element of a person‑centred care approach.
This question should be answered by a pilot qualitative study of shared decision‑making to determine what, if any, key aspects of shared decision‑making are preferred by service users. The pilot should be followed by a randomised controlled trial on shared decision‑making in community mental health teams (CMHTs) compared with standard decision‑making, which would be carefully characterised by in‑depth qualitative interview. Evaluation would quantify the impact on service user knowledge, the experience of care, rates of side effects and perceived benefits from treatment. Purposive‑selected service users would undertake in‑depth interviews to identify themes related to an improved experience of care associated with the shared decision‑making and the standard approach.
# Activities and occupations on inpatient wards
For people receiving adult mental health hospital care, what activities and occupations do service users want when staying on inpatient wards?
## Why this is important
Qualitative research and experience surveys suggest that many service users find there are insufficient activities and occupations available to them when staying on an inpatient ward. However, little is known about what service users want and how to improve the experience of care.
This question should be answered by a qualitative study to identify what activities and occupations service users want on inpatient wards. This would include service users currently on inpatient wards as well as those who have left. This would allow a future cluster randomised trial evaluating the inclusion of occupations and activities preferred by the service users compared with standard care.
# Compulsion, control and restraint
For people using adult mental health services, how is compulsory treatment and 'control and restraint' used in different settings and what is the impact on the service user?
## Why this is important
Qualitative research and experience surveys suggest that service users experience many problems relating to compulsory treatment and the use of control and restraint. However, information is needed about current practice, which can then be used to help improve the experience of care.
This question should be answered by a quantitative audit and an ethnographic study of the use of compulsion and control and restraint and its impact on the service user in a variety of locations. The audit would aim to quantify the:
frequency of compulsion, control and restraint
frequency of de‑escalation
record‑keeping
debriefing (individual, staff, and witnesses)
writing own account in notes.
The ethnographic study, undertaken on the same wards, would be partly by participant observation and partly by in‑depth interview, both after compulsory treatment or restraint has been used, and after discharge and at 1‑year follow‑up. The ethnographic study would aim to capture the impact of compulsory treatment and restraint on service user experience, and its longer‑term impact.
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{'Introduction': "Over the past few years several documents and initiatives have highlighted the importance of the service user's experience and the need to focus on improving this experience where possible.\n\nLord Darzi's report High quality care for all (2008) highlighted the importance of the entire service user experience within the NHS, ensuring people are treated with compassion, dignity and respect within a clean, safe and well‑managed environment.\n\nThe development of the NHS Constitution (2009 to 2010) was one of several recommendations from Lord Darzi's report. The Constitution describes the purpose, principles and values of the NHS and illustrates what staff, service users and the public can expect from the service. Since the Health Act came into force in January 2010, service providers and commissioners of NHS care have had a legal obligation to take the Constitution into account in all their decisions and actions.\n\nThe King's Fund charitable foundation has developed a comprehensive policy resource – Seeing the person in the patient: the point of care review paper (2008). Some of the topics explored in the paper are used in the development of this guidance and quality standard.\n\nNational initiatives aimed at improving service users' experience of healthcare include NHS Choices, a comprehensive information service that helps people to manage their healthcare and provides service users and carers with information and choice about their care. Initiatives, such as patient advice and liaison services (PALS), have also been introduced.\n\nDespite these initiatives, there is evidence to suggest that further work is needed to deliver the best possible experience for users of NHS services. The Government signalled in its White Paper, Equity and excellence: liberating the NHS (July 2010) that more emphasis needs to be placed on improving service users' experience of NHS care. This guidance on service user experience in adult mental health services is a direct referral from the Department of Health.\n\nIn 2005 the Department of Health published Delivering race equality in mental health care: an action plan for reform inside and outside services and the government's response to the independent inquiry into the death of David Bennett. The report contained recommendations about the delivery of mental healthcare to service users, in particular those from black and minority ethnic communities. The recommendations also address wider issues in mental health settings, such as the safe use of physical interventions.\n\nHigh‑quality care should be clinically effective, safe and be provided in a way that ensures the service user has the best possible experience of care. This guidance on service user experience aims to ensure that users of mental health services have the best possible experience of care from the NHS.\n\nNICE's quality standard on service user experience in adult mental health services has been developed alongside this guidance. NICE quality standards are a set of specific, concise statements and associated measures. They set out aspirational, but achievable, markers of high‑quality, cost‑effective care. Quality standards are derived from the best available evidence and address three dimensions of quality: clinical effectiveness, service user safety and service user experience.\n\nNICE clinical guidelines are usually shaped around both clinical and economic evidence, and include recommendations concerned with ensuring a good service user experience, with the recognition that such advice should sit alongside evidence of clinical and cost effectiveness. The recommendations in the current guidance have been informed by research evidence, recommendations in previously published NICE clinical guidelines, national survey data and consensus processes that have identified the key elements that are important to service users and how these can be improved to ensure a good experience of care. The guidance draws on multiple evidence and data sources in developing the recommendations.", 'Guidance': "The following guidance is based on the best available evidence. The full guidance gives details of the methods and the evidence used to develop the guidance.\n\nIn this guidance, families and carers include relatives, friends, non‑professional advocates and significant others who play a supporting role for the person using mental health services. If the service user agrees, families and carers should have the opportunity to be involved in decisions about treatment and care. Families and carers should also be given the information and support they need.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Care and support across all points on the care pathway\n\n## Relationships and communication\n\nWork in partnership with people using mental health services and their families or carers. Offer help, treatment and care in an atmosphere of hope and optimism. Take time to build trusting, supportive, empathic and non‑judgemental relationships as an essential part of care.\n\nWhen working with people using mental health services:\n\naim to foster their autonomy, promote active participation in treatment decisions and support self‑management\n\nmaintain continuity of individual therapeutic relationships wherever possible\n\noffer access to a trained advocate.\n\nWhen working with people using mental health services and their family or carers:\n\nensure that you are easily identifiable (for example, by wearing appropriate identification) and approachable\n\naddress service users using the name and title they prefer\n\nclearly explain any clinical language and check that the service user understands what is being said\n\ntake into account communication needs, including those of people with learning disabilities, sight or hearing problems or language difficulties, and provide independent interpreters (that is, someone who does not have a relationship with the service user) or communication aids (such as using pictures, symbols, large print, Braille, different languages or sign language) if required.\n\nWhen working with people using mental health services:\n\nmake sure that discussions take place in settings in which confidentiality, privacy and dignity are respected\n\nbe clear with service users about limits of confidentiality (that is, which health and social care professionals have access to information about their diagnosis and its treatment and in what circumstances this may be shared with others).\n\n## Providing information\n\nWhen working with people using mental health services:\n\nensure that comprehensive written information about the nature of, and treatments and services for, their mental health problems is available in an appropriate language or format including any relevant text from NICE's information for the public\n\nensure that comprehensive information about other support groups, such as third sector, including voluntary organisations, is made available.\n\nEnsure that you are:\n\nfamiliar with local and national sources (organisations and websites) of information and/or support for people using mental health services\n\nable to discuss and advise how to access these resources\n\nable to discuss and actively support service users to engage with these resources.\n\n## Avoiding stigma and promoting social inclusion\n\nWhen working with people using mental health services:\n\ntake into account that stigma and discrimination are often associated with using mental health services\n\nbe respectful of and sensitive to service users' gender, sexual orientation, socioeconomic status, age, background (including cultural, ethnic and religious background) and any disability\n\nbe aware of possible variations in the presentation of mental health problems in service users of different genders, ages, cultural, ethnic, religious or other diverse backgrounds.\n\nHealth and social care professionals working with people using mental health services should have competence in:\n\nassessment skills and using explanatory models of illness for people from different cultural, ethnic, religious or other diverse backgrounds\n\nexplaining the possible causes of different mental health problems, and care, treatment and support options\n\naddressing cultural, ethnic, religious or other differences in treatment expectations and adherence\n\naddressing cultural, ethnic, religious or other beliefs about biological, social and familial influences on the possible causes of mental health problems\n\nconflict management and conflict resolution.\n\nHealth and social care providers' boards should work with local authorities and all other local organisations with an interest in mental health (including social services, other hospitals, third sector, including voluntary, organisations, local press and media groups, and local employer organisations) to develop a strategy to combat the stigma in the community and in the NHS associated with mental health problems and using mental health services.\n\n## Decisions, capacity and safeguarding\n\nHealth and social care professionals should ensure that they:\n\nunderstand and can apply the principles of the Mental Capacity Act (2005) appropriately\n\nare aware that mental capacity needs to be assessed for each decision separately\n\ncan assess mental capacity using the test in the Mental Capacity Act (2005)\n\nunderstand how the Mental Health Act (1983; amended 1995 and 2007) and the Mental Capacity Act (2005) relate to each other in practice.\n\nDevelop advance statements and advance decisions with the person using mental health services if they wish to do so, especially if their illness is severe and they have been previously treated under the Mental Health Act (1983; amended 1995 and 2007). Document these in their care plans and ensure copies are held by the service user and in primary and secondary care records.\n\nWhen a service user has impaired capacity, check their care record for advance statements and advance decisions before offering or starting treatment.\n\nConsider service users for assessment according to local safeguarding procedures for vulnerable adults if there are concerns regarding exploitation or self‑care, or if they have been in contact with the criminal justice system.\n\n## Involving families and carers\n\nDiscuss with the person using mental health services if and how they want their family or carers to be involved in their care. Such discussions should take place at intervals to take account of any changes in circumstances, and should not happen only once. As the involvement of families and carers can be quite complex, staff should receive training in the skills needed to negotiate and work with families and carers, and also in managing issues relating to information sharing and confidentiality.\n\nIf the person using mental health services wants their family or carers to be involved, encourage this involvement and:\n\nnegotiate between the service user and their family or carers about confidentiality and sharing of information on an ongoing basis\n\nexplain how families or carers can help support the service user and help with treatment plans\n\nensure that no services are withdrawn because of the family's or carers' involvement, unless this has been clearly agreed with the service user and their family or carers.\n\nIf the person using mental health services wants their family or carers to be involved, give the family or carers verbal and written information about:\n\nthe mental health problem(s) experienced by the service user and its treatment, including relevant text from NICE's information for the public\n\nstatutory and third sector, including voluntary, local support groups and services specifically for families and carers, and how to access these\n\ntheir right to a formal carer's assessment of their own physical and mental health needs, and how to access this (see NICE's guideline on supporting adult carers).\n\nIf the service user does not want their family or carers to be involved in their care:\n\nseek consent from the service user, and if they agree give the family or carers verbal and written information on the mental health problem(s) experienced by the service user and its treatments, including relevant text from NICE's information for the public\n\ngive the family or carers information about statutory and third sector, including voluntary, local support groups and services specifically for families or carers, and how to access these\n\ntell the family or carers about their right to a formal carer's assessment of their own physical and mental health needs, and how to access this (see NICE's guideline on supporting adult carers)\n\nbear in mind that service users may be ambivalent or negative towards their family for many different reasons, including as a result of the mental health problem or as a result of prior experience of violence or abuse.\n\nEnsure that service users who are parents with caring responsibilities receive support to access the full range of mental health and social care services, including:\n\ninformation about childcare to enable them to attend appointments, groups and therapy sessions\n\nhospital care in local mother and baby units for women in the late stages of pregnancy and within a year of childbirth\n\na family room or space in inpatient units where their children can visit them.\n\n## Engaging service users in improving care\n\nWhen providing training about any aspect of mental health and social care:\n\ninvolve people using mental health services in the planning and delivery of training\n\nensure that all training aims to improve the quality and experience of care for people using mental health services; evaluate training with this as an outcome.\n\nHealth and social care providers should consider employing service users to be involved in training teams of health and social care professionals and supporting staff (such as receptionists, administrators, secretaries and housekeeping staff) in 'person‑centred care'. Such training should be tailored to the needs of people who attend mental health services and should be evaluated using experience of care as an outcome. Service users themselves should be provided with training and supervision to undertake this role.\n\nManagers of health and social care providers should consider employing service users to monitor the experience of using mental health services, especially inpatient services, for example by paying them to undertake exit interviews with service users who have recently left a service. Offer service users training to do this.\n\nService managers should routinely commission reports on the experience of care across non‑acute and acute care pathways, including the experience of being treated under the Mental Health Act (1983; amended 1995 and 2007). These reports should:\n\ninclude data that allow direct comparisons of the experience of care according to gender, sexual orientation, socioeconomic status, age, background (including cultural, ethnic and religious background) and disability\n\ninclude analyses of data from multiple sources, particularly data collected by service users monitoring service user experience and complaints\n\nbe routinely communicated to the health and social care providers' board.\n\n# Access to care\n\nWhen people are referred to mental health services, ensure that:\n\nthey are given or sent a copy of the referral letter when this is sent to mental health services\n\nthey are offered a face‑to‑face appointment with a professional in mental health services taking place within 3 weeks of referral\n\nthey are informed that they can change the date and time of the appointment if they wish\n\nany change in appointment does not result in a delay of more than 2 weeks.\n\nWhen people are sent an appointment letter for mental health services it should:\n\ngive the name and professional designation of the person who will assess them\n\ninclude information about the service, including a website address where available, and different options about how to get there\n\nexplain the process of assessment using plain language\n\nspecify all the information needed for the assessment, including about current medication\n\naddress the likely anxiety and concern often experienced by people attending mental health services for assessment\n\nexplain that although they can be accompanied by a family member, carer or advocate if they wish for all or part of the time, it is preferable to see the person alone for some of the assessment\n\nask if they require anything to support their attendance (for example, an interpreter, hearing loop, wider access)\n\ngive a number to ring if they have problems getting to the appointment or wish to change it.\n\nMental health services should establish close working relationships with primary care services to ensure:\n\nagreed processes for referral, consistent with 1.2.1, are in place, and\n\nprimary care professionals can provide information about local mental health and social care services to the people they refer.\n\nTake into account the requirements of the Equality Act 2010 and make sure services are equally accessible to, and supportive of, all people using mental health services.\n\nLocal mental health services should work with primary care and local third sector, including voluntary, organisations to ensure that:\n\nall people with mental health problems have equal access to services based on clinical need and irrespective of gender, sexual orientation, socioeconomic status, age, background (including cultural, ethnic and religious background) and any disability\n\nservices are culturally appropriate.\n\n# Assessment\n\nOn arrival at mental health services for assessment, service users should be greeted and engaged by reception and other staff in a warm, friendly, empathic, respectful and professional manner, anticipating possible distress.\n\nBefore the assessment begins, the health or social care professional undertaking the assessment should ensure that the service user understands:\n\nthe process of assessment and how long the appointment will last\n\nthat the assessment will cover all aspects of their experiences and life\n\nconfidentiality and data protection as this applies to them\n\nthe basic approach of shared decision‑making (also see the NICE guideline on decision-making and mental capacity)\n\nthat although they can be accompanied by a family member, carer or advocate for all or part of the time, it is preferable to see the person alone for some of the assessment\n\nthat they can refuse permission for any other member of staff, such as a student, to be present.\n\nWhen carrying out an assessment:\n\nensure there is enough time for the service user to describe and discuss their problems\n\nallow enough time towards the end of the appointment for summarising the conclusions of the assessment and for discussion, with questions and answers\n\nexplain the use and meaning of any clinical terms used\n\nexplain and give written material in an accessible format about any diagnosis given\n\ngive information about different treatment options, including drug and psychological treatments, and their side effects, to promote discussion and shared understanding\n\noffer support after the assessment, particularly if sensitive issues, such as childhood trauma, have been discussed.\n\nIf a service user is unhappy about the assessment and diagnosis, give them time to discuss this and offer them the opportunity for a second opinion.\n\nCopy all written communications with other health or social care professionals to the service user at the address of their choice, unless the service user declines this.\n\nEnsure that if a service user needs to wait before an assessment, this is for no longer than 20 minutes after the agreed appointment time; explain the reasons for any delay.\n\nEnsure that waiting rooms are comfortable, clean and warm, and have areas of privacy, especially for those who are distressed or who request this, or are accompanied by children.\n\nInform service users of their right to a formal community care assessment (delivered through local authority social services), and how to access this.\n\nInform service users how to make complaints and how to do this safely without fear of retribution.\n\n# Community care\n\nWhen communicating with service users use diverse media, including letters, phone calls, emails or text messages, according to the service user's preference.\n\nDevelop care plans jointly with the service user, and:\n\ninclude activities that promote social inclusion such as education, employment, volunteering and other occupations such as leisure activities and caring for dependants\n\nprovide support to help the service user realise the plan\n\ngive the service user an up‑to‑date written copy of the care plan, and agree a suitable time to review it.\n\nSupport service users to develop strategies, including risk‑ and self‑management plans, to promote and maintain independence and self‑efficacy, wherever possible. Incorporate these strategies into the care plan.\n\nIf they are eligible, give service users the option to have a personal budget or direct payment so they can choose and control their social care and support, with appropriate professional and peer support as needed.\n\nFor people who may be at risk of crisis, a crisis plan should be developed by the service user and their care coordinator, which should be respected and implemented, and incorporated into the care plan. The crisis plan should include:\n\npossible early warning signs of a crisis and coping strategies\n\nsupport available to help prevent hospitalisation\n\nwhere the person would like to be admitted in the event of hospitalisation\n\nthe practical needs of the service user if they are admitted to hospital (for example, childcare or the care of other dependants, including pets)\n\ndetails of advance statements and advance decisions (see recommendation 1.1.11)\n\nwhether and the degree to which families or carers are involved\n\ninformation about 24‑hour access to services\n\nnamed contacts.\n\nEnsure that service users routinely have access to their care plan and care record, including electronic versions. Care records should contain a section in which the service user can document their views and preferences, and any differences of opinion with health and social care professionals.\n\nHealth and social care providers should ensure that service users:\n\ncan routinely receive care and treatment from a single multidisciplinary community team\n\nare not passed from one team to another unnecessarily\n\ndo not undergo multiple assessments unnecessarily.\n\nEnsure that service users have timely access to the psychological, psychosocial and pharmacological interventions recommended for their mental health problem in NICE guidance.\n\nMental health services should work with local third sector, including voluntary, black and minority ethnic and other minority groups to jointly ensure that culturally appropriate psychological and psychosocial treatments, consistent with NICE guidance and delivered by competent practitioners, are provided to service users from these groups.\n\nMental health and social care professionals inexperienced in working with service users from different cultural, ethnic, religious and other diverse backgrounds should seek advice, training and supervision from health and social care professionals who are experienced in working with these groups.\n\n# Assessment and referral in a crisis\n\nImmediately before assessing a service user who has been referred in crisis, find out if they have had experience of acute or non‑acute mental health services, and consult their crisis plan and advance statements or advance decisions if they have made them. Find out if they have an advocate and contact them if the service user wishes. Ask if the service user has a preference for a male or female health or social care professional to conduct the assessment, and comply with their wishes wherever possible.\n\nWhen undertaking a crisis assessment:\n\naddress and engage service users in a supportive and respectful way\n\nprovide clear information about the process and its possible outcomes, addressing the individual needs of the service user, as set out in the section on assessment\n\ntake extra care to understand and emotionally support the service user in crisis, considering their level of distress and associated fear, especially if they have never been in contact with services before, or if their prior experience of services has been difficult and/or they have had compulsory treatment under the Mental Health Act (1983; amended 1995 and 2007).\n\nAssessment in crisis should be undertaken by experienced health and social care professionals competent in crisis working, and should include an assessment of the service user's relationships, social and living circumstances and level of functioning, as well as their symptoms, behaviour, diagnosis and current treatment.\n\nIf assessment in the service user's home environment is not possible, or if they do not want an assessment at home, take full consideration of their preferences when selecting a place for assessment.\n\nWhen a person is referred in crisis they should be seen by specialist mental health secondary care services within 4 hours of referral.\n\nHealth and social care providers should provide local 24‑hour helplines, staffed by mental health and social care professionals, and ensure that all GPs in the area know the telephone number.\n\nHealth and social care providers should ensure that crisis resolution and home treatment teams are accessible 24‑hours a day, 7 days a week, and available to service users in crisis regardless of their diagnosis.\n\nTo avoid admission, aim to:\n\nexplore with the service user what support systems they have, including family, carers and friends\n\nsupport a service user in crisis in their home environment\n\nmake early plans to help the service user maintain their day‑to‑day activities, including work, education, voluntary work, and other occupations such as caring for dependants and leisure activities, wherever possible.\n\nAt the end of a crisis assessment, ensure that the decision to start home treatment depends not on the diagnosis, but on:\n\nthe level of distress\n\nthe severity of the problems\n\nthe vulnerability of the service user\n\nissues of safety and support at home\n\nthe person's cooperation with treatment.\n\nConsider the support and care needs of families or carers of service users in crisis. Where needs are identified, ensure they are met when it is safe and practicable to do so.\n\nHealth and social care providers should support direct self‑referral to mental health services as an alternative to accessing urgent assessment via the emergency department.\n\n# Hospital care\n\nWhen a service user enters hospital, greet them using the name and title they prefer, in an atmosphere of hope and optimism, with a clear focus on their emotional and psychological needs, and their preferences. Ensure that the service user feels safe and address any concerns about their safety.\n\nGive verbal and written information to service users, and their families or carers where agreed by the service user, about:\n\nthe hospital and the ward in which the service user will stay\n\ntreatments, activities and services available\n\nexpected contact from health and social care professionals\n\nrules of the ward (including substance misuse policy)\n\nservice users' rights, responsibilities and freedom to move around the ward and outside\n\nmeal times\n\nvisiting arrangements.\n\nMake sure there is enough time for the service user to ask questions.\n\nUndertake shared decision‑making routinely with service users in hospital, including, whenever possible, service users who are subject to the Mental Health Act (1983; amended 1995 and 2007). See the NICE guideline on decision-making and mental capacity.\n\nCommence formal assessment and admission processes within 2\xa0hours of arrival.\n\nShortly after service users arrive in hospital, show them around the ward and introduce them to the health and social care team as soon as possible and within the first 12 hours if the admission is at night. If possible, this should include the named healthcare professional who will be involved throughout the person's stay.\n\nOffer service users in hospital:\n\ndaily one‑to‑one sessions lasting at least 1 hour with a healthcare professional known to the service user\n\nregular (at least weekly) one‑to‑one sessions lasting at least 20\xa0minutes with their consultant\n\nan opportunity to meet with a specialist mental health pharmacist to discuss medication choices and any associated risks and benefits.\n\nEnsure that the overall coordination and management of care takes place at a regular multidisciplinary meeting led by the consultant and team manager with full access to the service user's paper and/or electronic record. Service users and their advocates should be encouraged to participate in discussions about their care and treatment, especially those relating to the use of the Mental Health Act (1983; amended 1995 and 2007). However, these meetings should not be used to see service users or carers as an alternative to their daily meeting with a known healthcare professional or their weekly one‑to‑one meeting with their consultant.\n\nHealth and social care providers should ensure that service users in hospital have access to the pharmacological, psychological and psychosocial treatments recommended in NICE guidance provided by competent health or social care professionals. Psychological and psychosocial treatments may be provided by health and social care professionals who work with the service user in the community.\n\nEnsure that service users in hospital have access to a wide range of meaningful and culturally appropriate occupations and activities 7 days per week, and not restricted to 9am to 5pm. These should include creative and leisure activities, exercise, self‑care and community access activities (where appropriate). Activities should be facilitated by appropriately trained health or social care professionals.\n\nEnsure that service users have access to the internet and telephone during their stay in hospital.\n\nAll health and social care professionals who work in a hospital setting should be trained as a team to use the same patient‑centred approach to treatment and care.\n\nService users receiving community care before hospital admission should be routinely visited while in hospital by the health and social care professionals responsible for their community care.\n\nEnsure that all service users in hospital have access to advocates who can regularly feed back to ward professionals any problems experienced by current service users on that ward. Advocates may be formal Independent Mental Health Advocate (IMHAs), or former inpatients who have been trained to be advocates for other service users not detained under the Mental Health Act (1983; amended 1995 and 2007).\n\nEnsure that hospital menus include a choice of foods, and that these are acceptable to service users from a range of ethnic, cultural and religious backgrounds and with specific physical health problems. Consider including service users in planning menus.\n\n# Discharge and transfer of care\n\nAnticipate that withdrawal and ending of treatments or services, and transition from one service to another, may evoke strong emotions and reactions in people using mental health services. Ensure that:\n\nsuch changes, especially discharge, are discussed and planned carefully beforehand with the service user and are structured and phased\n\nthe care plan supports effective collaboration with social care and other care providers during endings and transitions, and includes details of how to access services in times of crisis\n\nwhen referring a service user for an assessment in other services (including for psychological treatment), they are supported during the referral period and arrangements for support are agreed beforehand with them.\n\nAgree discharge plans with the service user and include contingency plans in the event of problems arising after discharge. Ensure that a 24‑hour helpline is available to service users so that they can discuss any problems arising after discharge.\n\nBefore discharge or transfer of care, discuss arrangements with any involved family or carers. Assess the service user's financial and home situation, including housing, before they are discharged from inpatient care.\n\nGive service users clear information about all possible support options available to them after discharge or transfer of care.\n\nWhen plans for discharge are initiated by the service, give service users at least 48 hours' notice of the date of their discharge from a ward.\n\nWhen preparing a service user for discharge, give them information about the local patient advice and liaison service (PALS) and inform them they can be trained as an advocate or become involved in monitoring services if they choose.\n\n# Assessment and treatment under the Mental Health Act\n\nDetain service users under the Mental Health Act (1983; amended 1995 and 2007) only after all alternatives have been fully considered in conjunction with the service user if possible, and with the family or carer if the service user agrees. Alternatives may include:\n\nmedicines review\n\nrespite care\n\nacute day facilities\n\nhome treatment\n\ncrisis houses.\n\nCarry out an assessment for possible detention under the Mental Health Act (1983; amended 1995 and 2007) in a calm and considered way. Respond to the service user's needs and treat them with dignity and, whenever possible, respect their wishes.\n\nExplain to service users, no matter how distressed, why the compulsory detention or treatment is being used. Repeat the explanation if the service user appears not to have understood or is pre‑occupied or confused. Ask if the service user would like a family member, carer or advocate with them.\n\nWhen detaining a service user under the Mental Health Act (1983; amended 1995 and 2007) inform the receiving mental health service about the service user so they are expecting them and ready to welcome them to the service.\n\nWhen detaining a service user under the Mental Health Act (1983; amended 1995 and 2007):\n\ngive them verbal and written information appropriate to the section of the Act used, including 'patient rights leaflets' detailing what is happening to them and why, and what their rights are\n\nrepeat this information if they appear not to have understood or are pre‑occupied or confused\n\ngive them, and their families or carers if they agree, information about the legal framework of the Mental Health Act (1983; amended 1995 and 2007)\n\nensure they have access to an Independent Mental Health Advocate (IMHA).\n\nInform service users detained under the Mental Health Act (1983; amended 1995 and 2007) of their right to appeal to a mental health tribunal and support them if they appeal; provide information about the structure and likely speed of the appeals process.\n\nInform the service user that if they are dissatisfied with their care and wish to make a complaint while under the Mental Health Act (1983; amended 1995 and 2007) they should, in the first instance, direct their complaint to the service detaining them. If they are dissatisfied with the service's response to their complaint, inform them they can complain to the Care Quality Commission and explain how to do this.\n\nWhen a service user is admitted to a 'place of safety' ensure they are assessed for the Mental Health Act (1983; amended 1995 and 2007) as soon as possible, and certainly within 4 hours.\n\nAfter application of the Mental Health Act (1983; amended 1995 and 2007) ensure that:\n\ntransition to the inpatient unit is smooth, efficient and comfortable\n\nfamily and carers can travel with the service user if safe to do so\n\nthe police are involved only if the safety of the service user, family, carers, dependent children or health and social care professionals is an important consideration and cannot be managed by other means, such as involving more professionals.\n\n## Control and restraint, and compulsory treatment\n\nControl and restraint, and compulsory treatment including rapid tranquillisation, should be used as a last resort, only after all means of negotiation and persuasion have been tried, and only by healthcare professionals trained and competent to do this. Document the reasons for such actions.\n\nWhen a service user is subject to control and restraint, or receives compulsory treatment including rapid tranquillisation under the Mental Health Act (1983; amended 1995 and 2007):\n\nrecognise that they may consider it a violation of their rights\n\nuse minimum force\n\ntry to involve healthcare professionals whom the service user trusts\n\nmake sure the service user is physically safe\n\nexplain reasons for the episode of compulsory treatment to the service user and involved family members or carers\n\noffer to discuss episodes of compulsory treatment with the service user at the time of discharge and do so in a calm and simple manner\n\nensure training in restraint involves service users.\n\nAfter any episode of control and restraint, or compulsory treatment including rapid tranquillisation:\n\nexplain the reasons for such action to the service user and offer them the opportunity to document their experience of it in their care record, and any disagreement with healthcare professionals\n\nensure that other service users on the ward who are distressed by these events are offered support and time to discuss their experience.", 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Training in the use of the national quality standard and guidance on service user experience of care\n\nFor people using adult mental health services, what is the effect of training community mental health teams (CMHTs) and inpatient ward staff in the use of the national quality standard and underpinning guidance on service user experience, when compared with no training, on service users' experience of care?\n\n## Why this is important\n\nThe primary purpose of NICE quality standards is to make it clear what quality care is by providing patients and the public, health and social care professionals, commissioners and service providers with definitions of high‑quality health and social care. However, little is known about the impact of training health and social care professionals in the use of quality standards.\n\nThis question should be answered using a cluster randomised trial of community mental health teams (CMHTs) and inpatient ward staff to evaluate the impact of training them in the use of the national quality standard and underpinning guidance on service user experience of care. Three types of intervention should be included in the design:\n\nCMHTs and wards with no training\n\nCMHTs and wards where training is delivered by a professional trainer\n\nCMHTs and wards where training is delivered by a professional trainer and service user(s).\n\nSatisfaction with care and other aspects of service user experience should be surveyed. Qualitative interviews with service users and providers should be used to increase the explanatory power of the study.\n\n# Late access to services and compulsory and intensive treatment\n\nFor people using adult mental health services, what are the personal and demographic factors associated with late access to services and an increased likelihood of compulsory and intensive treatment, and what are the key themes that are associated with poor engagement? This should include an examination of factors that impact on access to services among younger people and older adults.\n\n## Why this is important\n\nQualitative research and experience surveys suggest that service users experience many problems relating to compulsory treatment. However, little is known about the factors associated with accessing services late and the need for compulsory and intensive treatment.\n\nThis question should be answered by a case‑control study to identify service users from different ethnic groups who use inpatient and intensive treatment services in order to identify the personal and demographic factors associated with late access to services and an increased likelihood of compulsory and intensive treatment. In‑depth interviews with service users should be undertaken to identify key themes that are associated with poor engagement.\n\n# Shared decision‑making\n\nFor people using adult mental health services, what are the key aspects of 'shared decision‑making' that they prefer, and does a training programme for health and social care professionals designed around these key aspects, when compared with no training, improve service users' experience of care? A study should be undertaken to evaluate the impact on treatment choice, the experience of care and treatment effectiveness of training service users to deal with health and social care professionals assertively.\n\n## Why this is important\n\nIn healthcare, 'shared decision‑making' is the sharing of preferences and decisions by both the professional and the service user to reach a consensus regarding the preferred treatment options. However, the key aspects of shared decision‑making are unknown, although the principle of shared decision‑making is an important element of a person‑centred care approach.\n\nThis question should be answered by a pilot qualitative study of shared decision‑making to determine what, if any, key aspects of shared decision‑making are preferred by service users. The pilot should be followed by a randomised controlled trial on shared decision‑making in community mental health teams (CMHTs) compared with standard decision‑making, which would be carefully characterised by in‑depth qualitative interview. Evaluation would quantify the impact on service user knowledge, the experience of care, rates of side effects and perceived benefits from treatment. Purposive‑selected service users would undertake in‑depth interviews to identify themes related to an improved experience of care associated with the shared decision‑making and the standard approach.\n\n# Activities and occupations on inpatient wards\n\nFor people receiving adult mental health hospital care, what activities and occupations do service users want when staying on inpatient wards?\n\n## Why this is important\n\nQualitative research and experience surveys suggest that many service users find there are insufficient activities and occupations available to them when staying on an inpatient ward. However, little is known about what service users want and how to improve the experience of care.\n\nThis question should be answered by a qualitative study to identify what activities and occupations service users want on inpatient wards. This would include service users currently on inpatient wards as well as those who have left. This would allow a future cluster randomised trial evaluating the inclusion of occupations and activities preferred by the service users compared with standard care.\n\n# Compulsion, control and restraint\n\nFor people using adult mental health services, how is compulsory treatment and 'control and restraint' used in different settings and what is the impact on the service user?\n\n## Why this is important\n\nQualitative research and experience surveys suggest that service users experience many problems relating to compulsory treatment and the use of control and restraint. However, information is needed about current practice, which can then be used to help improve the experience of care.\n\nThis question should be answered by a quantitative audit and an ethnographic study of the use of compulsion and control and restraint and its impact on the service user in a variety of locations. The audit would aim to quantify the:\n\nfrequency of compulsion, control and restraint\n\nfrequency of de‑escalation\n\nrecord‑keeping\n\ndebriefing (individual, staff, and witnesses)\n\nwriting own account in notes.\n\nThe ethnographic study, undertaken on the same wards, would be partly by participant observation and partly by in‑depth interview, both after compulsory treatment or restraint has been used, and after discharge and at 1‑year follow‑up. The ethnographic study would aim to capture the impact of compulsory treatment and restraint on service user experience, and its longer‑term impact."}
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https://www.nice.org.uk/guidance/cg136
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This guideline covers the components of a good experience of service use. It aims to make sure that all adults using NHS mental health services have the best possible experience of care.
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559f3a2765af26da07dee8268a29ff55faa2ed72
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nice
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Magnetic resonance image-guided transcutaneous focused ultrasound for uterine fibroids
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Magnetic resonance image-guided transcutaneous focused ultrasound for uterine fibroids
# Guidance
This document replaces magnetic resonance image-guided transcutaneous focused ultrasound ablation for uterine fibroids (interventional procedure guidance 231). For details see 'About this guidance'.
Current evidence on the efficacy of magnetic resonance image (MRI)-guided transcutaneous focused ultrasound for uterine fibroids in the short term is adequate, although further treatment may be required and the effect on subsequent pregnancy is uncertain. There are well-recognised complications but the evidence on safety is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance and audit.
During the consent process clinicians should inform patients that their symptoms may not be relieved, that their symptoms may return, and that further procedures may therefore be required. They should also inform patients about the risk of skin burns. Patients contemplating pregnancy should be informed that the effects of the procedure on fertility and on pregnancy are uncertain.
Patient selection should be carried out by a multidisciplinary team including a gynaecologist and an appropriate imaging specialist.
The procedure should only be carried out by clinicians with specific training in this technique.
NICE encourages further research into the efficacy of MRI-guided transcutaneous focused ultrasound for uterine fibroids. Research studies should report long-term outcomes, including the need for further treatment. Data on the incidence and outcomes of subsequent pregnancy in patients who choose this procedure because they wish to maintain or improve their fertility are particularly important.# The procedure
# Indications and current treatments
Uterine fibroids are benign tumours of the uterine wall. Fibroids can be asymptomatic or cause symptoms including bleeding, urinary incontinence, pelvic pressure or pain. They can be associated with subfertility and miscarriage.
For symptomatic fibroids, treatment options include hysterectomy, myomectomy, uterine artery embolisation and endometrial ablation techniques.
# Outline of the procedure
MRI-guided transcutaneous focused ultrasound for uterine fibroids is carried out with the patient lying prone inside an MRI scanner, using imaging and thermal mapping guidance. The patient is usually under intravenous conscious sedation and is able to communicate with the operator about adverse symptoms such as burning sensations or pain. A catheter is inserted to keep the bladder empty during the procedure.
The head of the ultrasound device is placed in contact with the skin of the patient's lower abdomen. Low-power ultrasound is first used to target the centre of the fibroid, followed (after the aiming has been confirmed) by high-power pulses to ablate part of the fibroid. The patient may have to lie still for up to 3 hours. After treatment, imaging is used to evaluate the volume of the fibroid ablated.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A non-randomised comparative study of 192 patients treated by MRI-guided transcutaneous focused ultrasound or abdominal hysterectomy reported improvements in all Short Form-36 quality of life domains for both treatment groups, although scores at 6 months were better in patients treated by hysterectomy (significant for 5 of 8 domains with p values from 0.004 to 0.05). A case series of 40 patients reported a 40 percentile point improvement from baseline in quality of life score (0–100 scale) at 3-year follow-up (p < 0.001).
A case series of 359 patients reported a significantly greater reduction from baseline in symptom severity score (0–100; higher scores worse) at 3 months in patients with a non-perfused volume (NPV) ratio greater than 20% versus those with an NPV ratio of 20% or less (31 points versus 24 points, p < 0.001). The case series of 40 patients reported a 48 percentile point improvement from baseline in symptom severity score (0–100 scale) at 3-year follow-up (p < 0.01).
Case series of 130 and 80 patients reported that 5% (7/130) and 10% (8/80) of patients respectively had a hysterectomy within 12 months.
A case series of 51 women who conceived after the procedure (54 pregnancies) reported that 41% (22/54) of pregnancies resulted in deliveries; miscarriage occurred in 26% (14/54) and 13% (7/54) were electively terminated.
The Specialist Advisers listed key efficacy outcomes as quality of life, symptom improvement, avoidance of further surgery, and subsequent fertility.
# Safety
Sciatic nerve palsy was reported in 1 of 109 patients (1%) treated by the procedure in the non-randomised comparative study of 192 patients. The case series of 80 patients reported mild temporary sciatica in 1 patient (1%).
The case series of 287 patients reported skin burns in 7% (10/144) of patients treated in 2003–5 compared with 1% (2/143) of patients treated in 2005–6 (p = 0.04). A full-thickness burn in the lower abdomen was described in a case report (treated by excision and direct closure).
Spontaneous vaginal expulsion of treated fibroid tissue requiring hysteroscopic removal was documented in a case report.
Bowel perforation following treatment by the procedure was reported in 1 patient (total number treated unknown) in an adverse event report submitted to the US Food and Drug Administration (Manufacturer and User Facility Device Experience database). Surgical management was required, confirming perforation in 3 bowel sites.
The Specialist Advisers considered a theoretical adverse event to be damage to the bladder.
# Other comments
The Committee was informed that many women wish to avoid more invasive interventions for symptomatic fibroids, even if this choice carries an increased chance of requiring further treatments. Some women choose this procedure because they wish to preserve their fertility: the lack of evidence on subsequent fertility underlies the recommendation in 1.5.
The Committee noted that there is continuing evolution and development of the techniques used in this procedure.# Further information
For related NICE guidance see www.nice.org.uk
# Information for patients
NICE has produced information on this procedure for patients and carers (Understanding NICE guidance). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedures guidance process.
It updates and replaces NICE interventional procedure guidance 231.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Changes after publicationMay 2012: minor maintenance
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICENational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BTwww.nice.org.uknice@nice.org.uk0845 033 7780
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{'Guidance': "This document replaces magnetic resonance image-guided transcutaneous focused ultrasound ablation for uterine fibroids (interventional procedure guidance 231). For details see 'About this guidance'.\n\nCurrent evidence on the efficacy of magnetic resonance image (MRI)-guided transcutaneous focused ultrasound for uterine fibroids in the short term is adequate, although further treatment may be required and the effect on subsequent pregnancy is uncertain. There are well-recognised complications but the evidence on safety is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance and audit.\n\nDuring the consent process clinicians should inform patients that their symptoms may not be relieved, that their symptoms may return, and that further procedures may therefore be required. They should also inform patients about the risk of skin burns. Patients contemplating pregnancy should be informed that the effects of the procedure on fertility and on pregnancy are uncertain.\n\nPatient selection should be carried out by a multidisciplinary team including a gynaecologist and an appropriate imaging specialist.\n\nThe procedure should only be carried out by clinicians with specific training in this technique.\n\nNICE encourages further research into the efficacy of MRI-guided transcutaneous focused ultrasound for uterine fibroids. Research studies should report long-term outcomes, including the need for further treatment. Data on the incidence and outcomes of subsequent pregnancy in patients who choose this procedure because they wish to maintain or improve their fertility are particularly important.", 'The procedure': "# Indications and current treatments\n\nUterine fibroids are benign tumours of the uterine wall. Fibroids can be asymptomatic or cause symptoms including bleeding, urinary incontinence, pelvic pressure or pain. They can be associated with subfertility and miscarriage.\n\nFor symptomatic fibroids, treatment options include hysterectomy, myomectomy, uterine artery embolisation and endometrial ablation techniques.\n\n# Outline of the procedure\n\nMRI-guided transcutaneous focused ultrasound for uterine fibroids is carried out with the patient lying prone inside an MRI scanner, using imaging and thermal mapping guidance. The patient is usually under intravenous conscious sedation and is able to communicate with the operator about adverse symptoms such as burning sensations or pain. A catheter is inserted to keep the bladder empty during the procedure.\n\nThe head of the ultrasound device is placed in contact with the skin of the patient's lower abdomen. Low-power ultrasound is first used to target the centre of the fibroid, followed (after the aiming has been confirmed) by high-power pulses to ablate part of the fibroid. The patient may have to lie still for up to 3 hours. After treatment, imaging is used to evaluate the volume of the fibroid ablated.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA non-randomised comparative study of 192 patients treated by MRI-guided transcutaneous focused ultrasound or abdominal hysterectomy reported improvements in all Short Form-36 quality of life domains for both treatment groups, although scores at 6 months were better in patients treated by hysterectomy (significant for 5 of 8 domains with p\xa0values from 0.004 to 0.05). A case series of 40 patients reported a 40 percentile point improvement from baseline in quality of life score (0–100 scale) at 3-year follow-up (p\xa0<\xa00.001).\n\nA case series of 359 patients reported a significantly greater reduction from baseline in symptom severity score (0–100; higher scores worse) at 3 months in patients with a non-perfused volume (NPV) ratio greater than 20% versus those with an NPV ratio of 20% or less (31 points versus 24\xa0points, p\xa0<\xa00.001). The case series of 40 patients reported a 48 percentile point improvement from baseline in symptom severity score (0–100 scale) at 3-year follow-up (p < 0.01).\n\nCase series of 130 and 80 patients reported that 5% (7/130) and 10% (8/80) of patients respectively had a hysterectomy within 12\xa0months.\n\nA case series of 51 women who conceived after the procedure (54\xa0pregnancies) reported that 41% (22/54) of pregnancies resulted in deliveries; miscarriage occurred in 26% (14/54) and 13% (7/54) were electively terminated.\n\nThe Specialist Advisers listed key efficacy outcomes as quality of life, symptom improvement, avoidance of further surgery, and subsequent fertility.\n\n# Safety\n\nSciatic nerve palsy was reported in 1 of 109 patients (1%) treated by the procedure in the non-randomised comparative study of 192\xa0patients. The case series of 80 patients reported mild temporary sciatica in 1 patient (1%).\n\nThe case series of 287 patients reported skin burns in 7% (10/144) of patients treated in 2003–5 compared with 1% (2/143) of patients treated in 2005–6 (p\xa0=\xa00.04). A full-thickness burn in the lower abdomen was described in a case report (treated by excision and direct closure).\n\nSpontaneous vaginal expulsion of treated fibroid tissue requiring hysteroscopic removal was documented in a case report.\n\nBowel perforation following treatment by the procedure was reported in 1 patient (total number treated unknown) in an adverse event report submitted to the US Food and Drug Administration (Manufacturer and User Facility Device Experience [MAUDE] database). Surgical management was required, confirming perforation in 3 bowel sites.\n\nThe Specialist Advisers considered a theoretical adverse event to be damage to the bladder.\n\n# Other comments\n\nThe Committee was informed that many women wish to avoid more invasive interventions for symptomatic fibroids, even if this choice carries an increased chance of requiring further treatments. Some women choose this procedure because they wish to preserve their fertility: the lack of evidence on subsequent fertility underlies the recommendation in 1.5.\n\nThe Committee noted that there is continuing evolution and development of the techniques used in this procedure.", 'Further information': 'For related NICE guidance see www.nice.org.uk\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Understanding NICE guidance). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 231.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges after publicationMay 2012: minor maintenance\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICENational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BTwww.nice.org.uknice@nice.org.uk0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg413
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c9eeb04628100615a45e9cfcd93ed56e61cfac39
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nice
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Single-port laparoscopic nephrectomy
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Single-port laparoscopic nephrectomy
# Guidance
Evidence on the safety and efficacy of single-port laparoscopic nephrectomy is based on limited numbers of patients. Any advantage for patients of the procedure over conventional laparoscopic nephrectomy is uncertain and there is inadequate evidence on safety, including insufficient information about warm ischaemia time when used to harvest kidneys from live donors for transplantation. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake single-port laparoscopic nephrectomy should take the following actions.
Inform the clinical governance leads in their Trusts.
Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients (Understanding NICE guidance) is recommended.
Audit and review clinical outcomes of all patients having single-port laparoscopic nephrectomy (see section 3.1).
Patient selection is particularly important when the procedure is being considered for the treatment of patients with malignant disease.
Single-port laparoscopic nephrectomy is technically challenging and should only be carried out by experienced laparoscopic surgeons who have received specific training in the procedure.
NICE encourages the publication of further evidence on single-port laparoscopic nephrectomy. In particular, clinicians are encouraged to collect and publish data on long-term recurrence rates when the procedure is used to treat malignancy and on subsequent graft survival and renal function when it is used for donor nephrectomy. NICE may review the procedure on publication of further evidence.# The procedure
# Indications and current treatments
Indications for nephrectomy (including nephroureterectomy) include benign and malignant tumours; conditions that damage renal function such as chronic infection; and donation for transplantation. For these indications, other procedures that can be performed through a single port include partial nephrectomy and needle cryoablative therapy.
# Outline of the procedure
Single-port laparoscopic nephrectomy aims to reduce pain and recovery time, and to improve cosmesis, compared with standard laparoscopic nephrectomy.
Single-port laparoscopic nephrectomy is performed with the patient under general anaesthesia, usually using a transperitoneal approach. A single umbilical skin incision is used to insert multiple instruments, typically via a specially designed system. Following laparoscopic dissection the kidney is usually enclosed in a retrieval bag and removed through the umbilicus or vagina, either intact or morcellated.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A randomised controlled trial of 50 renal donors treated by single-port laparoscopic donor nephrectomy or standard laparoscopic donor nephrectomy reported significantly lower pain scores (on a visual analogue scale of 1–10) of 1.24 and 2.08 respectively at 96 postoperative hours (p = 0.0004).
A non-randomised comparative study of 57 patients treated by single-port or conventional laparoscopic nephrectomy reported no significant difference in analgesic use (40 mg versus 45 mg of pethidine), although the pain score was significantly lower on postoperative days 1–3 for patients in the single-port group (4.7, 3.4 and 2.7 versus 5.8, 4.6 and 4.0, respectively ).
A randomised controlled trial of 27 patients treated by single-port or conventional laparoscopic nephrectomy reported a return to normal activities within 11 days and 14 days respectively (p = 0.001). A non-randomised comparative study of 35 patients reported a faster return to work and shorter time to complete physical recovery for patients in the single-port group compared with those who had conventional laparoscopic nephrectomy (18 days versus 46 days, p = 0.0009, and 29 days versus 83 days, p = 0.03, respectively).
The Specialist Advisers listed key efficacy outcomes as improved cosmesis, and, when treating cancer, no new or recurrent cancer.
# Safety
Allograft thrombosis was reported in 1 patient in a non-randomised comparative study including 17 single-port laparoscopic donor nephrectomies: the recipient underwent an allograft nephrectomy after 1 week.
A case series of 18 patients reported 1 bowel injury and 1 diaphragm injury, both of which were repaired without the need for additional ports.
A case series of 62 patients reported that 1 single-port laparoscopic simple nephrectomy was converted to conventional laparoscopy to aid in dissection and 1 single-port nephroureterectomy was converted to conventional laparoscopy to control bleeding.
A case series of 12 patients reported that 1 single-port procedure was converted to conventional laparoscopy because of adhesions and bleeding (requiring blood transfusion). Two single-port laparoscopic nephroureterectomies were converted to open surgery, 1 for complete renal hilar lymphadenectomy and the other for severe adhesions.
In a case series of 15 patients, 1 patient who had bilateral nephrectomy developed severe abdominal distension and dehiscence of the umbilical extraction site. The authors noted that the patient had multiple comorbidities and was on chronic steroid therapy. Postoperative small bowel obstruction was reported in 1 patient 14 days after an uncomplicated single-port procedure: this required surgical exploration.
The Specialist Advisers considered theoretical adverse events to include injury to the great vessels and to adjacent organs including the spleen.
# Other comments
The Committee noted that the technology used for this procedure is evolving rapidly and these developments may influence its safety and efficacy.
The Committee noted that warm ischaemia time may be longer than with standard laparoscopic nephrectomy when using this procedure to harvest kidneys from live donors for transplantation, but any clinical effect of this is uncertain.# Further information
This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion), available when the guidance is published.
For related NICE guidance see www.nice.org.uk
# Information for patients
NICE has produced information on this procedure for patients and carers (Understanding NICE guidance). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedures guidance process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Changes after publicationMay 2012: minor maintenance
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICENational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BTwww.nice.org.uknice@nice.org.uk0845 033 7780
|
{'Guidance': "Evidence on the safety and efficacy of single-port laparoscopic nephrectomy is based on limited numbers of patients. Any advantage for patients of the procedure over conventional laparoscopic nephrectomy is uncertain and there is inadequate evidence on safety, including insufficient information about warm ischaemia time when used to harvest kidneys from live donors for transplantation. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake single-port laparoscopic nephrectomy should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients (Understanding NICE guidance) is recommended.\n\nAudit and review clinical outcomes of all patients having single-port laparoscopic nephrectomy (see section 3.1).\n\nPatient selection is particularly important when the procedure is being considered for the treatment of patients with malignant disease.\n\nSingle-port laparoscopic nephrectomy is technically challenging and should only be carried out by experienced laparoscopic surgeons who have received specific training in the procedure.\n\nNICE encourages the publication of further evidence on single-port laparoscopic nephrectomy. In particular, clinicians are encouraged to collect and publish data on long-term recurrence rates when the procedure is used to treat malignancy and on subsequent graft survival and renal function when it is used for donor nephrectomy. NICE may review the procedure on publication of further evidence.", 'The procedure': '# Indications and current treatments\n\nIndications for nephrectomy (including nephroureterectomy) include benign and malignant tumours; conditions that damage renal function such as chronic infection; and donation for transplantation. For these indications, other procedures that can be performed through a single port include partial nephrectomy and needle cryoablative therapy.\n\n# Outline of the procedure\n\nSingle-port laparoscopic nephrectomy aims to reduce pain and recovery time, and to improve cosmesis, compared with standard laparoscopic nephrectomy.\n\nSingle-port laparoscopic nephrectomy is performed with the patient under general anaesthesia, usually using a transperitoneal approach. A single umbilical skin incision is used to insert multiple instruments, typically via a specially designed system. Following laparoscopic dissection the kidney is usually enclosed in a retrieval bag and removed through the umbilicus or vagina, either intact or morcellated.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial of 50 renal donors treated by single-port laparoscopic donor nephrectomy or standard laparoscopic donor nephrectomy reported significantly lower pain scores (on a visual analogue scale of 1–10) of 1.24 and 2.08 respectively at 96 postoperative hours (p\xa0=\xa00.0004).\n\nA non-randomised comparative study of 57 patients treated by single-port or conventional laparoscopic nephrectomy reported no significant difference in analgesic use (40\xa0mg versus 45\xa0mg of pethidine), although the pain score was significantly lower on postoperative days 1–3 for patients in the single-port group (4.7, 3.4 and 2.7 versus 5.8, 4.6 and 4.0, respectively [p\xa0=\xa00.001, p\xa0<\xa00.001 and p\xa0=\xa00.008]).\n\nA randomised controlled trial of 27 patients treated by single-port or conventional laparoscopic nephrectomy reported a return to normal activities within 11 days and 14 days respectively (p\xa0=\xa00.001). A non-randomised comparative study of 35 patients reported a faster return to work and shorter time to complete physical recovery for patients in the single-port group compared with those who had conventional laparoscopic nephrectomy (18 days versus 46 days, p\xa0=\xa00.0009, and 29 days versus 83 days, p\xa0=\xa00.03, respectively).\n\nThe Specialist Advisers listed key efficacy outcomes as improved cosmesis, and, when treating cancer, no new or recurrent cancer.\n\n# Safety\n\nAllograft thrombosis was reported in 1 patient in a non-randomised comparative study including 17 single-port laparoscopic donor nephrectomies: the recipient underwent an allograft nephrectomy after 1 week.\n\nA case series of 18 patients reported 1 bowel injury and 1\xa0diaphragm injury, both of which were repaired without the need for additional ports.\n\nA case series of 62 patients reported that 1 single-port laparoscopic simple nephrectomy was converted to conventional laparoscopy to aid in dissection and 1 single-port nephroureterectomy was converted to conventional laparoscopy to control bleeding.\n\nA case series of 12 patients reported that 1 single-port procedure was converted to conventional laparoscopy because of adhesions and bleeding (requiring blood transfusion). Two single-port laparoscopic nephroureterectomies were converted to open surgery, 1 for complete renal hilar lymphadenectomy and the other for severe adhesions.\n\nIn a case series of 15 patients, 1 patient who had bilateral nephrectomy developed severe abdominal distension and dehiscence of the umbilical extraction site. The authors noted that the patient had multiple comorbidities and was on chronic steroid therapy. Postoperative small bowel obstruction was reported in 1 patient 14 days after an uncomplicated single-port procedure: this required surgical exploration.\n\nThe Specialist Advisers considered theoretical adverse events to include injury to the great vessels and to adjacent organs including the spleen.\n\n# Other comments\n\nThe Committee noted that the technology used for this procedure is evolving rapidly and these developments may influence its safety and efficacy.\n\nThe Committee noted that warm ischaemia time may be longer than with standard laparoscopic nephrectomy when using this procedure to harvest kidneys from live donors for transplantation, but any clinical effect of this is uncertain.', 'Further information': 'This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion), available when the guidance is published.\n\nFor related NICE guidance see www.nice.org.uk\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Understanding NICE guidance). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges after publicationMay 2012: minor maintenance\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICENational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BTwww.nice.org.uknice@nice.org.uk0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg414
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698bb2c4edd597f062b9fcd5b39153b1b621d5e6
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nice
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Drainage, irrigation and fibrinolytic therapy (DRIFT) for post-haemorrhagic hydrocephalus in preterm infants
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Drainage, irrigation and fibrinolytic therapy (DRIFT) for post-haemorrhagic hydrocephalus in preterm infants
# Guidance
Current evidence on the efficacy and safety of drainage, irrigation and fibrinolytic therapy (DRIFT) for post-haemorrhagic hydrocephalus in preterm infants is inadequate in quantity. Therefore this procedure should only be used in the context of research. Research should aim to establish the risk of secondary haemorrhage and its consequences, and the need for shunt insertion. Outcomes should include death and disability in the long-term: these should be reported separately.# The procedure
# Indications and current treatments
Intraventricular haemorrhage is a serious complication occurring within a few days of birth in a small proportion of preterm infants. It is more common and severe in infants born before 30 weeks of gestation and can be fatal. Among surviving infants, some will develop post-haemorrhagic hydrocephalus associated with varying degrees of neurodevelopmental disability.
Managing post-haemorrhagic hydrocephalus in preterm infants typically involves repeated cerebrospinal fluid (CSF) drainage followed by insertion of a ventriculo-peritoneal shunt. No particular treatment has been shown to improve neurological outcomes.
# Outline of the procedure
The aim of DRIFT is to reduce the risk of death, the risk of neurodevelopmental disability, and the need for shunt insertion.
The procedure is performed with the infant under general anaesthesia. Two catheters are inserted into the lateral ventricles from right frontal to left occipital or vice versa. A fibrinolytic agent is given intraventricularly with the aim of lysing thrombi in the ventricles. After 8 hours, ventricular irrigation is started by infusing artificial CSF through the frontal catheter (typically at a flow rate of 20 ml/h) and draining it through the occipital catheter to a closed drainage system. Outflow is adjusted so that intracranial pressure readings remain less than 7 mm Hg. Irrigation continues until the colour of the drained fluid becomes normal ('cola to white wine'), typically within 3 days.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A randomised controlled trial (RCT) of 70 infants treated by DRIFT (n = 34) or standard treatment (n = 36) reported that DRIFT did not reduce mortality at follow-up to 6 months of age or duration of hospital stay (whichever was longer) compared with standard treatment (relative risk 0.42, 95% confidence interval 0.09 to 2.04). A second publication from the same RCT, including an additional 7 infants, reported mortality rates of 8% (3/39) and 13% (5/38) respectively at 2-year follow-up (timing of death and significance not stated).
The RCT of 70 infants treated by DRIFT or standard treatment reported that DRIFT did not reduce the use of shunt surgery compared with standard treatment at follow-up to 6 months of age or discharge (RR 0.98, 95% CI 0.54 to 1.78). The subsequent publication from the same RCT reported that permanent shunting was required in 41% (16/39) of infants treated by DRIFT and 40% (15/38) treated by standard treatment within 2 years (timing not stated).
A case series of 24 infants reported that 26% (6/23) of the surviving infants required ventriculo-peritoneal shunt surgery (follow-up not stated).
The second publication from the RCT (77 infants) reported on crude and adjusted odds of mental and psychomotor infant development status scores (adjusted for sex, birth weight, and intraventricular haemorrhage grade) using Bayley Scales of Infant Development II (BSIDII; range: 0–100). Infants treated by DRIFT had significantly lower odds of a mental development index score of less than 55 (representing severe cognitive disability) at a mean follow-up of 25 months (crude odds ratio 0.31, 95% CI 0.11 to 0.86, p = 0.024, adjusted OR 0.17, 95% CI 0.05 to 0.57). Infants treated by DRIFT had lower odds of a psychomotor development index score of less than 55 (representing severe psychomotor disability) at a mean follow-up of 25 months (crude OR 0.54, 95% CI 0.20 to 1.45, p = 0.22, adjusted OR 0.21, 95% CI 0.05 to 0.85, p = 0.028).
The case series of 24 infants reported that 58% (11/19) of infants who were evaluated at 12 months post-term had developed disability, including 21% (4/19) with multiple disabilities (assessment of cognitive disability based on the Ruth Griffiths Scales of Infant Development, scores not reported).
The Specialist Advisers listed key efficacy outcomes as reduced need for a ventriculo-peritoneal shunt and improved cognitive and motor development in the long term.
# Safety
The RCT of 70 infants treated by DRIFT or standard treatment reported secondary IVH in 35% (12/34) and 8% (3/36) of infants respectively (p = 0.014). Secondary IVH was asymptomatic in all but 1 infant who developed acute thrombocytopenia. The case series of 24 infants reported clinically significant secondary IVH in 2 infants. One was successfully treated with intravenous tranexamic acid and the other stabilised without treatment (timing not stated).
The RCT of 70 infants treated by DRIFT or standard treatment reported mean numbers of blood transfusions required in the first 7 days after randomisation of 1.7 (range: 0–4) and 0.8 (range: 0–2) respectively (p < 0.001).
The Specialist Advisers listed anecdotal adverse events as further intraventricular bleeds after administering the thrombolytic agent. They considered theoretical adverse events to include infection, meningitis, displacement or blockage of catheters and trauma to the brain.
# Other comments
The Committee noted that there is a lack of effective treatments for post-haemorrhagic hydrocephalus in preterm infants, who may suffer severe disability as a result. The Committee acknowledged that there is a reasonable conceptual basis for DRIFT, but considered the current evidence on its potential efficacy to be insufficient.
# Information for patients
NICE has produced information on this procedure for patients and carers (Understanding NICE guidance). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedures guidance process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Changes after publicationMay 2012: minor maintenance
Your responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICENational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BTwww.nice.org.uknice@nice.org.uk0845 033 7780
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{'Guidance': 'Current evidence on the efficacy and safety of drainage, irrigation and fibrinolytic therapy (DRIFT) for post-haemorrhagic hydrocephalus in preterm infants is inadequate in quantity. Therefore this procedure should only be used in the context of research. Research should aim to establish the risk of secondary haemorrhage and its consequences, and the need for shunt insertion. Outcomes should include death and disability in the long-term: these should be reported separately.', 'The procedure': "# Indications and current treatments\n\nIntraventricular haemorrhage is a serious complication occurring within a few days of birth in a small proportion of preterm infants. It is more common and severe in infants born before 30 weeks of gestation and can be fatal. Among surviving infants, some will develop post-haemorrhagic hydrocephalus associated with varying degrees of neurodevelopmental disability.\n\nManaging post-haemorrhagic hydrocephalus in preterm infants typically involves repeated cerebrospinal fluid (CSF) drainage followed by insertion of a ventriculo-peritoneal shunt. No particular treatment has been shown to improve neurological outcomes.\n\n# Outline of the procedure\n\nThe aim of DRIFT is to reduce the risk of death, the risk of neurodevelopmental disability, and the need for shunt insertion.\n\nThe procedure is performed with the infant under general anaesthesia. Two catheters are inserted into the lateral ventricles from right frontal to left occipital or vice versa. A fibrinolytic agent is given intraventricularly with the aim of lysing thrombi in the ventricles. After 8 hours, ventricular irrigation is started by infusing artificial CSF through the frontal catheter (typically at a flow rate of 20 ml/h) and draining it through the occipital catheter to a closed drainage system. Outflow is adjusted so that intracranial pressure readings remain less than 7 mm Hg. Irrigation continues until the colour of the drained fluid becomes normal ('cola to white wine'), typically within 3 days.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 70 infants treated by DRIFT (n = 34) or standard treatment (n = 36) reported that DRIFT did not reduce mortality at follow-up to 6 months of age or duration of hospital stay (whichever was longer) compared with standard treatment (relative risk [RR] 0.42, 95% confidence interval [CI] 0.09 to 2.04). A second publication from the same RCT, including an additional 7 infants, reported mortality rates of 8% (3/39) and 13% (5/38) respectively at 2-year follow-up (timing of death and significance not stated).\n\nThe RCT of 70 infants treated by DRIFT or standard treatment reported that DRIFT did not reduce the use of shunt surgery compared with standard treatment at follow-up to 6 months of age or discharge (RR 0.98, 95% CI 0.54 to 1.78). The subsequent publication from the same RCT reported that permanent shunting was required in 41% (16/39) of infants treated by DRIFT and 40% (15/38) treated by standard treatment within 2 years (timing not stated).\n\nA case series of 24 infants reported that 26% (6/23) of the surviving infants required ventriculo-peritoneal shunt surgery (follow-up not stated).\n\nThe second publication from the RCT (77 infants) reported on crude and adjusted odds of mental and psychomotor infant development status scores (adjusted for sex, birth weight, and intraventricular haemorrhage [IVH] grade) using Bayley Scales of Infant Development II (BSIDII; range: 0–100). Infants treated by DRIFT had significantly lower odds of a mental development index score\xa0of less than\xa055 (representing severe cognitive disability) at a mean follow-up of 25 months (crude odds ratio [OR] 0.31, 95% CI 0.11 to 0.86, p\xa0=\xa00.024, adjusted OR 0.17, 95% CI 0.05 to 0.57). Infants treated by DRIFT had lower odds of a psychomotor development index score of less than 55 (representing severe psychomotor disability) at a mean follow-up of 25\xa0months (crude OR 0.54, 95% CI 0.20 to 1.45, p = 0.22, adjusted OR 0.21, 95% CI 0.05 to 0.85, p = 0.028).\n\nThe case series of 24 infants reported that 58% (11/19) of infants who were evaluated at 12 months post-term had developed disability, including 21% (4/19) with multiple disabilities (assessment of cognitive disability based on the Ruth Griffiths Scales of Infant Development, scores not reported).\n\nThe Specialist Advisers listed key efficacy outcomes as reduced need for a ventriculo-peritoneal shunt and improved cognitive and motor development in the long term.\n\n# Safety\n\nThe RCT of 70 infants treated by DRIFT or standard treatment reported secondary IVH in 35% (12/34) and 8% (3/36) of infants respectively (p\xa0=\xa00.014). Secondary IVH was asymptomatic in all but 1 infant who developed acute thrombocytopenia. The case series of 24 infants reported clinically significant secondary IVH in 2\xa0infants. One was successfully treated with intravenous tranexamic acid and the other stabilised without treatment (timing not stated).\n\nThe RCT of 70 infants treated by DRIFT or standard treatment reported mean numbers of blood transfusions required in the first 7\xa0days after randomisation of 1.7 (range: 0–4) and 0.8 (range: 0–2) respectively (p < 0.001).\n\nThe Specialist Advisers listed anecdotal adverse events as further intraventricular bleeds after administering the thrombolytic agent. They considered theoretical adverse events to include infection, meningitis, displacement or blockage of catheters and trauma to the brain.\n\n# Other comments\n\nThe Committee noted that there is a lack of effective treatments for post-haemorrhagic hydrocephalus in preterm infants, who may suffer severe disability as a result. The Committee acknowledged that there is a reasonable conceptual basis for DRIFT, but considered the current evidence on its potential efficacy to be insufficient.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (Understanding NICE guidance). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges after publicationMay 2012: minor maintenance\n\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICENational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BTwww.nice.org.uknice@nice.org.uk0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg412
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6eb865820a7fc9533459fd47bd8cd8bc8c48e78d
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nice
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Healthcare-associated infections: prevention and control
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Healthcare-associated infections: prevention and control
This quality improvement guide was produced by NICE, in partnership with Public Health England (PHE). Its aim is twofold: to reduce the risk of harm from healthcare-associated infections for patients, staff and visitors; and to reduce the costs associated with preventable infection.
# Introduction
Following a referral from the Department of Health, NICE, in partnership with Public Health England (PHE), have developed this quality improvement guide. The guide offers advice on management or organisational actions to prevent and control healthcare-associated infections (HCAIs) in secondary care settings.
The guide is aimed at board members working in (or with) secondary care. It may also be of use to senior managers, those working elsewhere in the NHS, as well as those working in local authorities and the wider public, private, voluntary and community sectors.
In producing this guide, NICE and PHE have assumed that all secondary care settings are compliant with the current code of practice on preventing and controlling infections (Department of Health's Health and Social Care Act 2008: Code of practice on the prevention and control of infections).
The guide aims to help build on advice given in the code and elsewhere to improve the quality of care and practice in these areas over and above current standards. Taken together, the quality improvement statements contained in this guide describe excellence in care and practice to prevent and control HCAIs. Examples of evidence and other data to demonstrate progress against each statement are provided.
NICE and PHE recognise that a range of factors associated with infection prevention and control have the potential to impact on health inequalities (for example, in relation to age, ethnicity, gender and disability). However, the relative impact of different factors will vary for different organisations. NICE and PHE expect trusts and other secondary care organisations to consider local issues in relation to health inequalities when implementing this guide.
# What is a healthcare-associated infection?
Healthcare-associated infections (HCAIs) can develop either as a direct result of healthcare interventions such as medical or surgical treatment, or from being in contact with a healthcare setting.
The term HCAI covers a wide range of infections. The most well known include those caused by meticillin-resistant Staphylococcus aureus (MRSA), meticillin-sensitive Staphylococcus aureus (MSSA), Clostridium difficile (C. difficile) and Escherichia coli (E. coli). HCAIs cover any infection contracted:
as a direct result of treatment in, or contact with, a health or social care setting
as a result of healthcare delivered in the community
-utside a healthcare setting (for example, in the community) and brought in by patients, staff or visitors and transmitted to others (for example, norovirus).
HCAIs pose a serious risk to patients, staff and visitors. They can incur significant costs for the NHS and cause significant morbidity to those infected. As a result, infection prevention and control is a key priority for the NHS (Department of Health's board to ward: How to embed a culture of HCAI prevention in acute trusts).
# What action has been taken?
Following National Audit Office reports highlighting concerns about HCAIs, the Department of Health introduced a range of policies and measures designed to reduce rates of infection. (National Audit Office The management and control of hospital acquired infection in acute NHS trusts in England; National Audit Office Improving patient care by reducing the risk of hospital acquired infection: a progress report.)
For example, mandatory surveillance for meticillin-resistant Staphylococcus aureus (MRSA) was introduced in 2001. In 2004, a target was introduced to reduce MRSA bloodstream infections by 50% by 2008 in all NHS acute and foundation trusts. With the introduction of the Health Act in 2006, for the first time it became a legal requirement to have systems in place to minimise the risk of HCAIs (Department of Health's Health Act 2006: code of practice for the prevention and control of healthcare associated infections).
# What action is needed now?
The 2009 National Audit Office report on reducing healthcare associated infections in hospitals in England identified four systemic issues that still needed to be tackled locally and nationally to reduce infection rates. It highlighted the need:
for a culture of continuous improvement
for a whole-system approach, with clear structures, roles and responsibilities
to ensure staff compliance with good infection control practice
to monitor and record hospital prescriptions and the use of antibiotics.
# What is this guide for?
This guide will help secondary care and other healthcare organisations improve the quality of care and practice, reduce the risk of harm from HCAIs to patients, staff and visitors and reduce the costs associated with preventable infection. The 11 quality improvement statements provide clear markers of excellence in infection prevention and control at a management or organisational level. Each statement is supported by examples of the type of evidence that could be used to prove the organisation has achieved excellence, and examples of what this would mean in practice on a day-to-day basis.
The aim is to help boards:
assess current practice in relation to the prevention of HCAIs
identify areas for quality improvement
monitor progress
provide leadership and support to infection prevention and control teams and other staff working to implement the guide.
The guide may also help inform investment decisions.
It will also give patients and the public information about the quality of care they can expect, and how secondary care organisations can improve patient safety and outcomes by improving quality in key areas.
# How should the guide be used?
This guide is not mandatory. Rather, each quality improvement statement describes a level of excellence that could be achieved to prevent and control infections. Key areas of practice that underpin infection prevention and control, such as hand hygiene, antimicrobial stewardship and environmental cleanliness are included as measures and examples, where appropriate.
Organisations wishing to use the guide for quality assessment and improvement may choose a selection of the most appropriate measures for their setting as potential evidence of achievement. In organisations where, for example, tertiary care services are provided alongside secondary care, senior management should consider the applicability of each statement to their setting.
The examples of measures that could be taken may not be appropriate in all cases – and secondary care organisations may identify and use alternate measures as evidence of achievement, as necessary.
Performance in each statement area will depend upon healthcare professionals and other trust staff who have HCAI prevention and control – and public health, generally – as part of their remit.
Much of the information required to support the measures is already available and a range of other guidance can be used alongside this guide to assess and improve quality in secondary care settings. Overlaps between the statements and certain aspects of the code of practice are highlighted. In addition, where data routinely collated may help trusts monitor progress in an area covered by one of the statements, this is also highlighted.
# How was the guide developed?
This guide was developed as a pilot project, based on processes and methods used by NICE to develop other types of guidance. A topic expert group was set up and led by an independent chair. It consisted of practitioners from the NHS, local authorities and the voluntary sector, as well as academics and patient and public representatives. The group worked with NICE and PHE to develop the guide.
The resulting quality improvement statements are based on recommendations from seven source guidance documents. They have been refined as a result of stakeholder consultation and committee discussion.
The following documents provide further information on the referral, scope, and methodology used as the basis for this guide:
Advice on the prevention and control of healthcare-associated infections: scope – this sets out the referral and scope for the work
Quality improvement guide – prevention and control of healthcare-associated infections: topic briefing paper - this summarises the methods and process used to develop this guide and lists the source documents# Quality improvement statement 1: Board-level leadership to prevent HCAIs
# Statement
Trust boards demonstrate leadership in infection prevention and control to ensure a culture of continuous quality improvement and to minimise risk to patients.
# What does this mean for people visiting, or receiving treatment in, hospitals?
People visiting, or receiving treatment in, hospitals can expect all trust staff – from board to ward level – to take responsibility, and be accountable for, continuous quality improvement in relation to infection prevention and control.
# What does it mean for trust boards?
Boards are proactive in ensuring continuous quality improvement by leading on, and regularly monitoring compliance with, all relevant infection prevention and control objectives, policies and procedures.
# Evidence of achievement
. Evidence that the board is up-to-date with, and has a working knowledge and understanding of, infection prevention and control.
. Evidence that the board has an agreed set of key performance indicators for infection prevention and control which includes compliance with antibiotic prescribing policy.
. Evidence that the agreed key performance indicators are used by the board to monitor the trust's infection prevention and control performance.
. Evidence that the trust's aims and objectives for infection prevention and control are included in the board's 'Balanced score card'.
. Evidence that a board member has been assigned to lead on infection prevention and control.
. Evidence of a board-approved infection prevention and control accountability framework. This includes evidence of specific responsibilities allocated to staff working in, or coming into contact with, clinical areas (reflected in their job descriptions and appraisals).
. Evidence that a mechanism is in place to report regularly to board meetings on important infection risks and the control measures that have been implemented.
. Evidence that the board has agreed an annual improvement programme on infection prevention and control which is linked to the business planning cycle and has identified actions and resources.
. Evidence that the trust promotes a 'self-governance' culture for infection prevention and control. This includes evidence that all staff, from board to ward, are accountable and take ownership and responsibility for continuous quality improvement.
. Evidence that the board is assured that monitoring mechanisms are in place in each clinical area, and that each area is accountable for compliance with relevant aspects of the code of practice.
. Evidence of regular communication from the chief executive on the trust's expectation of patients, visitors and staff in relation to infection prevention and control.
. Evidence that the director of infection prevention and control is involved in contract negotiations with commissioners on the key performance indicators for infection prevention and control.
. Evidence that the board demonstrates to patients, the public, staff and itself that it is making continuous progress towards meeting all relevant statements in this guide.
. Evidence of mechanisms to ensure transparent communication of all relevant surveillance outputs to staff and patients in line with duty of candour requirements.
# Practical examples
Annual improvement plans include comparative data on progress towards relevant quality improvement statement goals, as well as in areas covered by other relevant guidance. (An example is NICE's guideline on surgical site infections: prevention and treatment.)
Regular audit of board infection prevention and control accountability framework.
Infection prevention and control features in the planned board development programme.
Audit of infection prevention and control objectives within annual work programme.
# Health and Social Care Act code of practice
Criterion 1: Guidance for compliance 1.1, 1.5
Criterion 6: Guidance for compliance 6.2
# Relevant national indicators
None identified.# Quality improvement statement 2: Be a learning organisation
# Statement
Trusts use information from a range of sources to inform and drive continuous quality improvement to minimise risk from infection.
# What does this mean for people visiting, or receiving treatment in, hospitals?
People visiting, or receiving treatment in, hospitals can expect the trust to learn from its own and other healthcare providers' experience, and to use this learning to improve the quality of care and practice in infection prevention and control.
# What does it mean for trust boards?
Boards ensure mechanisms are in place for the trust to use a range of information, in addition to surveillance data, to minimise risk of infection to patients, staff and visitors. This includes information about both good and bad practice.
# Evidence of achievement
. Evidence that processes have been put in place to learn from experiences outside the organisation in relation to infection prevention and control. This includes evidence that learning is occurring on a continual basis.
. Evidence of regular, systematic generation and sharing of learning from trust's own experiences of infection prevention and control – including good practice and adverse events. This includes evidence that learning is based on a range of intelligence sources and is used to inform, and feed into, clinical and risk management processes.
. Evidence that mechanisms are in place to disseminate learning among relevant staff groups
. Evidence that the trust promotes a culture of learning in relation to infection prevention and control, and ensures staff have time to participate in preventive learning activities.
. Evidence that recommendations and actions identified as being needed following an incident, surveillance or learning activities have been implemented.
. Evidence that the continuous quality improvement cycle is informed by conclusions from robust learning methodologies.
. Evidence that the trust works with local health partners (including health protection units) to capture and learn lessons from the management of major infection outbreaks and other HCAI-related incidents.
. Evidence that the trust promotes innovation to minimise harm from infection, for example by promoting research opportunities, practice development initiatives and action learning sets for staff.
# Practical examples
Local gap analyses performed on official reports and action plan developed to address identified gaps in local practice.
Surveys of patient and staff experiences on infection prevention and control are fed into learning activities.
A range of forums give staff the opportunity to learn from each others' experiences in relation to infection prevention and control.
Audit of infection prevention activities undertaken across the trust as a result of learning from others.
Audit of antimicrobial drug usage to check it complies with trust policy. Feedback given to relevant staff.
Audit of hand-hygiene practices and feedback given to relevant staff.
Feedback given to individual surgeons on wound infection rates.
Audit of appropriate isolation facility usage.
# Health and Social Care Act code of practice
Criterion 1: Guidance for compliance 1.1, 1.3
# Relevant national indicators
Quality improvement indicators include National Library of Quality Indicators:
patient safety incident reporting (NHSOF)
patient safety incident reporting (CCGOIS)
severity of harm of patient safety incidents reported.# Quality improvement statement 3: HCAI surveillance
# Statement
Trusts have a surveillance system in place to routinely gather data and to carry out mandatory monitoring of HCAIs and other infections of local relevance to inform the local response to HCAIs.
# What does this mean for people visiting, or receiving treatment in, hospitals?
People visiting, or receiving treatment in, hospitals can expect the trust to monitor infection levels across all service areas and use this information to adjust practice, where necessary. For example, they can expect the trust to close beds, or a ward to visitors, in response to an outbreak.
# What does it mean for trust boards?
Boards ensure there is a fully resourced and flexible surveillance system to monitor infection levels in the trust. Outputs are shared across the organisation and used to drive continuous quality improvement.
# Evidence of achievement
. Evidence of an adequately resourced surveillance system with specific, locally defined objectives and priorities for preventing and managing HCAIs. The system should be able to detect organisms and infections and promptly register any abnormal trends.
. Evidence of clearly defined responsibilities for the recording, analysis, interpretation and communication of surveillance outputs.
. Evidence of arrangements for regular review of the surveillance programme to ensure it supports the trust's quality improvement targets for infection prevention.
. Evidence of fit-for-purpose IT systems to support surveillance activity. This includes evidence of validation processes that ensure data accuracy and resources that can analyse and interpret surveillance data in meaningful ways.
. Evidence of surveillance systems that allow data from multiple sources to be combined in real time (epidemiological, clinical, microbiological, surgical and pharmacy).
. Evidence that surveillance systems capture surgical-site and post-discharge infections.
. Evidence that trusts share relevant surveillance outputs and data with other local health and social care organisations to improve their infection prevention and control.
. Evidence that systems are in place for timely recognition of incidents in different spaces (for example, wards, clinical teams, clinical areas, the whole trust). This includes evidence of regular time-series analyses of data.
. Evidence that the trust reports all outbreaks, serious untoward incidents (SUIs) and any other significant HCAI-related risk and incident to the local health protection unit.
. Evidence that surveillance data in key areas is regularly compared with other local and national data and, where appropriate, is available at clinical unit level.
. Evidence of a process for surveillance outputs to feed into accountability frameworks, inform audit priorities and be used to set objectives for quality improvement programmes in relation to HCAI prevention.
. Evidence of surveillance outputs being analysed alongside comparative data to ensure continual improvement.
. Evidence of surveillance outputs being fed back to relevant staff and stakeholders, including patients, in an appropriate format to support preventive action.
. Evidence that the trust has developed, and regularly reviews, a hospital-wide incident plan to investigate and manage major infection outbreaks and HCAI incidents. This includes evidence that high-level managerial and clinical mechanisms are in place for coordinating, communication (including with other agencies) and deploying adequate resources.
# Practical examples
Surveillance data (for example, on antimicrobial resistance) is routinely communicated to the board and to individual clinical units. This includes comparative data on performance within the trust over time and compared with other local or national data.
Regular publication of outputs from the surveillance system, for example, on post-surgical infection rates and rates of compliance with recommendations on surgical prophylaxis.
Analysis of trends from local and national surveillance data informs practice across the trust or setting. For example, it could be used to initiate a review of how prepared the trust is for an infection outbreak.
Surveillance outputs are used to monitor progress against local quality improvement objectives.
# Health and Social Care Act code of practice
Criterion 9: Guidance for compliance 9.3m, 9.3u
# Relevant national indicators
Quality improvement indicators:
Incidence of C.difficile: National Library of Quality Indicators: incidence of healthcare-associated infection - C. difficile infection (NHSOF) and incidence of healthcare-associated infection - C. difficile infection (CCGOIS)
Incidence of MRSA bacteraemia: National Library of Quality Indicators: incidence of healthcare-associated infection - MRSA (NHSOF) and incidence of healthcare-associated infection - MRSA (CCGOIS)
Surgical site infections: NICE Clinical Commissioning Group indicator: readmission rates for surgical site infections within 30 days of discharge from surgery.# Quality improvement statement 4: Workforce capacity and capability
# Statement
Trusts prioritise the need for a skilled, knowledgeable and healthy workforce that delivers continuous quality improvement to minimise the risk from infections. This includes support staff, volunteers, agency/locum staff and those employed by contractors.
# What does this mean for patients and trust boards?
Patients can expect staff to have the necessary skills and knowledge to undertake infection prevention and control procedures in their area of work.
Boards ensure staff have the skills and training required for infection prevention and control.
# Evidence of achievement
. Evidence of local arrangements to ensure all staff working in clinical areas have an appraisal and development plan that includes discussion of infection prevention and control. This includes evidence that staff working in both clinical and non-clinical areas have clear objectives in relation to infection prevention and control which are linked to the trust's objectives.
. Evidence that all staff working in clinical areas, including specialist link practitioners, have sufficient time to fulfil their responsibilities on (and objectives for) infection prevention and control.
. Evidence that staff are provided with feedback on their performance in relation to infection prevention and control (for example, on hand hygiene or when prescribing antimicrobial drugs). This includes evidence that they are given support to fulfil this role.
. Evidence of local arrangements to ensure all staff working in clinical areas complete infection prevention and control training within 1 week of commencing work.
. Evidence of local arrangements to ensure infection prevention and control training and competencies are updated and checked at appropriate intervals.
. Evidence that local workforce planning and workforce reviews explicitly consider, and are informed by, the trust's infection prevention and control strategy and local HCAI outcomes.
. Evidence of local arrangements for an annual review of training resources to ensure consistency with the national evidence base and professional and occupational standards.
. Evidence of local arrangements to ensure consultant medical staff from a range of specialities champion infection prevention control. This includes evidence that they are given protected time to achieve defined objectives in this role.
. Evidence that all staff working in clinical areas are familiar with, and competent in applying, the trust's infection prevention and control policies and procedures.
. Evidence of local arrangements to train all staff in the communication skills needed to discuss HCAIs with patients and the public.
. Evidence that the trust has a proactive, accessible and user-sensitive occupational health service. This includes evidence of a high level of competence in all areas of healthcare infection prevention and control to ensure the welfare of healthcare workers (including short-term and agency workers). In addition, evidence is needed that the service puts an emphasis on preventing blood-borne viruses, tuberculosis, vaccine-preventable diseases and acute respiratory and gastrointestinal infections.
# Practical examples
An agreed performance indicator for the proportion of staff appraisals that include infection prevention and control. Performance against this indicator is checked on a regular basis.
Monitoring of proportion of new staff who undergo pre-employment occupational health screening or assessment within a given timeframe.
Trust programme in place to review the immunisation status of staff and to ensure vaccines are offered, when necessary.
Trust programme in place to review the skills, competence and capacity of the multi-disciplinary infection prevention and control team to ensure it is fit-for-purpose.
A mechanism is in place to ensure the need to reduce HCAIs across the organisation is explicitly considered during workforce planning.
Presence of an infection prevention and control 'link practitioner' or member of staff in every clinical and support unit (with protected time).
Training needs-analysis is informed by the trust's infection prevention and control strategy and local HCAI outcomes and is reviewed annually.
Staff education on the occupational health aspects of how to prevent and control healthcare infections is provided by occupational health service. (For example, this may include advice on the number of days staff should not work following an episode of sickness and diarrhoea.)
Monitoring of the proportion of new staff undertaking mandatory infection prevention and control training within 1 week of commencing work.
Presence of escalation procedures and processes for individuals who repeatedly do not fulfill their specified infection prevention and control responsibilities.
Patient surveys of their experience of staff skills and knowledge in relation to infection prevention and control.
Monitoring of the proportion of staff whose post-exposure prophylaxis (PEP) management to HIV is delayed.
# Health and Social Care Act code of practice
Criterion 1: Guidance for compliance 1.1
Criterion 6: Guidance for compliance 6.2
Criterion 10: Guidance for compliance 10.1
# Relevant national indicators
None identified.# Quality improvement statement 5: Environmental cleanliness
# Statement
Trusts ensure standards of environmental cleanliness are maintained and improved beyond current national guidance.
# What does this mean for: people visiting, or receiving treatment in, hospitals?
People visiting, or receiving treatment in, hospitals can expect secondary care settings to meet high standards of cleanliness, with each trust monitoring the condition of its premises to ensure levels exceed the minimum required standard.
# What does it mean for trust boards?
Boards ensure policies, procedures and resources are in place to maintain and continuously raise the level of cleanliness across the trust.
# Evidence of achievement
. Evidence that the trust clearly sets out, and adheres to, a standard of cleanliness that is beyond current national guidance (for example, British Standards Institution PAS 5748 and/or National Patient Safety Agency specifications).
. Evidence of clear and accessible local policies on cleaning and environmental decontamination. This includes evidence that they take into account the needs of different patient care areas and allow for flexibility in the deployment of resources. There should be evidence, for example, that individual staff understand their role and responsibilities.
. Evidence of local arrangements for a risk-based, cleaning responsibility matrix and frequency schedule for each patient care area.
. Evidence of a local framework for monitoring of environmental cleanliness routinely and in an 'outbreak' situation. This includes evidence of a patient feedback system.
. Evidence that the results of routine and outbreak monitoring are reviewed and cleaning arrangements updated, where appropriate
. Evidence of local arrangements to ensure awareness of health and safety and environmental issues regarding the use of disinfectant preparations for decontamination purposes.
. Evidence of regular, appropriate training and education of staff with responsibility for cleaning in the use of equipment, disinfection and decontamination.
. Evidence that the trust incorporates patient feedback and involves patients and carers in its cleanliness monitoring programmes, with evidence that this impacts on standards.
# Practical examples
Mechanism is in place to ensure rapid response cleaning is initiated within appropriate timeframe.
Clearly defined policy for cleaning and environmental decontamination (including roles, responsibilities and accountability).
Trust collects visual and/or objective environmental monitoring data for different clinical areas. Visual and scientific methods are used for both routine and outbreak environmental assessment and the findings are used to inform improvements to the cleanliness programme.
# Health and Social Care Act code of practice
Criterion 1: Guidance for compliance 1.1
Criterion 2: Guidance for compliance 2.1, 2.3, 2.4, 2.5, 2.6
## Relevant national indicators
None identified.# Quality improvement statement 6: Multi-agency working to reduce HCAIs
# Statement
Trusts work proactively in multi-agency collaborations with other local health and social care providers to reduce risk from infection.
# What does this mean for people visiting, or receiving treatment in, hospitals?
People visiting, or receiving treatment in, hospitals can expect the trust to be working collaboratively with other local health and social care providers to prevent and reduce harm from infection.
# What does it mean for trust boards?
Boards are actively involved in local networks. They share governance structures, objectives and learning with other local health and social care providers to promote good practice among them.
# Evidence of achievement
. Evidence that a board member has been nominated as the trust's lead and representative for a multi-agency collaboration to prevent and manage HCAIs.
. Evidence of support for, and participation in, joint working initiatives beyond mandatory or contractual requirements, to reduce HCAIs locally.
. Evidence of an agreed policy for data sharing on HCAIs between local organisations.
. Evidence of timely sharing of information risk assessments and strategic efforts to minimise harm from infection with other agencies.
. Evidence of a defined, shared and agreed governance structure with other local health and social care providers that includes clear lines of accountability.
. Evidence of support for, and participation in, the development and implementation of a joint local strategy, policy and pathway on HCAIs between local health and social care providers.
. Evidence of participation in the development of shared targets and joint working with other local health and social care providers to improve outcomes locally relating to HCAIs.
. Evidence that the trust works collaboratively with the local health protection unit and other health partners to investigate and manage HCAI outbreaks and incidents. Evidence is particularly needed of collaboration to deal with incidents which may impact on the health of the wider community.
# Practical examples
Documented terms of reference for multi-agency collaboration to reduce HCAIs.
Audit of outputs from collaboration disseminated to relevant trust committees (for example, clinical governance and policy development groups).
Audits of outputs from relevant learning methodologies are shared with other local health and social care providers.
# Health and Social Care Act code of practice
No relevant criteria identified.
# Relevant national indicators
None identified.# Quality improvement statement 7: Communication
# Statement
Trusts ensure there is clear communication with all staff, patients and carers throughout the care pathway about HCAIs, infection risks and how to prevent HCAIs, to reduce harm from infection.
# What does this mean for people visiting, or receiving treatment in, hospitals?
People visiting, or receiving treatment in, hospitals can expect to be provided with information on how to reduce the risks of an HCAI and to be given the opportunity to discuss HCAIs with staff.
Patients who have an HCAI can expect to be:
notified of their infection
told about the impact it will have on their care
given relevant information about minimising the risk to others.
# What does it mean for trust boards?
Boards ensure processes are in place to communicate relevant information about minimising the risk of (and from) HCAIs to patients, carers, visitors and staff. They also ensure staff have access to relevant patient information resources and up-to-date local surveillance information so they can communicate about HCAIs effectively.
# Evidence of achievement
. Evidence of mechanisms to ensure transparent communication of all relevant surveillance outputs to staff and patients.
. Evidence that local health and social care services provide consistent patient and carer information on infection prevention and control.
. Evidence that trust policies on infection prevention and control are available to, and used by, all staff.
. Evidence that arrangements are in place to ensure providers in different settings can identify and communicate infection risks as the patient moves between services.
. Evidence that patients, carers and visitors have access to up-to-date, accurate and easy to understand information about their own HCAI (if applicable) or HCAIs generally, in a suitable format. This includes evidence that they have access to information on the potential risk of infection and existing treatment and control measures.
. Evidence that patients with an HCAI are informed of their infection and the implications for their care.
. Evidence that staff are trained to (and can) communicate in an appropriate manner with patients and their carers about how to prevent, and reduce harm from, HCAIs.
. Evidence of ongoing and timely dialogue with patients and carers throughout the trust's care pathway regarding the risk of HCAIs and how to prevent them.
# Practical examples
Audit of communications between different health and social care providers detailing any infections (for example, an audit of discharge summaries to GPs and admission letters from care homes).
Audit of patient records for communication about HCAIs (for example, their MRSA status) throughout their hospital episode.
Audit of patient records for communication about how to prevent HCAIs (for example, hand-hygiene procedures) throughout their hospital episode.
Patient surveys on the trust's communication about HCAIs, and about their understanding of the risks.
Availability of easy to understand, standardised information on HCAIs for patients, carers and staff.
Availability of standardised trust policies on infection prevention and control.
Audit central venous catheter and indwelling catheter procedures to check they follow trust policies on infection prevention and control.
Audit of antimicrobial stewardship programmes to ensure good prescribing practice (for example, appropriate use of prophylactic antibiotics in surgery).
# Health and Social Care Act code of practice
Criterion 3: Guidance for compliance 3.1
Criterion 4: Guidance for compliance 4.1, 4.2
# Relevant national indicators
None identified.# Quality improvement statement 8: Admission, discharge and transfer
# Statement
Trusts have a multi-agency patient admission, discharge and transfer policy which gives clear, relevant guidance to local health and social care providers on the critical steps to take to minimise harm from infection.
# What does this mean for patients and trust boards?
Patients with an infection can expect relevant information about it to be shared between providers when they are admitted, transferred to, or discharged from a hospital to ensure seamless care.
Boards lead on the development of an agreed multi-agency admission, discharge and transfer policy. They ensure mechanisms are in place to support and monitor adherence to the policy.
# Evidence of achievement
. Evidence of an admission, discharge and transfer policy for patients with an infection that has been agreed by all agencies involved in the patient's care pathway, including local community and public health teams.
. Evidence that the agreed policy includes a risk assessment on admission, and for all transfers, to determine the presence or risk of acquiring or transmitting infection.
. Evidence of a procedure for documenting and sharing information about infections and their treatment. This includes evidence of information sharing to manage and support patients with an infection on an ongoing basis (including transfer and isolation arrangements for them) during admission, transfer and discharge.
. Evidence of clear advice being given to patients on antimicrobial prescribing for their ongoing care.
. Evidence of clear advice being given to patients on the management of medical devices for their ongoing care.
# Practical examples
Audit of adherence to relevant policy on admissions/transfers/discharges of patients with an HCAI.
Reduction in the number of adverse events recorded as a result of discharge and transfer of a patient with an infection.
# Health and Social Care Act code of practice
Criterion 1: Guidance for compliance 1.1, 1.9, 1.10
# Relevant national indicators
None identified.# Quality improvement statement 9: Patient and public involvement
# Statement
Trusts use input from local patient and public experience for continuous quality improvement to minimise harm from HCAIs.
# What does this mean for patients, the public and trust boards?
Patients and the public can expect the trust to provide opportunities for them to be involved with planning and decision-making on quality improvement activities to prevent and control infections.
Boards ensure the trust has mechanisms in place to seek patient and public views and involve them in decisions related to quality improvement for infection prevention and control.
# Evidence of achievement
. Evidence that a non-executive director or equivalent (for example, a trust governor) has been assigned to lead on patient and public involvement in infection prevention and control.
. Evidence of a range of mechanisms to involve patients and the public in the trust's decision-making to ensure continuous quality improvement in infection prevention and control.
. Evidence that a variety of information sources and participation methods are used to gain insight into patient experiences of infection prevention and control.
. Evidence that patient and public involvement groups for infection prevention and control reflect local demographics.
. Evidence of mechanisms to ensure patient experiences of HCAIs are used to inform reviews or investigations (such as outbreak investigations and root-cause analysis). This includes evidence that they are used to provide patients and carers with feedback on the outcome.
. Evidence that patients' and the general public's perspective and priorities on infection prevention and control are taken into account in the trust's quality improvement programme.
# Practical examples
Patient and public representation on relevant groups and committees.
Audit of HCAI reviews and investigations that include comment from patients and the public.
Meetings between trust lead and patient and public representatives to discuss infection prevention and control.
# Health and Social Care Act code of practice
No relevant criteria identified.
# Relevant national indicators
None identified.# Quality improvement statement 10: Trust estate management
# Statement
Trusts consider infection prevention and control when procuring, commissioning, planning, designing and completing new and refurbished hospital services and facilities (and during subsequent routine maintenance).
# What does this mean for people visiting, or receiving treatment in, hospitals?
People visiting, or receiving treatment in, hospitals can expect hospitals, and other parts of the trust estate, to be built and maintained in such a way as to minimise the risk of infection.
# What does it mean for trust boards?
Boards ensure the whole estate is managed and maintained to minimise risk from infection.
# Evidence of achievement
. Evidence of local arrangements for involving infection prevention and control teams in the planning, design, commissioning, completion and maintenance of services and facilities used by the trust.
. Evidence of local procedures to ensure infection prevention and control is considered during the commissioning and handover of facilities.
. Evidence of local procedures to ensure infection prevention and control is considered during the selection, commissioning and installation of equipment.
. Evidence of local arrangements (for example, a standard operating procedure) for involving the infection prevention and control team (or other appropriate expertise) in the development of estates policy.
. Evidence of a planning process that 'designs out' potential infection risks and focuses on effective infection prevention.
. Evidence of local arrangements to ensure estate management is considered and integrated into routine practice to reduce infection risk.
. Evidence that estates and clinical staff, including temporary staff and subcontractors, receive annual training in infection prevention and control. This should include an assessment of their relevant competencies.
. Evidence of mechanisms for consideration of current national estates policy and whether or not it should be incorporated into local practice.
# Practical examples
Record of adherence to the trust estates policy, including the infection prevention and control (IPC) team's involvement. This should include sign-off of documents at relevant stages of the building and maintenance process.
Briefs and specifications outline the need to consider infection prevention and control when procuring, commissioning, planning, designing and completing new and refurbished services and facilities.
Record of completed and due maintenance tasks, including an assessment of whether the infection prevention and control objectives have been achieved.
Record of estates risk assessments that have considered infection prevention and control in areas of high HCAI risk (for example, in patient care areas and for facilities such as water-storage tanks).
IPC team-approved written protocols for routine, planned preventive maintenance (PPM), remedial and interventional maintenance activity.
Record of planned preventive, remedial and interventional maintenance works that adheres to IPC team-approved protocols.
Impact of planned preventive, remedial and interventional maintenance works in minimising the risk of infection to patients is regularly reviewed and considered.
An appropriately competent person regularly reviews, verifies, confirms and signs off work delivered in accordance with infection-control protocols.
IPC staff (or another recognised source of appropriate expertise) have allocated time and availability to review and advise on IPC issues during the initiation, planning, procurement, design and construction stages of projects.
# Health and Social Care Act code of practice
Criterion 2: Guidance for compliance 2.1, 2.3
# Relevant national indicators
None identified.# Quality improvement statement 11: New technology and innovation
# Statement
Trusts regularly review evidence-based assessments of new technology and other innovations to minimise harm from HCAIs and antimicrobial resistance (AMR).
# What does this mean for people visiting, or receiving treatment in, hospitals?
People visiting, or receiving treatment in, hospitals can expect the trust to assess relevant new technologies and innovation to help improve the quality of care and practice to prevent, and reduce the harm from, infection.
# What does it mean for trust boards?
Boards routinely identify technology needs relevant to HCAI prevention and control and assess the potential of new technologies and innovation to meet those needs. Where new technologies and methods are identified, they are evaluated and implemented, as appropriate.
# Evidence of achievement
. Evidence that a mechanism is in place to undertake a regular gap analysis of technology needs relevant to infection prevention and control.
. Evidence that information on relevant new technologies and innovation is disseminated to directorates, along with guidance on evaluation and implementation.
. Evidence of a mechanism to assess the evidence base underpinning technology and innovation in reducing HCAIs. This includes evidence that, where relevant, new technology, innovation and practice is incorporated into policies and procedures.
. Evidence of local arrangements to help individuals or clinical teams conduct relevant research (for example, translational research) to prevent or reduce the harm from HCAIs. This could include evidence that arrangements have been made with academic centres, or that trust-based preventive interventions have been assessed internally.
# Practical examples
Programme in place to consider current research activity and developments in HCAI innovation and technology.
Mechanism is in place to support people who wish to conduct research into quality improvement methodology, behavioural sciences or other areas to improve the way HCAIs are prevented or controlled.
Regular gap analyses carried out in relation to infection prevention and control.
Relevant gaps in technology identified and communicated to appropriate research and funding bodies.
# Health and Social Care Act code of practice
No relevant criteria identified.
# Relevant national data indicators
None identified.# Glossary
# Accountability framework
The policies, procedures and lines of accountability for specific areas within an organisation.
# Adverse event
An unplanned or unanticipated event involving actual (or potential) risk or harm to patients. In the context of this guide, this would be an infection occurring as a result of medical or surgical intervention or contact with a healthcare setting.
# Continuous quality improvement (CQI)
Improving the provision of services and practice by using a range of audit and statistical tools to assess the current situation, identify areas for improvement and measure the results.
# Hand hygiene
The use of soap or solution (non-antimicrobial or antimicrobial) and water, or a waterless antimicrobial agent, to remove transient or residual organisms from the hands.
# Key performance indicators (KPIs)
Measures that provide an indication of performance in key areas.
# Learning methodologies
Techniques and approaches that provide an opportunity to evaluate current practice, identify areas for improvement and disseminate the findings.
# Link practitioners
Local leaders and role models – either within a trust, or working in settings that link to that trust – promote the principles of safe, clean care or good prescribing practices during the day-to-day operation of their service. Link practitioners may have a clinical or lay background. An example of the former could be a nurse or pharmacist. An example of the latter could be a patient liaison officer.
# Medical device
A product used to diagnose, treat or prevent disease or injury.
# Planned preventive maintenance
The scheduling of planned maintenance to prevent damage, breakdown and functional failures.
# Surveillance
Active monitoring of infection at patient, ward, trust or national level. This involves counting cases over time and recognising and controlling outbreaks and adverse trends. It also involves producing complete epidemiological records of infection outbreaks and adverse incidents which describe and summarise all cases.
# Trust estates
All the buildings and grounds that fall under the management and control of the trust.# Supporting documents
See supporting evidence for a full list of supporting documents for this guidance.
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{'Introduction': "Following a referral from the Department of Health, NICE, in partnership with Public Health England (PHE), have developed this quality improvement guide. The guide offers advice on management or organisational actions to prevent and control healthcare-associated infections (HCAIs) in secondary care settings.\n\nThe guide is aimed at board members working in (or with) secondary care. It may also be of use to senior managers, those working elsewhere in the NHS, as well as those working in local authorities and the wider public, private, voluntary and community sectors.\n\nIn producing this guide, NICE and PHE have assumed that all secondary care settings are compliant with the current code of practice on preventing and controlling infections (Department of Health's Health and Social Care Act 2008: Code of practice on the prevention and control of infections).\n\nThe guide aims to help build on advice given in the code and elsewhere to improve the quality of care and practice in these areas over and above current standards. Taken together, the quality improvement statements contained in this guide describe excellence in care and practice to prevent and control HCAIs. Examples of evidence and other data to demonstrate progress against each statement are provided.\n\nNICE and PHE recognise that a range of factors associated with infection prevention and control have the potential to impact on health inequalities (for example, in relation to age, ethnicity, gender and disability). However, the relative impact of different factors will vary for different organisations. NICE and PHE expect trusts and other secondary care organisations to consider local issues in relation to health inequalities when implementing this guide.\n\n# What is a healthcare-associated infection?\n\nHealthcare-associated infections (HCAIs) can develop either as a direct result of healthcare interventions such as medical or surgical treatment, or from being in contact with a healthcare setting.\n\nThe term HCAI covers a wide range of infections. The most well known include those caused by meticillin-resistant Staphylococcus aureus (MRSA), meticillin-sensitive Staphylococcus aureus (MSSA), Clostridium difficile (C. difficile) and Escherichia coli (E. coli). HCAIs cover any infection contracted:\n\nas a direct result of treatment in, or contact with, a health or social care setting\n\nas a result of healthcare delivered in the community\n\noutside a healthcare setting (for example, in the community) and brought in by patients, staff or visitors and transmitted to others (for example, norovirus).\n\nHCAIs pose a serious risk to patients, staff and visitors. They can incur significant costs for the NHS and cause significant morbidity to those infected. As a result, infection prevention and control is a key priority for the NHS (Department of Health's board to ward: How to embed a culture of HCAI prevention in acute trusts).\n\n# What action has been taken?\n\nFollowing National Audit Office reports highlighting concerns about HCAIs, the Department of Health introduced a range of policies and measures designed to reduce rates of infection. (National Audit Office The management and control of hospital acquired infection in acute NHS trusts in England; National Audit Office Improving patient care by reducing the risk of hospital acquired infection: a progress report.)\n\nFor example, mandatory surveillance for meticillin-resistant Staphylococcus aureus (MRSA) was introduced in 2001. In 2004, a target was introduced to reduce MRSA bloodstream infections by 50% by 2008 in all NHS acute and foundation trusts. With the introduction of the Health Act in 2006, for the first time it became a legal requirement to have systems in place to minimise the risk of HCAIs (Department of Health's Health Act 2006: code of practice for the prevention and control of healthcare associated infections).\n\n# What action is needed now?\n\nThe 2009 National Audit Office report on reducing healthcare associated infections in hospitals in England identified four systemic issues that still needed to be tackled locally and nationally to reduce infection rates. It highlighted the need:\n\nfor a culture of continuous improvement\n\nfor a whole-system approach, with clear structures, roles and responsibilities\n\nto ensure staff compliance with good infection control practice\n\nto monitor and record hospital prescriptions and the use of antibiotics.\n\n# What is this guide for?\n\nThis guide will help secondary care and other healthcare organisations improve the quality of care and practice, reduce the risk of harm from HCAIs to patients, staff and visitors and reduce the costs associated with preventable infection. The 11 quality improvement statements provide clear markers of excellence in infection prevention and control at a management or organisational level. Each statement is supported by examples of the type of evidence that could be used to prove the organisation has achieved excellence, and examples of what this would mean in practice on a day-to-day basis.\n\nThe aim is to help boards:\n\nassess current practice in relation to the prevention of HCAIs\n\nidentify areas for quality improvement\n\nmonitor progress\n\nprovide leadership and support to infection prevention and control teams and other staff working to implement the guide.\n\nThe guide may also help inform investment decisions.\n\nIt will also give patients and the public information about the quality of care they can expect, and how secondary care organisations can improve patient safety and outcomes by improving quality in key areas.\n\n# How should the guide be used?\n\nThis guide is not mandatory. Rather, each quality improvement statement describes a level of excellence that could be achieved to prevent and control infections. Key areas of practice that underpin infection prevention and control, such as hand hygiene, antimicrobial stewardship and environmental cleanliness are included as measures and examples, where appropriate.\n\nOrganisations wishing to use the guide for quality assessment and improvement may choose a selection of the most appropriate measures for their setting as potential evidence of achievement. In organisations where, for example, tertiary care services are provided alongside secondary care, senior management should consider the applicability of each statement to their setting.\n\nThe examples of measures that could be taken may not be appropriate in all cases – and secondary care organisations may identify and use alternate measures as evidence of achievement, as necessary.\n\nPerformance in each statement area will depend upon healthcare professionals and other trust staff who have HCAI prevention and control – and public health, generally – as part of their remit.\n\nMuch of the information required to support the measures is already available and a range of other guidance can be used alongside this guide to assess and improve quality in secondary care settings. Overlaps between the statements and certain aspects of the code of practice are highlighted. In addition, where data routinely collated may help trusts monitor progress in an area covered by one of the statements, this is also highlighted.\n\n# How was the guide developed?\n\nThis guide was developed as a pilot project, based on processes and methods used by NICE to develop other types of guidance. A topic expert group was set up and led by an independent chair. It consisted of practitioners from the NHS, local authorities and the voluntary sector, as well as academics and patient and public representatives. The group worked with NICE and PHE to develop the guide.\n\nThe resulting quality improvement statements are based on recommendations from seven source guidance documents. They have been refined as a result of stakeholder consultation and committee discussion.\n\nThe following documents provide further information on the referral, scope, and methodology used as the basis for this guide:\n\nAdvice on the prevention and control of healthcare-associated infections: scope – this sets out the referral and scope for the work\n\nQuality improvement guide – prevention and control of healthcare-associated infections: topic briefing paper - this summarises the methods and process used to develop this guide and lists the source documents", 'Quality improvement statement 1: Board-level leadership to prevent HCAIs': "# Statement\n\nTrust boards demonstrate leadership in infection prevention and control to ensure a culture of continuous quality improvement and to minimise risk to patients.\n\n# What does this mean for people visiting, or receiving treatment in, hospitals?\n\nPeople visiting, or receiving treatment in, hospitals can expect all trust staff – from board to ward level – to take responsibility, and be accountable for, continuous quality improvement in relation to infection prevention and control.\n\n# What does it mean for trust boards?\n\nBoards are proactive in ensuring continuous quality improvement by leading on, and regularly monitoring compliance with, all relevant infection prevention and control objectives, policies and procedures.\n\n# Evidence of achievement\n\n. Evidence that the board is up-to-date with, and has a working knowledge and understanding of, infection prevention and control.\n\n. Evidence that the board has an agreed set of key performance indicators for infection prevention and control which includes compliance with antibiotic prescribing policy.\n\n. Evidence that the agreed key performance indicators are used by the board to monitor the trust's infection prevention and control performance.\n\n. Evidence that the trust's aims and objectives for infection prevention and control are included in the board's 'Balanced score card'.\n\n. Evidence that a board member has been assigned to lead on infection prevention and control.\n\n. Evidence of a board-approved infection prevention and control accountability framework. This includes evidence of specific responsibilities allocated to staff working in, or coming into contact with, clinical areas (reflected in their job descriptions and appraisals).\n\n. Evidence that a mechanism is in place to report regularly to board meetings on important infection risks and the control measures that have been implemented.\n\n. Evidence that the board has agreed an annual improvement programme on infection prevention and control which is linked to the business planning cycle and has identified actions and resources.\n\n. Evidence that the trust promotes a 'self-governance' culture for infection prevention and control. This includes evidence that all staff, from board to ward, are accountable and take ownership and responsibility for continuous quality improvement.\n\n. Evidence that the board is assured that monitoring mechanisms are in place in each clinical area, and that each area is accountable for compliance with relevant aspects of the code of practice.\n\n. Evidence of regular communication from the chief executive on the trust's expectation of patients, visitors and staff in relation to infection prevention and control.\n\n. Evidence that the director of infection prevention and control is involved in contract negotiations with commissioners on the key performance indicators for infection prevention and control.\n\n. Evidence that the board demonstrates to patients, the public, staff and itself that it is making continuous progress towards meeting all relevant statements in this guide.\n\n. Evidence of mechanisms to ensure transparent communication of all relevant surveillance outputs to staff and patients in line with duty of candour requirements.\n\n# Practical examples\n\nAnnual improvement plans include comparative data on progress towards relevant quality improvement statement goals, as well as in areas covered by other relevant guidance. (An example is NICE's guideline on surgical site infections: prevention and treatment.)\n\nRegular audit of board infection prevention and control accountability framework.\n\nInfection prevention and control features in the planned board development programme.\n\nAudit of infection prevention and control objectives within annual work programme.\n\n# Health and Social Care Act code of practice\n\nCriterion 1: Guidance for compliance 1.1, 1.5\n\nCriterion 6: Guidance for compliance 6.2\n\n# Relevant national indicators\n\nNone identified.", 'Quality improvement statement 2: Be a learning organisation': "# Statement\n\nTrusts use information from a range of sources to inform and drive continuous quality improvement to minimise risk from infection.\n\n# What does this mean for people visiting, or receiving treatment in, hospitals?\n\nPeople visiting, or receiving treatment in, hospitals can expect the trust to learn from its own and other healthcare providers' experience, and to use this learning to improve the quality of care and practice in infection prevention and control.\n\n# What does it mean for trust boards?\n\nBoards ensure mechanisms are in place for the trust to use a range of information, in addition to surveillance data, to minimise risk of infection to patients, staff and visitors. This includes information about both good and bad practice.\n\n# Evidence of achievement\n\n. Evidence that processes have been put in place to learn from experiences outside the organisation in relation to infection prevention and control. This includes evidence that learning is occurring on a continual basis.\n\n. Evidence of regular, systematic generation and sharing of learning from trust's own experiences of infection prevention and control – including good practice and adverse events. This includes evidence that learning is based on a range of intelligence sources and is used to inform, and feed into, clinical and risk management processes.\n\n. Evidence that mechanisms are in place to disseminate learning among relevant staff groups\n\n. Evidence that the trust promotes a culture of learning in relation to infection prevention and control, and ensures staff have time to participate in preventive learning activities.\n\n. Evidence that recommendations and actions identified as being needed following an incident, surveillance or learning activities have been implemented.\n\n. Evidence that the continuous quality improvement cycle is informed by conclusions from robust learning methodologies.\n\n. Evidence that the trust works with local health partners (including health protection units) to capture and learn lessons from the management of major infection outbreaks and other HCAI-related incidents.\n\n. Evidence that the trust promotes innovation to minimise harm from infection, for example by promoting research opportunities, practice development initiatives and action learning sets for staff.\n\n# Practical examples\n\nLocal gap analyses performed on official reports and action plan developed to address identified gaps in local practice.\n\nSurveys of patient and staff experiences on infection prevention and control are fed into learning activities.\n\nA range of forums give staff the opportunity to learn from each others' experiences in relation to infection prevention and control.\n\nAudit of infection prevention activities undertaken across the trust as a result of learning from others.\n\nAudit of antimicrobial drug usage to check it complies with trust policy. Feedback given to relevant staff.\n\nAudit of hand-hygiene practices and feedback given to relevant staff.\n\nFeedback given to individual surgeons on wound infection rates.\n\nAudit of appropriate isolation facility usage.\n\n# Health and Social Care Act code of practice\n\nCriterion 1: Guidance for compliance 1.1, 1.3\n\n# Relevant national indicators\n\nQuality improvement indicators include National Library of Quality Indicators:\n\npatient safety incident reporting (NHSOF)\n\npatient safety incident reporting (CCGOIS)\n\nseverity of harm of patient safety incidents reported.", 'Quality improvement statement 3: HCAI surveillance': "# Statement\n\nTrusts have a surveillance system in place to routinely gather data and to carry out mandatory monitoring of HCAIs and other infections of local relevance to inform the local response to HCAIs.\n\n# What does this mean for people visiting, or receiving treatment in, hospitals?\n\nPeople visiting, or receiving treatment in, hospitals can expect the trust to monitor infection levels across all service areas and use this information to adjust practice, where necessary. For example, they can expect the trust to close beds, or a ward to visitors, in response to an outbreak.\n\n# What does it mean for trust boards?\n\nBoards ensure there is a fully resourced and flexible surveillance system to monitor infection levels in the trust. Outputs are shared across the organisation and used to drive continuous quality improvement.\n\n# Evidence of achievement\n\n. Evidence of an adequately resourced surveillance system with specific, locally defined objectives and priorities for preventing and managing HCAIs. The system should be able to detect organisms and infections and promptly register any abnormal trends.\n\n. Evidence of clearly defined responsibilities for the recording, analysis, interpretation and communication of surveillance outputs.\n\n. Evidence of arrangements for regular review of the surveillance programme to ensure it supports the trust's quality improvement targets for infection prevention.\n\n. Evidence of fit-for-purpose IT systems to support surveillance activity. This includes evidence of validation processes that ensure data accuracy and resources that can analyse and interpret surveillance data in meaningful ways.\n\n. Evidence of surveillance systems that allow data from multiple sources to be combined in real time (epidemiological, clinical, microbiological, surgical and pharmacy).\n\n. Evidence that surveillance systems capture surgical-site and post-discharge infections.\n\n. Evidence that trusts share relevant surveillance outputs and data with other local health and social care organisations to improve their infection prevention and control.\n\n. Evidence that systems are in place for timely recognition of incidents in different spaces (for example, wards, clinical teams, clinical areas, the whole trust). This includes evidence of regular time-series analyses of data.\n\n. Evidence that the trust reports all outbreaks, serious untoward incidents (SUIs) and any other significant HCAI-related risk and incident to the local health protection unit.\n\n. Evidence that surveillance data in key areas is regularly compared with other local and national data and, where appropriate, is available at clinical unit level.\n\n. Evidence of a process for surveillance outputs to feed into accountability frameworks, inform audit priorities and be used to set objectives for quality improvement programmes in relation to HCAI prevention.\n\n. Evidence of surveillance outputs being analysed alongside comparative data to ensure continual improvement.\n\n. Evidence of surveillance outputs being fed back to relevant staff and stakeholders, including patients, in an appropriate format to support preventive action.\n\n. Evidence that the trust has developed, and regularly reviews, a hospital-wide incident plan to investigate and manage major infection outbreaks and HCAI incidents. This includes evidence that high-level managerial and clinical mechanisms are in place for coordinating, communication (including with other agencies) and deploying adequate resources.\n\n# Practical examples\n\nSurveillance data (for example, on antimicrobial resistance) is routinely communicated to the board and to individual clinical units. This includes comparative data on performance within the trust over time and compared with other local or national data.\n\nRegular publication of outputs from the surveillance system, for example, on post-surgical infection rates and rates of compliance with recommendations on surgical prophylaxis.\n\nAnalysis of trends from local and national surveillance data informs practice across the trust or setting. For example, it could be used to initiate a review of how prepared the trust is for an infection outbreak.\n\nSurveillance outputs are used to monitor progress against local quality improvement objectives.\n\n# Health and Social Care Act code of practice\n\nCriterion 9: Guidance for compliance 9.3m, 9.3u\n\n# Relevant national indicators\n\nQuality improvement indicators:\n\nIncidence of C.difficile: National Library of Quality Indicators: incidence of healthcare-associated infection - C. difficile infection (NHSOF) and incidence of healthcare-associated infection - C. difficile infection (CCGOIS)\n\nIncidence of MRSA bacteraemia: National Library of Quality Indicators: incidence of healthcare-associated infection - MRSA (NHSOF) and incidence of healthcare-associated infection - MRSA (CCGOIS)\n\nSurgical site infections: NICE Clinical Commissioning Group indicator: readmission rates for surgical site infections within 30 days of discharge from surgery.", 'Quality improvement statement 4: Workforce capacity and capability': "# Statement\n\nTrusts prioritise the need for a skilled, knowledgeable and healthy workforce that delivers continuous quality improvement to minimise the risk from infections. This includes support staff, volunteers, agency/locum staff and those employed by contractors.\n\n# What does this mean for patients and trust boards?\n\nPatients can expect staff to have the necessary skills and knowledge to undertake infection prevention and control procedures in their area of work.\n\nBoards ensure staff have the skills and training required for infection prevention and control.\n\n# Evidence of achievement\n\n. Evidence of local arrangements to ensure all staff working in clinical areas have an appraisal and development plan that includes discussion of infection prevention and control. This includes evidence that staff working in both clinical and non-clinical areas have clear objectives in relation to infection prevention and control which are linked to the trust's objectives.\n\n. Evidence that all staff working in clinical areas, including specialist link practitioners, have sufficient time to fulfil their responsibilities on (and objectives for) infection prevention and control.\n\n. Evidence that staff are provided with feedback on their performance in relation to infection prevention and control (for example, on hand hygiene or when prescribing antimicrobial drugs). This includes evidence that they are given support to fulfil this role.\n\n. Evidence of local arrangements to ensure all staff working in clinical areas complete infection prevention and control training within 1 week of commencing work.\n\n. Evidence of local arrangements to ensure infection prevention and control training and competencies are updated and checked at appropriate intervals.\n\n. Evidence that local workforce planning and workforce reviews explicitly consider, and are informed by, the trust's infection prevention and control strategy and local HCAI outcomes.\n\n. Evidence of local arrangements for an annual review of training resources to ensure consistency with the national evidence base and professional and occupational standards.\n\n. Evidence of local arrangements to ensure consultant medical staff from a range of specialities champion infection prevention control. This includes evidence that they are given protected time to achieve defined objectives in this role.\n\n. Evidence that all staff working in clinical areas are familiar with, and competent in applying, the trust's infection prevention and control policies and procedures.\n\n. Evidence of local arrangements to train all staff in the communication skills needed to discuss HCAIs with patients and the public.\n\n. Evidence that the trust has a proactive, accessible and user-sensitive occupational health service. This includes evidence of a high level of competence in all areas of healthcare infection prevention and control to ensure the welfare of healthcare workers (including short-term and agency workers). In addition, evidence is needed that the service puts an emphasis on preventing blood-borne viruses, tuberculosis, vaccine-preventable diseases and acute respiratory and gastrointestinal infections.\n\n# Practical examples\n\nAn agreed performance indicator for the proportion of staff appraisals that include infection prevention and control. Performance against this indicator is checked on a regular basis.\n\nMonitoring of proportion of new staff who undergo pre-employment occupational health screening or assessment within a given timeframe.\n\nTrust programme in place to review the immunisation status of staff and to ensure vaccines are offered, when necessary.\n\nTrust programme in place to review the skills, competence and capacity of the multi-disciplinary infection prevention and control team to ensure it is fit-for-purpose.\n\nA mechanism is in place to ensure the need to reduce HCAIs across the organisation is explicitly considered during workforce planning.\n\nPresence of an infection prevention and control 'link practitioner' or member of staff in every clinical and support unit (with protected time).\n\nTraining needs-analysis is informed by the trust's infection prevention and control strategy and local HCAI outcomes and is reviewed annually.\n\nStaff education on the occupational health aspects of how to prevent and control healthcare infections is provided by occupational health service. (For example, this may include advice on the number of days staff should not work following an episode of sickness and diarrhoea.)\n\nMonitoring of the proportion of new staff undertaking mandatory infection prevention and control training within 1 week of commencing work.\n\nPresence of escalation procedures and processes for individuals who repeatedly do not fulfill their specified infection prevention and control responsibilities.\n\nPatient surveys of their experience of staff skills and knowledge in relation to infection prevention and control.\n\nMonitoring of the proportion of staff whose post-exposure prophylaxis (PEP) management to HIV is delayed.\n\n# Health and Social Care Act code of practice\n\nCriterion 1: Guidance for compliance 1.1\n\nCriterion 6: Guidance for compliance 6.2\n\nCriterion 10: Guidance for compliance 10.1\n\n# Relevant national indicators\n\nNone identified.", 'Quality improvement statement 5: Environmental cleanliness': "# Statement\n\nTrusts ensure standards of environmental cleanliness are maintained and improved beyond current national guidance.\n\n# What does this mean for: people visiting, or receiving treatment in, hospitals?\n\nPeople visiting, or receiving treatment in, hospitals can expect secondary care settings to meet high standards of cleanliness, with each trust monitoring the condition of its premises to ensure levels exceed the minimum required standard.\n\n# What does it mean for trust boards?\n\nBoards ensure policies, procedures and resources are in place to maintain and continuously raise the level of cleanliness across the trust.\n\n# Evidence of achievement\n\n. Evidence that the trust clearly sets out, and adheres to, a standard of cleanliness that is beyond current national guidance (for example, British Standards Institution PAS 5748 and/or National Patient Safety Agency specifications).\n\n. Evidence of clear and accessible local policies on cleaning and environmental decontamination. This includes evidence that they take into account the needs of different patient care areas and allow for flexibility in the deployment of resources. There should be evidence, for example, that individual staff understand their role and responsibilities.\n\n. Evidence of local arrangements for a risk-based, cleaning responsibility matrix and frequency schedule for each patient care area.\n\n. Evidence of a local framework for monitoring of environmental cleanliness routinely and in an 'outbreak' situation. This includes evidence of a patient feedback system.\n\n. Evidence that the results of routine and outbreak monitoring are reviewed and cleaning arrangements updated, where appropriate\n\n. Evidence of local arrangements to ensure awareness of health and safety and environmental issues regarding the use of disinfectant preparations for decontamination purposes.\n\n. Evidence of regular, appropriate training and education of staff with responsibility for cleaning in the use of equipment, disinfection and decontamination.\n\n. Evidence that the trust incorporates patient feedback and involves patients and carers in its cleanliness monitoring programmes, with evidence that this impacts on standards.\n\n# Practical examples\n\nMechanism is in place to ensure rapid response cleaning is initiated within appropriate timeframe.\n\nClearly defined policy for cleaning and environmental decontamination (including roles, responsibilities and accountability).\n\nTrust collects visual and/or objective environmental monitoring data for different clinical areas. Visual and scientific methods are used for both routine and outbreak environmental assessment and the findings are used to inform improvements to the cleanliness programme.\n\n# Health and Social Care Act code of practice\n\nCriterion 1: Guidance for compliance 1.1\n\nCriterion 2: Guidance for compliance 2.1, 2.3, 2.4, 2.5, 2.6\n\n## Relevant national indicators\n\nNone identified.", 'Quality improvement statement 6: Multi-agency working to reduce HCAIs': "# Statement\n\nTrusts work proactively in multi-agency collaborations with other local health and social care providers to reduce risk from infection.\n\n# What does this mean for people visiting, or receiving treatment in, hospitals?\n\nPeople visiting, or receiving treatment in, hospitals can expect the trust to be working collaboratively with other local health and social care providers to prevent and reduce harm from infection.\n\n# What does it mean for trust boards?\n\nBoards are actively involved in local networks. They share governance structures, objectives and learning with other local health and social care providers to promote good practice among them.\n\n# Evidence of achievement\n\n. Evidence that a board member has been nominated as the trust's lead and representative for a multi-agency collaboration to prevent and manage HCAIs.\n\n. Evidence of support for, and participation in, joint working initiatives beyond mandatory or contractual requirements, to reduce HCAIs locally.\n\n. Evidence of an agreed policy for data sharing on HCAIs between local organisations.\n\n. Evidence of timely sharing of information risk assessments and strategic efforts to minimise harm from infection with other agencies.\n\n. Evidence of a defined, shared and agreed governance structure with other local health and social care providers that includes clear lines of accountability.\n\n. Evidence of support for, and participation in, the development and implementation of a joint local strategy, policy and pathway on HCAIs between local health and social care providers.\n\n. Evidence of participation in the development of shared targets and joint working with other local health and social care providers to improve outcomes locally relating to HCAIs.\n\n. Evidence that the trust works collaboratively with the local health protection unit and other health partners to investigate and manage HCAI outbreaks and incidents. Evidence is particularly needed of collaboration to deal with incidents which may impact on the health of the wider community.\n\n# Practical examples\n\nDocumented terms of reference for multi-agency collaboration to reduce HCAIs.\n\nAudit of outputs from collaboration disseminated to relevant trust committees (for example, clinical governance and policy development groups).\n\nAudits of outputs from relevant learning methodologies are shared with other local health and social care providers.\n\n# Health and Social Care Act code of practice\n\nNo relevant criteria identified.\n\n# Relevant national indicators\n\nNone identified.", 'Quality improvement statement 7: Communication': "# Statement\n\nTrusts ensure there is clear communication with all staff, patients and carers throughout the care pathway about HCAIs, infection risks and how to prevent HCAIs, to reduce harm from infection.\n\n# What does this mean for people visiting, or receiving treatment in, hospitals?\n\nPeople visiting, or receiving treatment in, hospitals can expect to be provided with information on how to reduce the risks of an HCAI and to be given the opportunity to discuss HCAIs with staff.\n\nPatients who have an HCAI can expect to be:\n\nnotified of their infection\n\ntold about the impact it will have on their care\n\ngiven relevant information about minimising the risk to others.\n\n# What does it mean for trust boards?\n\nBoards ensure processes are in place to communicate relevant information about minimising the risk of (and from) HCAIs to patients, carers, visitors and staff. They also ensure staff have access to relevant patient information resources and up-to-date local surveillance information so they can communicate about HCAIs effectively.\n\n# Evidence of achievement\n\n. Evidence of mechanisms to ensure transparent communication of all relevant surveillance outputs to staff and patients.\n\n. Evidence that local health and social care services provide consistent patient and carer information on infection prevention and control.\n\n. Evidence that trust policies on infection prevention and control are available to, and used by, all staff.\n\n. Evidence that arrangements are in place to ensure providers in different settings can identify and communicate infection risks as the patient moves between services.\n\n. Evidence that patients, carers and visitors have access to up-to-date, accurate and easy to understand information about their own HCAI (if applicable) or HCAIs generally, in a suitable format. This includes evidence that they have access to information on the potential risk of infection and existing treatment and control measures.\n\n. Evidence that patients with an HCAI are informed of their infection and the implications for their care.\n\n. Evidence that staff are trained to (and can) communicate in an appropriate manner with patients and their carers about how to prevent, and reduce harm from, HCAIs.\n\n. Evidence of ongoing and timely dialogue with patients and carers throughout the trust's care pathway regarding the risk of HCAIs and how to prevent them.\n\n# Practical examples\n\nAudit of communications between different health and social care providers detailing any infections (for example, an audit of discharge summaries to GPs and admission letters from care homes).\n\nAudit of patient records for communication about HCAIs (for example, their MRSA status) throughout their hospital episode.\n\nAudit of patient records for communication about how to prevent HCAIs (for example, hand-hygiene procedures) throughout their hospital episode.\n\nPatient surveys on the trust's communication about HCAIs, and about their understanding of the risks.\n\nAvailability of easy to understand, standardised information on HCAIs for patients, carers and staff.\n\nAvailability of standardised trust policies on infection prevention and control.\n\nAudit central venous catheter and indwelling catheter procedures to check they follow trust policies on infection prevention and control.\n\nAudit of antimicrobial stewardship programmes to ensure good prescribing practice (for example, appropriate use of prophylactic antibiotics in surgery).\n\n# Health and Social Care Act code of practice\n\nCriterion 3: Guidance for compliance 3.1\n\nCriterion 4: Guidance for compliance 4.1, 4.2\n\n# Relevant national indicators\n\nNone identified.", 'Quality improvement statement 8: Admission, discharge and transfer': "# Statement\n\nTrusts have a multi-agency patient admission, discharge and transfer policy which gives clear, relevant guidance to local health and social care providers on the critical steps to take to minimise harm from infection.\n\n# What does this mean for patients and trust boards?\n\nPatients with an infection can expect relevant information about it to be shared between providers when they are admitted, transferred to, or discharged from a hospital to ensure seamless care.\n\nBoards lead on the development of an agreed multi-agency admission, discharge and transfer policy. They ensure mechanisms are in place to support and monitor adherence to the policy.\n\n# Evidence of achievement\n\n. Evidence of an admission, discharge and transfer policy for patients with an infection that has been agreed by all agencies involved in the patient's care pathway, including local community and public health teams.\n\n. Evidence that the agreed policy includes a risk assessment on admission, and for all transfers, to determine the presence or risk of acquiring or transmitting infection.\n\n. Evidence of a procedure for documenting and sharing information about infections and their treatment. This includes evidence of information sharing to manage and support patients with an infection on an ongoing basis (including transfer and isolation arrangements for them) during admission, transfer and discharge.\n\n. Evidence of clear advice being given to patients on antimicrobial prescribing for their ongoing care.\n\n. Evidence of clear advice being given to patients on the management of medical devices for their ongoing care.\n\n# Practical examples\n\nAudit of adherence to relevant policy on admissions/transfers/discharges of patients with an HCAI.\n\nReduction in the number of adverse events recorded as a result of discharge and transfer of a patient with an infection.\n\n# Health and Social Care Act code of practice\n\nCriterion 1: Guidance for compliance 1.1, 1.9, 1.10\n\n# Relevant national indicators\n\nNone identified.", 'Quality improvement statement 9: Patient and public involvement': "# Statement\n\nTrusts use input from local patient and public experience for continuous quality improvement to minimise harm from HCAIs.\n\n# What does this mean for patients, the public and trust boards?\n\nPatients and the public can expect the trust to provide opportunities for them to be involved with planning and decision-making on quality improvement activities to prevent and control infections.\n\nBoards ensure the trust has mechanisms in place to seek patient and public views and involve them in decisions related to quality improvement for infection prevention and control.\n\n# Evidence of achievement\n\n. Evidence that a non-executive director or equivalent (for example, a trust governor) has been assigned to lead on patient and public involvement in infection prevention and control.\n\n. Evidence of a range of mechanisms to involve patients and the public in the trust's decision-making to ensure continuous quality improvement in infection prevention and control.\n\n. Evidence that a variety of information sources and participation methods are used to gain insight into patient experiences of infection prevention and control.\n\n. Evidence that patient and public involvement groups for infection prevention and control reflect local demographics.\n\n. Evidence of mechanisms to ensure patient experiences of HCAIs are used to inform reviews or investigations (such as outbreak investigations and root-cause analysis). This includes evidence that they are used to provide patients and carers with feedback on the outcome.\n\n. Evidence that patients' and the general public's perspective and priorities on infection prevention and control are taken into account in the trust's quality improvement programme.\n\n# Practical examples\n\nPatient and public representation on relevant groups and committees.\n\nAudit of HCAI reviews and investigations that include comment from patients and the public.\n\nMeetings between trust lead and patient and public representatives to discuss infection prevention and control.\n\n# Health and Social Care Act code of practice\n\nNo relevant criteria identified.\n\n# Relevant national indicators\n\nNone identified.", 'Quality improvement statement 10: Trust estate management': "# Statement\n\nTrusts consider infection prevention and control when procuring, commissioning, planning, designing and completing new and refurbished hospital services and facilities (and during subsequent routine maintenance).\n\n# What does this mean for people visiting, or receiving treatment in, hospitals?\n\nPeople visiting, or receiving treatment in, hospitals can expect hospitals, and other parts of the trust estate, to be built and maintained in such a way as to minimise the risk of infection.\n\n# What does it mean for trust boards?\n\nBoards ensure the whole estate is managed and maintained to minimise risk from infection.\n\n# Evidence of achievement\n\n. Evidence of local arrangements for involving infection prevention and control teams in the planning, design, commissioning, completion and maintenance of services and facilities used by the trust.\n\n. Evidence of local procedures to ensure infection prevention and control is considered during the commissioning and handover of facilities.\n\n. Evidence of local procedures to ensure infection prevention and control is considered during the selection, commissioning and installation of equipment.\n\n. Evidence of local arrangements (for example, a standard operating procedure) for involving the infection prevention and control team (or other appropriate expertise) in the development of estates policy.\n\n. Evidence of a planning process that 'designs out' potential infection risks and focuses on effective infection prevention.\n\n. Evidence of local arrangements to ensure estate management is considered and integrated into routine practice to reduce infection risk.\n\n. Evidence that estates and clinical staff, including temporary staff and subcontractors, receive annual training in infection prevention and control. This should include an assessment of their relevant competencies.\n\n. Evidence of mechanisms for consideration of current national estates policy and whether or not it should be incorporated into local practice.\n\n# Practical examples\n\nRecord of adherence to the trust estates policy, including the infection prevention and control (IPC) team's involvement. This should include sign-off of documents at relevant stages of the building and maintenance process.\n\nBriefs and specifications outline the need to consider infection prevention and control when procuring, commissioning, planning, designing and completing new and refurbished services and facilities.\n\nRecord of completed and due maintenance tasks, including an assessment of whether the infection prevention and control objectives have been achieved.\n\nRecord of estates risk assessments that have considered infection prevention and control in areas of high HCAI risk (for example, in patient care areas and for facilities such as water-storage tanks).\n\nIPC team-approved written protocols for routine, planned preventive maintenance (PPM), remedial and interventional maintenance activity.\n\nRecord of planned preventive, remedial and interventional maintenance works that adheres to IPC team-approved protocols.\n\nImpact of planned preventive, remedial and interventional maintenance works in minimising the risk of infection to patients is regularly reviewed and considered.\n\nAn appropriately competent person regularly reviews, verifies, confirms and signs off work delivered in accordance with infection-control protocols.\n\nIPC staff (or another recognised source of appropriate expertise) have allocated time and availability to review and advise on IPC issues during the initiation, planning, procurement, design and construction stages of projects.\n\n# Health and Social Care Act code of practice\n\nCriterion 2: Guidance for compliance 2.1, 2.3\n\n# Relevant national indicators\n\nNone identified.", 'Quality improvement statement 11: New technology and innovation': '# Statement\n\nTrusts regularly review evidence-based assessments of new technology and other innovations to minimise harm from HCAIs and antimicrobial resistance (AMR).\n\n# What does this mean for people visiting, or receiving treatment in, hospitals?\n\nPeople visiting, or receiving treatment in, hospitals can expect the trust to assess relevant new technologies and innovation to help improve the quality of care and practice to prevent, and reduce the harm from, infection.\n\n# What does it mean for trust boards?\n\nBoards routinely identify technology needs relevant to HCAI prevention and control and assess the potential of new technologies and innovation to meet those needs. Where new technologies and methods are identified, they are evaluated and implemented, as appropriate.\n\n# Evidence of achievement\n\n. Evidence that a mechanism is in place to undertake a regular gap analysis of technology needs relevant to infection prevention and control.\n\n. Evidence that information on relevant new technologies and innovation is disseminated to directorates, along with guidance on evaluation and implementation.\n\n. Evidence of a mechanism to assess the evidence base underpinning technology and innovation in reducing HCAIs. This includes evidence that, where relevant, new technology, innovation and practice is incorporated into policies and procedures.\n\n. Evidence of local arrangements to help individuals or clinical teams conduct relevant research (for example, translational research) to prevent or reduce the harm from HCAIs. This could include evidence that arrangements have been made with academic centres, or that trust-based preventive interventions have been assessed internally.\n\n# Practical examples\n\nProgramme in place to consider current research activity and developments in HCAI innovation and technology.\n\nMechanism is in place to support people who wish to conduct research into quality improvement methodology, behavioural sciences or other areas to improve the way HCAIs are prevented or controlled.\n\nRegular gap analyses carried out in relation to infection prevention and control.\n\nRelevant gaps in technology identified and communicated to appropriate research and funding bodies.\n\n# Health and Social Care Act code of practice\n\nNo relevant criteria identified.\n\n# Relevant national data indicators\n\nNone identified.', 'Glossary': '# Accountability framework\n\nThe policies, procedures and lines of accountability for specific areas within an organisation.\n\n# Adverse event\n\nAn unplanned or unanticipated event involving actual (or potential) risk or harm to patients. In the context of this guide, this would be an infection occurring as a result of medical or surgical intervention or contact with a healthcare setting.\n\n# Continuous quality improvement (CQI)\n\nImproving the provision of services and practice by using a range of audit and statistical tools to assess the current situation, identify areas for improvement and measure the results.\n\n# Hand hygiene\n\nThe use of soap or solution (non-antimicrobial or antimicrobial) and water, or a waterless antimicrobial agent, to remove transient or residual organisms from the hands.\n\n# Key performance indicators (KPIs)\n\nMeasures that provide an indication of performance in key areas.\n\n# Learning methodologies\n\nTechniques and approaches that provide an opportunity to evaluate current practice, identify areas for improvement and disseminate the findings.\n\n# Link practitioners\n\nLocal leaders and role models – either within a trust, or working in settings that link to that trust – promote the principles of safe, clean care or good prescribing practices during the day-to-day operation of their service. Link practitioners may have a clinical or lay background. An example of the former could be a nurse or pharmacist. An example of the latter could be a patient liaison officer.\n\n# Medical device\n\nA product used to diagnose, treat or prevent disease or injury.\n\n# Planned preventive maintenance\n\nThe scheduling of planned maintenance to prevent damage, breakdown and functional failures.\n\n# Surveillance\n\nActive monitoring of infection at patient, ward, trust or national level. This involves counting cases over time and recognising and controlling outbreaks and adverse trends. It also involves producing complete epidemiological records of infection outbreaks and adverse incidents which describe and summarise all cases.\n\n# Trust estates\n\nAll the buildings and grounds that fall under the management and control of the trust.', 'Supporting documents': 'See supporting evidence for a full list of supporting documents for this guidance.'}
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https://www.nice.org.uk/guidance/ph36
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This quality improvement guide was produced by NICE, in partnership with Public Health England (PHE). Its aim is twofold: to reduce the risk of harm from healthcare-associated infections for patients, staff and visitors; and to reduce the costs associated with preventable infection.
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a01a4b951b56726fcad86ca63b9793aa0dd840fd
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nice
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Mifamurtide for the treatment of osteosarcoma
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Mifamurtide for the treatment of osteosarcoma
Evidence-based recommendations on mifamurtide (Mepact) for treating osteosarcoma in people aged 2 to 30 years.
# Guidance
Mifamurtide in combination with postoperative multi-agent chemotherapy is recommended within its licensed indication as an option for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection in children, adolescents and young adults and when mifamurtide is made available at a reduced cost to the NHS under the patient access scheme.# The technology
Mifamurtide (Mepact, Takeda) is an immune macrophage stimulant. It has a marketing authorisation for use in 'children, adolescents and young adults for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection'. The marketing authorisation further states that mifamurtide is used in combination with postoperative multi-agent chemotherapy, and that safety and efficacy have been assessed in studies of patients 2 to 30 years of age at initial diagnosis. It is not recommended for use in children below the age of 2 years.
The summary of product characteristics lists the following adverse events that may be associated with mifamurtide treatment: respiratory distress, neutropenia, pronounced inflammatory response, cardiovascular disorders, allergic reactions and gastrointestinal toxicity. The results of a clinical study also suggested that mifamurtide significantly increased the incidence of objective and subjective hearing loss. For full details of side effects and contraindications, see the summary of product characteristics.
Mifamurtide is available as a powder for suspension for intravenous infusion, with each vial containing 4 mg of mifamurtide. The recommended dose of mifamurtide for all patients is 2 mg/m2 body surface area. Mifamurtide should be administered as adjuvant therapy after macroscopically complete resection: twice weekly at least 3 days apart for 12 weeks, followed by once-weekly treatments for an additional 24 weeks for a total of 48 doses in 36 weeks. For full details of dosage and administration, see the summary of product characteristics.
The acquisition cost of mifamurtide is £2375 for a 4 mg vial (excluding VAT, 'British national formulary' edition 61). The manufacturer's submission states that the cost of a full treatment course of 48 doses of mifamurtide is £114,000.
The manufacturer of mifamurtide has agreed a revised patient access scheme with the Department of Health (which replaces an earlier patient access scheme, referred to as the 'original' patient access scheme in this document), in which mifamurtide for the treatment of osteosarcoma will be available at a reduced cost to the NHS. The nature of this cost reduction is confidential. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of mifamurtide and a review of this submission by the Evidence Review Group (ERG; appendix B).
In the submission, the manufacturer compared mifamurtide as an add-on treatment to postoperative multi-agent adjuvant chemotherapy (three- or four-agent adjuvant chemotherapy using high-dose methotrexate, doxorubicin and cisplatin with or without ifosfamide) with postoperative multi-agent adjuvant chemotherapy (three- or four-agent) alone in patients with high-grade, resectable, non-metastatic osteosarcoma.
The evidence for the efficacy of mifamurtide in the manufacturer's submission was obtained from one multicentre, open-label randomised controlled trial, the Intergroup study 0133 (INT-0133). Most of the patients who participated in INT-0133 (n = 678) were recruited in the USA. They received 10 weeks of neoadjuvant induction therapy with either chemotherapy regimen A (methotrexate, doxorubicin and cisplatin) or chemotherapy regimen B (methotrexate, doxorubicin, cisplatin and ifosfamide) before surgical resection of their tumour. Surgical resection was performed during weeks 10–11, when patients were not receiving chemotherapy. Adjuvant therapy was scheduled to begin at week 12 when patients received one of four regimens: regimen A, regimen A+ (regimen A with the addition of mifamurtide), regimen B, or regimen B+ (regimen B with the addition of mifamurtide). Using a two by two factorial design, the study compared mifamurtide plus multi-agent chemotherapy (regimens A+ and B+) with multi-agent chemotherapy alone (regimens A and B). Similarly the study assessed the efficacy of ifosfamide (regimens B and B+ compared with A and A+). The primary endpoint was overall survival. However, the study was powered for the first planned analysis of the intermediate endpoint, which was disease-free survival (that is, time to progression or death).
The patients in the study were under 30 years of age with a new diagnosis of malignant high-grade osteosarcoma. Exclusion criteria included metastatic disease or unresectable primary disease, low-grade osteosarcoma, parosteal or periosteal sarcoma, radiation-induced sarcoma or osteosarcoma arising in premalignant bony lesions, or previous chemotherapy or radiation therapy.
The manufacturer presented analyses based on three datasets. The clinical study report presented data collected up to June 2003 (2003 dataset), and August 2006 (2006 dataset); an addendum provided the updated findings based on data to March 2007 (2007 dataset). Intention-to-treat (ITT) analyses were carried out on all three datasets. Both the manufacturer and the ERG considered the 2007 dataset to be the most up-to-date and comprehensive. Therefore, only the 2007 dataset is referred to in this document. The overall survival data in INT-0133 showed that after a median follow-up of 7.9 years, adding mifamurtide to chemotherapy (regimens A+ and B+ combined) statistically significantly improved overall survival compared with chemotherapy alone (regimens A and B combined) with an overall survival of 71% in the control arm (chemotherapy alone) and 78% in the mifamurtide arm (chemotherapy plus mifamurtide). For the ITT population, the hazard ratio for death was 0.72 (95% confidence interval 0.53 to 0.97). However, adding mifamurtide to chemotherapy (regimens A+ and B+ combined) did not statistically significantly increase disease-free survival compared with chemotherapy alone (regimens A and B combined). For the ITT population, the hazard ratio for disease-free survival was 0.78 (95% CI 0.61 to 1.01).
The manufacturer presented a number of post hoc subgroup analyses for the dataset combining regimens A and B. These analyses showed consistent increases in overall survival with mifamurtide plus chemotherapy compared with chemotherapy alone across a broad range of demographic factors (age, gender, ethnicity, study site and geographic location) and prognostic factors (tumour size, lactate dehydrogenase level, alkaline phosphatase level, cooperative study group and background chemotherapy).
The ERG requested additional post hoc analyses for both overall and disease-free survival comparing individual mifamurtide-containing regimens (regimen A+ or B+) with individual regimens not containing mifamurtide (regimen A or B). The analyses that compared mifamurtide plus three-agent chemotherapy (regimen A+) with the chemotherapy regimen most commonly used in UK clinical practice (regimen A) gave non-significant increases in overall survival (hazard ratio for death 0.75; 95% CI 0.49 to 1.16) and disease-free survival (hazard ratio for progression 0.96; 95% CI 0.67 to 1.38) for regimen A+. For regimen B+ compared with four-agent chemotherapy regimen B (both including ifosfamide), there was no significant improvement in overall survival (hazard ratio 0.68; 95% CI 0.44 to 1.05) but a significant improvement in disease-free survival for regimen B+ (hazard ratio 0.63; 95% CI 0.44 to 0.91).
In INT-0133, only severe adverse events (grade 3 or 4) were recorded. With the exception of hearing loss, the number of adverse events was similar in patients receiving mifamurtide plus multi-agent chemotherapy (regimens A+ and B+ combined) compared with multi-agent chemotherapy alone (regimens A and B combined). Adding mifamurtide to multi-agent chemotherapy significantly increased the incidence of objective hearing loss (11.5% with mifamurtide versus 7.1% without; p = 0.047) and subjective hearing loss (3.6% with mifamurtide versus 0.6% without; p = 0.007). The post hoc subgroup analyses by treatment regimen suggested that the increased incidence of hearing problems occurred only in those treated with three-agent chemotherapy plus mifamurtide (regimen A+).
Additional data from phase I and II studies of over 700 patients suggested that the most common adverse events in patients and healthy volunteers treated with mifamurtide alone were fever, chills, fatigue, headache, nausea/vomiting, myalgia and tachycardia, hypotension, hypertension and dyspnoea. Chills and fever were reported as mild to moderate.
In INT-0133, the rates of discontinuation were higher in both mifamurtide groups (22% for regimen A+ and 30% for regimen B+) than in the groups not receiving mifamurtide (13% for regimen A and 17% for regimen B). The manufacturer stated that most of the withdrawals were not caused by adverse events that required clinically significant intervention. The manufacturer also stated that the adverse events were not life threatening, and did not require mifamurtide to be stopped. The manufacturer assumed that many patients, or their parents, decided to withdraw from mifamurtide treatment because it was an investigational drug of unproven benefit and was uncomfortable or inconvenient (no further details were provided by the manufacturer) when added to existing multi-agent chemotherapy.
The manufacturer presented an economic model of the cost effectiveness of adding mifamurtide to three- and four-agent chemotherapy regimens combining cisplatin, doxorubicin and methotrexate with or without ifosfamide. The economic model had six health states. These were: disease free (start state), disease progression (optional start state), recurrence, disease free post recurrence, disease progression post recurrence, and death. The model had a cycle length of 6 months and a time horizon of 60 years. The manufacturer assumed that patients in the disease-free health state at 12.25 years had a mortality rate equivalent to the general population. Patients in the disease-free post recurrence state were assumed to have a mortality rate dependent on the time to recurrence, which was derived from a study by Ferrari et al. (2003). For patients who had recurrence within 2 years, the 6-monthly mortality rate was 14.87% and for those who had recurrence after 2 years, the 6-monthly mortality rate was 4.98%.
The transition probabilities used in the deterministic base case were derived from INT-0133 for 604 patients who entered the adjuvant phase, while the post-recurrence estimates were mostly derived from the literature, except when death was recorded as an event post recurrence.
The number of mifamurtide doses to be administered to each patient was assumed to be 38.4, which was the average number of mifamurtide doses administered in INT-0133. The utility values used in the economic model were taken from a study using the EQ-5D in 22 patients from INT-0133 (for the recurrence health state), and a review by the manufacturer of utility values used in other NICE technology appraisals (for all other health states), including treatments of colon, colorectal, renal cell, and prostate cancer, myeloid leukaemia and glioma. The utility values used in the model were: 0.39 for disease progression, 0.85 for patients who remained disease free, 0.61 for recurrence, 0.85 for patients who were disease free post recurrence, 0.39 for disease progression post recurrence, and 0.00 for death. The manufacturer's submission only included adverse events considered clinically relevant (such as those associated with infusion) in the base-case analyses. From INT-0133, hearing loss was identified as the main adverse event for mifamurtide. A decrease in utility value associated with this adverse event was not included in the model because it was considered to be an anomaly of the data; hearing loss is associated with cisplatin and the number of additional cases seen in one of the mifamurtide arms was within the reported range for cisplatin-related hearing loss. An 18% decrease in utility value for hearing loss was explored in sensitivity analyses, based on data derived from one study found in the manufacturer's Medline search on hearing loss in people with cancer.
The economic model included the following costs: adjuvant chemotherapy (cisplatin, doxorubicin, ifosfamide and methotrexate) with or without mifamurtide, treating adverse events during the maintenance phase, routine monitoring, diagnostic tests, surgery, and second-line chemotherapy for disease progression (ifosfamide and etoposide). Costs and resource utilisation information were taken from NHS reference costs 2007/08. Information on healthcare resource use was not collected in the study and the costs of these resources were therefore estimated from information provided by clinical specialists.
The ERG questioned whether using all the INT-0133 data from the three- and four-agent chemotherapy regimens (that is regimens A+ and B+ combined and regimens A and B combined) was appropriate. The ERG noted that the absence of an interaction between ifosfamide and mifamurtide was crucial to the validity of the manufacturer's statistical approach. However the ERG highlighted a potential interaction between ifosfamide and mifamurtide in the INT-0133 results. The ERG noted that there were potentially significant differences in clinical effectiveness among the four groups, as demonstrated by the analyses that compared individual mifamurtide regimens (A+ or B+) with regimens without mifamurtide (A or B). This led to a high degree of variability in the cost-effectiveness results for the groups with and without mifamurtide. The ERG stated that if it was accepted that there was no such interaction, then the results could indeed be considered to represent two separate trials, of mifamurtide and of ifosfamide for osteosarcoma, which would indicate a high degree of uncertainty in the true cost effectiveness of mifamurtide.
The ERG considered that the model lacked face validity because the modelled survival rates at 6 years (83% with mifamurtide and 77% without mifamurtide) were higher than those seen in the clinical trial (78% with mifamurtide and 70% without mifamurtide). It was unclear what was driving this difference in estimated survival. If, for example, it was simply the length of the time cycle in the Markov model, then a more appropriate time cycle should have been chosen in the model. The ERG stated that although this lack of face validity increases the uncertainty in the results of the economic analysis, it is unclear what effect this would have on the incremental cost-effectiveness ratio (ICER) if the mortality rates seen in INT-0133 were accurately replicated in the model.
The results of the economic analysis included in the manufacturer's original submission, which incorporated the original patient access scheme, have been replaced by updated analyses. These updated analyses incorporated a revised patient access scheme (designated as commercial-in-confidence by the manufacturer) and were submitted by the manufacturer in response to the draft final appraisal determination released in August 2010. Sections 3.17−3.23 below give details of the original economic analyses and the related ERG critique. Sections 3.24−3.26 describe the updated analyses, including the revised patient access scheme, the related ERG critique and the impact of altering the yearly discount rate for outcomes while fixing the discount rate for cost at 3.5%.
The manufacturer presented the following total costs per treated patient and total quality-adjusted life years (QALYs) per patient for the base case (excluding any patient access scheme):
Regimen A and B combined: total costs £31,481; total QALYs 15.38.
Regimen A+ and B+ combined: total costs £123,852; total QALYs 16.72.
Regimen A: total costs £29,709; total QALYs 16.10.
Regimen A+: total costs £122,604; total QALYs 16.69.
Regimen B: total costs £33,244; total QALYs 14.66.
Regimen B+: total costs £125,121; total QALYs 16.71.
The manufacturer conducted a series of one-way sensitivity analyses. The results showed that the model was very sensitive to the discount rate for outcomes. The model has a time horizon of 60 years, over which the benefits associated with treatment are accumulated and discounted. The larger the discount rate used for outcomes, the smaller the difference in QALYs gained between treatment with mifamurtide and treatment without mifamurtide. It should be noted that all treatment acquisition costs for mifamurtide are incurred in the first year of the model, and are therefore not affected by discounting. The sensitivity analysis also showed that the model was sensitive to the health-related utility value used for the disease-free health state.
The manufacturer's economic submission also presented a scenario analysis evaluating the effect of the following model assumptions on its base case, including the original patient access scheme and using the combined dataset:
Including amputation and limb salvage costs increased the ICER from £56,683 to £59,231 per QALY gained.
Including adverse events related to hearing loss increased the ICER from £56,683 to £71,065 per QALY gained.
Setting the post-recurrence mortality rate for patients who remain disease free after 5 years to the general population mortality rate increased the ICER from £56,683 to £61,580 per QALY gained.
Applying age-adjusted utility rates increased the ICER from £56,683 to £62,112 per QALY gained.
The manufacturer also carried out a scenario analysis that assessed applying all the assumptions described in section 3.19 simultaneously. This increased the base-case ICER from £56,683 to £91,442 per QALY gained. The manufacturer also carried out probabilistic sensitivity analyses, with analyses assuming a payment threshold of £50,000. The results showed that approximately 30% of the iterations were below this level.
The ERG noted that the base-case assumptions used by the manufacturer were favourable to mifamurtide and had concerns about the selection of the parameters entered in the model (for example, whether the most appropriate comparator was used, whether the effects of hearing loss should be included, whether a general population mortality rate should be used if there is no recurrence in 5 years, whether amputation or limb salvage costs should be used and whether age-related utility values should be used). The ERG stated that, as a result, the ICER for regimen A+ and B+ combined compared with regimen A and B combined was likely to be substantially higher than the £56,683 per QALY gained reported in the manufacturer's base-case analysis.
The ERG was concerned that the statistically significant difference between hearing loss rates reported in INT-0133 was omitted from the base-case economic analysis. The rates were included only in the scenario analyses; 15% for objective or subjective hearing loss for the mifamurtide regimens compared with 8% for the regimens without mifamurtide.
The ERG carried out a number of exploratory sensitivity analyses that included:
comparing regimen A+ with regimen A rather than using all the INT-0133 data from the three- and four-agent chemotherapy regimens (that is, regimens A+ and B+ combined and regimens A and B combined)
applying age-adjusted utility values
setting post-recurrence mortality rates to those of the age-matched general population if patients were disease free for 5 years
including amputation and limb salvage costs.
All increased the cost per QALY gained compared with the manufacturer's base case. The ERG's base-case analysis produced a deterministic ICER of £109,296 (probabilistic ICER of £103,494) per QALY gained. These analyses have been replaced by those described below.
After submission of a revised patient access scheme (see section 2.5), the manufacturer provided further updated analyses based on the Committee's preferred assumptions in the economic model (that is, applying age-adjusted utility values, setting post-recurrence mortality rates to those of the age-matched general population if patients were disease free for 5 years, including amputation and limb salvage costs, but still excluding hearing loss as an adverse event) over a 60-year time horizon. The deterministic analysis of regimens A+ and B+ combined compared with regimens A and B combined gave an ICER of £60,205 per QALY gained and the probabilistic analysis gave an ICER of £56,677 per QALY gained. The manufacturer conducted a series of one-way sensitivity analyses on its deterministic base-case results. This showed that the model was sensitive to the discount rates used for outcomes. A discount rate of 0% for outcomes (while fixing the discount rate for costs at 3.5%) reduced the ICER to £25,135 per QALY gained. A discount rate of 6% for outcomes (while fixing the discount rate for costs at 3.5%) increased the ICER to £95,097 per QALY gained.
The ERG carried out a number of exploratory sensitivity analyses on the manufacturer's updated analyses that included:
comparing regimen A+ with regimen A rather than using all the INT-0133 data from the three- and four-agent chemotherapy regimens (that is, regimens A+ and B+ combined and regimens A and B combined)
assuming that people receiving mifamurtide experienced hearing loss, as seen in the trial
assuming that a small proportion of patients enter the model in the disease progression health state
assuming that 8% of patients would require two vials of mifamurtide per dose.
All these increased the cost per QALY gained compared with the manufacturer's base case. The ERG stated that the sensitivity analyses showed that even with the revised patient access scheme, it was unlikely that the cost per QALY gained was below £60,000. The ERG reported that if clinically meaningful hearing loss can be attributed to mifamurtide, the cost per QALY gained could plausibly be much higher.
The ERG also undertook an analysis to assess the impact of altering the yearly discount rate used for outcomes (while fixing the discount rate for costs at 3.5%) on the manufacturer's and ERG's probabilistic ICERs:
A discount rate of 0% for outcomes reduced the manufacturer's probabilistic ICER to £23,831 per QALY gained and the ERG's probabilistic ICER to £36,893 per QALY gained.
A discount rate of 1.5% for outcomes reduced the manufacturer's probabilistic ICER to £36,076 per QALY gained and the ERG's probabilistic ICER to £54,334 per QALY gained.
A discount rate of 6% increased the manufacturer's probabilistic ICER to £89,810 per QALY gained and the ERG's probabilistic ICER to £141,766 per QALY gained.
Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA235# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of mifamurtide for osteosarcoma, having considered evidence on the nature of osteosarcoma and the value placed on the benefits of mifamurtide by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
# Management of high-grade resectable non-metastatic osteosarcoma in UK clinical practice
The Committee discussed the clinical needs of patients with high-grade resectable non-metastatic osteosarcoma. The patient experts stated that diagnosing and treating osteosarcoma has a significant impact on patients and their families and friends. This includes disruption of family life, strain on family relationships, additional stress at work and financial pressures, and a negative effect on the health of families, friends and carers. The Committee heard from the clinical specialists and patient experts that the main aim of treatment is to cure the patient. The patient experts and clinical specialists stated that there had been few developments that had improved treatment outcomes for osteosarcoma over the past 20 years, and that any improvement in overall survival from adding mifamurtide to standard chemotherapy was clinically significant and important. The clinical specialists stated that the only development in the past 10 years had been to add high-dose methotrexate to the treatment regimen for osteosarcoma, but that there is currently limited evidence available about whether overall survival rates in the UK have improved in the last decade. The Committee heard from the clinical specialists that current UK clinical practice is neoadjuvant multi-agent chemotherapy and surgical resection, followed by postoperative adjuvant multi-agent chemotherapy. The clinical specialists stated that the standard adjuvant multi-agent chemotherapy regimen in the UK is doxorubicin, methotrexate and cisplatin and the 5-year overall survival rate is approximately 55%. The Committee noted that this survival rate is for all patients, including some with more advanced disease for whom mifamurtide would not be indicated. The Committee heard from the clinical specialists that ifosfamide is currently being investigated in an ongoing European and US osteosarcoma study (EURAMOS 1) as part of an adjuvant regimen (with etoposide, cisplatin, doxorubicin and methotrexate). Only patients with tumours showing a poor histological response to pre-operative chemotherapy can receive ifosfamide. The clinical specialists stated that study recruitment should be complete in 2011, with results anticipated in 2015–20, and the study may establish a role for ifosfamide in UK clinical practice. They explained that meaningful research in osteosarcoma is difficult to carry out because of the small number of patients and the long follow-up required. The Committee heard that a significant number of patients in the UK are taking part in EURAMOS 1 and some may be taking ifosfamide in that context. Patients would not be eligible for mifamurtide while they are receiving the study drug regimens. It also heard that a follow-up trial to EURAMOS 1 is in development. It is expected that the EURAMOS 2 trial will commence in 2012/2013. The Committee welcomed continued research into the best regimen for this condition. The Committee concluded that the current established chemotherapy regimen in England and Wales is doxorubicin, methotrexate and cisplatin, and that the extent of ifosfamide use in UK clinical practice outside the EURAMOS 1 study had not been quantified.
The Committee noted evidence from the clinical specialists and patient experts that treatment with mifamurtide is safe and well tolerated. The Committee noted that standard neoadjuvant and adjuvant chemotherapy in the UK (regimen A) is completed in approximately 30 weeks, and that an additional 18 weeks of treatment with mifamurtide would be required to be consistent with the administration schedule in INT-0133. The Committee heard from the clinical specialists that in INT-0133 a significant proportion of patients (22–30%) did not complete treatment with mifamurtide, and, based on evidence from the ongoing EURAMOS 1 study, this may have been because patients did not want to extend treatment beyond the duration of standard multi-agent chemotherapy in a trial setting. Patient experts stated that increased overall survival is so important that patients would accept the option of prolonged treatment with mifamurtide if it was shown to improve overall survival. The Committee agreed that patients would be more willing to extend treatment in clinical practice if mifamurtide provided them with a higher chance of cure.
# Clinical effectiveness
The Committee considered the evidence on the clinical effectiveness of mifamurtide as presented in the manufacturer's submission and the ERG's critique. It considered the evidence from the only relevant randomised clinical trial (INT-0133). The Committee noted that the study was generally well conducted, but it agreed that there were substantial methodological issues identified by the ERG that led to uncertainty about the estimates of disease-free survival and overall survival. These included delayed or non-administration of mifamurtide and an imbalance in histological response to neoadjuvant therapy between treatment groups. The imbalance was particularly pronounced for patients assigned to regimen A+, who had a greater proportion of tumours showing a poor (greater than 5% remaining viable tumour) histological response, which may have disadvantaged mifamurtide. The Committee concluded that these aspects of the study made interpretation of the survival data more difficult, and that the effect of these factors on the results could not be reliably predicted.
The Committee noted that the manufacturer had presented an analysis of all the INT-0133 data from the three- and four-agent chemotherapy regimens (that is, regimens A+ and B+ combined and regimens A and B combined) for overall survival and a number of post hoc efficacy analyses. The Committee was aware that the combined analysis was the primary prespecified analysis of the trial and noted that this suggested a statistically significant improvement in overall survival, from 71% in the control arm to 78% in the mifamurtide arm over a median follow-up period of 7.9 years (hazard ratio 0.72, 95% CI 0.53 to 0.97). Although the study was powered for the intermediate endpoint of disease-free survival, it did not show a statistically significant increase in disease-free survival for regimens of chemotherapy plus mifamurtide (regimens A+ and B+ combined) compared with chemotherapy alone (regimens A and B combined) (hazard ratio 0.78, 95% CI 0.61 to 1.01). The Committee noted that a greater proportion of patients assigned to regimen A+ had tumours showing a poor (greater than 5% remaining viable tumour) histological response to neoadjuvant pre-operative therapy. It accepted the view of the clinical specialists that there was evidence of a link between poor histological response to neoadjuvant therapy and prognosis, but concluded that it was not possible to establish whether this variation in histological response before adjuvant therapy in the different treatment groups might have affected the results, or by how much. The Committee also noted the ERG's concerns that there may have been interaction between treatments (that is, there may be synergy between ifosfamide and mifamurtide), given that the test for statistical interaction for disease-free survival was very close to the prespecified threshold for interaction of 0.10 (p = 0.102). The Committee heard from the clinical specialists that factorial trials are designed on the assumption that there is no interaction between the study drugs, and that power to detect plausible interactions requires greatly increased sample sizes. The Committee accepted that the statistical test for interaction did not suggest a strong interaction between the drugs in the analysis of overall survival. It also accepted the clinical specialists' views that there was no biologically plausible reason for such an effect.
The Committee then discussed the post hoc analyses requested by the ERG that compared regimen A+ with A, and regimen B+ with B. It was aware that this was an alternative approach to the analysis and that INT-0133 was not designed for these comparisons or powered for this analysis. The Committee noted that for regimen A+ compared with A, there was a non-statistically significant improvement in overall survival (hazard ratio 0.75; 95% CI 0.49 to 1.16). For regimen B+ compared with B, there was also a non-statistically significant improvement in overall survival (hazard ratio 0.68; 95% CI 0.44 to 1.05). Both comparisons were consistent with the overall estimate but the confidence intervals were wider, possibly because of smaller patient numbers in the subgroups. The Committee understood that in trials for the treatment of rare diseases such as this, recruiting the numbers of patients needed to adequately power the trial is difficult, and even more so to allow subgroup analyses of this nature. The Committee then discussed the analyses in the context of UK clinical practice. It noted that currently ifosfamide is usually only administered in a clinical trial setting in the UK. The comparison most relevant to UK clinical practice was therefore agreed to be the mifamurtide regimen (A+) compared with the regimen reflecting current UK clinical practice (A). However, for the reasons above, the Committee accepted that the combined analysis of all the INT-0133 data was more appropriate in determining the effect of adding mifamurtide to the standard UK regimen than the post hoc analysis directly comparing regimen A+ with A.
The Committee discussed the adverse effects of mifamurtide plus multi-agent chemotherapy and noted that the combined analysis of all the INT-0133 data from the three- and four-agent chemotherapy regimens showed a statistically significant increase in subjective and objective hearing loss in patients receiving mifamurtide regimens. The Committee was aware that in the post hoc subgroup analyses an increased incidence of hearing loss occurred only in patients treated with regimen A+. It noted that there was uncertainty about which agent in the regimen could be associated with hearing loss. The Committee accepted the clinical specialists' views that cisplatin was used in all arms of the study and there is a known risk of hearing loss associated with its use (usually in the range 5–15%). Accordingly, the rate of hearing loss seen in INT-0133 was not unusual and could be an effect of cisplatin rather than mifamurtide. The Committee also accepted the clinical specialists' views that objective hearing loss after treatment may not be clinically important or necessarily require the use of hearing aids, and that this risk should be considered in the context of a possible higher cure rate for osteosarcoma.
# Cost effectiveness
The Committee considered the manufacturer's economic analyses and the respective critiques and exploratory sensitivity analyses performed by the ERG. The Committee noted that the efficacy data for the manufacturer's analyses were taken from INT-0133 for regimens A+ and B+ combined compared with regimens A and B combined, but that on the request of the ERG the manufacturer had also presented cost-effectiveness estimates for the post hoc analyses for regimen A+ compared with regimen A and regimen B+ compared with regimen B. The Committee noted that the manufacturer's most recent additional analyses incorporated a revised patient access scheme agreed by the Department of Health (see section 2.5). The Committee discussed the following assumptions in the analyses:
including amputation and limb salvage costs
including the hearing loss adverse events
setting the post-recurrence mortality rate to the general population rate after 5 years' disease-free survival
applying age-adjusted utility values.
The Committee considered including the costs associated with amputation and limb salvage. It noted from the scenario analyses carried out by the manufacturer (see section 3.19) that there was a marginal increase in the ICER when these costs were included. The Committee agreed with the ERG that it was appropriate to include amputation and limb salvage costs in the model.
The Committee noted that hearing loss adverse events were not included in the manufacturer's economic analyses. However, the Committee accepted the views of the clinical specialists that although hearing loss was the main adverse event, occurring more frequently with mifamurtide treatment in the clinical study, the rate of hearing loss seen in INT-0133 was not unusual in cisplatin-containing regimens and its exclusion from the model could be justified.
The Committee considered the mortality rates used by the manufacturer in its economic analyses. The Committee heard from the clinical specialists that 25% of patients with recurrent disease may be cured and that the prognosis after recurrence depends on time to recurrence (that is, patients with a longer time to recurrence have a better prognosis). The Committee agreed that after 5 years free of disease, it was reasonable to use the mortality rates of the general population.
The Committee considered the utility values used in the model. It noted that the manufacturer's model contained utility values from two different sources: a review of NICE technology appraisals for cancer treatments and a small study using the EQ-5D in patients from INT-0133. The Committee noted that the technology appraisals included in the review were from very different populations and did not generally use NICE's preferred method to derive the utility values. The Committee also noted that although the sample size for the study using the EQ-5D was small, it included the population of interest (that is, only patients with osteosarcoma) and used a method to derive the utility values that met NICE's reference case. The Committee was aware that a utility value of 0.85, derived from the manufacturer's review of NICE technology appraisals, had been applied to the disease-free state in the model. The Committee discussed whether this utility value should be maintained throughout the length of the model. It noted that the ICER increased when age-adjusted utility values were used. The Committee heard from the patient experts that young people with osteosarcoma are able to live full lives and they have a similar quality of life to their peers, with many adapting well to any remaining disability, and in some cases being empowered by their experience. The Committee agreed that in the general population utility declines with age, and therefore age-adjusted utility values should be used in the model.
The Committee considered the most recent additional analyses carried out by the manufacturer (see section 3.24), including the Committee's preferred assumptions (see sections 4.8–4.11), the results for regimens A+ and B+ combined compared with regimens A and B combined (that is, independent of ifosfamide) over a 60-year time horizon and the revised patient access scheme. The Committee noted that the ERG had carried out exploratory sensitivity analyses (see section 3.25) on the manufacturer's most recent additional analyses using data from regimen A+ compared with regimen A rather than all the INT-0133 data from the three- and four-agent chemotherapy regimen. The Committee agreed that it was appropriate for the discussion to focus on the manufacturer's most recent additional analyses rather than the ERG's exploratory sensitivity analyses. The most recent analyses by the manufacturer (regimens A+ and B+ combined compared with regimens A and B combined) reported 'best-case' ICERs of £60,200 per QALY gained (deterministic analysis) and £56,700 per QALY gained (probabilistic analysis).
The Committee discussed the sensitivity of the manufacturer's 'best-case' ICER to the discount rate applied (see section 3.26). The Committee noted the exploratory sensitivity analysis carried out by the manufacturer which showed that applying a discount rate of 0% on QALYs gained (but keeping the discount rate on costs at 3.5%) decreased the manufacturer's deterministic ICER from £60,200 to £25,100 per QALY gained and a discount rate of 6% increased the manufacturer's deterministic ICER to £95,100 per QALY gained. It also noted the wide range in these figures. The Committee noted the clarification to the 'Guide to the methods of technology appraisal' issued by the Board of NICE, which states that 'where the Appraisal Committee has considered it appropriate to undertake sensitivity analysis on the effects of discounting because treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30 years), the Committee should apply a rate of 1.5% for health effects and 3.5% for costs'. The Committee discussed whether these criteria were met in the case of mifamurtide. It noted that mifamurtide is a treatment with curative intent that increased the overall survival from 71% to 78% compared with chemotherapy alone in the whole trial (regimens A+ and B+ combined versus regimens A and B combined). It also noted that patients who are cured are expected to have a long and sustained benefit and regain normal life expectancy. The Committee concluded that both criteria were met and a discount rate of 1.5% should be used for health effects. This resulted in a manufacturer's best-case probabilistic ICER of £36,000 per QALY gained (see section 3.26).
The Committee noted that the ICER of £36,000 per QALY gained is higher than what is normally considered an effective use of NHS resources and that the NICE 'Guide to the methods of technology appraisal' states that a strong case should be identified for an ICER that is higher than £30,000 per QALY gained. The Committee noted that, in these circumstances, the NICE 'Guide to methods of technology appraisal' states that judgements about the acceptability of the technology, as an effective use of NHS resources, will specifically take account of any strong reasons to indicate that the assessment of the change in health-related quality of life has been inadequately captured or whether the innovative nature of the technology may not have been adequately captured in the QALY measure. The Committee discussed whether the assessment of the change in health-related quality of life had been inadequately captured in the economic analysis. It heard from patient experts that successfully treated patients could lead an active and fulfilling life and were able to contribute to society. The Committee also heard from the patient experts that supporting a young person with osteosarcoma has a profound impact on the health-related quality of life of the family and friends of the person affected, particularly when treatment is not successful. For example, parents and siblings may develop mental health problems and family relationships may be strained. The Committee concluded that these are very important issues affecting the health-related quality of life of those close to the person with osteosarcoma which should be taken into account but on this occasion had not been adequately captured in the economic analysis.
Furthermore the Committee accepted that mifamurtide plus adjuvant chemotherapy may represent a potentially valuable new therapy and that the mechanism of action was novel. It acknowledged that few advances had been made in the treatment of osteosarcoma in recent years and mifamurtide could be considered a significant innovation for a rare disease. The Committee concluded that the combined value of these factors, in addition to the potential uncaptured QALY benefits, meant that mifamurtide could be considered a cost-effective use of NHS resources.
The Committee considered whether there were issues relating to equality to be taken into account in light of its duties under the equalities legislation. The Committee discussed comments made at the scoping stage. These included the observation that osteosarcoma mainly affects children, teenagers and young adults, and that osteosarcoma is a rare disease. The Committee considered that no different recommendations were made for the patient population within the licensed indication, that is, the recommendations are not based on age and do not vary according to the age of the patient. The Committee was therefore satisfied that there were no equalities issues relating to age in this appraisal and that the recommendations were consistent with NICE's obligations under the equalities legislation and the requirement for fairness.
# Summary of the Appraisal Committee's key conclusions
TA235
Appraisal title: Mifamurtide for the treatment of osteosarcoma
Section
Key conclusion
Mifamurtide in combination with postoperative multi-agent chemotherapy is recommended within its licensed indication as an option for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection in children, adolescents and young adults and when mifamurtide is made available at a reduced cost to the NHS under the patient access scheme.
The Committee accepted that clinical data showed that adding mifamurtide to chemotherapy regimens statistically significantly improved overall survival compared with chemotherapy alone, with an overall survival of 71% in the control arm (chemotherapy alone) and 78% in the mifamurtide arm (chemotherapy plus mifamurtide). The Committee concluded that mifamurtide plus postoperative multi agent chemotherapy represented a clinically effective therapy.
The Committee accepted the most plausible probabilistic ICER of £56,700 per QALY gained, which included the revised patient access scheme. It also noted the clarification to the 'Guide to the methods of technology appraisal' issued by the Board of NICE, which states that 'where the Appraisal Committee has considered it appropriate to undertake sensitivity analysis on the effects of discounting because treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30 years), the Committee should apply a rate of 1.5% for health effects and 3.5% for costs'. This resulted in a manufacturer's best-case probabilistic ICER of £36,000 per QALY gained.
The Committee concluded that given the innovative nature of the drug for a rare disease, and that health-related quality of life may not have been adequately captured in the economic analysis, mifamurtide plus postoperative multi-agent chemotherapy could be accepted as a cost-effective use of NHS resources for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection in children, adolescents and young adults.
Current practice
Clinical need of patients, including the availability of alternative treatments
The main aim of treatment is to cure the patient.
The current standard adjuvant multi-agent chemotherapy regimen in the UK is doxorubicin, methotrexate and cisplatin and the 5-year overall survival rate is approximately 55%. The patient experts and clinical specialists stated that there had been few developments that had improved treatment outcomes for osteosarcoma over the past 20 years. The clinical specialists stated that the only development in the past 10 years had been to add high-dose methotrexate to the treatment regimen for osteosarcoma, but that there is currently limited evidence available about whether overall survival rates in the UK have improved in the last decade.
A significant number of patients in the UK are taking part in the EURAMOS 1 study. The Committee concluded that the extent of ifosfamide use in UK clinical practice outside the EURAMOS 1 study had not been quantified.
The technology
Proposed benefits of the technology.
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The patient experts and clinical specialists stated that any improvement in overall survival from adding mifamurtide to standard chemotherapy was clinically significant and important.
What is the position of the treatment in the pathway of care for the condition?
Mifamurtide is intended to be used after macroscopically complete surgical resection in combination with postoperative multi-agent chemotherapy consisting of methotrexate, doxorubicin and cisplatin.
Adverse effects
INT-0133 showed a statistically significant increase in subjective and objective hearing loss in patients receiving mifamurtide regimens. The Committee accepted the clinical specialists' views that cisplatin was used in all arms of the study and there is a known risk of hearing loss associated with its use (usually in the range 5–15%). The Committee also accepted the clinical specialists' views that objective hearing loss after treatment may not be clinically important or necessarily require the use of hearing aids, and that this risk should be considered in the context of a possible higher cure rate for osteosarcoma.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee noted that INT-0133 was generally well conducted, but it agreed that there were substantial methodological issues identified by the ERG. The Committee concluded that these aspects of the study made interpretation of the survival data more difficult, and that the effect of these factors on the results could not be reliably predicted.
The Committee understood that in trials for the treatment of rare diseases such as this, recruiting the numbers of patients needed to adequately power the trial is difficult.
Relevance to general clinical practice in the NHS
The Committee accepted that the combined analysis of all the INT-0133 data was more appropriate in determining the effect of adding mifamurtide to the standard UK regimen than the post hoc analysis directly comparing regimen A+ with A.
Uncertainties generated by the evidence
The ERG was concerned that there may have been interaction between ifosfamide and mifamurtide. The Committee accepted that the statistical test for interaction did not suggest a strong interaction between the drugs in the analysis of overall survival. It also accepted the clinical specialists' views that there was no biologically plausible reason for such an effect.
A greater proportion of patients assigned to regimen A+ had tumours showing a poor histological response to neoadjuvant pre-operative therapy. The Committee accepted the view of the clinical specialists that there was evidence of a link between poor histological response to neoadjuvant therapy and prognosis, but concluded that it was not possible to establish whether this variation in histological response before adjuvant therapy in the different treatment groups might have affected the results, or by how much.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
Apart from analyses by treatment regimen, no other subgroups were considered. There was a consistent increase in overall survival with mifamurtide plus chemotherapy compared with chemotherapy alone across a broad range of demographic and prognostic factors.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee noted that the combined analysis, which was the primary prespecified analysis of the trial, showed that adding mifamurtide to multi-agent chemotherapy increased overall survival compared with multi-agent chemotherapy alone (hazard ratio 0.72, 95% CI 0.53 to 0.97). Although the study was powered for the intermediate endpoint of disease-free survival, it did not show a statistically significant increase in disease-free survival for regimens of chemotherapy plus mifamurtide (regimens A+ and B+ combined) compared with chemotherapy alone (regimens A and B combined) (hazard ratio 0.78, 95% CI 0.61 to 1.01).
The Committee noted that a greater proportion of patients assigned to regimen A+ had tumours showing a poor (greater than 5% remaining viable tumour) histological response to neoadjuvant pre-operative therapy. It accepted the view of the clinical specialists that there was evidence of a link between poor histological response to neoadjuvant therapy and prognosis, but concluded that it was not possible to establish whether this variation in histological response before adjuvant therapy in the different treatment groups might have affected the results, or by how much.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee noted that efficacy data for the manufacturer's analyses were taken from INT-0133 for regimens A+ and B+ combined compared with regimens A and B combined, and that post hoc analyses for regimen A+ compared with regimen A and regimen B+ compared with regimen B had been requested by the ERG.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee agreed that it was appropriate to include the following assumptions in the cost-effectiveness analysis:
including amputation and limb salvage costs
using post-recurrence mortality rates of the general population after 5 years' free of disease
applying age-adjusted utility values
The Committee accepted the views of the clinical specialists that although hearing loss was the main adverse event, occurring more frequently with mifamurtide treatment in the clinical study, the rate of hearing loss seen in INT-0133 was not unusual in cisplatin-containing regimens and its exclusion from the model could be justified.
Incorporation of health-related quality of life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee noted that the manufacturer's model contained utility values from two different sources: a review of NICE technology appraisals for cancer treatments and a small study using the EQ-5D in patients from INT-0133. The latter study included the population of interest. The Committee noted that the ICER increased when age-adjusted utility values were used. It agreed that in the general population utility declines with age, and therefore age-adjusted utility values should be used in the model.
The Committee accepted that mifamurtide plus adjuvant chemotherapy may represent a potentially valuable new therapy and that the mechanism of action was novel. It acknowledged that few advances had been made in the treatment of osteosarcoma in recent years and mifamurtide could be considered a significant innovation for a rare disease.
The Committee heard from patient experts that successfully treated patients could lead an active and fulfilling life and were able to contribute to society. The Committee also heard from the patient experts that supporting a young person with osteosarcoma has a profound impact on the health-related quality of life of the family and friends of the person affected, particularly when treatment is not successful. For example, parents and siblings may develop mental health problems and family relationships may be strained. The Committee concluded that these are very important issues affecting the health-related quality of life of those close to the person with osteosarcoma which should be taken into account but on this occasion had not been adequately captured in the economic analysis.
The Committee concluded that the combined value of these factors, in addition to the potential uncaptured QALY benefits, meant that mifamurtide could be considered a cost-effective use of NHS resources.
Are there specific groups of people for whom the technology is particularly cost effective?
There were consistent increases in overall survival with mifamurtide plus chemotherapy compared with chemotherapy alone across a broad range of demographic and prognostic factors. Apart from analyses by treatment regimen, no other subgroups were considered.
What are the key drivers of cost effectiveness?
The key drivers were identified as the differences in overall survival.
Most likely cost-effectiveness estimate (given as an ICER)
The manufacturer's additional analyses were based on regimens A+ and B+ combined compared with regimens A and B combined. These analyses reported 'best-case' ICERs of £60,200 per QALY gained (deterministic analysis) and £56,700 per QALY gained (probabilistic analysis), both including the revised patient access scheme.
The Committee noted the clarification to the 'Guide to the methods of technology appraisal' issued by the Board of NICE, which states that 'where the Appraisal Committee has considered it appropriate to undertake sensitivity analysis on the effects of discounting because treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30 years), the Committee should apply a rate of 1.5% for health effects and 3.5% for costs'. The Committee discussed whether these criteria were met in the case of mifamurtide. It noted that mifamurtide is a treatment with curative intent that increased the overall survival from 71% to 78% compared with chemotherapy alone in the whole trial (regimens A+ and B+ combined versus. regimens A and B combined). It also noted that patients who are cured are expected to have a long and sustained benefit and regain normal life expectancy. The Committee concluded that both criteria were met and a discount rate of 1.5% should be used for health effects. This resulted in a manufacturer's best-case probabilistic ICER of £36,000 per QALY gained.
Additional factors taken into account
Patient access schemes (PPRS)
The Committee noted that the manufacturer's most recent additional analyses incorporated a revised patient access scheme agreed by the Department of Health.
End-of-life considerations
Not applicable because the treatment is indicated for patients with a life expectancy of more than 24 months.
Equalities considerations, social value judgements
Comments made at the scoping stage relating to equalities issues included the observation that osteosarcoma mainly affects children, teenagers and young adults, and that osteosarcoma is a rare disease. The Committee considered that no different recommendations were made for the patient population within the licensed indication, that is, the recommendations are not based on age and do not vary according to the age of the patient. The Committee was therefore satisfied that there were no equalities issues relating to age in this appraisal and that the recommendations were consistent with NICE's obligations under the equalities legislation and the requirement for fairness.
# Recommendations for further research
Further studies on the clinical effectiveness of mifamurtide when combined with the chemotherapy typical of UK clinical practice would be useful to determine the size of the effect of mifamurtide.
Further collection of quality of life data from people who are cured and who have experience of amputation and chemotherapy are also needed. Additional data on the health effects on parents, siblings and others with life-threatening illness would also be of value.# Related NICE guidance
Improving outcomes for people with sarcoma. NICE cancer service guidance (2006).# Review of guidance
The guidance on this technology will be considered for review in November 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew Dillon
Chief Executive
October 2011# Changes after publication
February 2014: implementation section updated to clarify that mifamurtide is recommended as an option for treating osteosarcoma. Additional minor maintenance update also carried out.# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Mifamurtide in combination with postoperative multi-agent chemotherapy is recommended within its licensed indication as an option for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection in children, adolescents and young adults and when mifamurtide is made available at a reduced cost to the NHS under the patient access scheme.', 'The technology ': "Mifamurtide (Mepact, Takeda) is an immune macrophage stimulant. It has a marketing authorisation for use in 'children, adolescents and young adults for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection'. The marketing authorisation further states that mifamurtide is used in combination with postoperative multi-agent chemotherapy, and that safety and efficacy have been assessed in studies of patients 2 to 30\xa0years of age at initial diagnosis. It is not recommended for use in children below the age of 2\xa0years.\n\nThe summary of product characteristics lists the following adverse events that may be associated with mifamurtide treatment: respiratory distress, neutropenia, pronounced inflammatory response, cardiovascular disorders, allergic reactions and gastrointestinal toxicity. The results of a clinical study also suggested that mifamurtide significantly increased the incidence of objective and subjective hearing loss. For full details of side effects and contraindications, see the summary of product characteristics.\n\nMifamurtide is available as a powder for suspension for intravenous infusion, with each vial containing 4\xa0mg of mifamurtide. The recommended dose of mifamurtide for all patients is 2\xa0mg/m2 body surface area. Mifamurtide should be administered as adjuvant therapy after macroscopically complete resection: twice weekly at least 3\xa0days apart for 12\xa0weeks, followed by once-weekly treatments for an additional 24\xa0weeks for a total of 48\xa0doses in 36\xa0weeks. For full details of dosage and administration, see the summary of product characteristics.\n\nThe acquisition cost of mifamurtide is £2375 for a 4\xa0mg vial (excluding VAT, 'British national formulary' [BNF] edition 61). The manufacturer's submission states that the cost of a full treatment course of 48\xa0doses of mifamurtide is £114,000.\n\nThe manufacturer of mifamurtide has agreed a revised patient access scheme with the Department of Health (which replaces an earlier patient access scheme, referred to as the 'original' patient access scheme in this document), in which mifamurtide for the treatment of osteosarcoma will be available at a reduced cost to the NHS. The nature of this cost reduction is confidential. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of mifamurtide and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nIn the submission, the manufacturer compared mifamurtide as an add-on treatment to postoperative multi-agent adjuvant chemotherapy (three- or four-agent adjuvant chemotherapy using high-dose methotrexate, doxorubicin and cisplatin with or without ifosfamide) with postoperative multi-agent adjuvant chemotherapy (three- or four-agent) alone in patients with high-grade, resectable, non-metastatic osteosarcoma.\n\nThe evidence for the efficacy of mifamurtide in the manufacturer's submission was obtained from one multicentre, open-label randomised controlled trial, the Intergroup study 0133 (INT-0133). Most of the patients who participated in INT-0133 (n\xa0=\xa0678) were recruited in the USA. They received 10\xa0weeks of neoadjuvant induction therapy with either chemotherapy regimen A (methotrexate, doxorubicin and cisplatin) or chemotherapy regimen B (methotrexate, doxorubicin, cisplatin and ifosfamide) before surgical resection of their tumour. Surgical resection was performed during weeks 10–11, when patients were not receiving chemotherapy. Adjuvant therapy was scheduled to begin at week\xa012 when patients received one of four regimens: regimen A, regimen A+ (regimen A with the addition of mifamurtide), regimen B, or regimen B+ (regimen B with the addition of mifamurtide). Using a two by two factorial design, the study compared mifamurtide plus multi-agent chemotherapy (regimens A+ and B+) with multi-agent chemotherapy alone (regimens A and B). Similarly the study assessed the efficacy of ifosfamide (regimens B and B+ compared with A and A+). The primary endpoint was overall survival. However, the study was powered for the first planned analysis of the intermediate endpoint, which was disease-free survival (that is, time to progression or death).\n\nThe patients in the study were under 30\xa0years of age with a new diagnosis of malignant high-grade osteosarcoma. Exclusion criteria included metastatic disease or unresectable primary disease, low-grade osteosarcoma, parosteal or periosteal sarcoma, radiation-induced sarcoma or osteosarcoma arising in premalignant bony lesions, or previous chemotherapy or radiation therapy.\n\nThe manufacturer presented analyses based on three datasets. The clinical study report presented data collected up to June 2003 (2003 dataset), and August 2006 (2006 dataset); an addendum provided the updated findings based on data to March 2007 (2007 dataset). Intention-to-treat (ITT) analyses were carried out on all three datasets. Both the manufacturer and the ERG considered the 2007 dataset to be the most up-to-date and comprehensive. Therefore, only the 2007 dataset is referred to in this document. The overall survival data in INT-0133 showed that after a median follow-up of 7.9\xa0years, adding mifamurtide to chemotherapy (regimens A+ and B+ combined) statistically significantly improved overall survival compared with chemotherapy alone (regimens A and B combined) with an overall survival of 71% in the control arm (chemotherapy alone) and 78% in the mifamurtide arm (chemotherapy plus mifamurtide). For the ITT population, the hazard ratio for death was 0.72 (95% confidence interval [CI] 0.53 to 0.97). However, adding mifamurtide to chemotherapy (regimens A+ and B+ combined) did not statistically significantly increase disease-free survival compared with chemotherapy alone (regimens A and B combined). For the ITT population, the hazard ratio for disease-free survival was 0.78 (95% CI 0.61 to 1.01).\n\nThe manufacturer presented a number of post hoc subgroup analyses for the dataset combining regimens A and B. These analyses showed consistent increases in overall survival with mifamurtide plus chemotherapy compared with chemotherapy alone across a broad range of demographic factors (age, gender, ethnicity, study site and geographic location) and prognostic factors (tumour size, lactate dehydrogenase level, alkaline phosphatase level, cooperative study group and background chemotherapy).\n\nThe ERG requested additional post hoc analyses for both overall and disease-free survival comparing individual mifamurtide-containing regimens (regimen A+ or B+) with individual regimens not containing mifamurtide (regimen A or B). The analyses that compared mifamurtide plus three-agent chemotherapy (regimen A+) with the chemotherapy regimen most commonly used in UK clinical practice (regimen A) gave non-significant increases in overall survival (hazard ratio for death 0.75; 95% CI 0.49 to 1.16) and disease-free survival (hazard ratio for progression 0.96; 95% CI 0.67 to 1.38) for regimen A+. For regimen B+ compared with four-agent chemotherapy regimen B (both including ifosfamide), there was no significant improvement in overall survival (hazard ratio 0.68; 95% CI 0.44 to 1.05) but a significant improvement in disease-free survival for regimen B+ (hazard ratio 0.63; 95% CI 0.44 to 0.91).\n\nIn INT-0133, only severe adverse events (grade 3 or 4) were recorded. With the exception of hearing loss, the number of adverse events was similar in patients receiving mifamurtide plus multi-agent chemotherapy (regimens A+ and B+ combined) compared with multi-agent chemotherapy alone (regimens A and B combined). Adding mifamurtide to multi-agent chemotherapy significantly increased the incidence of objective hearing loss (11.5% with mifamurtide versus 7.1% without; p\xa0=\xa00.047) and subjective hearing loss (3.6% with mifamurtide versus 0.6% without; p\xa0=\xa00.007). The post hoc subgroup analyses by treatment regimen suggested that the increased incidence of hearing problems occurred only in those treated with three-agent chemotherapy plus mifamurtide (regimen A+).\n\nAdditional data from phase I and II studies of over 700\xa0patients suggested that the most common adverse events in patients and healthy volunteers treated with mifamurtide alone were fever, chills, fatigue, headache, nausea/vomiting, myalgia and tachycardia, hypotension, hypertension and dyspnoea. Chills and fever were reported as mild to moderate.\n\nIn INT-0133, the rates of discontinuation were higher in both mifamurtide groups (22% for regimen A+ and 30% for regimen B+) than in the groups not receiving mifamurtide (13% for regimen A and 17% for regimen B). The manufacturer stated that most of the withdrawals were not caused by adverse events that required clinically significant intervention. The manufacturer also stated that the adverse events were not life threatening, and did not require mifamurtide to be stopped. The manufacturer assumed that many patients, or their parents, decided to withdraw from mifamurtide treatment because it was an investigational drug of unproven benefit and was uncomfortable or inconvenient (no further details were provided by the manufacturer) when added to existing multi-agent chemotherapy.\n\nThe manufacturer presented an economic model of the cost effectiveness of adding mifamurtide to three- and four-agent chemotherapy regimens combining cisplatin, doxorubicin and methotrexate with or without ifosfamide. The economic model had six health states. These were: disease free (start state), disease progression (optional start state), recurrence, disease free post recurrence, disease progression post recurrence, and death. The model had a cycle length of 6\xa0months and a time horizon of 60\xa0years. The manufacturer assumed that patients in the disease-free health state at 12.25\xa0years had a mortality rate equivalent to the general population. Patients in the disease-free post recurrence state were assumed to have a mortality rate dependent on the time to recurrence, which was derived from a study by Ferrari et al. (2003). For patients who had recurrence within 2\xa0years, the 6-monthly mortality rate was 14.87% and for those who had recurrence after 2\xa0years, the 6-monthly mortality rate was 4.98%.\n\nThe transition probabilities used in the deterministic base case were derived from INT-0133 for 604\xa0patients who entered the adjuvant phase, while the post-recurrence estimates were mostly derived from the literature, except when death was recorded as an event post recurrence.\n\nThe number of mifamurtide doses to be administered to each patient was assumed to be 38.4, which was the average number of mifamurtide doses administered in INT-0133. The utility values used in the economic model were taken from a study using the EQ-5D in 22\xa0patients from INT-0133 (for the recurrence health state), and a review by the manufacturer of utility values used in other NICE technology appraisals (for all other health states), including treatments of colon, colorectal, renal cell, and prostate cancer, myeloid leukaemia and glioma. The utility values used in the model were: 0.39 for disease progression, 0.85 for patients who remained disease free, 0.61 for recurrence, 0.85 for patients who were disease free post recurrence, 0.39 for disease progression post recurrence, and 0.00 for death. The manufacturer's submission only included adverse events considered clinically relevant (such as those associated with infusion) in the base-case analyses. From INT-0133, hearing loss was identified as the main adverse event for mifamurtide. A decrease in utility value associated with this adverse event was not included in the model because it was considered to be an anomaly of the data; hearing loss is associated with cisplatin and the number of additional cases seen in one of the mifamurtide arms was within the reported range for cisplatin-related hearing loss. An 18% decrease in utility value for hearing loss was explored in sensitivity analyses, based on data derived from one study found in the manufacturer's Medline search on hearing loss in people with cancer.\n\nThe economic model included the following costs: adjuvant chemotherapy (cisplatin, doxorubicin, ifosfamide and methotrexate) with or without mifamurtide, treating adverse events during the maintenance phase, routine monitoring, diagnostic tests, surgery, and second-line chemotherapy for disease progression (ifosfamide and etoposide). Costs and resource utilisation information were taken from NHS reference costs 2007/08. Information on healthcare resource use was not collected in the study and the costs of these resources were therefore estimated from information provided by clinical specialists.\n\nThe ERG questioned whether using all the INT-0133 data from the three- and four-agent chemotherapy regimens (that is regimens A+ and B+ combined and regimens A and B combined) was appropriate. The ERG noted that the absence of an interaction between ifosfamide and mifamurtide was crucial to the validity of the manufacturer's statistical approach. However the ERG highlighted a potential interaction between ifosfamide and mifamurtide in the INT-0133 results. The ERG noted that there were potentially significant differences in clinical effectiveness among the four groups, as demonstrated by the analyses that compared individual mifamurtide regimens (A+ or B+) with regimens without mifamurtide (A or B). This led to a high degree of variability in the cost-effectiveness results for the groups with and without mifamurtide. The ERG stated that if it was accepted that there was no such interaction, then the results could indeed be considered to represent two separate trials, of mifamurtide and of ifosfamide for osteosarcoma, which would indicate a high degree of uncertainty in the true cost effectiveness of mifamurtide.\n\nThe ERG considered that the model lacked face validity because the modelled survival rates at 6\xa0years (83% with mifamurtide and 77% without mifamurtide) were higher than those seen in the clinical trial (78% with mifamurtide and 70% without mifamurtide). It was unclear what was driving this difference in estimated survival. If, for example, it was simply the length of the time cycle in the Markov model, then a more appropriate time cycle should have been chosen in the model. The ERG stated that although this lack of face validity increases the uncertainty in the results of the economic analysis, it is unclear what effect this would have on the incremental cost-effectiveness ratio (ICER) if the mortality rates seen in INT-0133 were accurately replicated in the model.\n\nThe results of the economic analysis included in the manufacturer's original submission, which incorporated the original patient access scheme, have been replaced by updated analyses. These updated analyses incorporated a revised patient access scheme (designated as commercial-in-confidence by the manufacturer) and were submitted by the manufacturer in response to the draft final appraisal determination released in August 2010. Sections 3.17−3.23 below give details of the original economic analyses and the related ERG critique. Sections 3.24−3.26 describe the updated analyses, including the revised patient access scheme, the related ERG critique and the impact of altering the yearly discount rate for outcomes while fixing the discount rate for cost at 3.5%.\n\nThe manufacturer presented the following total costs per treated patient and total quality-adjusted life years (QALYs) per patient for the base case (excluding any patient access scheme):\n\nRegimen A and B combined: total costs £31,481; total QALYs 15.38.\n\nRegimen A+ and B+ combined: total costs £123,852; total QALYs 16.72.\n\nRegimen A: total costs £29,709; total QALYs 16.10.\n\nRegimen A+: total costs £122,604; total QALYs 16.69.\n\nRegimen B: total costs £33,244; total QALYs 14.66.\n\nRegimen B+: total costs £125,121; total QALYs 16.71.\n\nThe manufacturer conducted a series of one-way sensitivity analyses. The results showed that the model was very sensitive to the discount rate for outcomes. The model has a time horizon of 60\xa0years, over which the benefits associated with treatment are accumulated and discounted. The larger the discount rate used for outcomes, the smaller the difference in QALYs gained between treatment with mifamurtide and treatment without mifamurtide. It should be noted that all treatment acquisition costs for mifamurtide are incurred in the first year of the model, and are therefore not affected by discounting. The sensitivity analysis also showed that the model was sensitive to the health-related utility value used for the disease-free health state.\n\nThe manufacturer's economic submission also presented a scenario analysis evaluating the effect of the following model assumptions on its base case, including the original patient access scheme and using the combined dataset:\n\nIncluding amputation and limb salvage costs increased the ICER from £56,683 to £59,231 per QALY gained.\n\nIncluding adverse events related to hearing loss increased the ICER from £56,683 to £71,065 per QALY gained.\n\nSetting the post-recurrence mortality rate for patients who remain disease free after 5\xa0years to the general population mortality rate increased the ICER from £56,683 to £61,580 per QALY gained.\n\nApplying age-adjusted utility rates increased the ICER from £56,683 to £62,112 per QALY gained.\n\nThe manufacturer also carried out a scenario analysis that assessed applying all the assumptions described in section 3.19 simultaneously. This increased the base-case ICER from £56,683 to £91,442 per QALY gained. The manufacturer also carried out probabilistic sensitivity analyses, with analyses assuming a payment threshold of £50,000. The results showed that approximately 30% of the iterations were below this level.\n\nThe ERG noted that the base-case assumptions used by the manufacturer were favourable to mifamurtide and had concerns about the selection of the parameters entered in the model (for example, whether the most appropriate comparator was used, whether the effects of hearing loss should be included, whether a general population mortality rate should be used if there is no recurrence in 5\xa0years, whether amputation or limb salvage costs should be used and whether age-related utility values should be used). The ERG stated that, as a result, the ICER for regimen A+ and B+ combined compared with regimen A and B combined was likely to be substantially higher than the £56,683 per QALY gained reported in the manufacturer's base-case analysis.\n\nThe ERG was concerned that the statistically significant difference between hearing loss rates reported in INT-0133 was omitted from the base-case economic analysis. The rates were included only in the scenario analyses; 15% for objective or subjective hearing loss for the mifamurtide regimens compared with 8% for the regimens without mifamurtide.\n\nThe ERG carried out a number of exploratory sensitivity analyses that included:\n\ncomparing regimen A+ with regimen A rather than using all the INT-0133 data from the three- and four-agent chemotherapy regimens (that is, regimens A+ and B+ combined and regimens A and B combined)\n\napplying age-adjusted utility values\n\nsetting post-recurrence mortality rates to those of the age-matched general population if patients were disease free for 5\xa0years\n\nincluding amputation and limb salvage costs.\n\nAll increased the cost per QALY gained compared with the manufacturer's base case. The ERG's base-case analysis produced a deterministic ICER of £109,296 (probabilistic ICER of £103,494) per QALY gained. These analyses have been replaced by those described below.\n\nAfter submission of a revised patient access scheme (see section 2.5), the manufacturer provided further updated analyses based on the Committee's preferred assumptions in the economic model (that is, applying age-adjusted utility values, setting post-recurrence mortality rates to those of the age-matched general population if patients were disease free for 5\xa0years, including amputation and limb salvage costs, but still excluding hearing loss as an adverse event) over a 60-year time horizon. The deterministic analysis of regimens A+ and B+ combined compared with regimens A and B combined gave an ICER of £60,205 per QALY gained and the probabilistic analysis gave an ICER of £56,677 per QALY gained. The manufacturer conducted a series of one-way sensitivity analyses on its deterministic base-case results. This showed that the model was sensitive to the discount rates used for outcomes. A discount rate of 0% for outcomes (while fixing the discount rate for costs at 3.5%) reduced the ICER to £25,135 per QALY gained. A discount rate of 6% for outcomes (while fixing the discount rate for costs at 3.5%) increased the ICER to £95,097 per QALY gained.\n\nThe ERG carried out a number of exploratory sensitivity analyses on the manufacturer's updated analyses that included:\n\ncomparing regimen A+ with regimen A rather than using all the INT-0133 data from the three- and four-agent chemotherapy regimens (that is, regimens A+ and B+ combined and regimens A and B combined)\n\nassuming that people receiving mifamurtide experienced hearing loss, as seen in the trial\n\nassuming that a small proportion of patients enter the model in the disease progression health state\n\nassuming that 8% of patients would require two vials of mifamurtide per dose.\n\nAll these increased the cost per QALY gained compared with the manufacturer's base case. The ERG stated that the sensitivity analyses showed that even with the revised patient access scheme, it was unlikely that the cost per QALY gained was below £60,000. The ERG reported that if clinically meaningful hearing loss can be attributed to mifamurtide, the cost per QALY gained could plausibly be much higher.\n\nThe ERG also undertook an analysis to assess the impact of altering the yearly discount rate used for outcomes (while fixing the discount rate for costs at 3.5%) on the manufacturer's and ERG's probabilistic ICERs:\n\nA discount rate of 0% for outcomes reduced the manufacturer's probabilistic ICER to £23,831 per QALY gained and the ERG's probabilistic ICER to £36,893 per QALY gained.\n\nA discount rate of 1.5% for outcomes reduced the manufacturer's probabilistic ICER to £36,076 per QALY gained and the ERG's probabilistic ICER to £54,334 per QALY gained.\n\nA discount rate of 6% increased the manufacturer's probabilistic ICER to £89,810 per QALY gained and the ERG's probabilistic ICER to £141,766 per QALY gained.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA235", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of mifamurtide for osteosarcoma, having considered evidence on the nature of osteosarcoma and the value placed on the benefits of mifamurtide by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Management of high-grade resectable non-metastatic osteosarcoma in UK clinical practice\n\nThe Committee discussed the clinical needs of patients with high-grade resectable non-metastatic osteosarcoma. The patient experts stated that diagnosing and treating osteosarcoma has a significant impact on patients and their families and friends. This includes disruption of family life, strain on family relationships, additional stress at work and financial pressures, and a negative effect on the health of families, friends and carers. The Committee heard from the clinical specialists and patient experts that the main aim of treatment is to cure the patient. The patient experts and clinical specialists stated that there had been few developments that had improved treatment outcomes for osteosarcoma over the past 20\xa0years, and that any improvement in overall survival from adding mifamurtide to standard chemotherapy was clinically significant and important. The clinical specialists stated that the only development in the past 10\xa0years had been to add high-dose methotrexate to the treatment regimen for osteosarcoma, but that there is currently limited evidence available about whether overall survival rates in the UK have improved in the last decade. The Committee heard from the clinical specialists that current UK clinical practice is neoadjuvant multi-agent chemotherapy and surgical resection, followed by postoperative adjuvant multi-agent chemotherapy. The clinical specialists stated that the standard adjuvant multi-agent chemotherapy regimen in the UK is doxorubicin, methotrexate and cisplatin and the 5-year overall survival rate is approximately 55%. The Committee noted that this survival rate is for all patients, including some with more advanced disease for whom mifamurtide would not be indicated. The Committee heard from the clinical specialists that ifosfamide is currently being investigated in an ongoing European and US osteosarcoma study (EURAMOS 1) as part of an adjuvant regimen (with etoposide, cisplatin, doxorubicin and methotrexate). Only patients with tumours showing a poor histological response to pre-operative chemotherapy can receive ifosfamide. The clinical specialists stated that study recruitment should be complete in 2011, with results anticipated in 2015–20, and the study may establish a role for ifosfamide in UK clinical practice. They explained that meaningful research in osteosarcoma is difficult to carry out because of the small number of patients and the long follow-up required. The Committee heard that a significant number of patients in the UK are taking part in EURAMOS 1 and some may be taking ifosfamide in that context. Patients would not be eligible for mifamurtide while they are receiving the study drug regimens. It also heard that a follow-up trial to EURAMOS 1 is in development. It is expected that the EURAMOS 2 trial will commence in 2012/2013. The Committee welcomed continued research into the best regimen for this condition. The Committee concluded that the current established chemotherapy regimen in England and Wales is doxorubicin, methotrexate and cisplatin, and that the extent of ifosfamide use in UK clinical practice outside the EURAMOS 1 study had not been quantified.\n\nThe Committee noted evidence from the clinical specialists and patient experts that treatment with mifamurtide is safe and well tolerated. The Committee noted that standard neoadjuvant and adjuvant chemotherapy in the UK (regimen A) is completed in approximately 30\xa0weeks, and that an additional 18\xa0weeks of treatment with mifamurtide would be required to be consistent with the administration schedule in INT-0133. The Committee heard from the clinical specialists that in INT-0133 a significant proportion of patients (22–30%) did not complete treatment with mifamurtide, and, based on evidence from the ongoing EURAMOS 1 study, this may have been because patients did not want to extend treatment beyond the duration of standard multi-agent chemotherapy in a trial setting. Patient experts stated that increased overall survival is so important that patients would accept the option of prolonged treatment with mifamurtide if it was shown to improve overall survival. The Committee agreed that patients would be more willing to extend treatment in clinical practice if mifamurtide provided them with a higher chance of cure.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence on the clinical effectiveness of mifamurtide as presented in the manufacturer's submission and the ERG's critique. It considered the evidence from the only relevant randomised clinical trial (INT-0133). The Committee noted that the study was generally well conducted, but it agreed that there were substantial methodological issues identified by the ERG that led to uncertainty about the estimates of disease-free survival and overall survival. These included delayed or non-administration of mifamurtide and an imbalance in histological response to neoadjuvant therapy between treatment groups. The imbalance was particularly pronounced for patients assigned to regimen A+, who had a greater proportion of tumours showing a poor (greater than 5% remaining viable tumour) histological response, which may have disadvantaged mifamurtide. The Committee concluded that these aspects of the study made interpretation of the survival data more difficult, and that the effect of these factors on the results could not be reliably predicted.\n\nThe Committee noted that the manufacturer had presented an analysis of all the INT-0133 data from the three- and four-agent chemotherapy regimens (that is, regimens A+ and B+ combined and regimens A and B combined) for overall survival and a number of post hoc efficacy analyses. The Committee was aware that the combined analysis was the primary prespecified analysis of the trial and noted that this suggested a statistically significant improvement in overall survival, from 71% in the control arm to 78% in the mifamurtide arm over a median follow-up period of 7.9\xa0years (hazard ratio 0.72, 95% CI 0.53 to 0.97). Although the study was powered for the intermediate endpoint of disease-free survival, it did not show a statistically significant increase in disease-free survival for regimens of chemotherapy plus mifamurtide (regimens A+ and B+ combined) compared with chemotherapy alone (regimens A and B combined) (hazard ratio 0.78, 95% CI 0.61 to 1.01). The Committee noted that a greater proportion of patients assigned to regimen A+ had tumours showing a poor (greater than 5% remaining viable tumour) histological response to neoadjuvant pre-operative therapy. It accepted the view of the clinical specialists that there was evidence of a link between poor histological response to neoadjuvant therapy and prognosis, but concluded that it was not possible to establish whether this variation in histological response before adjuvant therapy in the different treatment groups might have affected the results, or by how much. The Committee also noted the ERG's concerns that there may have been interaction between treatments (that is, there may be synergy between ifosfamide and mifamurtide), given that the test for statistical interaction for disease-free survival was very close to the prespecified threshold for interaction of 0.10 (p\xa0=\xa00.102). The Committee heard from the clinical specialists that factorial trials are designed on the assumption that there is no interaction between the study drugs, and that power to detect plausible interactions requires greatly increased sample sizes. The Committee accepted that the statistical test for interaction did not suggest a strong interaction between the drugs in the analysis of overall survival. It also accepted the clinical specialists' views that there was no biologically plausible reason for such an effect.\n\nThe Committee then discussed the post hoc analyses requested by the ERG that compared regimen A+ with A, and regimen B+ with B. It was aware that this was an alternative approach to the analysis and that INT-0133 was not designed for these comparisons or powered for this analysis. The Committee noted that for regimen A+ compared with A, there was a non-statistically significant improvement in overall survival (hazard ratio 0.75; 95% CI 0.49 to 1.16). For regimen B+ compared with B, there was also a non-statistically significant improvement in overall survival (hazard ratio 0.68; 95% CI 0.44 to 1.05). Both comparisons were consistent with the overall estimate but the confidence intervals were wider, possibly because of smaller patient numbers in the subgroups. The Committee understood that in trials for the treatment of rare diseases such as this, recruiting the numbers of patients needed to adequately power the trial is difficult, and even more so to allow subgroup analyses of this nature. The Committee then discussed the analyses in the context of UK clinical practice. It noted that currently ifosfamide is usually only administered in a clinical trial setting in the UK. The comparison most relevant to UK clinical practice was therefore agreed to be the mifamurtide regimen (A+) compared with the regimen reflecting current UK clinical practice (A). However, for the reasons above, the Committee accepted that the combined analysis of all the INT-0133 data was more appropriate in determining the effect of adding mifamurtide to the standard UK regimen than the post hoc analysis directly comparing regimen A+ with A.\n\nThe Committee discussed the adverse effects of mifamurtide plus multi-agent chemotherapy and noted that the combined analysis of all the INT-0133 data from the three- and four-agent chemotherapy regimens showed a statistically significant increase in subjective and objective hearing loss in patients receiving mifamurtide regimens. The Committee was aware that in the post hoc subgroup analyses an increased incidence of hearing loss occurred only in patients treated with regimen A+. It noted that there was uncertainty about which agent in the regimen could be associated with hearing loss. The Committee accepted the clinical specialists' views that cisplatin was used in all arms of the study and there is a known risk of hearing loss associated with its use (usually in the range 5–15%). Accordingly, the rate of hearing loss seen in INT-0133 was not unusual and could be an effect of cisplatin rather than mifamurtide. The Committee also accepted the clinical specialists' views that objective hearing loss after treatment may not be clinically important or necessarily require the use of hearing aids, and that this risk should be considered in the context of a possible higher cure rate for osteosarcoma.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's economic analyses and the respective critiques and exploratory sensitivity analyses performed by the ERG. The Committee noted that the efficacy data for the manufacturer's analyses were taken from INT-0133 for regimens A+ and B+ combined compared with regimens A and B combined, but that on the request of the ERG the manufacturer had also presented cost-effectiveness estimates for the post hoc analyses for regimen A+ compared with regimen A and regimen B+ compared with regimen B. The Committee noted that the manufacturer's most recent additional analyses incorporated a revised patient access scheme agreed by the Department of Health (see section 2.5). The Committee discussed the following assumptions in the analyses:\n\nincluding amputation and limb salvage costs\n\nincluding the hearing loss adverse events\n\nsetting the post-recurrence mortality rate to the general population rate after 5\xa0years' disease-free survival\n\napplying age-adjusted utility values.\n\nThe Committee considered including the costs associated with amputation and limb salvage. It noted from the scenario analyses carried out by the manufacturer (see section 3.19) that there was a marginal increase in the ICER when these costs were included. The Committee agreed with the ERG that it was appropriate to include amputation and limb salvage costs in the model.\n\nThe Committee noted that hearing loss adverse events were not included in the manufacturer's economic analyses. However, the Committee accepted the views of the clinical specialists that although hearing loss was the main adverse event, occurring more frequently with mifamurtide treatment in the clinical study, the rate of hearing loss seen in INT-0133 was not unusual in cisplatin-containing regimens and its exclusion from the model could be justified.\n\nThe Committee considered the mortality rates used by the manufacturer in its economic analyses. The Committee heard from the clinical specialists that 25% of patients with recurrent disease may be cured and that the prognosis after recurrence depends on time to recurrence (that is, patients with a longer time to recurrence have a better prognosis). The Committee agreed that after 5\xa0years free of disease, it was reasonable to use the mortality rates of the general population.\n\nThe Committee considered the utility values used in the model. It noted that the manufacturer's model contained utility values from two different sources: a review of NICE technology appraisals for cancer treatments and a small study using the EQ-5D in patients from INT-0133. The Committee noted that the technology appraisals included in the review were from very different populations and did not generally use NICE's preferred method to derive the utility values. The Committee also noted that although the sample size for the study using the EQ-5D was small, it included the population of interest (that is, only patients with osteosarcoma) and used a method to derive the utility values that met NICE's reference case. The Committee was aware that a utility value of 0.85, derived from the manufacturer's review of NICE technology appraisals, had been applied to the disease-free state in the model. The Committee discussed whether this utility value should be maintained throughout the length of the model. It noted that the ICER increased when age-adjusted utility values were used. The Committee heard from the patient experts that young people with osteosarcoma are able to live full lives and they have a similar quality of life to their peers, with many adapting well to any remaining disability, and in some cases being empowered by their experience. The Committee agreed that in the general population utility declines with age, and therefore age-adjusted utility values should be used in the model.\n\nThe Committee considered the most recent additional analyses carried out by the manufacturer (see section 3.24), including the Committee's preferred assumptions (see sections 4.8–4.11), the results for regimens A+ and B+ combined compared with regimens A and B combined (that is, independent of ifosfamide) over a 60-year time horizon and the revised patient access scheme. The Committee noted that the ERG had carried out exploratory sensitivity analyses (see section 3.25) on the manufacturer's most recent additional analyses using data from regimen A+ compared with regimen A rather than all the INT-0133 data from the three- and four-agent chemotherapy regimen. The Committee agreed that it was appropriate for the discussion to focus on the manufacturer's most recent additional analyses rather than the ERG's exploratory sensitivity analyses. The most recent analyses by the manufacturer (regimens A+ and B+ combined compared with regimens A and B combined) reported 'best-case' ICERs of £60,200 per QALY gained (deterministic analysis) and £56,700 per QALY gained (probabilistic analysis).\n\nThe Committee discussed the sensitivity of the manufacturer's 'best-case' ICER to the discount rate applied (see section 3.26). The Committee noted the exploratory sensitivity analysis carried out by the manufacturer which showed that applying a discount rate of 0% on QALYs gained (but keeping the discount rate on costs at 3.5%) decreased the manufacturer's deterministic ICER from £60,200 to £25,100 per QALY gained and a discount rate of 6% increased the manufacturer's deterministic ICER to £95,100 per QALY gained. It also noted the wide range in these figures. The Committee noted the clarification to the 'Guide to the methods of technology appraisal' issued by the Board of NICE, which states that 'where the Appraisal Committee has considered it appropriate to undertake sensitivity analysis on the effects of discounting because treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30 years), the Committee should apply a rate of 1.5% for health effects and 3.5% for costs'. The Committee discussed whether these criteria were met in the case of mifamurtide. It noted that mifamurtide is a treatment with curative intent that increased the overall survival from 71% to 78% compared with chemotherapy alone in the whole trial (regimens A+ and B+ combined versus regimens A and B combined). It also noted that patients who are cured are expected to have a long and sustained benefit and regain normal life expectancy. The Committee concluded that both criteria were met and a discount rate of 1.5% should be used for health effects. This resulted in a manufacturer's best-case probabilistic ICER of £36,000 per QALY gained (see section 3.26).\n\nThe Committee noted that the ICER of £36,000 per QALY gained is higher than what is normally considered an effective use of NHS resources and that the NICE 'Guide to the methods of technology appraisal' states that a strong case should be identified for an ICER that is higher than £30,000 per QALY gained. The Committee noted that, in these circumstances, the NICE 'Guide to methods of technology appraisal' states that judgements about the acceptability of the technology, as an effective use of NHS resources, will specifically take account of any strong reasons to indicate that the assessment of the change in health-related quality of life has been inadequately captured or whether the innovative nature of the technology may not have been adequately captured in the QALY measure. The Committee discussed whether the assessment of the change in health-related quality of life had been inadequately captured in the economic analysis. It heard from patient experts that successfully treated patients could lead an active and fulfilling life and were able to contribute to society. The Committee also heard from the patient experts that supporting a young person with osteosarcoma has a profound impact on the health-related quality of life of the family and friends of the person affected, particularly when treatment is not successful. For example, parents and siblings may develop mental health problems and family relationships may be strained. The Committee concluded that these are very important issues affecting the health-related quality of life of those close to the person with osteosarcoma which should be taken into account but on this occasion had not been adequately captured in the economic analysis.\n\nFurthermore the Committee accepted that mifamurtide plus adjuvant chemotherapy may represent a potentially valuable new therapy and that the mechanism of action was novel. It acknowledged that few advances had been made in the treatment of osteosarcoma in recent years and mifamurtide could be considered a significant innovation for a rare disease. The Committee concluded that the combined value of these factors, in addition to the potential uncaptured QALY benefits, meant that mifamurtide could be considered a cost-effective use of NHS resources.\n\nThe Committee considered whether there were issues relating to equality to be taken into account in light of its duties under the equalities legislation. The Committee discussed comments made at the scoping stage. These included the observation that osteosarcoma mainly affects children, teenagers and young adults, and that osteosarcoma is a rare disease. The Committee considered that no different recommendations were made for the patient population within the licensed indication, that is, the recommendations are not based on age and do not vary according to the age of the patient. The Committee was therefore satisfied that there were no equalities issues relating to age in this appraisal and that the recommendations were consistent with NICE's obligations under the equalities legislation and the requirement for fairness.\n\n# Summary of the Appraisal Committee's key conclusions\n\nTA235\n\n\n\nAppraisal title: Mifamurtide for the treatment of osteosarcoma\n\nSection\n\nKey conclusion\n\nMifamurtide in combination with postoperative multi-agent chemotherapy is recommended within its licensed indication as an option for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection in children, adolescents and young adults and when mifamurtide is made available at a reduced cost to the NHS under the patient access scheme.\n\nThe Committee accepted that clinical data showed that adding mifamurtide to chemotherapy regimens statistically significantly improved overall survival compared with chemotherapy alone, with an overall survival of 71% in the control arm (chemotherapy alone) and 78% in the mifamurtide arm (chemotherapy plus mifamurtide). The Committee concluded that mifamurtide plus postoperative multi agent chemotherapy represented a clinically effective therapy.\n\nThe Committee accepted the most plausible probabilistic ICER of £56,700 per QALY gained, which included the revised patient access scheme. It also noted the clarification to the 'Guide to the methods of technology appraisal' issued by the Board of NICE, which states that 'where the Appraisal Committee has considered it appropriate to undertake sensitivity analysis on the effects of discounting because treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30 years), the Committee should apply a rate of 1.5% for health effects and 3.5% for costs'. This resulted in a manufacturer's best-case probabilistic ICER of £36,000 per QALY gained.\n\nThe Committee concluded that given the innovative nature of the drug for a rare disease, and that health-related quality of life may not have been adequately captured in the economic analysis, mifamurtide plus postoperative multi-agent chemotherapy could be accepted as a cost-effective use of NHS resources for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection in children, adolescents and young adults.\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\n\n\nThe main aim of treatment is to cure the patient.\n\n\n\nThe current standard adjuvant multi-agent chemotherapy regimen in the UK is doxorubicin, methotrexate and cisplatin and the 5-year overall survival rate is approximately 55%. The patient experts and clinical specialists stated that there had been few developments that had improved treatment outcomes for osteosarcoma over the past 20\xa0years. The clinical specialists stated that the only development in the past 10\xa0years had been to add high-dose methotrexate to the treatment regimen for osteosarcoma, but that there is currently limited evidence available about whether overall survival rates in the UK have improved in the last decade.\n\n\n\nA significant number of patients in the UK are taking part in the EURAMOS 1 study. The Committee concluded that the extent of ifosfamide use in UK clinical practice outside the EURAMOS 1 study had not been quantified.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe technology\n\nProposed benefits of the technology.\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe patient experts and clinical specialists stated that any improvement in overall survival from adding mifamurtide to standard chemotherapy was clinically significant and important.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\n\n\nMifamurtide is intended to be used after macroscopically complete surgical resection in combination with postoperative multi-agent chemotherapy consisting of methotrexate, doxorubicin and cisplatin.\n\n, 4.1\n\nAdverse effects\n\nINT-0133 showed a statistically significant increase in subjective and objective hearing loss in patients receiving mifamurtide regimens. The Committee accepted the clinical specialists' views that cisplatin was used in all arms of the study and there is a known risk of hearing loss associated with its use (usually in the range 5–15%). The Committee also accepted the clinical specialists' views that objective hearing loss after treatment may not be clinically important or necessarily require the use of hearing aids, and that this risk should be considered in the context of a possible higher cure rate for osteosarcoma.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\n\n\nThe Committee noted that INT-0133 was generally well conducted, but it agreed that there were substantial methodological issues identified by the ERG. The Committee concluded that these aspects of the study made interpretation of the survival data more difficult, and that the effect of these factors on the results could not be reliably predicted.\n\n\n\nThe Committee understood that in trials for the treatment of rare diseases such as this, recruiting the numbers of patients needed to adequately power the trial is difficult.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\n\n\nThe Committee accepted that the combined analysis of all the INT-0133 data was more appropriate in determining the effect of adding mifamurtide to the standard UK regimen than the post hoc analysis directly comparing regimen A+ with A.\n\n\n\nUncertainties generated by the evidence\n\n\n\nThe ERG was concerned that there may have been interaction between ifosfamide and mifamurtide. The Committee accepted that the statistical test for interaction did not suggest a strong interaction between the drugs in the analysis of overall survival. It also accepted the clinical specialists' views that there was no biologically plausible reason for such an effect.\n\n\n\nA greater proportion of patients assigned to regimen A+ had tumours showing a poor histological response to neoadjuvant pre-operative therapy. The Committee accepted the view of the clinical specialists that there was evidence of a link between poor histological response to neoadjuvant therapy and prognosis, but concluded that it was not possible to establish whether this variation in histological response before adjuvant therapy in the different treatment groups might have affected the results, or by how much.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nApart from analyses by treatment regimen, no other subgroups were considered. There was a consistent increase in overall survival with mifamurtide plus chemotherapy compared with chemotherapy alone across a broad range of demographic and prognostic factors.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\n\n\nThe Committee noted that the combined analysis, which was the primary prespecified analysis of the trial, showed that adding mifamurtide to multi-agent chemotherapy increased overall survival compared with multi-agent chemotherapy alone (hazard ratio 0.72, 95% CI 0.53 to 0.97). Although the study was powered for the intermediate endpoint of disease-free survival, it did not show a statistically significant increase in disease-free survival for regimens of chemotherapy plus mifamurtide (regimens A+ and B+ combined) compared with chemotherapy alone (regimens A and B combined) (hazard ratio 0.78, 95% CI 0.61 to 1.01).\n\n\n\nThe Committee noted that a greater proportion of patients assigned to regimen A+ had tumours showing a poor (greater than 5% remaining viable tumour) histological response to neoadjuvant pre-operative therapy. It accepted the view of the clinical specialists that there was evidence of a link between poor histological response to neoadjuvant therapy and prognosis, but concluded that it was not possible to establish whether this variation in histological response before adjuvant therapy in the different treatment groups might have affected the results, or by how much.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nThe Committee noted that efficacy data for the manufacturer's analyses were taken from INT-0133 for regimens A+ and B+ combined compared with regimens A and B combined, and that post hoc analyses for regimen A+ compared with regimen A and regimen B+ compared with regimen B had been requested by the ERG.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee agreed that it was appropriate to include the following assumptions in the cost-effectiveness analysis:\n\nincluding amputation and limb salvage costs\n\nusing post-recurrence mortality rates of the general population after 5\xa0years' free of disease\n\napplying age-adjusted utility values\n\n\n\nThe Committee accepted the views of the clinical specialists that although hearing loss was the main adverse event, occurring more frequently with mifamurtide treatment in the clinical study, the rate of hearing loss seen in INT-0133 was not unusual in cisplatin-containing regimens and its exclusion from the model could be justified.\n\n, 4.10,\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nIncorporation of health-related quality of life benefits and utility values\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\n\n\nThe Committee noted that the manufacturer's model contained utility values from two different sources: a review of NICE technology appraisals for cancer treatments and a small study using the EQ-5D in patients from INT-0133. The latter study included the population of interest. The Committee noted that the ICER increased when age-adjusted utility values were used. It agreed that in the general population utility declines with age, and therefore age-adjusted utility values should be used in the model.\n\n\n\nThe Committee accepted that mifamurtide plus adjuvant chemotherapy may represent a potentially valuable new therapy and that the mechanism of action was novel. It acknowledged that few advances had been made in the treatment of osteosarcoma in recent years and mifamurtide could be considered a significant innovation for a rare disease.\n\n\n\nThe Committee heard from patient experts that successfully treated patients could lead an active and fulfilling life and were able to contribute to society. The Committee also heard from the patient experts that supporting a young person with osteosarcoma has a profound impact on the health-related quality of life of the family and friends of the person affected, particularly when treatment is not successful. For example, parents and siblings may develop mental health problems and family relationships may be strained. The Committee concluded that these are very important issues affecting the health-related quality of life of those close to the person with osteosarcoma which should be taken into account but on this occasion had not been adequately captured in the economic analysis.\n\n\n\nThe Committee concluded that the combined value of these factors, in addition to the potential uncaptured QALY benefits, meant that mifamurtide could be considered a cost-effective use of NHS resources.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThere were consistent increases in overall survival with mifamurtide plus chemotherapy compared with chemotherapy alone across a broad range of demographic and prognostic factors. Apart from analyses by treatment regimen, no other subgroups were considered.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe key drivers were identified as the differences in overall survival.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nThe manufacturer's additional analyses were based on regimens A+ and B+ combined compared with regimens A and B combined. These analyses reported 'best-case' ICERs of £60,200 per QALY gained (deterministic analysis) and £56,700 per QALY gained (probabilistic analysis), both including the revised patient access scheme.\n\n\n\nThe Committee noted the clarification to the 'Guide to the methods of technology appraisal' issued by the Board of NICE, which states that 'where the Appraisal Committee has considered it appropriate to undertake sensitivity analysis on the effects of discounting because treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30 years), the Committee should apply a rate of 1.5% for health effects and 3.5% for costs'. The Committee discussed whether these criteria were met in the case of mifamurtide. It noted that mifamurtide is a treatment with curative intent that increased the overall survival from 71% to 78% compared with chemotherapy alone in the whole trial (regimens A+ and B+ combined versus. regimens A and B combined). It also noted that patients who are cured are expected to have a long and sustained benefit and regain normal life expectancy. The Committee concluded that both criteria were met and a discount rate of 1.5% should be used for health effects. This resulted in a manufacturer's best-case probabilistic ICER of £36,000 per QALY gained.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\n\n\nThe Committee noted that the manufacturer's most recent additional analyses incorporated a revised patient access scheme agreed by the Department of Health.\n\n, 4.7\n\nEnd-of-life considerations\n\n\n\nNot applicable because the treatment is indicated for patients with a life expectancy of more than 24\xa0months.\n\n–\n\nEqualities considerations, social value judgements\n\n\n\nComments made at the scoping stage relating to equalities issues included the observation that osteosarcoma mainly affects children, teenagers and young adults, and that osteosarcoma is a rare disease. The Committee considered that no different recommendations were made for the patient population within the licensed indication, that is, the recommendations are not based on age and do not vary according to the age of the patient. The Committee was therefore satisfied that there were no equalities issues relating to age in this appraisal and that the recommendations were consistent with NICE's obligations under the equalities legislation and the requirement for fairness.\n\n", 'Recommendations for further research': 'Further studies on the clinical effectiveness of mifamurtide when combined with the chemotherapy typical of UK clinical practice would be useful to determine the size of the effect of mifamurtide.\n\nFurther collection of quality of life data from people who are cured and who have experience of amputation and chemotherapy are also needed. Additional data on the health effects on parents, siblings and others with life-threatening illness would also be of value.', 'Related NICE guidance': 'Improving outcomes for people with sarcoma. NICE cancer service guidance (2006).', 'Review of guidance': 'The guidance on this technology will be considered for review in November 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew Dillon\n\nChief Executive\n\nOctober 2011', 'Changes after publication': 'February 2014: implementation section updated to clarify that mifamurtide is recommended as an option for treating osteosarcoma. Additional minor maintenance update also carried out.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta235
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Evidence-based recommendations on mifamurtide (Mepact) for treating osteosarcoma in people aged 2 to 30 years.
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e643c042dba61a59aaf3164ee8a28356b5e8bf7d
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nice
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Ticagrelor for the treatment of acute coronary syndromes
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Ticagrelor for the treatment of acute coronary syndromes
Evidence-based recommendations on ticagrelor (Brilique) for treating acute coronary syndromes in adults.
# Guidance
Ticagrelor in combination with low-dose aspirin is recommended for up to 12 months as a treatment option in adults with acute coronary syndromes (ACS) that is, people:
with ST-segment-elevation myocardial infarction (STEMI) – defined as ST elevation or new left bundle branch block on electrocardiogram – that cardiologists intend to treat with primary percutaneous coronary intervention (PCI) or
with non-ST-segment-elevation myocardial infarction (NSTEMI) or
admitted to hospital with unstable angina – defined as ST or T wave changes on electrocardiogram suggestive of ischaemia plus one of the characteristics defined in section 1.2. Before ticagrelor is continued beyond the initial treatment, the diagnosis of unstable angina should first be confirmed, ideally by a cardiologist.
For the purposes of this guidance, characteristics to be used in defining treatment with ticagrelor for unstable angina are: age 60 years or older; previous myocardial infarction or previous coronary artery bypass grafting (CABG); coronary artery disease with stenosis of 50% or more in at least two vessels; previous ischaemic stroke; previous transient ischaemic attack, carotid stenosis of at least 50%, or cerebral revascularisation; diabetes mellitus; peripheral arterial disease; or chronic renal dysfunction, defined as a creatinine clearance of less than 60 ml per minute per 1.73 m2 of body-surface area.# The technology
Ticagrelor (Brilique, AstraZeneca) is an oral antagonist at the P2Y12 adenosine diphosphate receptor, which inhibits platelet aggregation and thrombus formation in atherosclerotic disease. The summary of product characteristics (SPC) states that ticagrelor, co-administered with low-dose aspirin, is indicated for the prevention of atherothrombotic events in adult patients with ACS, defined as STEMI, NSTEMI or unstable angina. Patients with ACS who receive ticagrelor and aspirin may receive drugs only (medical management) or may also undergo revascularisation with PCI or CABG.
According to the SPC, treatment should be initiated with a loading dose of 180 mg ticagrelor (two tablets of 90 mg) and then continued at 90 mg twice a day for up to 12 months. Patients taking ticagrelor should also take low-dose aspirin daily, unless specifically contraindicated. Following an initial loading dose of aspirin, the maintenance dose is 75–150 mg per day.
Ticagrelor is contraindicated in patients with active pathological bleeding, a history of intracranial haemorrhage, or moderate-to-severe hepatic impairment. Co-administration of ticagrelor with a strong CYP3A4 inhibitor (for example, ketoconazole, clarithromycin, nefazodone, ritonavir, or atazanavir) is also contraindicated. The most commonly reported adverse reactions to treatment with ticagrelor include dyspnoea, epistaxis, gastrointestinal haemorrhage,subcutaneous or dermal bleeding, and bruising. For full details of adverse effects and contraindications, see the SPC.
The manufacturer stated in its submission that the cost of 90 mg tablets of ticagrelor is £54.60 for a pack of 56 tablets (28 days). Costs may vary in different settings because of procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of ticagrelor and a review of this submission by the Evidence Review Group (ERG; appendix B). This evidence related to the clinical and cost effectiveness of ticagrelor plus aspirin.
# Clinical effectiveness
For the comparison of ticagrelor plus aspirin with clopidogrel plus aspirin, the manufacturer identified one trial, the PLATO trial, an international, multicentre, randomised, double-blind, double-dummy, parallel group, phase III study. The trial evaluated the efficacy and safety of ticagrelor plus aspirin compared with clopidogrel plus aspirin over 12 months in people with ACS whose symptoms began up to 24 hours before their admission to hospital. In the trial, 18,624 adult patients with ACS with or without ST-segment elevation on electrocardiogram from 43 countries including 18 UK centres (n = 281) were admitted to hospital, and randomised to either ticagrelor plus aspirin (n = 9333) or clopidogrel plus aspirin (n = 9291). In the ticagrelor group, patients received a loading dose of 180 mg of ticagrelor, then 90 mg twice a day. Patients randomised to clopidogrel received loading doses of 300–600 mg of clopidogrel, then 75 mg every day thereafter. Patients did not need loading doses of clopidogrel if they had taken clopidogrel before admission or had received clopidogrel after admission but before randomisation (median approximately 5 hours). In the time between admission and randomisation, 46% of patients in both the ticagrelor and clopidogrel groups received clopidogrel. All patients also received aspirin (in addition to ticagrelor or clopidogrel) with a loading dose of 325 mg, then 75–100 mg daily. Patients already taking aspirin did not need a loading dose of aspirin.
The primary end point was time to first event (a composite of myocardial infarction, stroke or death from vascular causes). The planned duration of treatment and follow-up was 12 months. If before this time 1780 individuals had a primary end point event, then patients who had not yet been followed for 12 months would finish the study at their 6 or 9-month visit. At the end of the trial, 1878 participants had experienced events and the median duration of treatment was 9.1 months. Secondary end points included: myocardial infarction; stroke; death from vascular causes; death from any cause; a composite of myocardial infarction, stroke and death from any cause; and a composite of myocardial infarction, stroke, severe recurrent cardiac ischaemia, recurrent cardiac ischaemia, transient ischaemic attack, other arterial thrombotic events and death from vascular causes.
The results showed that the relative risk of experiencing a primary end point event was 16% lower in the ticagrelor group compared with the clopidogrel group (hazard ratio 0.84; 95% confidence interval 0.77 to 0.92; p < 0.001). Of the components of the primary end point, randomisation to ticagrelor plus aspirin reduced the incidence of myocardial infarction (HR 0.84; 95% CI 0.75 to 0.95; p = 0.005) and death from vascular causes (HR 0.79; 95% CI 0.69 to 0.91; p = 0.001), but not of stroke (HR 1.17; 95% CI 0.91 to 1.52). Randomisation to ticagrelor plus aspirin reduced the absolute risk of experiencing the primary end point from 11.7% to 9.8% at 12 months (absolute risk reduction 1.9%) compared with clopidogrel plus aspirin.
The manufacturer explored the consistency of effects and safety end points in 25 pre-specified subgroups and eight post-hoc subgroups. An analysis was conducted of the primary end point in several predefined subgroups. The manufacturer's submission stated that analyses showed statistically significant differences in treatment efficacy in three groups: geographic region; body weight above or below a gender-specific median; and use of lipid-lowering drugs at randomisation. The HRs by type of ACS at presentation – unstable angina, NSTEMI and STEMI – were 0.96 (95% CI 0.75 to 1.22), 0.83 (95% CI 0.73 to 0.94) and 0.84 (95% CI 0.72 to 0.98) respectively with a non-statistically significant test for interaction (p = 0.41). The manufacturer presented six analyses in subgroups that included patients whose condition was managed invasively, managed medically, patients with STEMI, patients with diabetes, patients with genetic polymorphisms, and patients undergoing CABG. The results of these six subgroup analyses were generally consistent with the primary analysis.
The manufacturer reported adverse events from the PLATO study, specifically bleeding, dyspnoea and ventricular pauses. There was no statistically significant difference in the primary safety end point of 'major' bleeding between the ticagrelor plus aspirin and clopidogrel plus aspirin groups (11.6% versus 11.2% respectively; p = 0.43), or in the end point of bleeding defined by the Thrombolysis in Myocardial Infarction (TIMI) scale. Both were analysed according to which treatment a patient took, rather than to which a patient had been randomised; these findings were consistent across all major subgroups. Patients randomised to ticagrelor experienced more overall major and minor bleeding (HR 1.11; 95% CI 1.03 to 1.20; p = 0.008) as well as more major bleeding not related to CABG (HR 1.19; 95% CI 1.02 to 1.38; p = 0.03). Intracranial bleeding was more common in the ticagrelor plus aspirin group than in the clopidogrel plus aspirin group, with fatal intracranial bleeding statistically significantly more common in the ticagrelor plus aspirin group (HR not reported; p = 0.02). Fatal bleeding excluding intracranial bleeding was statistically significantly more common in the clopidogrel plus aspirin group (HR not reported; p = 0.03). There was no difference between the two groups in relation to overall fatal bleeding (0.3% in each group). Patients randomised to ticagrelor experienced dyspnoea statistically significantly more often than patients taking clopidogrel (13.8% versus 7.8% respectively; p < 0.001). More patients taking ticagrelor plus aspirin discontinued treatment because of dyspnoea than patients taking clopidogrel plus aspirin (0.9% versus 0.1% respectively; p < 0.001). Holter monitoring detected more ventricular pauses of 3 seconds or longer during the first week in the ticagrelor plus aspirin group than in the clopidogrel plus aspirin group, but these occurred infrequently at 30 days of treatment and were rarely associated with symptoms. Patients treated with ticagrelor had statistically significantly greater increases from baseline in levels of serum uric acid and serum creatinine compared with those on clopidogrel (p < 0.001 for both events throughout the study).
The manufacturer identified no trials directly comparing ticagrelor plus aspirin with prasugrel plus aspirin. Instead, the manufacturer identified two trials comparing prasugrel plus aspirin with clopidogrel plus aspirin that provided data for an indirect comparison: the PLATO trial (ticagrelor plus aspirin compared with clopidogrel plus aspirin) and TRITON-TIMI 38, which compared prasugrel plus aspirin with clopidogrel plus aspirin in patients (n = 13,608) with ACS and scheduled PCI. The manufacturer took the view that the trials were not comparable and, by inference, a comparison between prasugrel and ticagrelor based on these trials was inappropriate and should be viewed with caution. The manufacturer noted that the PLATO and TRITON-TIMI 38 trials were similar in many ways, both including populations with ACS, both comparing the intervention plus aspirin to clopidogrel plus aspirin, and both sharing the same primary end point. However, there were important differences in the use of PCI and medical management, in the size and timing of the loading dose of clopidogrel, and in assessing myocardial infarction. Although the manufacturer considered the indirect comparison inappropriate, it cited a published paper based on the PLATO and TRITON-TIMI 38 trials that showed no statistically significant differences in the occurrence of myocardial infarction, stroke, death from any cause or the composite of these outcomes between the two drugs. Ticagrelor plus aspirin was associated with a statistically significantly lower risk of major bleeding and major bleeding specifically associated with bypass grafting than prasugrel plus aspirin. The risk of major bleeding not related to CABG did not differ between patients taking prasugrel and those taking ticagrelor.
The PLATO trial included a pre-specified sub-study of health economics and quality of life that evaluated the health-related quality of life for ticagrelor plus aspirin compared with clopidogrel plus aspirin. Investigators administered the EuroQual 5D (EQ-5D) questionnaire to 8840 patients at discharge from hospital for the index ACS event, again at 6 months, and at the end of treatment in all countries where a version of EQ-5D in the country's official language was available. No differences in any of the items on the EQ-5D were found between the ticagrelor plus aspirin group and the clopidogrel plus aspirin group.
# Cost effectiveness
The manufacturer did not identify any publications that evaluated the cost effectiveness of ticagrelor for the treatment of ACS. The manufacturer developed a new economic model, informed by nine existing economic evaluations. For the health economics evaluation of ticagrelor plus aspirin compared with prasugrel plus aspirin, the manufacturer presented the results of a published indirect comparison of the TRITON-TIMI 38 trial and the PLATO trial, conducted by an independent group.
The manufacturer constructed a two-part cost−utility model with a 1-year decision tree to model effectiveness based on data from the PLATO study, and a Markov model to extrapolate costs and benefits to a lifetime horizon (40 years), and to incorporate major clinical events. Patients in the model had ACS (STEMI, NSTEMI or unstable angina) and included patients whose condition was managed medically or with PCI or CABG; the model therefore reflected the marketing authorisation for ticagrelor. The model compared ticagrelor plus aspirin with clopidogrel plus aspirin.
The 1-year decision tree contained four mutually exclusive health states: non-fatal myocardial infarction, non-fatal stroke, death from any cause, and no further event. The Markov model included six states: non-fatal myocardial infarction, post-myocardial infarction, non-fatal stroke, post-stroke, death, and no further event. Non-fatal myocardial infarction and non-fatal stroke were tunnel states, which allowed for a worse prognosis the first year after a non-fatal event compared with second and subsequent years. After the first year following a non-fatal event, patients proceeded to one of four mutually exclusive health states: post-myocardial infarction, post-stroke, death or no further event. Costs and health outcomes were discounted at 3.5%. The Markov model used a half-cycle correction to adjust for simulated costs and outcomes. The model did not permit a patient to discontinue treatment for any reason other than death.
In the model, costs, life years, and quality-adjusted life years (QALYs) accrued beyond the first year of treatment with ticagrelor or clopidogrel; however, the model assumed that the beneficial effect of ticagrelor does not persist beyond 1 year. This means that the transition probabilities between states in the Markov model were the same for both treatment arms; the only difference between treatment arms was the number of patients who started the Markov model in each state, which was based on the output of the 1-year decision tree. Adverse events (notably bleeding) were not included in the structure of the model but the increased costs and decreased health-related quality of life associated with adverse events recorded in PLATO (as part of PLATO-HECON) were included in the first year (decision tree) of the model. The manufacturer assumed that adverse events including bleeding and dyspnoea have no lasting effects beyond the 12-month duration of the trial. To model the incidence of cardiovascular complications beyond 1 year (in the Markov component of the model), the manufacturer assumed a constant probability of 3.15% per year for non-fatal myocardial infarction and 1.02% per year for non-fatal stroke. The risk of death from MI after the index event (STEMI, NSTEMI or unstable angina) was assumed to be the same as that of death at least 1 year after the index ACS event.
For the 1-year decision tree, the manufacturer used a parametric time-to-event survival model with a Weibull distribution to determine the baseline risk (that is, the risk of cardiovascular events and death in the clopidogrel group). The manufacturer then applied HRs reflective of the effectiveness of ticagrelor from the PLATO study to this baseline risk to determine the risk in patients taking ticagrelor. Using data in the 1-year decision tree derived from the PLATO study, the manufacturer estimated from patients in the clopidogrel group age-adjusted event rates (myocardial infarction, stroke, death from any cause and death from vascular causes) for a UK population with ACS (mean age of PLATO patients = 62.2 years; reported age of UK patients with ACS in 2009–10 = 69.7 years). In the Markov model, the transition probabilities from the no event health state to each of the non-fatal myocardial infarction or non-fatal stroke health states were estimated from a study that the manufacturer commissioned from the Myocardial Ischaemia National Audit Project and the General Practice Research Database. The probabilities of transitioning between all other health states were based on relative risks applied to the probability of death in standard life tables.
The manufacturer used the 12-month cohort (patients who were eligible for a 12-month follow-up) in the PLATO-HECON study to calculate the utility accrued in the study and reported it as the average utility value for a patient over the 12-month period using the EQ-5D. The manufacturer performed a literature search to assess the relationship between utility values in the PLATO study and in the literature. The lower values from the literature were used in sensitivity analyses. The utility scores from both the PLATO-HECON substudy and the literature were adjusted downwards by 0.0328 to better reflect the patient population that would be treated in UK clinical practice. In addition, because utility decreases with age, the manufacturer applied a utility decrement of 0.004 in the Markov model to each cycle beyond the first year.
The costs for the generic drugs clopidogrel and aspirin were taken from the NHS Drug Tariff, November 2010. The cost of the drugs used in the economic evaluation were: aspirin 28-pack = £0.82; clopidogrel 30-pack = £3.40; and ticagrelor 28-pack = £54.60. The PLATO-HECON substudy measured resource use and determined costs for all patients participating in the PLATO study by recording admissions to hospital, interventions, investigations, blood products, re-operations due to bleeding, and use of concomitant or study drugs to estimate total healthcare costs associated with ticagrelor and clopidogrel. Resource use included costs from randomisation to the time of discharge from hospital, as well as after discharge from hospital to the end of the PLATO study. The manufacturer also included in sensitivity analyses the costs of a visit to the GP and of a blood test to check renal function, as stipulated in the SPC for ticagrelor.
In its deterministic base case (40-year time horizon), the manufacturer's model estimated that ticagrelor provides an incremental health gain of 0.108 QALYs compared with clopidogrel, at an incremental cost of £379, resulting in an incremental cost-effectiveness ratio (ICER) of £3521 per QALY gained. The manufacturer also presented results using time horizons of 1 year, 5 years, 10 years and 20 years: the ICER differed substantially from the base-case ICER only when using the 1-year time horizon, with an ICER of £33,764 per QALY gained. The manufacturer also presented base-case ICERs for the subgroups of ACS specified in the scope, which were £2551 per QALY gained for STEMI, £5217 per QALY gained for NSTEMI and £5310 per QALY gained for unstable angina.
The manufacturer carried out deterministic sensitivity analyses to the base case and showed the effects of changing 43 model parameters. Only the change to the costs of the 'no further event' health state impacted substantially on the results. When the cost of the 'no further event' health state for ticagrelor plus aspirin was set to its lowest, ticagrelor plus aspirin dominated clopidogrel plus aspirin (that is, ticagrelor plus aspirin was more effective and less expensive than clopidogrel plus aspirin), whereas when the cost of the clopidogrel plus aspirin 'no further event' health state was set to its lowest, the ICER was £21,000 per QALY gained. Changes in all other parameters did not increase the ICER beyond £7620.
The manufacturer ran scenario analyses for 0% and 6% discount rates, using published rather than PLATO-derived utility values, removing the 0.0328 downwards utility adjustment and removing the age-related decrease in utility per cycle. The results of the scenario analyses showed that the ICER for ticagrelor plus aspirin compared with clopidogrel plus aspirin ranged from £2358–£4699 per QALY gained.
The cost-effectiveness acceptability curve showed that at £5000 per QALY gained, the probability of ticagrelor plus aspirin being cost effective compared with clopidogrel plus aspirin was 76.6%. At £20,000 per QALY gained, the probability of ticagrelor plus aspirin being cost effective compared with clopidogrel plus aspirin was 99.9%.
The manufacturer's submission also provided results for ticagrelor plus aspirin compared with prasugrel plus aspirin for the subgroup receiving PCI, based on the results of a published indirect comparison of the PLATO and TRITON-TIMI 38 trials. Because of the small proportion of patients who participated in the TRITON-TIMI 38 substudy of quality of life (EQ-5D was collected in only 461 of 13,608 patients at baseline), the model incorporated utility information from the literature, rather than from the substudy. If costs from the PLATO-HECON substudy were not available, the manufacturer used NHS reference costs in the analysis for prasugrel plus aspirin. The manufacturer obtained the cost of prasugrel from MIMS, October 2010. The analysis of ticagrelor plus aspirin compared with prasugrel plus aspirin resulted in an incremental cost of £227, incremental QALYs of 0.065 and an ICER of £3482 per QALY gained, with a 40-year time horizon. The manufacturer stated that the results of the indirect comparison should be viewed with caution because of the problems associated with the indirect comparison of ticagrelor plus aspirin with prasugrel plus aspirin discussed in section 3.6.
# ERG comments
The ERG conducted a literature search and agreed that the PLATO trial was the only trial relevant to the decision problem. The ERG considered that the PLATO trial was well designed with robust processes for randomisation and blinding. It noted that compliance and deviations in protocol were similar across treatment arms. Although only 281 patients in the PLATO trial were from centres in the UK, the ERG considered that they were not dissimilar to other European participants. The ERG also noted that participants in the PLATO trial were younger than patients with ACS in England and Wales, but that the manufacturer's model accounted for this difference.
The ERG noted that for patients with STEMI not undergoing PCI, NICE recommends dual antiplatelet therapy (clopidogrel plus aspirin) for at least 4 weeks (MI: secondary prevention ). From statements in the 'clinical need and practice' and 'evidence and interpretation' sections of Drug-eluting stents for the treatment of coronary artery disease (NICE technology appraisal guidance 152), the ERG concluded that standard practice for STEMI should include dual antiplatelet therapy for 3 months for patients undergoing revascularisation with bare-metal stents and 12 months for patients undergoing revascularisation with drug-eluting stents.
The ERG considered that the PLATO trial reflects current clinical practice and that all patients received antiplatelet treatment at a clinically appropriate dose. The ERG was satisfied with the manufacturer's means of categorising adverse events from bleeding. The ERG expressed concerns about the components of the primary efficacy end point in the PLATO trial. Firstly, the primary end point was inconsistent with the concept that all components of an end point should be of similar importance to patients. For example, the average utility values from the 12-month cohort in the PLATO-HECON study used in the manufacturer's model differed by end point and were 0.246 for death from a vascular cause, 0.812 for myocardial infarction and 0.736 for stroke. Secondly, the primary end point was inconsistent with the concept that all components of an end point occur with similar frequencies. For example, in 18,624 participants there were 795 vascular deaths, 1097 myocardial infarctions and 231 strokes during the median 9.1 month follow-up in the PLATO study. Thirdly, the primary end point was inconsistent with the concept that the effect of a treatment should have an effect of similar magnitude and direction on all components of a primary end point. For example, in the PLATO study, the HR for stroke (non-significantly higher with ticagrelor) differed from those for myocardial infarction and death from vascular causes (significantly lower with ticagrelor). The ERG concluded that the results of the overall composite end point should be interpreted cautiously. The ERG also noted that the manufacturer excluded 'silent' myocardial infarctions (defined as new or presumed pathological Q waves on ECG in the absence of symptoms). The ERG considered that the secondary end points and their components reflected those used in other cardiovascular trials.
The ERG noted that the manufacturer tested whether the effectiveness and safety of ticagrelor plus aspirin compared with clopidogrel plus aspirin differed across 25 pre-specified and eight post-hoc subgroups, without adjustment for multiple comparisons. The ERG expressed concern about the large number of subgroups and potential overemphasis of any statistically significant results from these analyses, which might have occurred by chance alone. With these caveats noted, the ERG observed that the regional analysis showed that in the USA, patients randomised to ticagrelor plus aspirin did worse than those randomised to clopidogrel plus aspirin.
For patients with STEMI who receive bare-metal stents, the ERG highlighted concerns about the comparator treatment included in the economic evaluation. It interpreted NICE technology appraisal guidance 152 as stating that dual antiplatelet therapy for 3 months was standard practice for patients undergoing revascularisation with bare-metal stents, whereas for patients undergoing revascularisation with drug-eluting stents, the guidance on secondary prevention of myocardial infarction (NICE clinical guideline 48) recommends dual antiplatelet therapy for 12 months. Another concern of the ERG was that the manufacturer treated the STEMI group as a homogeneous population and estimated a single ICER. By contrast, the ERG believed that STEMI has four distinct populations differing by treatment: STEMI with medical management, STEMI revascularised with drug-eluting stent, STEMI revascularised with bare-metal stent and STEMI with other intervention (for example, CABG).
The ERG stated that as the trial was designed to test the efficacy of 12 months of treatment, all patients should have been treated for 12 months. The ERG noted that the PLATO trial design did not involve uniform duration of treatment, instead, the protocol stipulated that patients could leave the study at their 6- or 9-month visit if a predetermined number of primary end-point events had occurred by that time. Approximately 44% of patients were followed up for 12 months in the trial. This increased the uncertainty in the estimates of effectiveness at the conclusion of the trial, which in turn was the prime driver of the Markov model and, therefore, the long-term benefits for patients.
The ERG noted that the model featured two separate paths. In one path, after first presentation with ACS, patients may have a subsequent non-fatal myocardial infarction at any time during the decision-tree part of the model and remain in the non-fatal myocardial infarction health state to the end of the decision-tree part of the model, then progress to the 'post-myocardial infarction' state for all remaining cycles until death (whether from cardiovascular or non-cardiovascular causes). Similarly, patients may instead have a non-fatal stroke as their first event (after the initial presentation with ACS) during a cycle, and then progress to the post-stroke state until death. The ERG considered that this structure does not represent reality, because it does not allow patients to have more than one myocardial infarction, more than one stroke, or both myocardial infarctions and strokes in their lifetime following their initial presentation with ACS, and that this may bias future costs and benefits. The ERG also noted that the model simplified the natural history of treated cardiovascular disease by keeping constant the transition probability of previously event-free patients (since initial treatment for ACS) experiencing a non-fatal myocardial infarction or stroke throughout the long-term Markov model. The modelling ignored the increase in risk associated with other factors, notably, increasing age. The ERG considered that this omission may have led to the manufacturer's model inaccurately estimating future events, costs and progressive changes in the outcomes and quality of life of patients.
The ERG was concerned that the model applied an average utility score for the first year, whereas clinical experience showed that ACS patients experience an initial decline in utility that steadily improves. Therefore, the ERG noted that the ICER at 12 months may be an underestimate.
The ERG noted that in the manufacturer's submission the subgroups of interest in the economic evaluation did not reflect the subgroups of interest in the clinical section. The ERG could not verify the estimates of clinical effectiveness used in the manufacturer's model ascribed to ticagrelor in patients with NSTEMI or unstable angina. The ERG also noted that the manufacturer considered the subgroup with unstable angina as a homogeneous group whereas, in clinical practice in England and Wales, physicians typically categorise patients into lowest, low, intermediate, high and highest risk groups using the Global Registry of Acute Coronary Events (GRACE) classification and treat them accordingly.
The ERG noted that the manufacturer adjusted the age of the modelled patients to reflect the UK population with ACS. The ERG noted potential problems with the methods chosen by the manufacturer, which may have led to inaccuracies. The ERG established that these inaccuracies represented an 8% underestimate of benefits from ticagrelor plus aspirin compared with clopidogrel plus aspirin and suggested that the ICER presented by the manufacturer may be an overestimate.
The ERG acknowledged that use of healthcare resources was estimated in the model using data from an imbedded health economic study, which collected details of hospital care received by patients during the PLATO trial. For the purposes of the model, only data for those patients in the 12-month cohort were included. This cohort comprised of patients who, based on timing of enrolment, had the potential to receive 12 months treatment with ticagrelor. The ERG also noted that for each patient category in the model, the resources used by each patient were calculated separately for each treatment arm, and these were multiplied by a corresponding unit cost and totalled for an estimated hospital-care cost per patient for the first 12-month period. The ERG had some concerns relating to this type of resource analysis, and conducted a combined analysis of resource use (taking the ticagrelor and clopidogrel groups together), making some adjustments for double-counting of costs. Results suggested that the health state costs with ticagrelor were £100 lower (rather than £371 lower, as in the manufacturer's base-case) than the health state costs of clopidogrel, which would have the effect of doubling the estimated ICER at the 1-year time horizon.
The ERG noted that the manufacturer's base-case analysis estimated costs for the study drugs assuming 100% use in the trial period, despite evidence of deaths before the end of follow-up, treatment withdrawals, and poor adherence in some participants. The ERG instead incorporated data on drug use from the PLATO trial and noted that this reduced the average cost of both ticagrelor and clopidogrel substantially, and the difference in drug costs of ticagrelor plus aspirin compared with clopidogrel plus aspirin reduced from £651 to £507 per patient. Applying the ERG's amended age adjustment, resource use, and costs of study drugs to the manufacturer's model resulted in a 42% increase in the manufacturer's ICER for the 1-year time horizon from £36,177 to £51,204 per QALY gained. However, the ERG emphasised that both the incremental costs and additional benefits associated with ticagrelor plus aspirin compared with clopidogrel plus aspirin were very small at longer time horizons, and subject to considerable uncertainty.
The ERG conducted a wide-ranging sensitivity analysis, calculating overall deterministic cost-effectiveness estimates for all combinations of four long-term variables – survival gain at 12 months, life expectancy at 12 months, the mean long-term utility value and the mean long-term discounted cost per patient year. The most favourable ICERs for ticagrelor plus aspirin are £3407 per QALY gained for all patients, £3551 per QALY gained for the STEMI group, £3350 per QALY gained for the NSTEMI group and £3405 per QALY gained for the group with unstable angina. Incorporating the least favourable combination of assumptions resulted in an estimated ICER for ticagrelor plus aspirin below £20,000 per QALY gained for each of the specified populations compared with 12 months' clopidogrel plus aspirin treatment. The central estimates from these sensitivity analyses were £7897 per QALY gained for all patients, £8872 per QALY gained for the STEMI group, £7215 per QALY gained for the NSTEMI group and £9131 for the subgroup with unstable angina.
The ERG noted that there are no head-to-head trial data comparing ticagrelor plus aspirin with prasugrel plus aspirin. With regard to the indirect comparison of ticagrelor plus aspirin with prasugrel plus aspirin, the ERG considered that any comparison of the PLATO and TRITON-TIMI 38 trials posed problems. The ERG agreed with the manufacturer that sufficient clinical evidence is not yet available for a credible indirect comparison of ticagrelor plus aspirin compared with prasugrel plus aspirin for patients with ACS. It concluded that the effectiveness and safety of ticagrelor compared with prasugrel remains unknown.
Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA236# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ticagrelor, having considered evidence on the nature of ACS and the value placed on the benefits of ticagrelor by people with these conditions, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee discussed the clinical management of ACS. It heard from the clinical specialists that, in the UK, treatment options for people with STEMI are prasugrel plus aspirin or clopidogrel plus aspirin, along with PCI with a bare-metal or drug-eluting stent followed by dual antiplatelet treatment. The Committee heard that the duration of treatment of clopidogrel does not vary whether a stent is bare-metal or drug-eluting, because all people with ACS who undergo PCI, in the acute setting, are treated with clopidogrel plus aspirin for 12 months. The Committee heard that in UK clinical practice people with NSTEMI are offered treatments depending on their GRACE or TIMI score; medical management is an option for people at lowest risk of future adverse cardiovascular events, whereas people at higher risk would be offered PCI and subsequent dual antiplatelet therapy with clopidogrel and aspirin. The Committee heard from the clinical specialists that in the UK most people with NSTEMI undergo PCI. The Committee understood that of people in the UK with ACS, few have unstable angina and often do not need revascularisation, but do receive dual antiplatelet therapy with clopidogrel and aspirin. The clinical specialists stated that in the UK it is unusual for a patient with STEMI to undergo CABG and that approximately 10% of patients with NSTEMI undergo CABG.
# Clinical effectiveness
The Committee considered the evidence for the clinical effectiveness of ticagrelor compared with clopidogrel. The Committee noted that the manufacturer based its submission on a large trial, PLATO, which compared ticagrelor plus aspirin with clopidogrel plus aspirin. The Committee noted that ticagrelor plus aspirin reduced the relative risk of myocardial infarction, stroke and death from vascular causes by 16% compared with clopidogrel plus aspirin. The Committee also noted that if the components of the primary end point were considered individually, the reductions in myocardial infarction and death from vascular causes were statistically significant (16% and 21% respectively) for patients randomised to the ticagrelor plus aspirin group. The Committee also noted the non-statistically significant increase in the incidence of stroke, in particular haemorrhagic stroke, in patients randomised to the ticagrelor group. The Committee considered the clinical evidence for ticagrelor plus aspirin compared with clopidogrel plus aspirin in the subgroups of patients that were specified in the scope (STEMI, NSTEMI and unstable angina) and noted that the test for interaction showed no statistical difference between the groups (p = 0.41), interpreting this as no difference in the effectiveness between treatments by clinical presentation of ACS. The Committee noted that the manufacturer had performed a large substudy of quality of life based on EQ-5D scores, which indicated no difference in the quality of life between people taking ticagrelor plus aspirin and those taking clopidogrel plus aspirin.
The Committee heard from the clinical specialists that in general the trial was representative of the population in the UK, although the trial had a younger population and a higher proportion of men than the population with ACS in the UK. The Committee understood that the manufacturer had accounted for age in its analysis. The Committee noted comments from consultees and commentators questioning the generalisability of the PLATO trial to UK clinical practice because most of the patients presenting with ACS in the UK would receive medical therapy only whereas 21% of patients in the PLATO trial received medical therapy only. However, the Committee noted the clinical specialists' testimonies that most STEMI and NSTEMI patients would receive PCI. The Committee was also aware that results of the PLATO study showed no statistically significant difference in effectiveness between the patients whose condition was managed medically or otherwise. The Committee concluded that the trial was broadly reflective of clinical practice in the UK.
The Committee was aware that nearly half (46%) of all patients in the study received clopidogrel in hospital before randomisation, and that of those randomised to clopidogrel, only approximately one fifth received a loading dose in the range (600–675 mg) recommended in the UK (600 mg). The Committee also noted that not all patients in the PLATO trial received treatment for 12 months and that the median duration of treatment was 9 months. The Committee heard that the results presented included those censored before 12 months. The Committee noted that the Kaplan–Meier curves depicting the two arms of the trial separated as early as 1 month and up to 1 year and, therefore, concluded that neither the difference in loading doses of clopidogrel nor censoring was likely to have substantially biased the results.
The Committee understood that ticagrelor is administered twice a day compared with once a day with clopidogrel and heard from the patient experts that, in practice, people may be less likely to take drugs twice a day. The Committee noted that no clear differences had been established on adherence between once-a-day clopidogrel and twice-a-day ticagrelor. The Committee noted comments from consultees and commentators that, particularly with a gastrointestinal bleed, the fast offset (time taken for ticagrelor to become inactive after it is stopped) could put a patient at increased risk of myocardial infarction and stroke more quickly than had the patient been taking clopidogrel, and with insufficient time to consult a cardiologist. However, the Committee heard from the manufacturer that missing a dose of ticagrelor would not result in a lower level of platelet activation than if the patient were treated with clopidogrel without missing a dose. The Committee heard that when a CABG is planned, the marketing authorisation recommends stopping ticagrelor 7 days before the procedure, suggesting that the offset is not as fast as had been suggested in the consultation comments. The Committee also noted comments from consultees and commentators that treatment with ticagrelor should be limited to people who clinicians have counselled on the importance of adherence. The Committee heard from the clinical specialists that people taking clopidogrel or ticagrelor would usually receive information to ensure that they understand why adherence is important and why stopping treatment early might increase the risk of recurrent cardiovascular disease. Therefore, the Committee agreed that advice on adherence should not explicitly be factored into the recommendations. Lastly, the Committee noted that most patients with cardiovascular disease take drugs twice a day, including statins in the evening. The Committee concluded that in the 'real world' setting, the need to take medication twice a day rather than once a day would be unlikely to substantially reduce the effectiveness of ticagrelor plus aspirin relative to clopidogrel plus aspirin.
The Committee discussed the concerns about safety and adverse effects associated with ticagrelor. The Committee heard that dyspnoea (shortness of breath), ventricular pauses, increases in serum uric acid and increases in serum creatinine from baseline were statistically significantly more common in the ticagrelor group compared with the clopidogrel group, and noted that patients randomised to ticagrelor were more likely to discontinue the study drug because of adverse reactions. The Committee heard from the patient experts that dyspnoea frustrated patients with ACS and the clinical specialists stated that a patient randomised to ticagrelor was nine times as likely to discontinue the study because of dyspnoea as a patient randomised to clopidogrel, but that the absolute risk, at less than 1%, was small. The Committee heard from the manufacturer that the effects of dyspnoea were limited mainly to mild episodes. The Committee noted no statistically significant difference in the primary safety end point of major bleeding between ticagrelor plus aspirin and clopidogrel plus aspirin but that patients on ticagrelor plus aspirin experienced more overall major and minor bleeding as well as more major bleeding not related to CABG. The Committee considered that the mortality benefit associated with ticagrelor outweighed the risks and concluded that ticagrelor was a clinically effective treatment option for people with ACS.
The Committee discussed whether ticagrelor plus aspirin would be more or less effective in any subgroups including patients with STEMI, NSTEMI or unstable angina. The Committee noted that several additional subgroups were presented in the trial. The Committee noted that among those defined in the scope (STEMI, NSTEMI, unstable angina) there was no statistically significant evidence of heterogeneity, consistent with no difference in effectiveness of ticagrelor compared with clopidogrel by clinical presentation of ACS. The Committee appreciated that the numbers of patients by subgroup may have been too small to detect a difference in effectiveness. The Committee heard from the manufacturer that it had not corrected for multiple comparisons when analysing the many subgroups. The Committee noted the comment from a consultee saying that patients with unstable angina are unlikely to benefit from ticagrelor because subgroup analysis shows benefit only for patients whose blood tests following the index event were positive for troponin. The Committee noted, however, that neither the test for interaction by clinical presentation of ACS nor the test for interaction by whether a patient had a positive or negative test for troponin were positive (p value for interaction 0.41 and 0.29 respectively). Lastly, no evidence of statistical or biological plausibility was presented to support effect modification by presentation of ACS, and there are no trials using ticagrelor for the primary prevention of cardiovascular disease. Therefore, the Committee concluded that providing specific recommendations only for patients with STEMI and NSTEMI and excluding those with unstable angina would be speculative, would counter the statistical evidence, and would risk excluding patients who could benefit from treatment with ticagrelor.
The Committee was aware of comments from consultees and commentators that the estimate of total mortality remained 'exploratory'. This was because the analysis plan for PLATO stated that secondary end points should be tested individually in a pre-specified order, so mortality should not have been included because it followed the non-statistically significant result for stroke. The Committee was aware that the result for the association between ticagrelor and total mortality, while exploratory, had a HR of 0.78 and a 95% CI of 0.69 to 0.89, so was likely to reflect a real decrease in total mortality associated with ticagrelor plus aspirin.
The Committee noted the concerns around the indirect comparison of ticagrelor plus aspirin and prasugrel plus aspirin highlighted in the manufacturer's submission and reiterated by the ERG. The Committee concurred with this view and concluded that the relative effectiveness of ticagrelor plus aspirin and prasugrel plus aspirin was uncertain. The Committee concluded that no separate recommendations could be made for ticagrelor compared with prasugrel.
# Cost effectiveness
The Committee considered the estimates of cost effectiveness presented in the manufacturer's submission and noted that all ICERs for ticagrelor were below £5400 for the whole population in which ticagrelor is licensed and the subgroups. The Committee was aware of the concerns raised by the ERG around the structure of the model adopted in the manufacturer's submission, and agreed that the assumption that patients could not experience multiple cardiovascular events over-simplified the clinical course of patients with ACS. The Committee noted that if the model had included the possibility of more than one cardiovascular event after the index event, and had accounted for the increased risk of a cardiovascular event associated with having had prior events, then the ICERs for ticagrelor compared with clopidogrel would be lower than in the manufacturer's base case. This is because at the end of the 1-year decision tree, more patients on clopidogrel than on ticagrelor had experienced a myocardial infarction or stroke, and were therefore at higher risk of experiencing another event. The Committee was aware of the ERG's concerns over the method used to adjust for age, but agreed that this would not result in major changes to the ICERs. The Committee also noted that it would have been more appropriate to incorporate a utility value that reflected clinical practice rather than modelling the average utility score, but acknowledged that this too was unlikely to have a large impact on the ICERs. The Committee noted comments from consultees that the adverse event profile should be fully built into the structure of the economic model. The Committee was aware that the 1-year decision tree part of the economic model took account of all costs and changes in quality of life associated with the adverse events of treatment.
The Committee was aware of the ERG's concerns about the manufacturer's method of estimating resource use and costs. It was aware that these limitations could skew the differences in total costs between the two treatment arms. The Committee accepted the ERG's adjustments to the manufacturer's model and noted the resulting estimates of cost effectiveness. The Committee agreed that the central ICERs from the ERG's sensitivity analysis (£7897 per QALY gained for all ACS, £8872 per QALY gained for STEMI, £7215 per QALY gained for NSTEMI and £9131 per QALY gained for unstable angina) represented the most plausible estimates for the cost effectiveness of ticagrelor compared with clopidogrel. The Committee noted that the ICERs produced with this analysis were within the range normally considered to be a cost-effective use of NHS resources and therefore ticagrelor plus low-dose aspirin should be recommended as a treatment option for up to 12 months in adults with ACS. However the Committee agreed that the patient populations for STEMI and unstable angina needed to be further specified.
The Committee noted that the inclusion criteria in the PLATO trial for patients with STEMI, defined as ST elevation or new left bundle branch block on electrocardiogram, included the 'intention to perform primary PCI'. The Committee therefore agreed that only patients with STEMI that cardiologists intend to treat with primary PCI should be treated with ticagrelor. The Committee heard that there is a spectrum of severity with respect to unstable angina. The Committee was aware that in clinical practice in the UK a diagnosis of unstable angina could be made using less stringent criteria than those defined in the PLATO trial. The Committee agreed that only patients with unstable angina aligned with the definition in the PLATO trial should be treated with ticagrelor. The Committee noted that the definition of unstable angina in the PLATO trial was that patients were hospitalised and had to have ST-segment changes on electrocardiography indicating ischemia, and that patients had at least one of the following characteristics: age 60 years or older; previous myocardial infarction or CABG; coronary artery disease with stenosis of 50% or more in at least two vessels; previous ischaemic stroke, transient ischaemic attack, carotid stenosis of at least 50%, or cerebral revascularisation; diabetes mellitus; peripheral arterial disease; or chronic renal dysfunction, defined as a creatinine clearance of less than 60 ml per minute per 1.73 m2 of body-surface area. The Committee was aware that it may be necessary to start treatment with ticagrelor immediately when a patient presents with symptoms. However, the Committee was concerned that a wrong diagnosis of unstable angina could result in the patient unnecessarily taking ticagrelor. The Committee therefore agreed that it would be appropriate to specify that before ticagrelor is continued beyond the initial treatment, the diagnosis of unstable angina should first be confirmed, ideally by a cardiologist.
The Committee noted the comments from consultees and commentators about whether 'lowest risk' patients (that is, patients who have a 6-month mortality of 1.5% or less as defined by the GRACE scoring system) should receive ticagrelor, given that Unstable angina and NSTEMI (NICE clinical guideline 94) stipulates that these patients would not receive clopidogrel because the harms potentially outweigh the benefits. The Committee concluded that, because patients potentially suitable for treatment with ticagrelor with unstable angina must have at least one specific risk factor for myocardial infarction as well as ST-segment changes on electrocardiography, these patients would therefore not be classed as 'lowest risk'.
The Committee heard from the primary care trust expert that although treatment with ticagrelor relative to clopidogrel appeared cost effective within the range considered to represent good value for money by NICE, the high incidence of ACS in England and Wales means that ticagrelor would substantially impact budgets were it approved for use. The primary care trust expert noted that this would invariably lead to reduced spending elsewhere for health, which would include cardiology services. The Committee noted further comments received from consultees that affordability was an issue that NHS commissioners needed to consider 'very seriously'. Although the Committee agreed that that budget impact would be substantial, it was possible that any services displaced might be less cost effective than ticagrelor relative to clopidogrel. Moreover, the Committee noted that NICE's current guide to the methods of technology appraisal states that budget impact and affordability are not relevant to its decision making.
# Summary of Appraisal Committee's key conclusions
TA236 (STA)
Ticagrelor for the treatment of acute coronary syndromes
FAD section
Key conclusion
Ticagrelor in combination with low-dose aspirin is recommended for up to 12 months as a treatment option in adults with acute coronary syndromes (ACS) that is, people:
- with ST-segment-elevation myocardial infarction (STEMI) – defined as ST elevation or new left bundle branch block on electrocardiogram – that cardiologists intend to treat with primary percutaneous coronary intervention (PCI) or
- with non-ST-segment-elevation myocardial infarction (NSTEMI) or
- admitted to hospital with unstable angina – defined as ST or T wave changes on electrocardiogram suggestive of ischaemia plus one of the characteristics defined in section 1.2. Before ticagrelor is continued beyond the initial treatment, the diagnosis of unstable angina should first be confirmed, ideally by a cardiologist.
The Committee noted that the incremental cost-effectiveness ratios (ICERs) produced with this analysis were within the range normally considered to be a cost-effective use of NHS resources.
Current practice
Clinical need of patients, including the availability of alternative treatments
Treatment options for people with STEMI are prasugrel plus aspirin or clopidogrel plus aspirin, along with PCI with a bare-metal or drug-eluting stent followed by dual antiplatelet treatment.
People with NSTEMI are offered treatments depending on their Global Registry of Acute Coronary Events (GRACE) or Thrombolysis in Myocardial Infarction (TIMI) score; medical management is an option for people at lowest risk of future adverse cardiovascular events, whereas people at higher risk would be offered PCI and subsequent dual antiplatelet therapy with clopidogrel and aspirin.
People with unstable angina often do not need revascularisation, but receive dual antiplatelet therapy with clopidogrel and aspirin. The clinical specialists stated that in the UK it is unusual for a patient with STEMI to undergo coronary artery bypass grafting (CABG) and that approximately 10% of patients with NSTEMI undergo CABG.
The technology
Proposed benefits of the technology
Ticagrelor is an oral antagonist at the P2Y12 adenosine diphosphate receptor, which inhibits platelet aggregation and thrombus formation in atherosclerotic disease.
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
No specific claim of innovation was made.
What is the position of the treatment in the pathway of care for the condition?
Ticagrelor, co-administered with low-dose aspirin, is indicated for the prevention of atherothrombotic events in adult patients with ACS, defined as STEMI, NSTEMI or unstable angina. Patients with ACS who receive ticagrelor and aspirin may receive drugs only or may also undergo revascularisation with PCI or CABG.
Adverse events
The Committee heard that dyspnoea (shortness of breath), ventricular pauses, increase in serum uric acid and increase in serum creatinine from baseline were statistically significantly more common in the ticagrelor group compared with the clopidogrel group.
The Committee noted that there was no statistically significant difference in the primary safety end point of major bleeding between ticagrelor and clopidogrel but that patients on ticagrelor plus aspirin experienced more overall major and minor bleeding as well as more major bleeding not related to CABG. The Committee considered that the mortality benefit associated with ticagrelor outweighed the risks and concluded that ticagrelor was a clinically effective treatment option for people with ACS.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The manufacturer based its submission on a large trial, PLATO, which compared ticagrelor plus aspirin with clopidogrel plus aspirin. The PLATO trial was an international, multicentre, randomised, double-blind, double-dummy, parallel group, phase III study.
The manufacturer had performed a large quality of life substudy based on EQ-5D scores.
There was no direct comparison of ticagrelor and prasugrel and there were concerns around the indirect comparison of ticagrelor and prasugrel.
Relevance to general clinical practice in the NHS
The Committee heard from the clinical specialists that overall the trial was representative of the population in the UK, although it was noted that the population in the trial was younger and had a higher proportion of men than the population with ACS in the UK.
The standard loading dose of clopidogrel in the UK is 600 mg but only a fifth of patients in the PLATO trial had received this dose. However, the Committee concluded that the trial was broadly reflective of clinical practice in the UK.
Uncertainties generated by the evidence
The population in the trial was younger and had a higher proportion of men than people with ACS in the UK, but the manufacturer had taken account of this in its economic modelling. With respect to how representative managing ACS in the PLATO trial was relative to management in the UK, the Committee heard from the clinical specialists that the standard loading dose of clopidogrel in the UK was 600 mg but noted that only a fifth of patients in the trial had received this dose.
The Committee was aware that nearly half (46%) of all patients in the study received clopidogrel in hospital before randomisation. However, the Committee noted that the Kaplan–Meier curves depicting the two arms of the trial separated prior to and up to 1 year and, therefore, concluded that the difference in loading doses of clopidogrel was unlikely to have substantially biased the results.
The Committee noted the concerns of the manufacturer and ERG around the indirect comparison of ticagrelor plus aspirin and prasugrel plus aspirin. The Committee concurred with this view and concluded that the relative effectiveness of ticagrelor plus aspirin and prasugrel plus aspirin was uncertain. The Committee concluded that no separate recommendations could be made for ticagrelor compared with prasugrel.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee noted that among those subgroups defined in the scope (STEMI, NSTEMI, unstable angina) there was no statistically significant evidence of heterogeneity, consistent with no difference in effectiveness of ticagrelor compared to clopidogrel by clinical presentation of ACS. The Committee appreciated that the numbers of patients by subgroup may have been too small to detect a real difference in effectiveness. The Committee heard from the manufacturer that it had not corrected for multiple comparisons when analysing the many subgroups. The Committee noted that neither the test for interaction by clinical presentation of ACS nor the test for interaction by whether a patient had a positive or negative test for troponin were positive (p value for heterogeneity 0.41 and 0.29 respectively). Lastly, no evidence of statistical or biological plausibility was presented to support effect modification by presentation of ACS, and there are no trials using ticagrelor for the primary prevention of cardiovascular disease, that is, in people who had not experienced an acute myocardial infarction. The Committee concluded that providing specific recommendations only for patients with STEMI and NSTEMI and excluding those with unstable angina would be speculative, would counter statistical evidence, and would risk excluding patients who could benefit from treatment with ticagrelor.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee noted that ticagrelor reduced the relative risk of myocardial infarction, stroke and death from vascular causes by 16% compared with clopidogrel.
The Committee also noted that if the components of the primary end point were considered individually, ticagrelor plus aspirin statistically significantly reduced myocardial infarctions by 16% and death from vascular causes by 21% compared with clopidogrel plus aspirin. Treatment with ticagrelor plus aspirin reduced the absolute risk of experiencing the primary end point from 11.7% to 9.8% at 12 months compared with clopidogrel plus aspirin.
Evidence for cost effectiveness
Availability and nature of evidence
The manufacturer constructed a two-part cost−utility model with a 1-year decision tree to model effectiveness based on data from the PLATO study, and a Markov model to extrapolate costs and benefits to the lifetime horizon (40 years), and to incorporate major clinical events and resource use.
For the health economics evaluation of ticagrelor plus aspirin compared with prasugrel plus aspirin, the manufacturer presented the results of a published indirect comparison of the TRITON-TIMI 38 trial and the PLATO trial, conducted by an independent group.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee agreed that the assumption that patients could not have multiple cardiovascular events over-simplified the clinical course of patients with ACS. The Committee noted that if the model had included the possibility of more than one cardiovascular event and an increased risk of further events associated with a first or subsequent event, then the ICERs for ticagrelor compared with clopidogrel would have been lower than in the manufacturer's base case. This is because at the end of the 1-year decision tree, more patients on clopidogrel than on ticagrelor had experienced a myocardial infarction or stroke, and were therefore at higher risk of experiencing another event.
The Committee was aware of the ERG's concerns over the method used to adjust for age but agreed that this would not result in major changes to the ICERs.
The Committee noted comments from consultees that the adverse event profile should be fully built into the structure of the economic model. The Committee was aware that the 1-year decision tree part of the economic model took account of all costs and changes in quality of life associated with the adverse events of treatment.
The Committee was aware of the ERG's concerns about the manufacturer's method of estimating resource use and costs. It was aware that these limitations could skew the differences in total costs between the two treatment arms, and accepted the ERG's adjustments to the manufacturer's model.
Incorporation of health-related quality of life benefits and utility values
The manufacturer used the 12-month cohort in the PLATO-HECON study to calculate the utility accrued in the study and reported it as the average utility value for a patient over the 12-month period.
The Committee noted that it would have been more appropriate to incorporate a utility value reflective of clinical practice rather than modelling the average utility score but acknowledged that this was unlikely to have a large impact on the ICERs.
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
Not identified.
Are there specific groups of people for whom the technology is particularly cost effective?
See section on subgroups above.
What are the key drivers of cost effectiveness?
Only the change to the costs of the health state in which a patient does not experience an additional cardiovascular event impacted substantially on the results. When the cost of the 'no further event' health state for ticagrelor plus aspirin was set to its lowest, ticagrelor plus aspirin dominated clopidogrel plus aspirin (that is, ticagrelor plus aspirin was more effective and less expensive than clopidogrel plus aspirin), whereas when the cost of the clopidogrel plus aspirin 'no further event' health state was set to its lowest, the ICER was £21,000 per quality-adjusted life year (QALY) gained. Changes in all other parameters did not increase the ICER beyond £7620 per QALY gained.
Results using time horizons of 1 year, 5 years, 10 years and 20 years were also presented: the ICER differed substantially from the base-case ICER only when using the 1-year time horizon, with an ICER of £33,764 per QALY gained.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee accepted the ERG's adjustments to the manufacturer's model and agreed that the central ICERs from the ERG's sensitivity analysis (£7897 per QALY gained for all ACS, £8872 per QALY gained for STEMI, £7215 per QALY gained for NSTEMI and £9131 per QALY gained for unstable angina) represented the most plausible estimates for the cost effectiveness of ticagrelor compared with clopidogrel.
Additional factors taken into account
Patient access scheme
Not applicable
End-of-life considerations
Not applicable
Equalities considerations, Social value judgements
No equality issues were identified during the scoping process or the appraisal.
-# Recommendations for further research
Clinical trials should be conducted comparing ticagrelor with prasugrel in people with ACS.
Further research into whether ticagrelor is particularly beneficial in any clinical or biological subgroups would be useful.# Related NICE guidance
Bivalirudin for the treatment of ST-segment elevation myocardial infarction.NICE technology appraisal guidance 230 (2011).
Unstable angina and NSTEMI: the early management of unstable angina and non-ST-segment-elevation myocardial infarction. NICE clinical guideline 94 (2010).
Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention. NICE technology appraisal guidance 182 (2008).
Drug-eluting stents for the treatment of coronary artery disease.NICE technology appraisal guidance 152 (2008).
MI – secondary prevention: secondary prevention in primary and secondary care for patients following a myocardial infarction. NICE clinical guideline 48 (2007).# Review of guidance
The guidance on this technology for people with STEMI will be incorporated into the forthcoming NICE clinical guideline on the management of myocardial infarction with ST-segment elevation.
The guidance on ticagrelor for people with NSTEMI and unstable angina will be considered for review at the same time as clinical guideline 94 (Unstable angina and NSTEMI: the early management of unstable angina and non-ST-segment elevation myocardial infarction), that is in March 2013.
Andrew Dillon
Chief Executive
October 2011# Changes after publication
February 2014: implementation section updated to clarify that ticagrelor is recommended as an option for treating acute coronary syndromes. Additional minor maintenance update also carried out.# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Ticagrelor in combination with low-dose aspirin is recommended for up to 12\xa0months as a treatment option in adults with acute coronary syndromes (ACS) that is, people:\n\nwith ST-segment-elevation myocardial infarction (STEMI) – defined as ST elevation or new left bundle branch block on electrocardiogram – that cardiologists intend to treat with primary percutaneous coronary intervention (PCI) or\n\nwith non-ST-segment-elevation myocardial infarction (NSTEMI) or\n\nadmitted to hospital with unstable angina – defined as ST or T wave changes on electrocardiogram suggestive of ischaemia plus one of the characteristics defined in section 1.2. Before ticagrelor is continued beyond the initial treatment, the diagnosis of unstable angina should first be confirmed, ideally by a cardiologist.\n\nFor the purposes of this guidance, characteristics to be used in defining treatment with ticagrelor for unstable angina are: age 60 years or older; previous myocardial infarction or previous coronary artery bypass grafting (CABG); coronary artery disease with stenosis of 50% or more in at least two vessels; previous ischaemic stroke; previous transient ischaemic attack, carotid stenosis of at least 50%, or cerebral revascularisation; diabetes mellitus; peripheral arterial disease; or chronic renal dysfunction, defined as a creatinine clearance of less than 60\xa0ml per minute per 1.73\xa0m2 of body-surface area.', 'The technology ': 'Ticagrelor (Brilique, AstraZeneca) is an oral antagonist at the P2Y12 adenosine diphosphate receptor, which inhibits platelet aggregation and thrombus formation in atherosclerotic disease. The summary of product characteristics (SPC) states that ticagrelor, co-administered with low-dose aspirin, is indicated for the prevention of atherothrombotic events in adult patients with ACS, defined as STEMI, NSTEMI or unstable angina. Patients with ACS who receive ticagrelor and aspirin may receive drugs only (medical management) or may also undergo revascularisation with PCI or CABG.\n\nAccording to the SPC, treatment should be initiated with a loading dose of 180 mg ticagrelor (two tablets of 90 mg) and then continued at 90\xa0mg twice a day for up to 12 months. Patients taking ticagrelor should also take low-dose aspirin daily, unless specifically contraindicated. Following an initial loading dose of aspirin, the maintenance dose is 75–150\xa0mg per day.\n\nTicagrelor is contraindicated in patients with active pathological bleeding, a history of intracranial haemorrhage, or moderate-to-severe hepatic impairment. Co-administration of ticagrelor with a strong CYP3A4 inhibitor (for example, ketoconazole, clarithromycin, nefazodone, ritonavir, or atazanavir) is also contraindicated. The most commonly reported adverse reactions to treatment with ticagrelor include dyspnoea, epistaxis, gastrointestinal haemorrhage,subcutaneous or dermal bleeding, and bruising. For full details of adverse effects and contraindications, see the SPC.\n\nThe manufacturer stated in its submission that the cost of 90\xa0mg tablets of ticagrelor is £54.60 for a pack of 56\xa0tablets (28 days). Costs may vary in different settings because of procurement discounts.', "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of ticagrelor and a review of this submission by the Evidence Review Group (ERG; appendix B). This evidence related to the clinical and cost effectiveness of ticagrelor plus aspirin.\n\n# Clinical effectiveness\n\nFor the comparison of ticagrelor plus aspirin with clopidogrel plus aspirin, the manufacturer identified one trial, the PLATO trial, an international, multicentre, randomised, double-blind, double-dummy, parallel group, phase III study. The trial evaluated the efficacy and safety of ticagrelor plus aspirin compared with clopidogrel plus aspirin over 12\xa0months in people with ACS whose symptoms began up to 24\xa0hours before their admission to hospital. In the trial, 18,624 adult patients with ACS with or without ST-segment elevation on electrocardiogram from 43\xa0countries including 18 UK centres (n\xa0=\xa0281) were admitted to hospital, and randomised to either ticagrelor plus aspirin (n\xa0=\xa09333) or clopidogrel plus aspirin (n\xa0=\xa09291). In the ticagrelor group, patients received a loading dose of 180\xa0mg of ticagrelor, then 90\xa0mg twice a day. Patients randomised to clopidogrel received loading doses of 300–600\xa0mg of clopidogrel, then 75\xa0mg every day thereafter. Patients did not need loading doses of clopidogrel if they had taken clopidogrel before admission or had received clopidogrel after admission but before randomisation (median approximately 5\xa0hours). In the time between admission and randomisation, 46% of patients in both the ticagrelor and clopidogrel groups received clopidogrel. All patients also received aspirin (in addition to ticagrelor or clopidogrel) with a loading dose of 325\xa0mg, then 75–100\xa0mg daily. Patients already taking aspirin did not need a loading dose of aspirin.\n\nThe primary end point was time to first event (a composite of myocardial infarction, stroke or death from vascular causes). The planned duration of treatment and follow-up was 12 months. If before this time 1780\xa0individuals had a primary end point event, then patients who had not yet been followed for 12\xa0months would finish the study at their 6 or 9-month visit. At the end of the trial, 1878 participants had experienced events and the median duration of treatment was 9.1\xa0months. Secondary end points included: myocardial infarction; stroke; death from vascular causes; death from any cause; a composite of myocardial infarction, stroke and death from any cause; and a composite of myocardial infarction, stroke, severe recurrent cardiac ischaemia, recurrent cardiac ischaemia, transient ischaemic attack, other arterial thrombotic events and death from vascular causes.\n\nThe results showed that the relative risk of experiencing a primary end point event was 16% lower in the ticagrelor group compared with the clopidogrel group (hazard ratio [HR] 0.84; 95% confidence interval [CI] 0.77 to 0.92; p\xa0<\xa00.001). Of the components of the primary end point, randomisation to ticagrelor plus aspirin reduced the incidence of myocardial infarction (HR\xa00.84; 95% CI 0.75 to 0.95; p\xa0=\xa00.005) and death from vascular causes (HR\xa00.79; 95%\xa0CI 0.69 to 0.91; p\xa0=\xa00.001), but not of stroke (HR\xa01.17; 95%\xa0CI 0.91 to 1.52). Randomisation to ticagrelor plus aspirin reduced the absolute risk of experiencing the primary end point from 11.7% to 9.8% at 12\xa0months (absolute risk reduction 1.9%) compared with clopidogrel plus aspirin.\n\nThe manufacturer explored the consistency of effects and safety end points in 25 pre-specified subgroups and eight post-hoc subgroups. An analysis was conducted of the primary end point in several predefined subgroups. The manufacturer's submission stated that analyses showed statistically significant differences in treatment efficacy in three groups: geographic region; body weight above or below a gender-specific median; and use of lipid-lowering drugs at randomisation. The HRs by type of ACS at presentation – unstable angina, NSTEMI and STEMI – were 0.96 (95% CI 0.75 to 1.22), 0.83 (95% CI 0.73 to 0.94) and 0.84 (95% CI 0.72 to 0.98) respectively with a non-statistically significant test for interaction (p\xa0=\xa00.41). The manufacturer presented six analyses in subgroups that included patients whose condition was managed invasively, managed medically, patients with STEMI, patients with diabetes, patients with genetic polymorphisms, and patients undergoing CABG. The results of these six subgroup analyses were generally consistent with the primary analysis.\n\nThe manufacturer reported adverse events from the PLATO study, specifically bleeding, dyspnoea and ventricular pauses. There was no statistically significant difference in the primary safety end point of 'major' bleeding between the ticagrelor plus aspirin and clopidogrel plus aspirin groups (11.6% versus 11.2% respectively; p\xa0=\xa00.43), or in the end point of bleeding defined by the Thrombolysis in Myocardial Infarction (TIMI) scale. Both were analysed according to which treatment a patient took, rather than to which a patient had been randomised; these findings were consistent across all major subgroups. Patients randomised to ticagrelor experienced more overall major and minor bleeding (HR 1.11; 95% CI 1.03 to 1.20; p\xa0=\xa00.008) as well as more major bleeding not related to CABG (HR 1.19; 95% CI 1.02 to 1.38; p\xa0=\xa00.03). Intracranial bleeding was more common in the ticagrelor plus aspirin group than in the clopidogrel plus aspirin group, with fatal intracranial bleeding statistically significantly more common in the ticagrelor plus aspirin group (HR not reported; p\xa0=\xa00.02). Fatal bleeding excluding intracranial bleeding was statistically significantly more common in the clopidogrel plus aspirin group (HR not reported; p\xa0=\xa00.03). There was no difference between the two groups in relation to overall fatal bleeding (0.3% in each group). Patients randomised to ticagrelor experienced dyspnoea statistically significantly more often than patients taking clopidogrel (13.8% versus 7.8% respectively; p\xa0<\xa00.001). More patients taking ticagrelor plus aspirin discontinued treatment because of dyspnoea than patients taking clopidogrel plus aspirin (0.9% versus 0.1% respectively; p\xa0<\xa00.001). Holter monitoring detected more ventricular pauses of 3\xa0seconds or longer during the first week in the ticagrelor plus aspirin group than in the clopidogrel plus aspirin group, but these occurred infrequently at 30\xa0days of treatment and were rarely associated with symptoms. Patients treated with ticagrelor had statistically significantly greater increases from baseline in levels of serum uric acid and serum creatinine compared with those on clopidogrel (p\xa0<\xa00.001 for both events throughout the study).\n\nThe manufacturer identified no trials directly comparing ticagrelor plus aspirin with prasugrel plus aspirin. Instead, the manufacturer identified two trials comparing prasugrel plus aspirin with clopidogrel plus aspirin that provided data for an indirect comparison: the PLATO trial (ticagrelor plus aspirin compared with clopidogrel plus aspirin) and TRITON-TIMI 38, which compared prasugrel plus aspirin with clopidogrel plus aspirin in patients (n\xa0=\xa013,608) with ACS and scheduled PCI. The manufacturer took the view that the trials were not comparable and, by inference, a comparison between prasugrel and ticagrelor based on these trials was inappropriate and should be viewed with caution. The manufacturer noted that the PLATO and TRITON-TIMI 38 trials were similar in many ways, both including populations with ACS, both comparing the intervention plus aspirin to clopidogrel plus aspirin, and both sharing the same primary end point. However, there were important differences in the use of PCI and medical management, in the size and timing of the loading dose of clopidogrel, and in assessing myocardial infarction. Although the manufacturer considered the indirect comparison inappropriate, it cited a published paper based on the PLATO and TRITON-TIMI 38 trials that showed no statistically significant differences in the occurrence of myocardial infarction, stroke, death from any cause or the composite of these outcomes between the two drugs. Ticagrelor plus aspirin was associated with a statistically significantly lower risk of major bleeding and major bleeding specifically associated with bypass grafting than prasugrel plus aspirin. The risk of major bleeding not related to CABG did not differ between patients taking prasugrel and those taking ticagrelor.\n\nThe PLATO trial included a pre-specified sub-study of health economics and quality of life that evaluated the health-related quality of life for ticagrelor plus aspirin compared with clopidogrel plus aspirin. Investigators administered the EuroQual 5D (EQ-5D) questionnaire to 8840 patients at discharge from hospital for the index ACS event, again at 6\xa0months, and at the end of treatment in all countries where a version of EQ-5D in the country's official language was available. No differences in any of the items on the EQ-5D were found between the ticagrelor plus aspirin group and the clopidogrel plus aspirin group.\n\n# Cost effectiveness\n\nThe manufacturer did not identify any publications that evaluated the cost effectiveness of ticagrelor for the treatment of ACS. The manufacturer developed a new economic model, informed by nine existing economic evaluations. For the health economics evaluation of ticagrelor plus aspirin compared with prasugrel plus aspirin, the manufacturer presented the results of a published indirect comparison of the TRITON-TIMI 38 trial and the PLATO trial, conducted by an independent group.\n\nThe manufacturer constructed a two-part cost−utility model with a 1-year decision tree to model effectiveness based on data from the PLATO study, and a Markov model to extrapolate costs and benefits to a lifetime horizon (40\xa0years), and to incorporate major clinical events. Patients in the model had ACS (STEMI, NSTEMI or unstable angina) and included patients whose condition was managed medically or with PCI or CABG; the model therefore reflected the marketing authorisation for ticagrelor. The model compared ticagrelor plus aspirin with clopidogrel plus aspirin.\n\nThe 1-year decision tree contained four mutually exclusive health states: non-fatal myocardial infarction, non-fatal stroke, death from any cause, and no further event. The Markov model included six states: non-fatal myocardial infarction, post-myocardial infarction, non-fatal stroke, post-stroke, death, and no further event. Non-fatal myocardial infarction and non-fatal stroke were tunnel states, which allowed for a worse prognosis the first year after a non-fatal event compared with second and subsequent years. After the first year following a non-fatal event, patients proceeded to one of four mutually exclusive health states: post-myocardial infarction, post-stroke, death or no further event. Costs and health outcomes were discounted at 3.5%. The Markov model used a half-cycle correction to adjust for simulated costs and outcomes. The model did not permit a patient to discontinue treatment for any reason other than death.\n\nIn the model, costs, life years, and quality-adjusted life years (QALYs) accrued beyond the first\xa0year of treatment with ticagrelor or clopidogrel; however, the model assumed that the beneficial effect of ticagrelor does not persist beyond 1\xa0year. This means that the transition probabilities between states in the Markov model were the same for both treatment arms; the only difference between treatment arms was the number of patients who started the Markov model in each state, which was based on the output of the 1-year decision tree. Adverse events (notably bleeding) were not included in the structure of the model but the increased costs and decreased health-related quality of life associated with adverse events recorded in PLATO (as part of PLATO-HECON) were included in the first year (decision tree) of the model. The manufacturer assumed that adverse events including bleeding and dyspnoea have no lasting effects beyond the 12-month duration of the trial. To model the incidence of cardiovascular complications beyond 1\xa0year (in the Markov component of the model), the manufacturer assumed a constant probability of 3.15% per year for non-fatal myocardial infarction and 1.02% per year for non-fatal stroke. The risk of death from MI after the index event (STEMI, NSTEMI or unstable angina) was assumed to be the same as that of death at least 1 year after the index ACS event.\n\nFor the 1-year decision tree, the manufacturer used a parametric time-to-event survival model with a Weibull distribution to determine the baseline risk (that is, the risk of cardiovascular events and death in the clopidogrel group). The manufacturer then applied HRs reflective of the effectiveness of ticagrelor from the PLATO study to this baseline risk to determine the risk in patients taking ticagrelor. Using data in the 1-year decision tree derived from the PLATO study, the manufacturer estimated from patients in the clopidogrel group age-adjusted event rates (myocardial infarction, stroke, death from any cause and death from vascular causes) for a UK population with ACS (mean age of PLATO patients\xa0=\xa062.2\xa0years; reported age of UK patients with ACS in 2009–10\xa0=\xa069.7\xa0years). In the Markov model, the transition probabilities from the no event health state to each of the non-fatal myocardial infarction or non-fatal stroke health states were estimated from a study that the manufacturer commissioned from the Myocardial Ischaemia National Audit Project and the General Practice Research Database. The probabilities of transitioning between all other health states were based on relative risks applied to the probability of death in standard life tables.\n\nThe manufacturer used the 12-month cohort (patients who were eligible for a 12-month follow-up) in the PLATO-HECON study to calculate the utility accrued in the study and reported it as the average utility value for a patient over the 12-month period using the EQ-5D. The manufacturer performed a literature search to assess the relationship between utility values in the PLATO study and in the literature. The lower values from the literature were used in sensitivity analyses. The utility scores from both the PLATO-HECON substudy and the literature were adjusted downwards by 0.0328 to better reflect the patient population that would be treated in UK clinical practice. In addition, because utility decreases with age, the manufacturer applied a utility decrement of 0.004 in the Markov model to each cycle beyond the first year.\n\nThe costs for the generic drugs clopidogrel and aspirin were taken from the NHS Drug Tariff, November 2010. The cost of the drugs used in the economic evaluation were: aspirin 28-pack = £0.82; clopidogrel 30-pack = £3.40; and ticagrelor 28-pack = £54.60. The PLATO-HECON substudy measured resource use and determined costs for all patients participating in the PLATO study by recording admissions to hospital, interventions, investigations, blood products, re-operations due to bleeding, and use of concomitant or study drugs to estimate total healthcare costs associated with ticagrelor and clopidogrel. Resource use included costs from randomisation to the time of discharge from hospital, as well as after discharge from hospital to the end of the PLATO study. The manufacturer also included in sensitivity analyses the costs of a visit to the GP and of a blood test to check renal function, as stipulated in the SPC for ticagrelor.\n\nIn its deterministic base case (40-year time horizon), the manufacturer's model estimated that ticagrelor provides an incremental health gain of 0.108 QALYs compared with clopidogrel, at an incremental cost of £379, resulting in an incremental cost-effectiveness ratio (ICER) of £3521 per QALY gained. The manufacturer also presented results using time horizons of 1\xa0year, 5\xa0years, 10\xa0years and 20\xa0years: the ICER differed substantially from the base-case ICER only when using the 1-year time horizon, with an ICER of £33,764 per QALY gained. The manufacturer also presented base-case ICERs for the subgroups of ACS specified in the scope, which were £2551 per QALY gained for STEMI, £5217 per QALY gained for NSTEMI and £5310 per QALY gained for unstable angina.\n\nThe manufacturer carried out deterministic sensitivity analyses to the base case and showed the effects of changing 43\xa0model parameters. Only the change to the costs of the 'no further event' health state impacted substantially on the results. When the cost of the 'no further event' health state for ticagrelor plus aspirin was set to its lowest, ticagrelor plus aspirin dominated clopidogrel plus aspirin (that is, ticagrelor plus aspirin was more effective and less expensive than clopidogrel plus aspirin), whereas when the cost of the clopidogrel plus aspirin 'no further event' health state was set to its lowest, the ICER was £21,000 per QALY gained. Changes in all other parameters did not increase the ICER beyond £7620.\n\nThe manufacturer ran scenario analyses for 0% and 6% discount rates, using published rather than PLATO-derived utility values, removing the 0.0328 downwards utility adjustment and removing the age-related decrease in utility per cycle. The results of the scenario analyses showed that the ICER for ticagrelor plus aspirin compared with clopidogrel plus aspirin ranged from £2358–£4699 per QALY gained.\n\nThe cost-effectiveness acceptability curve showed that at £5000 per QALY gained, the probability of ticagrelor plus aspirin being cost effective compared with clopidogrel plus aspirin was 76.6%. At £20,000 per QALY gained, the probability of ticagrelor plus aspirin being cost effective compared with clopidogrel plus aspirin was 99.9%.\n\nThe manufacturer's submission also provided results for ticagrelor plus aspirin compared with prasugrel plus aspirin for the subgroup receiving PCI, based on the results of a published indirect comparison of the PLATO and TRITON-TIMI 38 trials. Because of the small proportion of patients who participated in the TRITON-TIMI 38 substudy of quality of life (EQ-5D was collected in only 461 of 13,608 patients at baseline), the model incorporated utility information from the literature, rather than from the substudy. If costs from the PLATO-HECON substudy were not available, the manufacturer used NHS reference costs in the analysis for prasugrel plus aspirin. The manufacturer obtained the cost of prasugrel from MIMS, October 2010. The analysis of ticagrelor plus aspirin compared with prasugrel plus aspirin resulted in an incremental cost of £227, incremental QALYs of 0.065 and an ICER of £3482 per QALY gained, with a 40-year time horizon. The manufacturer stated that the results of the indirect comparison should be viewed with caution because of the problems associated with the indirect comparison of ticagrelor plus aspirin with prasugrel plus aspirin discussed in section 3.6.\n\n# ERG comments\n\nThe ERG conducted a literature search and agreed that the PLATO trial was the only trial relevant to the decision problem. The ERG considered that the PLATO trial was well designed with robust processes for randomisation and blinding. It noted that compliance and deviations in protocol were similar across treatment arms. Although only 281 patients in the PLATO trial were from centres in the UK, the ERG considered that they were not dissimilar to other European participants. The ERG also noted that participants in the PLATO trial were younger than patients with ACS in England and Wales, but that the manufacturer's model accounted for this difference.\n\nThe ERG noted that for patients with STEMI not undergoing PCI, NICE recommends dual antiplatelet therapy (clopidogrel plus aspirin) for at least 4 weeks (MI: secondary prevention [NICE clinical guideline 48]). From statements in the 'clinical need and practice' and 'evidence and interpretation' sections of Drug-eluting stents for the treatment of coronary artery disease (NICE technology appraisal guidance 152), the ERG concluded that standard practice for STEMI should include dual antiplatelet therapy for 3\xa0months for patients undergoing revascularisation with bare-metal stents and 12\xa0months for patients undergoing revascularisation with drug-eluting stents.\n\nThe ERG considered that the PLATO trial reflects current clinical practice and that all patients received antiplatelet treatment at a clinically appropriate dose. The ERG was satisfied with the manufacturer's means of categorising adverse events from bleeding. The ERG expressed concerns about the components of the primary efficacy end point in the PLATO trial. Firstly, the primary end point was inconsistent with the concept that all components of an end point should be of similar importance to patients. For example, the average utility values from the 12-month cohort in the PLATO-HECON study used in the manufacturer's model differed by end point and were 0.246 for death from a vascular cause, 0.812 for myocardial infarction and 0.736 for stroke. Secondly, the primary end point was inconsistent with the concept that all components of an end point occur with similar frequencies. For example, in 18,624 participants there were 795 vascular deaths, 1097 myocardial infarctions and 231 strokes during the median 9.1 month follow-up in the PLATO study. Thirdly, the primary end point was inconsistent with the concept that the effect of a treatment should have an effect of similar magnitude and direction on all components of a primary end point. For example, in the PLATO study, the HR for stroke (non-significantly higher with ticagrelor) differed from those for myocardial infarction and death from vascular causes (significantly lower with ticagrelor). The ERG concluded that the results of the overall composite end point should be interpreted cautiously. The ERG also noted that the manufacturer excluded 'silent' myocardial infarctions (defined as new or presumed pathological Q waves on ECG in the absence of symptoms). The ERG considered that the secondary end points and their components reflected those used in other cardiovascular trials.\n\nThe ERG noted that the manufacturer tested whether the effectiveness and safety of ticagrelor plus aspirin compared with clopidogrel plus aspirin differed across 25 pre-specified and eight post-hoc subgroups, without adjustment for multiple comparisons. The ERG expressed concern about the large number of subgroups and potential overemphasis of any statistically significant results from these analyses, which might have occurred by chance alone. With these caveats noted, the ERG observed that the regional analysis showed that in the USA, patients randomised to ticagrelor plus aspirin did worse than those randomised to clopidogrel plus aspirin.\n\nFor patients with STEMI who receive bare-metal stents, the ERG highlighted concerns about the comparator treatment included in the economic evaluation. It interpreted NICE technology appraisal guidance 152 as stating that dual antiplatelet therapy for 3\xa0months was standard practice for patients undergoing revascularisation with bare-metal stents, whereas for patients undergoing revascularisation with drug-eluting stents, the guidance on secondary prevention of myocardial infarction (NICE clinical guideline 48) recommends dual antiplatelet therapy for 12\xa0months. Another concern of the ERG was that the manufacturer treated the STEMI group as a homogeneous population and estimated a single ICER. By contrast, the ERG believed that STEMI has four distinct populations differing by treatment: STEMI with medical management, STEMI revascularised with drug-eluting stent, STEMI revascularised with bare-metal stent and STEMI with other intervention (for example, CABG).\n\nThe ERG stated that as the trial was designed to test the efficacy of 12\xa0months of treatment, all patients should have been treated for 12\xa0months. The ERG noted that the PLATO trial design did not involve uniform duration of treatment, instead, the protocol stipulated that patients could leave the study at their 6- or 9-month visit if a predetermined number of primary end-point events had occurred by that time. Approximately 44% of patients were followed up for 12\xa0months in the trial. This increased the uncertainty in the estimates of effectiveness at the conclusion of the trial, which in turn was the prime driver of the Markov model and, therefore, the long-term benefits for patients.\n\nThe ERG noted that the model featured two separate paths. In one path, after first presentation with ACS, patients may have a subsequent non-fatal myocardial infarction at any time during the decision-tree part of the model and remain in the non-fatal myocardial infarction health state to the end of the decision-tree part of the model, then progress to the 'post-myocardial infarction' state for all remaining cycles until death (whether from cardiovascular or non-cardiovascular causes). Similarly, patients may instead have a non-fatal stroke as their first event (after the initial presentation with ACS) during a cycle, and then progress to the post-stroke state until death. The ERG considered that this structure does not represent reality, because it does not allow patients to have more than one myocardial infarction, more than one stroke, or both myocardial infarctions and strokes in their lifetime following their initial presentation with ACS, and that this may bias future costs and benefits. The ERG also noted that the model simplified the natural history of treated cardiovascular disease by keeping constant the transition probability of previously event-free patients (since initial treatment for ACS) experiencing a non-fatal myocardial infarction or stroke throughout the long-term Markov model. The modelling ignored the increase in risk associated with other factors, notably, increasing age. The ERG considered that this omission may have led to the manufacturer's model inaccurately estimating future events, costs and progressive changes in the outcomes and quality of life of patients.\n\nThe ERG was concerned that the model applied an average utility score for the first year, whereas clinical experience showed that ACS patients experience an initial decline in utility that steadily improves. Therefore, the ERG noted that the ICER at 12\xa0months may be an underestimate.\n\nThe ERG noted that in the manufacturer's submission the subgroups of interest in the economic evaluation did not reflect the subgroups of interest in the clinical section. The ERG could not verify the estimates of clinical effectiveness used in the manufacturer's model ascribed to ticagrelor in patients with NSTEMI or unstable angina. The ERG also noted that the manufacturer considered the subgroup with unstable angina as a homogeneous group whereas, in clinical practice in England and Wales, physicians typically categorise patients into lowest, low, intermediate, high and highest risk groups using the Global Registry of Acute Coronary Events (GRACE) classification and treat them accordingly.\n\nThe ERG noted that the manufacturer adjusted the age of the modelled patients to reflect the UK population with ACS. The ERG noted potential problems with the methods chosen by the manufacturer, which may have led to inaccuracies. The ERG established that these inaccuracies represented an 8% underestimate of benefits from ticagrelor plus aspirin compared with clopidogrel plus aspirin and suggested that the ICER presented by the manufacturer may be an overestimate.\n\nThe ERG acknowledged that use of healthcare resources was estimated in the model using data from an imbedded health economic study, which collected details of hospital care received by patients during the PLATO trial. For the purposes of the model, only data for those patients in the 12-month cohort were included. This cohort comprised of patients who, based on timing of enrolment, had the potential to receive 12 months treatment with ticagrelor. The ERG also noted that for each patient category in the model, the resources used by each patient were calculated separately for each treatment arm, and these were multiplied by a corresponding unit cost and totalled for an estimated hospital-care cost per patient for the first 12-month period. The ERG had some concerns relating to this type of resource analysis, and conducted a combined analysis of resource use (taking the ticagrelor and clopidogrel groups together), making some adjustments for double-counting of costs. Results suggested that the health state costs with ticagrelor were £100 lower (rather than £371 lower, as in the manufacturer's base-case) than the health state costs of clopidogrel, which would have the effect of doubling the estimated ICER at the 1-year time horizon.\n\nThe ERG noted that the manufacturer's base-case analysis estimated costs for the study drugs assuming 100% use in the trial period, despite evidence of deaths before the end of follow-up, treatment withdrawals, and poor adherence in some participants. The ERG instead incorporated data on drug use from the PLATO trial and noted that this reduced the average cost of both ticagrelor and clopidogrel substantially, and the difference in drug costs of ticagrelor plus aspirin compared with clopidogrel plus aspirin reduced from £651 to £507 per patient. Applying the ERG's amended age adjustment, resource use, and costs of study drugs to the manufacturer's model resulted in a 42% increase in the manufacturer's ICER for the 1-year time horizon from £36,177 to £51,204 per QALY gained. However, the ERG emphasised that both the incremental costs and additional benefits associated with ticagrelor plus aspirin compared with clopidogrel plus aspirin were very small at longer time horizons, and subject to considerable uncertainty.\n\nThe ERG conducted a wide-ranging sensitivity analysis, calculating overall deterministic cost-effectiveness estimates for all combinations of four long-term variables – survival gain at 12\xa0months, life expectancy at 12\xa0months, the mean long-term utility value and the mean long-term discounted cost per patient year. The most favourable ICERs for ticagrelor plus aspirin are £3407 per QALY gained for all patients, £3551 per QALY gained for the STEMI group, £3350 per QALY gained for the NSTEMI group and £3405 per QALY gained for the group with unstable angina. Incorporating the least favourable combination of assumptions resulted in an estimated ICER for ticagrelor plus aspirin below £20,000 per QALY gained for each of the specified populations compared with 12\xa0months' clopidogrel plus aspirin treatment. The central estimates from these sensitivity analyses were £7897 per QALY gained for all patients, £8872 per QALY gained for the STEMI group, £7215 per QALY gained for the NSTEMI group and £9131 for the subgroup with unstable angina.\n\nThe ERG noted that there are no head-to-head trial data comparing ticagrelor plus aspirin with prasugrel plus aspirin. With regard to the indirect comparison of ticagrelor plus aspirin with prasugrel plus aspirin, the ERG considered that any comparison of the PLATO and TRITON-TIMI 38 trials posed problems. The ERG agreed with the manufacturer that sufficient clinical evidence is not yet available for a credible indirect comparison of ticagrelor plus aspirin compared with prasugrel plus aspirin for patients with ACS. It concluded that the effectiveness and safety of ticagrelor compared with prasugrel remains unknown.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA236", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ticagrelor, having considered evidence on the nature of ACS and the value placed on the benefits of ticagrelor by people with these conditions, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the clinical management of ACS. It heard from the clinical specialists that, in the UK, treatment options for people with STEMI are prasugrel plus aspirin or clopidogrel plus aspirin, along with PCI with a bare-metal or drug-eluting stent followed by dual antiplatelet treatment. The Committee heard that the duration of treatment of clopidogrel does not vary whether a stent is bare-metal or drug-eluting, because all people with ACS who undergo PCI, in the acute setting, are treated with clopidogrel plus aspirin for 12\xa0months. The Committee heard that in UK clinical practice people with NSTEMI are offered treatments depending on their GRACE or TIMI score; medical management is an option for people at lowest risk of future adverse cardiovascular events, whereas people at higher risk would be offered PCI and subsequent dual antiplatelet therapy with clopidogrel and aspirin. The Committee heard from the clinical specialists that in the UK most people with NSTEMI undergo PCI. The Committee understood that of people in the UK with ACS, few have unstable angina and often do not need revascularisation, but do receive dual antiplatelet therapy with clopidogrel and aspirin. The clinical specialists stated that in the UK it is unusual for a patient with STEMI to undergo CABG and that approximately 10% of patients with NSTEMI undergo CABG.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence for the clinical effectiveness of ticagrelor compared with clopidogrel. The Committee noted that the manufacturer based its submission on a large trial, PLATO, which compared ticagrelor plus aspirin with clopidogrel plus aspirin. The Committee noted that ticagrelor plus aspirin reduced the relative risk of myocardial infarction, stroke and death from vascular causes by 16% compared with clopidogrel plus aspirin. The Committee also noted that if the components of the primary end point were considered individually, the reductions in myocardial infarction and death from vascular causes were statistically significant (16% and 21% respectively) for patients randomised to the ticagrelor plus aspirin group. The Committee also noted the non-statistically significant increase in the incidence of stroke, in particular haemorrhagic stroke, in patients randomised to the ticagrelor group. The Committee considered the clinical evidence for ticagrelor plus aspirin compared with clopidogrel plus aspirin in the subgroups of patients that were specified in the scope (STEMI, NSTEMI and unstable angina) and noted that the test for interaction showed no statistical difference between the groups (p\xa0=\xa00.41), interpreting this as no difference in the effectiveness between treatments by clinical presentation of ACS. The Committee noted that the manufacturer had performed a large substudy of quality of life based on EQ-5D scores, which indicated no difference in the quality of life between people taking ticagrelor plus aspirin and those taking clopidogrel plus aspirin.\n\nThe Committee heard from the clinical specialists that in general the trial was representative of the population in the UK, although the trial had a younger population and a higher proportion of men than the population with ACS in the UK. The Committee understood that the manufacturer had accounted for age in its analysis. The Committee noted comments from consultees and commentators questioning the generalisability of the PLATO trial to UK clinical practice because most of the patients presenting with ACS in the UK would receive medical therapy only whereas 21% of patients in the PLATO trial received medical therapy only. However, the Committee noted the clinical specialists' testimonies that most STEMI and NSTEMI patients would receive PCI. The Committee was also aware that results of the PLATO study showed no statistically significant difference in effectiveness between the patients whose condition was managed medically or otherwise. The Committee concluded that the trial was broadly reflective of clinical practice in the UK.\n\nThe Committee was aware that nearly half (46%) of all patients in the study received clopidogrel in hospital before randomisation, and that of those randomised to clopidogrel, only approximately one fifth received a loading dose in the range (600–675\xa0mg) recommended in the UK (600\xa0mg). The Committee also noted that not all patients in the PLATO trial received treatment for 12\xa0months and that the median duration of treatment was 9\xa0months. The Committee heard that the results presented included those censored before 12\xa0months. The Committee noted that the Kaplan–Meier curves depicting the two arms of the trial separated as early as 1 month and up to 1\xa0year and, therefore, concluded that neither the difference in loading doses of clopidogrel nor censoring was likely to have substantially biased the results.\n\nThe Committee understood that ticagrelor is administered twice a day compared with once a day with clopidogrel and heard from the patient experts that, in practice, people may be less likely to take drugs twice a day. The Committee noted that no clear differences had been established on adherence between once-a-day clopidogrel and twice-a-day ticagrelor. The Committee noted comments from consultees and commentators that, particularly with a gastrointestinal bleed, the fast offset (time taken for ticagrelor to become inactive after it is stopped) could put a patient at increased risk of myocardial infarction and stroke more quickly than had the patient been taking clopidogrel, and with insufficient time to consult a cardiologist. However, the Committee heard from the manufacturer that missing a dose of ticagrelor would not result in a lower level of platelet activation than if the patient were treated with clopidogrel without missing a dose. The Committee heard that when a CABG is planned, the marketing authorisation recommends stopping ticagrelor 7\xa0days before the procedure, suggesting that the offset is not as fast as had been suggested in the consultation comments. The Committee also noted comments from consultees and commentators that treatment with ticagrelor should be limited to people who clinicians have counselled on the importance of adherence. The Committee heard from the clinical specialists that people taking clopidogrel or ticagrelor would usually receive information to ensure that they understand why adherence is important and why stopping treatment early might increase the risk of recurrent cardiovascular disease. Therefore, the Committee agreed that advice on adherence should not explicitly be factored into the recommendations. Lastly, the Committee noted that most patients with cardiovascular disease take drugs twice a day, including statins in the evening. The Committee concluded that in the 'real world' setting, the need to take medication twice a day rather than once a day would be unlikely to substantially reduce the effectiveness of ticagrelor plus aspirin relative to clopidogrel plus aspirin.\n\nThe Committee discussed the concerns about safety and adverse effects associated with ticagrelor. The Committee heard that dyspnoea (shortness of breath), ventricular pauses, increases in serum uric acid and increases in serum creatinine from baseline were statistically significantly more common in the ticagrelor group compared with the clopidogrel group, and noted that patients randomised to ticagrelor were more likely to discontinue the study drug because of adverse reactions. The Committee heard from the patient experts that dyspnoea frustrated patients with ACS and the clinical specialists stated that a patient randomised to ticagrelor was nine times as likely to discontinue the study because of dyspnoea as a patient randomised to clopidogrel, but that the absolute risk, at less than 1%, was small. The Committee heard from the manufacturer that the effects of dyspnoea were limited mainly to mild episodes. The Committee noted no statistically significant difference in the primary safety end point of major bleeding between ticagrelor plus aspirin and clopidogrel plus aspirin but that patients on ticagrelor plus aspirin experienced more overall major and minor bleeding as well as more major bleeding not related to CABG. The Committee considered that the mortality benefit associated with ticagrelor outweighed the risks and concluded that ticagrelor was a clinically effective treatment option for people with ACS.\n\nThe Committee discussed whether ticagrelor plus aspirin would be more or less effective in any subgroups including patients with STEMI, NSTEMI or unstable angina. The Committee noted that several additional subgroups were presented in the trial. The Committee noted that among those defined in the scope (STEMI, NSTEMI, unstable angina) there was no statistically significant evidence of heterogeneity, consistent with no difference in effectiveness of ticagrelor compared with clopidogrel by clinical presentation of ACS. The Committee appreciated that the numbers of patients by subgroup may have been too small to detect a difference in effectiveness. The Committee heard from the manufacturer that it had not corrected for multiple comparisons when analysing the many subgroups. The Committee noted the comment from a consultee saying that patients with unstable angina are unlikely to benefit from ticagrelor because subgroup analysis shows benefit only for patients whose blood tests following the index event were positive for troponin. The Committee noted, however, that neither the test for interaction by clinical presentation of ACS nor the test for interaction by whether a patient had a positive or negative test for troponin were positive (p value for interaction 0.41 and 0.29 respectively). Lastly, no evidence of statistical or biological plausibility was presented to support effect modification by presentation of ACS, and there are no trials using ticagrelor for the primary prevention of cardiovascular disease. Therefore, the Committee concluded that providing specific recommendations only for patients with STEMI and NSTEMI and excluding those with unstable angina would be speculative, would counter the statistical evidence, and would risk excluding patients who could benefit from treatment with ticagrelor.\n\nThe Committee was aware of comments from consultees and commentators that the estimate of total mortality remained 'exploratory'. This was because the analysis plan for PLATO stated that secondary end points should be tested individually in a pre-specified order, so mortality should not have been included because it followed the non-statistically significant result for stroke. The Committee was aware that the result for the association between ticagrelor and total mortality, while exploratory, had a HR of 0.78 and a 95% CI of 0.69 to 0.89, so was likely to reflect a real decrease in total mortality associated with ticagrelor plus aspirin.\n\nThe Committee noted the concerns around the indirect comparison of ticagrelor plus aspirin and prasugrel plus aspirin highlighted in the manufacturer's submission and reiterated by the ERG. The Committee concurred with this view and concluded that the relative effectiveness of ticagrelor plus aspirin and prasugrel plus aspirin was uncertain. The Committee concluded that no separate recommendations could be made for ticagrelor compared with prasugrel.\n\n# Cost effectiveness\n\nThe Committee considered the estimates of cost effectiveness presented in the manufacturer's submission and noted that all ICERs for ticagrelor were below £5400 for the whole population in which ticagrelor is licensed and the subgroups. The Committee was aware of the concerns raised by the ERG around the structure of the model adopted in the manufacturer's submission, and agreed that the assumption that patients could not experience multiple cardiovascular events over-simplified the clinical course of patients with ACS. The Committee noted that if the model had included the possibility of more than one cardiovascular event after the index event, and had accounted for the increased risk of a cardiovascular event associated with having had prior events, then the ICERs for ticagrelor compared with clopidogrel would be lower than in the manufacturer's base case. This is because at the end of the 1-year decision tree, more patients on clopidogrel than on ticagrelor had experienced a myocardial infarction or stroke, and were therefore at higher risk of experiencing another event. The Committee was aware of the ERG's concerns over the method used to adjust for age, but agreed that this would not result in major changes to the ICERs. The Committee also noted that it would have been more appropriate to incorporate a utility value that reflected clinical practice rather than modelling the average utility score, but acknowledged that this too was unlikely to have a large impact on the ICERs. The Committee noted comments from consultees that the adverse event profile should be fully built into the structure of the economic model. The Committee was aware that the 1-year decision tree part of the economic model took account of all costs and changes in quality of life associated with the adverse events of treatment.\n\nThe Committee was aware of the ERG's concerns about the manufacturer's method of estimating resource use and costs. It was aware that these limitations could skew the differences in total costs between the two treatment arms. The Committee accepted the ERG's adjustments to the manufacturer's model and noted the resulting estimates of cost effectiveness. The Committee agreed that the central ICERs from the ERG's sensitivity analysis (£7897 per QALY gained for all ACS, £8872 per QALY gained for STEMI, £7215 per QALY gained for NSTEMI and £9131 per QALY gained for unstable angina) represented the most plausible estimates for the cost effectiveness of ticagrelor compared with clopidogrel. The Committee noted that the ICERs produced with this analysis were within the range normally considered to be a cost-effective use of NHS resources and therefore ticagrelor plus low-dose aspirin should be recommended as a treatment option for up to 12\xa0months in adults with ACS. However the Committee agreed that the patient populations for STEMI and unstable angina needed to be further specified.\n\nThe Committee noted that the inclusion criteria in the PLATO trial for patients with STEMI, defined as ST elevation or new left bundle branch block on electrocardiogram, included the 'intention to perform primary PCI'. The Committee therefore agreed that only patients with STEMI that cardiologists intend to treat with primary PCI should be treated with ticagrelor. The Committee heard that there is a spectrum of severity with respect to unstable angina. The Committee was aware that in clinical practice in the UK a diagnosis of unstable angina could be made using less stringent criteria than those defined in the PLATO trial. The Committee agreed that only patients with unstable angina aligned with the definition in the PLATO trial should be treated with ticagrelor. The Committee noted that the definition of unstable angina in the PLATO trial was that patients were hospitalised and had to have ST-segment changes on electrocardiography indicating ischemia, and that patients had at least one of the following characteristics: age 60 years or older; previous myocardial infarction or CABG; coronary artery disease with stenosis of 50% or more in at least two vessels; previous ischaemic stroke, transient ischaemic attack, carotid stenosis of at least 50%, or cerebral revascularisation; diabetes mellitus; peripheral arterial disease; or chronic renal dysfunction, defined as a creatinine clearance of less than 60\xa0ml per minute per 1.73\xa0m2 of body-surface area. The Committee was aware that it may be necessary to start treatment with ticagrelor immediately when a patient presents with symptoms. However, the Committee was concerned that a wrong diagnosis of unstable angina could result in the patient unnecessarily taking ticagrelor. The Committee therefore agreed that it would be appropriate to specify that before ticagrelor is continued beyond the initial treatment, the diagnosis of unstable angina should first be confirmed, ideally by a cardiologist.\n\nThe Committee noted the comments from consultees and commentators about whether 'lowest risk' patients (that is, patients who have a 6-month mortality of 1.5% or less as defined by the GRACE scoring system) should receive ticagrelor, given that Unstable angina and NSTEMI (NICE clinical guideline 94) stipulates that these patients would not receive clopidogrel because the harms potentially outweigh the benefits. The Committee concluded that, because patients potentially suitable for treatment with ticagrelor with unstable angina must have at least one specific risk factor for myocardial infarction as well as ST-segment changes on electrocardiography, these patients would therefore not be classed as 'lowest risk'.\n\nThe Committee heard from the primary care trust expert that although treatment with ticagrelor relative to clopidogrel appeared cost effective within the range considered to represent good value for money by NICE, the high incidence of ACS in England and Wales means that ticagrelor would substantially impact budgets were it approved for use. The primary care trust expert noted that this would invariably lead to reduced spending elsewhere for health, which would include cardiology services. The Committee noted further comments received from consultees that affordability was an issue that NHS commissioners needed to consider 'very seriously'. Although the Committee agreed that that budget impact would be substantial, it was possible that any services displaced might be less cost effective than ticagrelor relative to clopidogrel. Moreover, the Committee noted that NICE's current guide to the methods of technology appraisal states that budget impact and affordability are not relevant to its decision making.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA236 (STA)\n\n\n\nTicagrelor for the treatment of acute coronary syndromes\n\nFAD section\n\nKey conclusion\n\nTicagrelor in combination with low-dose aspirin is recommended for up to 12\xa0months as a treatment option in adults with acute coronary syndromes (ACS) that is, people:\n\n• with ST-segment-elevation myocardial infarction (STEMI) – defined as ST elevation or new left bundle branch block on electrocardiogram – that cardiologists intend to treat with primary percutaneous coronary intervention (PCI) or\n\n• with non-ST-segment-elevation myocardial infarction (NSTEMI) or\n\n• admitted to hospital with unstable angina – defined as ST or T wave changes on electrocardiogram suggestive of ischaemia plus one of the characteristics defined in section 1.2. Before ticagrelor is continued beyond the initial treatment, the diagnosis of unstable angina should first be confirmed, ideally by a cardiologist.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee noted that the incremental cost-effectiveness ratios (ICERs) produced with this analysis were within the range normally considered to be a cost-effective use of NHS resources.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\n\n\nTreatment options for people with STEMI are prasugrel plus aspirin or clopidogrel plus aspirin, along with PCI with a bare-metal or drug-eluting stent followed by dual antiplatelet treatment.\n\nPeople with NSTEMI are offered treatments depending on their Global Registry of Acute Coronary Events (GRACE) or Thrombolysis in Myocardial Infarction (TIMI) score; medical management is an option for people at lowest risk of future adverse cardiovascular events, whereas people at higher risk would be offered PCI and subsequent dual antiplatelet therapy with clopidogrel and aspirin.\n\nPeople with unstable angina often do not need revascularisation, but receive dual antiplatelet therapy with clopidogrel and aspirin. The clinical specialists stated that in the UK it is unusual for a patient with STEMI to undergo coronary artery bypass grafting (CABG) and that approximately 10% of patients with NSTEMI undergo CABG.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\nTicagrelor is an oral antagonist at the P2Y12 adenosine diphosphate receptor, which inhibits platelet aggregation and thrombus formation in atherosclerotic disease.\n\n\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nNo specific claim of innovation was made.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nTicagrelor, co-administered with low-dose aspirin, is indicated for the prevention of atherothrombotic events in adult patients with ACS, defined as STEMI, NSTEMI or unstable angina. Patients with ACS who receive ticagrelor and aspirin may receive drugs only or may also undergo revascularisation with PCI or CABG.\n\n\n\nAdverse events\n\n\n\nThe Committee heard that dyspnoea (shortness of breath), ventricular pauses, increase in serum uric acid and increase in serum creatinine from baseline were statistically significantly more common in the ticagrelor group compared with the clopidogrel group.\n\n\n\n\n\n\n\nThe Committee noted that there was no statistically significant difference in the primary safety end point of major bleeding between ticagrelor and clopidogrel but that patients on ticagrelor plus aspirin experienced more overall major and minor bleeding as well as more major bleeding not related to CABG. The Committee considered that the mortality benefit associated with ticagrelor outweighed the risks and concluded that ticagrelor was a clinically effective treatment option for people with ACS.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe manufacturer based its submission on a large trial, PLATO, which compared ticagrelor plus aspirin with clopidogrel plus aspirin. The PLATO trial was an international, multicentre, randomised, double-blind, double-dummy, parallel group, phase III study.\n\n\n\n\n\nThe manufacturer had performed a large quality of life substudy based on EQ-5D scores.\n\n\n\n\n\nThere was no direct comparison of ticagrelor and prasugrel and there were concerns around the indirect comparison of ticagrelor and prasugrel.\n\n\n\nRelevance to general clinical practice in the NHS\n\n\n\nThe Committee heard from the clinical specialists that overall the trial was representative of the population in the UK, although it was noted that the population in the trial was younger and had a higher proportion of men than the population with ACS in the UK.\n\n\n\n\n\n\n\n\n\nThe standard loading dose of clopidogrel in the UK is 600 mg but only a fifth of patients in the PLATO trial had received this dose. However, the Committee concluded that the trial was broadly reflective of clinical practice in the UK.\n\n\n\nUncertainties generated by the evidence\n\n\n\nThe population in the trial was younger and had a higher proportion of men than people with ACS in the UK, but the manufacturer had taken account of this in its economic modelling. With respect to how representative managing ACS in the PLATO trial was relative to management in the UK, the Committee heard from the clinical specialists that the standard loading dose of clopidogrel in the UK was 600 mg but noted that only a fifth of patients in the trial had received this dose.\n\n\n\n\n\n\n\n\n\nThe Committee was aware that nearly half (46%) of all patients in the study received clopidogrel in hospital before randomisation. However, the Committee noted that the Kaplan–Meier curves depicting the two arms of the trial separated prior to and up to 1 year and, therefore, concluded that the difference in loading doses of clopidogrel was unlikely to have substantially biased the results.\n\n\n\n\n\n\n\nThe Committee noted the concerns of the manufacturer and ERG around the indirect comparison of ticagrelor plus aspirin and prasugrel plus aspirin. The Committee concurred with this view and concluded that the relative effectiveness of ticagrelor plus aspirin and prasugrel plus aspirin was uncertain. The Committee concluded that no separate recommendations could be made for ticagrelor compared with prasugrel.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee noted that among those subgroups defined in the scope (STEMI, NSTEMI, unstable angina) there was no statistically significant evidence of heterogeneity, consistent with no difference in effectiveness of ticagrelor compared to clopidogrel by clinical presentation of ACS. The Committee appreciated that the numbers of patients by subgroup may have been too small to detect a real difference in effectiveness. The Committee heard from the manufacturer that it had not corrected for multiple comparisons when analysing the many subgroups. The Committee noted that neither the test for interaction by clinical presentation of ACS nor the test for interaction by whether a patient had a positive or negative test for troponin were positive (p value for heterogeneity 0.41 and 0.29 respectively). Lastly, no evidence of statistical or biological plausibility was presented to support effect modification by presentation of ACS, and there are no trials using ticagrelor for the primary prevention of cardiovascular disease, that is, in people who had not experienced an acute myocardial infarction. The Committee concluded that providing specific recommendations only for patients with STEMI and NSTEMI and excluding those with unstable angina would be speculative, would counter statistical evidence, and would risk excluding patients who could benefit from treatment with ticagrelor.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee noted that ticagrelor reduced the relative risk of myocardial infarction, stroke and death from vascular causes by 16% compared with clopidogrel.\n\n\n\nThe Committee also noted that if the components of the primary end point were considered individually, ticagrelor plus aspirin statistically significantly reduced myocardial infarctions by 16% and death from vascular causes by 21% compared with clopidogrel plus aspirin. Treatment with ticagrelor plus aspirin reduced the absolute risk of experiencing the primary end point from 11.7% to 9.8% at 12\xa0months compared with clopidogrel plus aspirin.\n\n, 4.3\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nThe manufacturer constructed a two-part cost−utility model with a 1-year decision tree to model effectiveness based on data from the PLATO study, and a Markov model to extrapolate costs and benefits to the lifetime horizon (40\xa0years), and to incorporate major clinical events and resource use.\n\n\n\n\n\n\n\nFor the health economics evaluation of ticagrelor plus aspirin compared with prasugrel plus aspirin, the manufacturer presented the results of a published indirect comparison of the TRITON-TIMI 38 trial and the PLATO trial, conducted by an independent group.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee agreed that the assumption that patients could not have multiple cardiovascular events over-simplified the clinical course of patients with ACS. The Committee noted that if the model had included the possibility of more than one cardiovascular event and an increased risk of further events associated with a first or subsequent event, then the ICERs for ticagrelor compared with clopidogrel would have been lower than in the manufacturer's base case. This is because at the end of the 1-year decision tree, more patients on clopidogrel than on ticagrelor had experienced a myocardial infarction or stroke, and were therefore at higher risk of experiencing another event.\n\n\n\nThe Committee was aware of the ERG's concerns over the method used to adjust for age but agreed that this would not result in major changes to the ICERs.\n\n\n\nThe Committee noted comments from consultees that the adverse event profile should be fully built into the structure of the economic model. The Committee was aware that the 1-year decision tree part of the economic model took account of all costs and changes in quality of life associated with the adverse events of treatment.\n\n\n\nThe Committee was aware of the ERG's concerns about the manufacturer's method of estimating resource use and costs. It was aware that these limitations could skew the differences in total costs between the two treatment arms, and accepted the ERG's adjustments to the manufacturer's model.\n\n, 4.12\n\nIncorporation of health-related quality of life benefits and utility values\n\nThe manufacturer used the 12-month cohort in the PLATO-HECON study to calculate the utility accrued in the study and reported it as the average utility value for a patient over the 12-month period.\n\n\n\n\n\n\n\n\n\nThe Committee noted that it would have been more appropriate to incorporate a utility value reflective of clinical practice rather than modelling the average utility score but acknowledged that this was unlikely to have a large impact on the ICERs.\n\n\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nNot identified.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nSee section on subgroups above.\n\n\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nOnly the change to the costs of the health state in which a patient does not experience an additional cardiovascular event impacted substantially on the results. When the cost of the 'no further event' health state for ticagrelor plus aspirin was set to its lowest, ticagrelor plus aspirin dominated clopidogrel plus aspirin (that is, ticagrelor plus aspirin was more effective and less expensive than clopidogrel plus aspirin), whereas when the cost of the clopidogrel plus aspirin 'no further event' health state was set to its lowest, the ICER was £21,000 per quality-adjusted life year (QALY) gained. Changes in all other parameters did not increase the ICER beyond £7620 per QALY gained.\n\n\n\n\n\n\n\n\n\nResults using time horizons of 1 year, 5 years, 10 years and 20 years were also presented: the ICER differed substantially from the base-case ICER only when using the 1-year time horizon, with an ICER of £33,764 per QALY gained.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nThe Committee accepted the ERG's adjustments to the manufacturer's model and agreed that the central ICERs from the ERG's sensitivity analysis (£7897 per QALY gained for all ACS, £8872 per QALY gained for STEMI, £7215 per QALY gained for NSTEMI and £9131 per QALY gained for unstable angina) represented the most plausible estimates for the cost effectiveness of ticagrelor compared with clopidogrel.\n\n\n\nAdditional factors taken into account\n\nPatient access scheme\n\n\n\nNot applicable\n\n-\n\nEnd-of-life considerations\n\n\n\nNot applicable\n\n-\n\nEqualities considerations, Social value judgements\n\nNo equality issues were identified during the scoping process or the appraisal.\n\n-", 'Recommendations for further research ': 'Clinical trials should be conducted comparing ticagrelor with prasugrel in people with ACS.\n\nFurther research into whether ticagrelor is particularly beneficial in any clinical or biological subgroups would be useful.', 'Related NICE guidance': 'Bivalirudin for the treatment of ST-segment elevation myocardial infarction.NICE technology appraisal guidance 230 (2011).\n\nUnstable angina and NSTEMI: the early management of unstable angina and non-ST-segment-elevation myocardial infarction. NICE clinical guideline 94 (2010).\n\nPrasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention. NICE technology appraisal guidance 182 (2008).\n\nDrug-eluting stents for the treatment of coronary artery disease.NICE technology appraisal guidance 152 (2008).\n\nMI – secondary prevention: secondary prevention in primary and secondary care for patients following a myocardial infarction. NICE clinical guideline 48 (2007).', 'Review of guidance': 'The guidance on this technology for people with STEMI will be incorporated into the forthcoming NICE clinical guideline on the management of myocardial infarction with ST-segment elevation.\n\nThe guidance on ticagrelor for people with NSTEMI and unstable angina will be considered for review at the same time as clinical guideline 94 (Unstable angina and NSTEMI: the early management of unstable angina and non-ST-segment elevation myocardial infarction), that is in March 2013.\n\nAndrew Dillon\n\nChief Executive\n\nOctober 2011', 'Changes after publication': 'February 2014: implementation section updated to clarify that ticagrelor is recommended as an option for treating acute coronary syndromes. Additional minor maintenance update also carried out.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta236
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Evidence-based recommendations on ticagrelor (Brilique) for treating acute coronary syndromes in adults.
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The EOS 2D/3D imaging system
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The EOS 2D/3D imaging system
Evidence-based recommendations on the EOS 2D/3D imaging system for producing 2D and 3D images of the skeleton.
# Recommendations
The EOS 2D/3D imaging system is an emerging technology with potentially important clinical benefits. Current evidence shows there are some patient benefits for people with spinal deformities in terms of radiation dose reduction and increased throughput. However, those benefits alone are insufficient to justify the cost of the system. No clinical evidence was available to quantify the extent of patient benefits from the EOS system's imaging features including 3D reconstruction, weight-bearing whole-body imaging, and simultaneous posteroanterior (PA) and lateral imaging. Therefore, the EOS 2D/3D imaging system is not currently recommended for routine use in the NHS.
NICE encourages use of the EOS 2D/3D imaging system in specialist research settings to collect evidence about potentially important clinical benefits associated with 3D reconstruction, single image weight-bearing whole-body imaging and simultaneous PA and lateral imaging.# The technology
The EOS 2D/3D imaging system (EOS Imaging – formerly Biospace Med) is a novel device that produces 2D images similar to those derived by conventional means as well as 3D reconstructions for some bony body parts. It differs from conventional film, computed, and digital radiography systems in several respects. First, it uses slot-scan technology (that is, scanning a line at a time rather than taking the entire image at the same instant) to vertically scan all or part of the body in a weight-bearing position. Second, it takes simultaneous images in two planes (PA and lateral). Third, by using computer models, it can construct 3D surface images from the simultaneous two-plane images. Additional details are provided in section 4.# Clinical need and practice
# The conditions
The EOS 2D/3D imaging system can be used for many types of radiological examinations, but is likely to offer particular benefits for weight-bearing imaging, full-body imaging, simultaneous PA and lateral imaging, and 3D reconstruction, or where a reduced radiation dose is important.
The experts agreed that the most important applications of this technology for inclusion in the scope were the management of spinal deformities and lower limb problems such as leg length discrepancy, leg alignment and conditions that affect the hip and knee (notably hip and knee replacement planning).
The indications included in the scope can be divided into those affecting children and adolescents, and those affecting adults. Indications in children and adolescents included:
spinal deformity, principally scoliosis but also including other conditions such as Scheuermann's disease
leg length discrepancy and alignment.Indications in adults included:
spinal deformity, including degenerative scoliosis, progressive kyphosis and osteoporotic fractures
loss of sagittal and coronal balance, including issues relating to the hips and knees for which full-body or full leg length images are currently requested.
The management of scoliosis and other spinal deformities involves repeated imaging, which leads to increased radiation exposure, a particular concern for children and adolescents. Leg length discrepancy and leg alignment problems in children and adolescents are often assessed and monitored with multiple images that may require 'stitching' together (that is, aligning and combining).
For adults, the principal spinal deformities are those associated with degenerative diseases that lead to arthritic changes, kyphosis or scoliosis. In some cases, problems resulting from adolescent scoliosis may appear with other symptoms in adulthood. Full leg and hip or full-body radiographs may be used to diagnose and manage degenerative conditions of the hips and knees, and may also be used to plan joint replacement.
During the initial phase of this assessment, the External Assessment Group (EAG) identified no evidence meeting the inclusion criteria for the review for some of the conditions that were initially included in the scope and, therefore, did not include these conditions in the diagnostics assessment report (see appendix C). These conditions included lordosis, acquired kyphosis, neurofibromatosis, osteoporotic fracture and issues relating to hip and knee replacement for which full-body or full leg length images are currently requested. In some cases these conditions can be sufficiently severe to cause significant disability. According to clinical experts, lordosis is very rare on its own and is almost always associated with scoliosis. Therefore the inclusion of scoliosis should encompass patients with lordosis secondary to scoliosis. Acquired kyphosis and neurofibromatosis were excluded because of high variability in patient groups and the relatively small numbers of patients needing surgery. Osteoporotic fracture was not considered because clinical experts advised that it is only rarely associated with spinal deformity.
In addition to the conditions included in the scope, the EOS system is capable of providing most images that are currently done with conventional radiography, the comparator.
# The diagnostic and care pathways
The management of spinal deformity primarily involves monitoring at intervals to assess disease progression and guide treatment decisions. Progression is measured in terms of the degree of spinal curvature, which is typically monitored using serial X-rays in the upright weight-bearing position. The frequency of monitoring depends on the age of the patient, their rate of growth and the nature of the curvature. The frequency of monitoring for kyphosis and other deforming dorsopathies is broadly similar to that for scoliosis, which tends to range from every 4 months to almost 2 years. Patients are also monitored using X-rays in the weight-bearing position before surgery, for up to 2 years after surgery or up to the age of 20 years. Patients with congenital deformities of the lower limbs, hips or spine are likely to undergo surgery at a younger age than patients with scoliosis, kyphosis or other deforming dorsopathies. Therefore, X-ray monitoring for congenital deformities usually continues for a shorter period.
Imaging in the weight-bearing position is important for evaluating deformities of the spine because of the effect of gravity. The American College of Radiology Practice Guideline for the Performance of Radiography for Scoliosis in Children recommends PA and lateral radiography of the spine in an upright position for initial examination or for screening. Imaging in a non-weight-bearing position can lead to misinterpretation of images and misdiagnosis. Full-body images also provide information about the position of the pelvis and legs, and so help to avoid misinterpretation of the degree of spinal curvature.
Erect weight-bearing PA and lateral images of the spine and lower limbs are also used in adults to evaluate sagittal balance and spinal deformity (lordosis and kyphosis) as well as coronal plane deformity (scoliosis). According to NHS Hospital Episode Statistics, admissions for instrumental correction of deformity of the spine (code V41) have nearly doubled to 2643 over the 5-year period ending 2009–2010.# The diagnostic tests
# The referred technology: EOS 2D/3D imaging system
The EOS 2D/3D imaging system is a biplane system that uses slot-scanning technology to produce images of comparable or better quality with less irradiation than standard imaging techniques as well as 3D images of osseous structures. The EOS system allows imaging in an upright weight-bearing (or seated or squatting) position, and can image the full length of the body (up to 175 cm), removing the need for 'stitching' of multiple images. The system takes approximately 20 seconds for an adult full-body scan and 4–6 seconds to scan just the spine, depending on the patient's height. As for all spine radiographs, the patient is asked to remain still, with their arms folded at 45°, and to hold their breath during the scan.
The EOS system takes PA and lateral images simultaneously, using a c-shaped imaging device. The digital image is available immediately on a 2D workstation. A 3D image can be reconstructed on the separate sterEOS workstation using the PA and lateral images and a statistical 3D spine model, generated from data from multiple patients. The reconstruction of a 3D image takes 5–10 minutes for each part of the skeleton (for example, the spine or femur). The EOS system takes up a similar amount of space and uses a similar amount of power as other computed or digital X-ray suites.
The acquisition cost of the EOS system in the UK is approximately £400,000, with a current annual maintenance cost of approximately £32,000. The maintenance contract covers all parts except X-ray tubes, which require replacement every 3–5 years at a cost of approximately £25,000 (including fitting). In addition to the cost of purchasing and maintaining the equipment, there may be some building costs if existing rooms complying with radiation legislation requirements are not available. The EOS system requires the same room planning and shielding as a general X-ray room and the same radiation protection protocols apply. The EOS system is not currently in general use in the NHS, although it has been used in research settings.
# The comparator: conventional radiography
Currently available imaging technologies that can be used in an upright weight-bearing position include X-ray film, computed radiography and digital radiography, although X-ray film has been replaced by computed radiography and digital radiography in standard UK practice. X-ray film, computed radiography and digital radiography can only take images from one angle at a time; simultaneous PA and lateral images, and 3D reconstruction are not possible. When a full-body image is required, these conventional X-ray imaging technologies need adjustment for distortion or stitching of multiple images.
The acquisition cost of a computed radiography system is approximately £95,000, with an annual maintenance cost of approximately £10,000. Cassettes for computed radiography need replacing every 3–5 years at a cost of £150–200. The acquisition cost of a digital radiography system is between approximately £105,000 and £230,000, with an annual maintenance cost of approximately £18,000. Upgrading software to improve the functionality and performance of digital radiography costs approximately £2000 and was assumed to occur every 4 years.# Outcomes
The Diagnostics Advisory Committee (appendix B) considered a review of the evidence by the External Assessment Group (EAG, appendix C).
# How outcomes were assessed
The assessment consisted of a systematic review of clinical effectiveness data for the EOS system for the conditions described in the scope, followed by modelling to assess final patient outcomes and cost effectiveness when evidence was found. No studies followed patients to final outcomes, and therefore modelling was necessary to assess clinical effectiveness as well as cost effectiveness. Descriptions of the assessment process are contained in chapter 4 of the diagnostics assessment report. The only relevant data uncovered dealt with image quality and radiation dose reduction.
Three studies of image quality were found – two comparing the EOS system with X-ray film (Kalifa et al. 1998; Le Bras et al. unpublished data) and one comparing it with computed radiography (Deschênes et al. 2010). All found images from the EOS system to be comparable with or better than the comparator in most cases.
These three studies also reported radiation dose reductions with ratios of means ranging from 2.9 to 18.8, depending on the study and body part imaged. No direct comparisons with digital radiography were found, but similar dose reductions were assumed in the base-case models. A separate scenario assuming that digital radiography used two-thirds the radiation dose of computed radiography was also modelled.
Additional reviews were conducted to establish the impact of radiation dose reduction. Two different approaches to modelling cancer risk, identified in these reviews, were included in the assessment. These included data from a personal communication from the Health Protection Agency and data from the BIER VII phase 2 report.
# Test accuracy: intermediate outcomes
No data meeting the inclusion criteria for the review were found to specifically compare the diagnostic accuracy of the EOS system with that of conventional radiological examinations beyond the three studies (described above), which showed comparable or better images. No evidence for sensitivity and specificity of the EOS system for any specific condition was uncovered.
# Clinical outcomes
The only clinical outcomes assessed came from modelling, and were focused on the impact of radiation dose reduction in people with spinal deformities. Although direct evidence was available showing significant radiation dose reductions with the EOS system, modelling was needed to link dose reduction to reduced cancer occurrence. The base-case analysis used computed radiography as the comparator. Modelling of digital radiography was also performed as part of sensitivity analyses. Extensive modelling of the impact of radiation dose on future cancer was performed. The basic structure of the model is shown in appendix A. The modelling explored only the most prevalent forms of cancer, namely breast, lung, colorectal and prostate. In the base case, incremental quality-adjusted life years (QALYs) from cancer reduction as a result of radiation dose reduction varied by indication from about 0.0001 to 0.0009.
The original scope included spinal deformities (most of which were included in the model) and lower limb problems (which were excluded from the model because of a lack of evidence meeting inclusion criteria). In addition, the EOS system could be used for other conditions in which conventional radiography would usually be used. People with these other conditions might benefit from a reduced radiation dose as well. The EOS system also offers imaging enhancement for spinal conditions and lower limb problems, but the benefit associated with this enhancement could not be estimated from the existing evidence.
# Cost and cost effectiveness
The EOS system costs 3–4 times as much as computed radiography machines and 2–3 times as much as digital radiography machines.
The cost-effectiveness analysis was performed using cancer reduction as the primary measure of benefit. The impact of throughput on cost effectiveness was modelled using three different assumptions about the throughput of the EOS system. The base-case throughput assumption (TA1) was based on using a single machine for the entire country and limiting use to only the number of cases of the studied conditions that actually exist in the country, with no other use of the machine. Additional throughput assumptions were based on full use of the machine for the indicated uses at the same throughput as computed radiography, namely 30 cases per day (TA2), or at a higher throughput, specifically, 48 cases per day (TA3). Because there are not enough cases of the indicated conditions to make full use of the machine, these last two assumptions were used to explore the impact on cost effectiveness of full use of the machine. If a machine that was fully used imaging the indicated conditions was found to be cost effective, then further analysis would have been needed to determine whether a machine partially used for the indicated conditions and also used for other conditions could still be cost effective. Thirty cases per day was the assumed rate of utilisation of the comparator. One reason the higher throughput of 48 cases per day may be justified is that the EOS system can take simultaneous PA and lateral images.
The base-case analysis showed the incremental cost-effectiveness ratio (ICER) to range from approximately £148,000 to over £15,000,000 per QALY gained, depending on the indicated use. The width of this range is primarily because the base case limits the use of the machine to the estimated number of cases of the studied conditions. For the throughput assumptions that are not limited by number of cases, the ICERs range from about £97,000 to £700,000 per QALY gained (TA2) and from £47,000 to £351,000 per QALY gained (TA3).
Additional scenarios modelled included:
earlier age for cancer diagnosis (55 years versus the average age of diagnosis in the population for the cancers modelled)
reduced discount rate for both costs and benefits (0% versus 3.5%)
further reductions in radiation dose (3 times the reduction of base case)
probabilistic modelling of QALYs gained from cancer reduction
increased cancer risk from radiation (using 1999 US data versus newer models from the Health Protection Agency)
comparison with digital radiography (with digital radiography assumed to have a dose rate of two-thirds that of computed radiography).
None of these scenarios reduced the ICER to less than £30,000 using the throughput assumptions TA1 and TA2. The earlier age for cancer diagnosis or the alternative risk data reduced the ICER to less than £30,000 for scoliosis and Scheuermann's disease in adolescents for throughput assumption TA3.
Threshold analysis was performed to determine what level of additional benefits from imaging improvements would be required to reach levels that might normally be considered cost effective for each of the three throughput assumptions. This showed that additional QALYs required for cost effectiveness ranged from 0.0002 to 0.435, depending on the throughput assumptions and the condition being imaged. Threshold analyses of QALY gains required to reach an ICER of £20,000 under the six additional scenarios listed above varied from less than 0.001 to over 700 depending on the scenario, the condition, and the throughput assumptions.# Considerations
The Diagnostics Advisory Committee was informed that the evidence suggests that the EOS system creates images with significant radiation dose reductions compared with other modalities. However, there was uncertainty about the overall impact of that benefit. The External Assessment Group explored one scenario in which cancers were averted at the same time as similar cancers not caused by radiation and one scenario in which cancer occurred at the earlier age of 55. The Committee understood that cancers induced by radiation may occur even earlier, and averting these would result in increased QALYs. The Committee also heard that some rare conditions, such as congenital scoliosis, arising from complex genetic syndromes, might make people more susceptible to radiation damage. The Committee identified no other equality issues.
The Committee noted that the EOS system may provide throughput improvements because it takes simultaneous images in two planes, but no evidence meeting inclusion criteria was available to quantify these improvements.
The Committee noted that for the EOS system to be cost effective, benefits relating to the nature of the image need to translate into health benefits for patients. For example, the full-body weight-bearing image generated by the EOS system should provide more accurate information, which might translate into an improved management strategy, and consequently into a health benefit.
On the basis of clinical advice, the Committee considered that the EOS system could be an important emerging technology and could offer significant benefits from imaging improvements resulting in better clinical decision-making. The imaging improvements include 3D reconstruction, simultaneous PA and lateral imaging, and whole-body imaging in a single image. Health outcome benefits could result from better decisions about surgery, in particular planning hip and knee replacements, for which knowledge of the position of the pelvis can be important, and possibly managing rare skeletal conditions in children. Other health outcome benefits are possible. No evidence was available for the use of the EOS system for these purposes. Thus, the Committee considered further research into these benefits to be necessary and that use of the EOS system in a research setting to develop estimates of these benefits was warranted.
The Committee particularly felt there could be specific benefits from the use of the 3D reconstruction from weight-bearing images for both spinal and lower limb conditions. Such reconstructed 3D images are not currently available with existing imaging equipment and are a unique aspect of the EOS system. The Committee was unclear about the magnitude of any such benefits, although clinical specialists advised the Committee that such benefits may exist. For example, curvature in multiple planes may more accurately predict worsening of scoliosis than the standard approach, which is by measuring the Cobb angle. No data were found to substantiate these benefits.
Based on current evidence, the Committee did not consider that the EOS system would be a cost-effective use of NHS resources given the cost of the system and the size of the benefits associated with radiation dose reduction and possible throughput improvements.
As discussed in section 5.7, the EOS system was evaluated primarily for patients with spinal deformities. The Committee noted that these are not common enough to allow an EOS system to be fully utilised in most settings. In the Committee's view, even adding people with all the conditions included in the scope would not be likely to fully utilise many of the machines that would be needed by the NHS. The EOS system can also be used for other conditions in which conventional radiography would usually be used. The Committee considered that all people having imaging with the EOS system might gain from the reduced radiation dose and the system might provide throughput improvements. The Committee considered that these benefits were likely to be similar to those in people with spinal conditions (see section 5.6). Considering only these benefits and based on current costs and evidence, it is unlikely that the EOS system would represent a cost-effective use of NHS resources. The EOS system might be found to be cost effective if sufficient benefits arising from the imaging improvements are identified in people with spinal conditions or lower limb problems. These benefits would need to be established by further research.# Recommendations for further research
Research is needed to quantify the health outcome benefits associated with imaging improvements with the EOS system. Examples of such benefits might include reduced back pain or reduced postural difficulties in people with scoliosis, or longer lasting and less painful joint replacements. Although research into the use of the EOS system is appropriate for all the indications included in the scope, the research most likely to be useful is for planning hip and knee replacement, including patient selection, device selection, and surgical approach. Joint replacement operations are more common than the other indications and the EOS system is thought to be most likely to provide benefit to these patients.
Additional methodological research is needed to determine the most appropriate model structures to assess the benefit arising from radiation dose reduction. Additional work is needed to assess when the radiation-induced cancers actually occur and the impact of the timing of the emergence of cancer on health status.
Research is needed to determine whether, and for which conditions, use of the EOS system for 3D reconstruction provides benefit for diagnosis or treatment planning.# Related NICE guidance
There is no related NICE guidance.# Review
No specific time for review has been set, but NICE will monitor improvements in the evidence base for the EOS system to determine when a review would be appropriate.
Andrew DillonChief ExecutiveOctober 2011# Appendix A Schematic representation of the modelling approach
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{'Recommendations': "The EOS 2D/3D imaging system is an emerging technology with potentially important clinical benefits. Current evidence shows there are some patient benefits for people with spinal deformities in terms of radiation dose reduction and increased throughput. However, those benefits alone are insufficient to justify the cost of the system. No clinical evidence was available to quantify the extent of patient benefits from the EOS system's imaging features including 3D reconstruction, weight-bearing whole-body imaging, and simultaneous posteroanterior (PA) and lateral imaging. Therefore, the EOS 2D/3D imaging system is not currently recommended for routine use in the NHS.\n\nNICE encourages use of the EOS 2D/3D imaging system in specialist research settings to collect evidence about potentially important clinical benefits associated with 3D reconstruction, single image weight-bearing whole-body imaging and simultaneous PA and lateral imaging.", 'The technology': 'The EOS 2D/3D imaging system (EOS Imaging – formerly Biospace Med) is a novel device that produces 2D images similar to those derived by conventional means as well as 3D reconstructions for some bony body parts. It differs from conventional film, computed, and digital radiography systems in several respects. First, it uses slot-scan technology (that is, scanning a line at a time rather than taking the entire image at the same instant) to vertically scan all or part of the body in a weight-bearing position. Second, it takes simultaneous images in two planes (PA and lateral). Third, by using computer models, it can construct 3D surface images from the simultaneous two-plane images. Additional details are provided in section 4.', 'Clinical need and practice': "# The conditions\n\nThe EOS 2D/3D imaging system can be used for many types of radiological examinations, but is likely to offer particular benefits for weight-bearing imaging, full-body imaging, simultaneous PA and lateral imaging, and 3D reconstruction, or where a reduced radiation dose is important.\n\nThe experts agreed that the most important applications of this technology for inclusion in the scope were the management of spinal deformities and lower limb problems such as leg length discrepancy, leg alignment and conditions that affect the hip and knee (notably hip and knee replacement planning).\n\nThe indications included in the scope can be divided into those affecting children and adolescents, and those affecting adults. Indications in children and adolescents included:\n\nspinal deformity, principally scoliosis but also including other conditions such as Scheuermann's disease\n\nleg length discrepancy and alignment.Indications in adults included:\n\nspinal deformity, including degenerative scoliosis, progressive kyphosis and osteoporotic fractures\n\nloss of sagittal and coronal balance, including issues relating to the hips and knees for which full-body or full leg length images are currently requested.\n\nThe management of scoliosis and other spinal deformities involves repeated imaging, which leads to increased radiation exposure, a particular concern for children and adolescents. Leg length discrepancy and leg alignment problems in children and adolescents are often assessed and monitored with multiple images that may require 'stitching' together (that is, aligning and combining).\n\nFor adults, the principal spinal deformities are those associated with degenerative diseases that lead to arthritic changes, kyphosis or scoliosis. In some cases, problems resulting from adolescent scoliosis may appear with other symptoms in adulthood. Full leg and hip or full-body radiographs may be used to diagnose and manage degenerative conditions of the hips and knees, and may also be used to plan joint replacement.\n\nDuring the initial phase of this assessment, the External Assessment Group (EAG) identified no evidence meeting the inclusion criteria for the review for some of the conditions that were initially included in the scope and, therefore, did not include these conditions in the diagnostics assessment report (see appendix C). These conditions included lordosis, acquired kyphosis, neurofibromatosis, osteoporotic fracture and issues relating to hip and knee replacement for which full-body or full leg length images are currently requested. In some cases these conditions can be sufficiently severe to cause significant disability. According to clinical experts, lordosis is very rare on its own and is almost always associated with scoliosis. Therefore the inclusion of scoliosis should encompass patients with lordosis secondary to scoliosis. Acquired kyphosis and neurofibromatosis were excluded because of high variability in patient groups and the relatively small numbers of patients needing surgery. Osteoporotic fracture was not considered because clinical experts advised that it is only rarely associated with spinal deformity.\n\nIn addition to the conditions included in the scope, the EOS system is capable of providing most images that are currently done with conventional radiography, the comparator.\n\n# The diagnostic and care pathways\n\nThe management of spinal deformity primarily involves monitoring at intervals to assess disease progression and guide treatment decisions. Progression is measured in terms of the degree of spinal curvature, which is typically monitored using serial X-rays in the upright weight-bearing position. The frequency of monitoring depends on the age of the patient, their rate of growth and the nature of the curvature. The frequency of monitoring for kyphosis and other deforming dorsopathies is broadly similar to that for scoliosis, which tends to range from every 4 months to almost 2 years. Patients are also monitored using X-rays in the weight-bearing position before surgery, for up to 2 years after surgery or up to the age of 20 years. Patients with congenital deformities of the lower limbs, hips or spine are likely to undergo surgery at a younger age than patients with scoliosis, kyphosis or other deforming dorsopathies. Therefore, X-ray monitoring for congenital deformities usually continues for a shorter period.\n\nImaging in the weight-bearing position is important for evaluating deformities of the spine because of the effect of gravity. The American College of Radiology Practice Guideline for the Performance of Radiography for Scoliosis in Children recommends PA and lateral radiography of the spine in an upright position for initial examination or for screening. Imaging in a non-weight-bearing position can lead to misinterpretation of images and misdiagnosis. Full-body images also provide information about the position of the pelvis and legs, and so help to avoid misinterpretation of the degree of spinal curvature.\n\nErect weight-bearing PA and lateral images of the spine and lower limbs are also used in adults to evaluate sagittal balance and spinal deformity (lordosis and kyphosis) as well as coronal plane deformity (scoliosis). According to NHS Hospital Episode Statistics, admissions for instrumental correction of deformity of the spine (code V41) have nearly doubled to 2643 over the 5-year period ending 2009–2010.", 'The diagnostic tests': "# The referred technology: EOS 2D/3D imaging system\n\nThe EOS 2D/3D imaging system is a biplane system that uses slot-scanning technology to produce images of comparable or better quality with less irradiation than standard imaging techniques as well as 3D images of osseous structures. The EOS system allows imaging in an upright weight-bearing (or seated or squatting) position, and can image the full length of the body (up to 175 cm), removing the need for 'stitching' of multiple images. The system takes approximately 20 seconds for an adult full-body scan and 4–6 seconds to scan just the spine, depending on the patient's height. As for all spine radiographs, the patient is asked to remain still, with their arms folded at 45°, and to hold their breath during the scan.\n\nThe EOS system takes PA and lateral images simultaneously, using a c-shaped imaging device. The digital image is available immediately on a 2D workstation. A 3D image can be reconstructed on the separate sterEOS workstation using the PA and lateral images and a statistical 3D spine model, generated from data from multiple patients. The reconstruction of a 3D image takes 5–10 minutes for each part of the skeleton (for example, the spine or femur). The EOS system takes up a similar amount of space and uses a similar amount of power as other computed or digital X-ray suites.\n\nThe acquisition cost of the EOS system in the UK is approximately £400,000, with a current annual maintenance cost of approximately £32,000. The maintenance contract covers all parts except X-ray tubes, which require replacement every 3–5 years at a cost of approximately £25,000 (including fitting). In addition to the cost of purchasing and maintaining the equipment, there may be some building costs if existing rooms complying with radiation legislation requirements are not available. The EOS system requires the same room planning and shielding as a general X-ray room and the same radiation protection protocols apply. The EOS system is not currently in general use in the NHS, although it has been used in research settings.\n\n# The comparator: conventional radiography\n\nCurrently available imaging technologies that can be used in an upright weight-bearing position include X-ray film, computed radiography and digital radiography, although X-ray film has been replaced by computed radiography and digital radiography in standard UK practice. X-ray film, computed radiography and digital radiography can only take images from one angle at a time; simultaneous PA and lateral images, and 3D reconstruction are not possible. When a full-body image is required, these conventional X-ray imaging technologies need adjustment for distortion or stitching of multiple images.\n\nThe acquisition cost of a computed radiography system is approximately £95,000, with an annual maintenance cost of approximately £10,000. Cassettes for computed radiography need replacing every 3–5 years at a cost of £150–200. The acquisition cost of a digital radiography system is between approximately £105,000 and £230,000, with an annual maintenance cost of approximately £18,000. Upgrading software to improve the functionality and performance of digital radiography costs approximately £2000 and was assumed to occur every 4 years.", 'Outcomes': "The Diagnostics Advisory Committee (appendix B) considered a review of the evidence by the External Assessment Group (EAG, appendix C).\n\n# How outcomes were assessed\n\nThe assessment consisted of a systematic review of clinical effectiveness data for the EOS system for the conditions described in the scope, followed by modelling to assess final patient outcomes and cost effectiveness when evidence was found. No studies followed patients to final outcomes, and therefore modelling was necessary to assess clinical effectiveness as well as cost effectiveness. Descriptions of the assessment process are contained in chapter 4 of the diagnostics assessment report. The only relevant data uncovered dealt with image quality and radiation dose reduction.\n\nThree studies of image quality were found – two comparing the EOS system with X-ray film (Kalifa et al. 1998; Le Bras et al. unpublished data) and one comparing it with computed radiography (Deschênes et al. 2010). All found images from the EOS system to be comparable with or better than the comparator in most cases.\n\nThese three studies also reported radiation dose reductions with ratios of means ranging from 2.9 to 18.8, depending on the study and body part imaged. No direct comparisons with digital radiography were found, but similar dose reductions were assumed in the base-case models. A separate scenario assuming that digital radiography used two-thirds the radiation dose of computed radiography was also modelled.\n\nAdditional reviews were conducted to establish the impact of radiation dose reduction. Two different approaches to modelling cancer risk, identified in these reviews, were included in the assessment. These included data from a personal communication from the Health Protection Agency and data from the BIER VII phase 2 report.\n\n# Test accuracy: intermediate outcomes\n\nNo data meeting the inclusion criteria for the review were found to specifically compare the diagnostic accuracy of the EOS system with that of conventional radiological examinations beyond the three studies (described above), which showed comparable or better images. No evidence for sensitivity and specificity of the EOS system for any specific condition was uncovered.\n\n# Clinical outcomes\n\nThe only clinical outcomes assessed came from modelling, and were focused on the impact of radiation dose reduction in people with spinal deformities. Although direct evidence was available showing significant radiation dose reductions with the EOS system, modelling was needed to link dose reduction to reduced cancer occurrence. The base-case analysis used computed radiography as the comparator. Modelling of digital radiography was also performed as part of sensitivity analyses. Extensive modelling of the impact of radiation dose on future cancer was performed. The basic structure of the model is shown in appendix A. The modelling explored only the most prevalent forms of cancer, namely breast, lung, colorectal and prostate. In the base case, incremental quality-adjusted life years (QALYs) from cancer reduction as a result of radiation dose reduction varied by indication from about 0.0001 to 0.0009.\n\nThe original scope included spinal deformities (most of which were included in the model) and lower limb problems (which were excluded from the model because of a lack of evidence meeting inclusion criteria). In addition, the EOS system could be used for other conditions in which conventional radiography would usually be used. People with these other conditions might benefit from a reduced radiation dose as well. The EOS system also offers imaging enhancement for spinal conditions and lower limb problems, but the benefit associated with this enhancement could not be estimated from the existing evidence.\n\n# Cost and cost effectiveness\n\nThe EOS system costs 3–4 times as much as computed radiography machines and 2–3 times as much as digital radiography machines.\n\nThe cost-effectiveness analysis was performed using cancer reduction as the primary measure of benefit. The impact of throughput on cost effectiveness was modelled using three different assumptions about the throughput of the EOS system. The base-case throughput assumption (TA1) was based on using a single machine for the entire country and limiting use to only the number of cases of the studied conditions that actually exist in the country, with no other use of the machine. Additional throughput assumptions were based on full use of the machine for the indicated uses at the same throughput as computed radiography, namely 30 cases per day (TA2), or at a higher throughput, specifically, 48 cases per day (TA3). Because there are not enough cases of the indicated conditions to make full use of the machine, these last two assumptions were used to explore the impact on cost effectiveness of full use of the machine. If a machine that was fully used imaging the indicated conditions was found to be cost effective, then further analysis would have been needed to determine whether a machine partially used for the indicated conditions and also used for other conditions could still be cost effective. Thirty cases per day was the assumed rate of utilisation of the comparator. One reason the higher throughput of 48 cases per day may be justified is that the EOS system can take simultaneous PA and lateral images.\n\nThe base-case analysis showed the incremental cost-effectiveness ratio (ICER) to range from approximately £148,000 to over £15,000,000 per QALY gained, depending on the indicated use. The width of this range is primarily because the base case limits the use of the machine to the estimated number of cases of the studied conditions. For the throughput assumptions that are not limited by number of cases, the ICERs range from about £97,000 to £700,000 per QALY gained (TA2) and from £47,000 to £351,000 per QALY gained (TA3).\n\nAdditional scenarios modelled included:\n\nearlier age for cancer diagnosis (55 years versus the average age of diagnosis in the population for the cancers modelled)\n\nreduced discount rate for both costs and benefits (0% versus 3.5%)\n\nfurther reductions in radiation dose (3 times the reduction of base case)\n\nprobabilistic modelling of QALYs gained from cancer reduction\n\nincreased cancer risk from radiation (using 1999 US data [BIER VII phase 2] versus newer models from the Health Protection Agency)\n\ncomparison with digital radiography (with digital radiography assumed to have a dose rate of two-thirds that of computed radiography).\n\nNone of these scenarios reduced the ICER to less than £30,000 using the throughput assumptions TA1 and TA2. The earlier age for cancer diagnosis or the alternative risk data reduced the ICER to less than £30,000 for scoliosis and Scheuermann's disease in adolescents for throughput assumption TA3.\n\nThreshold analysis was performed to determine what level of additional benefits from imaging improvements would be required to reach levels that might normally be considered cost effective for each of the three throughput assumptions. This showed that additional QALYs required for cost effectiveness ranged from 0.0002 to 0.435, depending on the throughput assumptions and the condition being imaged. Threshold analyses of QALY gains required to reach an ICER of £20,000 under the six additional scenarios listed above varied from less than 0.001 to over 700 depending on the scenario, the condition, and the throughput assumptions.", 'Considerations': "The Diagnostics Advisory Committee was informed that the evidence suggests that the EOS system creates images with significant radiation dose reductions compared with other modalities. However, there was uncertainty about the overall impact of that benefit. The External Assessment Group explored one scenario in which cancers were averted at the same time as similar cancers not caused by radiation and one scenario in which cancer occurred at the earlier age of 55. The Committee understood that cancers induced by radiation may occur even earlier, and averting these would result in increased QALYs. The Committee also heard that some rare conditions, such as congenital scoliosis, arising from complex genetic syndromes, might make people more susceptible to radiation damage. The Committee identified no other equality issues.\n\nThe Committee noted that the EOS system may provide throughput improvements because it takes simultaneous images in two planes, but no evidence meeting inclusion criteria was available to quantify these improvements.\n\nThe Committee noted that for the EOS system to be cost effective, benefits relating to the nature of the image need to translate into health benefits for patients. For example, the full-body weight-bearing image generated by the EOS system should provide more accurate information, which might translate into an improved management strategy, and consequently into a health benefit.\n\nOn the basis of clinical advice, the Committee considered that the EOS system could be an important emerging technology and could offer significant benefits from imaging improvements resulting in better clinical decision-making. The imaging improvements include 3D reconstruction, simultaneous PA and lateral imaging, and whole-body imaging in a single image. Health outcome benefits could result from better decisions about surgery, in particular planning hip and knee replacements, for which knowledge of the position of the pelvis can be important, and possibly managing rare skeletal conditions in children. Other health outcome benefits are possible. No evidence was available for the use of the EOS system for these purposes. Thus, the Committee considered further research into these benefits to be necessary and that use of the EOS system in a research setting to develop estimates of these benefits was warranted.\n\nThe Committee particularly felt there could be specific benefits from the use of the 3D reconstruction from weight-bearing images for both spinal and lower limb conditions. Such reconstructed 3D images are not currently available with existing imaging equipment and are a unique aspect of the EOS system. The Committee was unclear about the magnitude of any such benefits, although clinical specialists advised the Committee that such benefits may exist. For example, curvature in multiple planes may more accurately predict worsening of scoliosis than the standard approach, which is by measuring the Cobb angle. No data were found to substantiate these benefits.\n\nBased on current evidence, the Committee did not consider that the EOS system would be a cost-effective use of NHS resources given the cost of the system and the size of the benefits associated with radiation dose reduction and possible throughput improvements.\n\nAs discussed in section 5.7, the EOS system was evaluated primarily for patients with spinal deformities. The Committee noted that these are not common enough to allow an EOS system to be fully utilised in most settings. In the Committee's view, even adding people with all the conditions included in the scope would not be likely to fully utilise many of the machines that would be needed by the NHS. The EOS system can also be used for other conditions in which conventional radiography would usually be used. The Committee considered that all people having imaging with the EOS system might gain from the reduced radiation dose and the system might provide throughput improvements. The Committee considered that these benefits were likely to be similar to those in people with spinal conditions (see section 5.6). Considering only these benefits and based on current costs and evidence, it is unlikely that the EOS system would represent a cost-effective use of NHS resources. The EOS system might be found to be cost effective if sufficient benefits arising from the imaging improvements are identified in people with spinal conditions or lower limb problems. These benefits would need to be established by further research.", 'Recommendations for further research': 'Research is needed to quantify the health outcome benefits associated with imaging improvements with the EOS system. Examples of such benefits might include reduced back pain or reduced postural difficulties in people with scoliosis, or longer lasting and less painful joint replacements. Although research into the use of the EOS system is appropriate for all the indications included in the scope, the research most likely to be useful is for planning hip and knee replacement, including patient selection, device selection, and surgical approach. Joint replacement operations are more common than the other indications and the EOS system is thought to be most likely to provide benefit to these patients.\n\nAdditional methodological research is needed to determine the most appropriate model structures to assess the benefit arising from radiation dose reduction. Additional work is needed to assess when the radiation-induced cancers actually occur and the impact of the timing of the emergence of cancer on health status.\n\nResearch is needed to determine whether, and for which conditions, use of the EOS system for 3D reconstruction provides benefit for diagnosis or treatment planning.', 'Related NICE guidance': 'There is no related NICE guidance.', 'Review': 'No specific time for review has been set, but NICE will monitor improvements in the evidence base for the EOS system to determine when a review would be appropriate.\n\nAndrew DillonChief ExecutiveOctober 2011', 'Appendix A Schematic representation of the modelling approach': ''}
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https://www.nice.org.uk/guidance/dg1
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Evidence-based recommendations on the EOS 2D/3D imaging system for producing 2D and 3D images of the skeleton.
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85b1cfed5b2be8df6b1248d006041d89655d4a1a
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nice
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Minimally invasive oesophagectomy
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Minimally invasive oesophagectomy
# Important information about this guidance
This document replaces previous guidance on thoracoscopically assisted oesophagectomy (interventional procedure guidance 189).# Guidance
Current evidence on the efficacy and safety of minimally invasive oesophagectomy (MIO) is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit with local review of results.
Patient selection should be done by a multidisciplinary team specialising in the management of oesophageal cancer.
MIO is a technically challenging procedure, which should only be carried out by surgeons with special expertise and specific training. They should perform their initial operations with an experienced mentor.
Clinicians should enter details about all patients undergoing MIO onto the National Oesophago-gastric Cancer Audit (www.ic.nhs.uk/services/national-clinical-audit-support-programme-ncasp/cancer).# The procedure
# Indications and current treatments
Oesophagectomy is used to treat resectable cancer of the oesophagus. It is also a treatment option for Barrett's oesophagus with high-grade dysplasia. Conventionally, oesophagectomy is performed using open surgery.
Depending on the tumour type, location and stage, oesophagectomy may involve a total or partial resection of the oesophagus, with or without dissection of regional lymph nodes. Total oesophagectomy involves both a thoracic incision to mobilise the oesophagus and an abdominal incision to dissect and prepare the stomach (or sometimes intestine) for anastomosis to the remaining upper oesophagus or pharynx. The new gastric tube is then drawn up the chest to the level of the healthy oesophageal remnant, and an anastomosis is performed, usually via a cervical incision. In some patients (typically with lower-third tumours), partial oesophagectomy may be carried out transhiatally using only an abdominal incision. There are a number of technical variations in the way the open oesophagectomy can be done.
# Outline of the procedure
MIO aims to achieve the same result as open oesophagectomy but with less postoperative morbidity.
The procedure is performed with the patient under general anaesthesia. Single-lung ventilation is required for the thoracic part of the operation (except for transhiatal techniques). MIO involves performing oesophagectomy under thoracoscopic and laparoscopic visualisation. However, hybrid MIO (HMIO) techniques, which combine either thoracoscopy or laparoscopy with open surgery (for the abdominal or the thoracic component of the procedure respectively), are also described as minimally invasive.
Thoracic and/or abdominal CO2 insufflation is used, and a number of incisions are made to accommodate camera and instrument ports. Following resection of the oesophagus, anastomosis is performed either via an (open) cervical approach or an intrathoracic endoscopic approach using stapling devices.
MIO is a complex procedure and the operating time may be long.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/326/overview
# Efficacy
A study of routine hospital episodes statistics data compared 699 patients treated by MIO or HMIO versus 17,974 patients treated by open oesophagectomy. Based on data available for 41% (7724/18,673) of patients, and after adjusting for age, gender, socioeconomic deprivation, comorbidity score, year of operation and number of emergency hospital admissions in the previous year, there was some evidence that patients undergoing MIO or HMIO had lower 1-year mortality than patients treated by open oesophagectomy (odds ratio 0.68, 95% confidence interval 0.46 to 1.01, p = 0.058).
Two non-randomised studies comparing HMIO versus open oesophagectomy reported cancer recurrence rates of 6% (1/17) and 0% (0/14) respectively (undefined follow-up interval); and 19% (3/16) and 7% (2/28) at 44-month follow-up (significance not stated). Three non-randomised comparative studies, including in total 143 patients, 73 treated by HMIO and 70 treated by open surgery, reported recurrence rates ranging from 0% to 44% in patients treated by HMIO and from 3% to 50% in those treated by open surgery (follow-up ranging from 6 months to 54 months). Another non-randomised comparative study comparing 165 patients treated by HMIO versus 56 treated by open surgery reported no significant association for either technique with cancer recurrence (rate of recurrence: 58% for HMIO and 68% for open surgery; follow-up not stated).
A non-randomised comparative study comparing 27 patients treated by HMIO against 29 patients treated by open surgery assessed quality of life in 5 domains of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-OES18 questionnaires (fatigue, pain, dyspnoea, physical functioning, global quality of life). Both patient groups had similar preoperative scores. Compared with baseline, quality of life scores deteriorated in all 5 domains at 2 weeks in both groups, although the scores were worse in the open surgery group. Over time, quality of life scores improved in both groups. At 24-week follow-up there were statistically significant differences between the 2 groups for physical functioning (mean score of 84 for HMIO vs 76 for open surgery) and global quality of life (mean score of 75 for HMIO vs 68 in the open surgery group).
The Specialist Advisers considered key efficacy outcomes to include speed of postoperative recovery compared with open surgery, cancer recurrence, overall survival, quality of life, and more frequent need for cervical anastomosis compared with open surgery.
# Safety
Thirty-day in-hospital mortality was reported as 2% (1/50) in patients treated by MIO and 3% (1/30) in patients treated by open surgery in a non‑randomised comparative study of 80 patients. Two non-randomised comparative studies comparing 15 and 18 patients treated by MIO with 30 and 36 patients treated by open surgery, respectively, reported no in-hospital deaths within 30 days of the procedure. A non-randomised comparative study of 90 patients reported 30-day in-hospital mortality of 7% (3/44) after MIO and 4% (2/46) after open oesophagectomy.
Two non-randomised comparative studies reported 30-day in-hospital mortality of 2% (1/45) and 5% (1/22) in patients treated by HMIO, while no deaths were reported in the 26 and 63 patients treated by open oesophagectomy. Six non-randomised comparative studies comparing a total of 475 patients treated by MIO with 434 treated by open surgery reported that 30-day in-hospital mortality was higher after open surgery (10% vs 14%, 6% vs 11%, 0% vs 5%, 0% vs 7%, 3% vs 6%, and 3% vs 8%; level of significance not stated).
Two non-randomised comparative studies reported 30-day in-hospital mortality of 5% (1/22) and 4% (2/56) in patients treated by MIO or HMIO, and 9% (4/43) or 6% (6/98) in those treated by open oesophagectomy (follow-up and significance not stated).
In the study of routine hospital episodes statistics data comparing 699 patients treated by MIO or HMIO versus 17,974 patients treated by open oesophagectomy, and based on data available for 49% (9217/18,673) of patients, after adjusting for age, gender, socioeconomic deprivation, comorbidity score, year of operation, and number of emergency hospital admissions in the previous year, there was no significant difference between the comparator groups for 30-day in-hospital mortality (OR = 0.99, 95% CI 0.68 to 1.44, p = 0.936).
A non-randomised comparative study of 41 patients treated by MIO, 34 by HMIO and 46 by open surgery reported 30-day in-hospital mortalities of 2%, 6% and 2% respectively. A non-randomised comparative study of 23 patients treated by MIO, 309 by HMIO and 114 by open surgery reported 30-day in‑hospital mortalities of 0%, 2% and 3% respectively.
Anastomotic leakage rates ranged from 0% to 20% among patients treated by either MIO or HMIO, and from 2% to 29% among patients treated by open surgery in 21 non-randomised comparative studies (total number of patients: 1371 MIO or HMIO, 1114 open). Among patients with anastomotic leakage, rates of reoperation ranged from 0% to 19% in patients treated by MIO or HMIO and from 0% to 26% in patients treated by open surgery in all but 1 study, which reported a 76% reoperation rate for open surgery patients. Case series of 222 and 282 patients reported that 12% (26/222) and 13% (36/282) of patients developed an anastomotic leak.
Tracheal perforation occurred in 5% (1/22) and 0% (0/21) of patients treated by HMIO and in 13% (8/63) and 5% (1/21) of patients treated by open surgery in 2 non-randomised comparative studies. Intraoperative tracheal perforation (described as minor) occurred in less than 1% (2/222) of patients in a case series. Tracheal tear occurred in 2 patients in each of 2 case series (222 and 282 patients).
Damage to adjacent organs (not otherwise specified) occurred in 0% to 8% of patients treated by MIO or HMIO and in 0% to 15% of patients treated by open surgery in 5 non-randomised comparative studies (total number of patients: 157 MIO or HMIO, 176 open). One case report described injury to the supradiaphragmatic aorta during the laparoscopic phase of an oesophagectomy requiring conversion to open surgery. Another case report described injury to an aberrant right subclavian artery during thoracoscopic mobilisation of the oesophagus which was successfully repaired.
Tension capnothorax was described in 1 case report, requiring conversion to open surgery.
Chyle leakage rates ranged from 0% to 9% in patients treated by MIO or HMIO and 0% to 7% in patients treated by open surgery in 11 non‑randomised comparative studies (total number of patients: 752 MIO or HMIO, 525 open). Two case series reported chylothorax in 3% (7/222) and 2% (7/282) of patients.
Laryngeal nerve or vocal cord damage rates ranged from 0% to 33% in patients treated by MIO or HMIO and 0% to 42% in patients treated by open surgery in 17 non-randomised comparative studies (total number of patients: 965 MIO or HMIO, 757 open). The case series of 222 patients reported vocal cord palsy in 4% (8/222) of patients. The case series of 282 patients reported recurrent laryngeal nerve injury in 5% (15/282) of patients.
The Specialist Advisers listed anecdotal adverse events as major intrathoracic bleeding, damage to vital structures, injury to the trachea and bronchi during thoracoscopic dissection, and gastric necrosis.
# Other comments
The Committee noted the possibility of bias and confounding within the published studies. However, the studies included large numbers of patients and showed no consistent differences in any efficacy or safety outcomes compared with open surgery.# Further information
For related NICE guidance see www.nice.org.uk
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG407/publicinfo
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{'Important information about this guidance': 'This document replaces previous guidance on thoracoscopically assisted oesophagectomy (interventional procedure guidance 189).', 'Guidance': 'Current evidence on the efficacy and safety of minimally invasive oesophagectomy (MIO) is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit with local review of results.\n\nPatient selection should be done by a multidisciplinary team specialising in the management of oesophageal cancer.\n\nMIO is a technically challenging procedure, which should only be carried out by surgeons with special expertise and specific training. They should perform their initial operations with an experienced mentor.\n\nClinicians should enter details about all patients undergoing MIO onto the National Oesophago-gastric Cancer Audit (www.ic.nhs.uk/services/national-clinical-audit-support-programme-ncasp/cancer).', 'The procedure': "# Indications and current treatments\n\nOesophagectomy is used to treat resectable cancer of the oesophagus. It is also a treatment option for Barrett's oesophagus with high-grade dysplasia. Conventionally, oesophagectomy is performed using open surgery.\n\nDepending on the tumour type, location and stage, oesophagectomy may involve a total or partial resection of the oesophagus, with or without dissection of regional lymph nodes. Total oesophagectomy involves both a thoracic incision to mobilise the oesophagus and an abdominal incision to dissect and prepare the stomach (or sometimes intestine) for anastomosis to the remaining upper oesophagus or pharynx. The new gastric tube is then drawn up the chest to the level of the healthy oesophageal remnant, and an anastomosis is performed, usually via a cervical incision. In some patients (typically with lower-third tumours), partial oesophagectomy may be carried out transhiatally using only an abdominal incision. There are a number of technical variations in the way the open oesophagectomy can be done.\n\n# Outline of the procedure\n\nMIO aims to achieve the same result as open oesophagectomy but with less postoperative morbidity.\n\nThe procedure is performed with the patient under general anaesthesia. Single-lung ventilation is required for the thoracic part of the operation (except for transhiatal techniques). MIO involves performing oesophagectomy under thoracoscopic and laparoscopic visualisation. However, hybrid MIO (HMIO) techniques, which combine either thoracoscopy or laparoscopy with open surgery (for the abdominal or the thoracic component of the procedure respectively), are also described as minimally invasive.\n\nThoracic and/or abdominal CO2 insufflation is used, and a number of incisions are made to accommodate camera and instrument ports. Following resection of the oesophagus, anastomosis is performed either via an (open) cervical approach or an intrathoracic endoscopic approach using stapling devices.\n\nMIO is a complex procedure and the operating time may be long.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/326/overview\n\n# Efficacy\n\nA study of routine hospital episodes statistics data compared 699\xa0patients treated by MIO or HMIO versus 17,974 patients treated by open oesophagectomy. Based on data available for 41% (7724/18,673) of patients, and after adjusting for age, gender, socioeconomic deprivation, comorbidity score, year of operation and number of emergency hospital admissions in the previous year, there was some evidence that patients undergoing MIO or HMIO had lower 1-year mortality than patients treated by open oesophagectomy (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.46 to 1.01, p\xa0=\xa00.058).\n\nTwo non-randomised studies comparing HMIO versus open oesophagectomy reported cancer recurrence rates of 6% (1/17) and 0% (0/14) respectively (undefined follow-up interval); and 19% (3/16) and 7% (2/28) at 44-month follow-up (significance not stated). Three non-randomised comparative studies, including in total 143 patients, 73 treated by HMIO and 70 treated by open surgery, reported recurrence rates ranging from 0% to 44% in patients treated by HMIO and from 3% to 50% in those treated by open surgery (follow-up ranging from 6 months to 54 months). Another non-randomised comparative study comparing 165 patients treated by HMIO versus 56 treated by open surgery reported no significant association for either technique with cancer recurrence (rate of recurrence: 58% for HMIO and 68% for open surgery; follow-up not stated).\n\nA non-randomised comparative study comparing 27 patients treated by HMIO against 29 patients treated by open surgery assessed quality of life in 5\xa0domains of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-OES18 questionnaires (fatigue, pain, dyspnoea, physical functioning, global quality of life). Both patient groups had similar preoperative scores. Compared with baseline, quality of life scores deteriorated in all 5 domains at 2 weeks in both groups, although the scores were worse in the open surgery group. Over time, quality of life scores improved in both groups. At 24-week follow-up there were statistically significant differences between the 2 groups for physical functioning (mean score of 84 for HMIO vs 76 for open surgery) and global quality of life (mean score of 75 for HMIO vs 68 in the open surgery group).\n\nThe Specialist Advisers considered key efficacy outcomes to include speed of postoperative recovery compared with open surgery, cancer recurrence, overall survival, quality of life, and more frequent need for cervical anastomosis compared with open surgery.\n\n# Safety\n\nThirty-day in-hospital mortality was reported as 2% (1/50) in patients treated by MIO and 3% (1/30) in patients treated by open surgery in a non‑randomised comparative study of 80 patients. Two non-randomised comparative studies comparing 15 and 18 patients treated by MIO with 30 and 36 patients treated by open surgery, respectively, reported no in-hospital deaths within 30 days of the procedure. A non-randomised comparative study of 90 patients reported 30-day in-hospital mortality of 7% (3/44) after MIO and 4% (2/46) after open oesophagectomy.\n\nTwo non-randomised comparative studies reported 30-day in-hospital mortality of 2% (1/45) and 5% (1/22) in patients treated by HMIO, while no deaths were reported in the 26 and 63 patients treated by open oesophagectomy. Six non-randomised comparative studies comparing a total of 475 patients treated by MIO with 434 treated by open surgery reported that 30-day in-hospital mortality was higher after open surgery (10% vs 14%, 6% vs 11%, 0% vs 5%, 0% vs 7%, 3% vs 6%, and 3% vs 8%; level of significance not stated).\n\nTwo non-randomised comparative studies reported 30-day in-hospital mortality of 5% (1/22) and 4% (2/56) in patients treated by MIO or HMIO, and 9% (4/43) or 6% (6/98) in those treated by open oesophagectomy (follow-up and significance not stated).\n\nIn the study of routine hospital episodes statistics data comparing 699\xa0patients treated by MIO or HMIO versus 17,974 patients treated by open oesophagectomy, and based on data available for 49% (9217/18,673) of patients, after adjusting for age, gender, socioeconomic deprivation, comorbidity score, year of operation, and number of emergency hospital admissions in the previous year, there was no significant difference between the comparator groups for 30-day in-hospital mortality (OR\xa0=\xa00.99, 95%\xa0CI\xa00.68 to 1.44, p\xa0=\xa00.936).\n\nA non-randomised comparative study of 41 patients treated by MIO, 34 by HMIO and 46 by open surgery reported 30-day in-hospital mortalities of 2%, 6% and 2% respectively. A non-randomised comparative study of 23 patients treated by MIO, 309 by HMIO and 114 by open surgery reported 30-day in‑hospital mortalities of 0%, 2% and 3% respectively.\n\nAnastomotic leakage rates ranged from 0% to 20% among patients treated by either MIO or HMIO, and from 2% to 29% among patients treated by open surgery in 21 non-randomised comparative studies (total number of patients: 1371 MIO or HMIO, 1114 open). Among patients with anastomotic leakage, rates of reoperation ranged from 0% to 19% in patients treated by MIO or HMIO and from 0% to 26% in patients treated by open surgery in all but 1\xa0study, which reported a 76% reoperation rate for open surgery patients. Case series of 222 and 282 patients reported that 12% (26/222) and 13% (36/282) of patients developed an anastomotic leak.\n\nTracheal perforation occurred in 5% (1/22) and 0% (0/21) of patients treated by HMIO and in 13% (8/63) and 5% (1/21) of patients treated by open surgery in 2 non-randomised comparative studies. Intraoperative tracheal perforation (described as minor) occurred in less than 1% (2/222) of patients in a case series. Tracheal tear occurred in 2 patients in each of 2 case series (222 and 282 patients).\n\nDamage to adjacent organs (not otherwise specified) occurred in 0% to 8% of patients treated by MIO or HMIO and in 0% to 15% of patients treated by open surgery in 5 non-randomised comparative studies (total number of patients: 157 MIO or HMIO, 176 open). One case report described injury to the supradiaphragmatic aorta during the laparoscopic phase of an oesophagectomy requiring conversion to open surgery. Another case report described injury to an aberrant right subclavian artery during thoracoscopic mobilisation of the oesophagus which was successfully repaired.\n\nTension capnothorax was described in 1 case report, requiring conversion to open surgery.\n\nChyle leakage rates ranged from 0% to 9% in patients treated by MIO or HMIO and 0% to 7% in patients treated by open surgery in 11 non‑randomised comparative studies (total number of patients: 752 MIO or HMIO, 525 open). Two case series reported chylothorax in 3% (7/222) and 2% (7/282) of patients.\n\nLaryngeal nerve or vocal cord damage rates ranged from 0% to 33% in patients treated by MIO or HMIO and 0% to 42% in patients treated by open surgery in 17 non-randomised comparative studies (total number of patients: 965 MIO or HMIO, 757 open). The case series of 222 patients reported vocal cord palsy in 4% (8/222) of patients. The case series of 282 patients reported recurrent laryngeal nerve injury in 5% (15/282) of patients.\n\nThe Specialist Advisers listed anecdotal adverse events as major intrathoracic bleeding, damage to vital structures, injury to the trachea and bronchi during thoracoscopic dissection, and gastric necrosis.\n\n# Other comments\n\nThe Committee noted the possibility of bias and confounding within the published studies. However, the studies included large numbers of patients and showed no consistent differences in any efficacy or safety outcomes compared with open surgery.", 'Further information': "For related NICE guidance see www.nice.org.uk\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG407/publicinfo"}
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https://www.nice.org.uk/guidance/ipg407
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610694c991230455cf87fd9950fe6280a3d55c13
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nice
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Arthroscopic femoro–acetabular surgery for hip impingement syndrome
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Arthroscopic femoro–acetabular surgery for hip impingement syndrome
# Guidance
This document replaces previous guidance on arthroscopic femoro–acetabular surgery for hip impingement syndrome (interventional procedure guidance 213).
Current evidence on the efficacy of arthroscopic femoro–acetabular surgery for hip impingement syndrome is adequate in terms of symptom relief in the short and medium term. With regard to safety, there are well recognised complications. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit with local review of outcomes.
The British Hip Society is establishing a register for arthroscopic femoro–acetabular surgery for hip impingement syndrome and clinicians should submit details of all patients undergoing this procedure to the register once it is available. A prime purpose of the register is to provide information about long-term outcomes. It is important that both the register and other studies report details of patient selection to allow clear understanding of these outcomes.
Arthroscopic femoro–acetabular surgery for hip impingement syndrome should only be carried out by surgeons with specialist expertise in arthroscopic hip surgery.# The procedure
# Indications and current treatments
Hip or femoro–acetabular impingement results from abnormalities of the femoral head or the acetabulum. It can be caused by jamming of an abnormally shaped femoral head into the acetabulum, or by contact between the acetabular rim and the femoral head–neck junction. It is believed that it may lead to the development of osteoarthritis.
Symptoms may include restriction of hip-joint movement, pain and 'clicking' of the hip. Symptoms are typically exacerbated by hip flexion or prolonged sitting.
The management of hip impingement syndrome includes conservative measures, such as modification of activity and non-steroidal anti-inflammatory medication. Surgical treatment options include open femoro–acetabular hip impingement surgery. Patients with advanced osteoarthritic degeneration may require a total hip replacement.
# Outline of the procedure
The aim of arthroscopic femoro–acetabular surgery for hip impingement syndrome is to reduce pain and improve the hip-joint range of movement.
The procedure is carried out with the patient under general anaesthesia. The hip is distracted using leg traction and an arthroscope and surgical instruments are inserted into the joint. Non-spherical sections of the femoral head, and prominent sections of the anterior femoral neck and acetabular rim, are resected. Labral lesions are debrided using a shaver or radiothermal device, and the labrum may be repaired.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/365/overview
# Efficacy
In a non-randomised controlled study comparing arthroscopic femoro–acetabular impingement surgery with labral refixation (36 hips) versus arthroscopic femoro–acetabular impingement surgery with labral debridement (39 hips), mean Harris hip score (HHS) (on a scale 0–100; higher scores better) was 94.3 points and 88.9 points respectively at 1-year follow-up (p = 0.029; both groups improved from baseline but these figures were not reported).
A case series of 200 patients (207 hips) reported a mean improvement in HHS of 20 points from baseline at a mean follow-up of 16 months (significance not stated); 1 patient required total hip arthroplasty after 8 months due to persistent pain.
The case series of 112 patients reported improvement in mean activities of daily living score (scoring system not described) from 70.0 points at baseline to 87.8 points at 2.3-year follow-up (p < 0.001). Mean sport activity score (scoring system not described) improved from 43.0 points at baseline to 69.0 points at 2.3-year follow-up (p < 0.001).
A case series of 110 patients reported that 77% (85/110) of patients were satisfied or very satisfied with their treatment at 10-month follow up.
The case series of 110 patients reported a significant improvement in femoral head–neck offset angle from 64.6° at baseline to 50.6° at 10-month follow up (p < 0.001).
The Specialist Advisers listed key efficacy outcomes as pain relief and delayed progression to osteoarthritis.
# Safety
A case series of 183 patients (194 hips) reported pathological fracture in 1% (2/183) of patients. A case series of 97 patients (100 hips) reported femoral neck fracture (healed without surgery) in 1 patient.
A case series of 97 patients (100 hips) reported no occurrence of avascular necrosis following the procedure. A case report described femoral head osteonecrosis following arthroscopic femoro–acetabular surgery for pincer impingement, which required arthroscopic decompression and bone marrow graft.
The case series of 200 patients reported neurapraxia of the lateral femoral cutaneous nerve (resolved at 1-month follow-up) in 1 out of 207 hips. The case series of 110 patients reported 1 case of femoral neurapraxia which resolved 'within a few months'.
The non-randomised controlled study of 75 hips reported heterotopic ossification in 8% (3/36) of patients treated with labral debridement and in 0% (0/39) of patients undergoing labral refixation at a mean 19-month follow-up (significance not stated). Heterotopic ossification was reported in 1 out of 207 hips in the case series of 200 patients with a mean follow-up of 16 months.
The Specialist Advisers listed adverse events seen or reported in the literature as genital and perineal trauma from the traction post, neurological damage (sometimes related to traction), infection, postoperative hip dislocation, haemorrhage and instrument breakage. They considered theoretical adverse events to include iatrogenic articular cartilage damage.
# Other comments
The Committee noted that the available evidence was from observational studies. While this was considered adequate for the present recommendation, further studies would be useful. The Committee recognised the difficulties of comparative research and acquisition of long-term data on this procedure.
This guidance relates to the use of arthroscopic hip surgery for femoro–acetabular impingement syndrome and not other indications.# Further information
For related NICE guidance see www.nice.org.uk
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG408/publicinfo
|
{'Guidance': 'This document replaces previous guidance on arthroscopic femoro–acetabular surgery for hip impingement syndrome (interventional procedure guidance 213).\n\nCurrent evidence on the efficacy of arthroscopic femoro–acetabular surgery for hip impingement syndrome is adequate in terms of symptom relief in the short and medium term. With regard to safety, there are well recognised complications. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit with local review of outcomes.\n\nThe British Hip Society is establishing a register for arthroscopic femoro–acetabular surgery for hip impingement syndrome and clinicians should submit details of all patients undergoing this procedure to the register once it is available.\xa0A prime purpose of the register is to provide information about long-term outcomes. It is important that both the register and other studies report details of patient selection to allow clear understanding of these outcomes.\n\nArthroscopic femoro–acetabular surgery for hip impingement syndrome should only be carried out by surgeons with specialist expertise in arthroscopic hip surgery.', 'The procedure': "# Indications and current treatments\n\nHip or femoro–acetabular impingement results from abnormalities of the femoral head or the acetabulum. It can be caused by jamming of an abnormally shaped femoral head into the acetabulum, or by contact between the acetabular rim and the femoral head–neck junction. It is believed that it may lead to the development of osteoarthritis.\n\nSymptoms may include restriction of hip-joint movement, pain and 'clicking' of the hip. Symptoms are typically exacerbated by hip flexion or prolonged sitting.\n\nThe management of hip impingement syndrome includes conservative measures, such as modification of activity and non-steroidal anti-inflammatory medication. Surgical treatment options include open femoro–acetabular hip impingement surgery. Patients with advanced osteoarthritic degeneration may require a total hip replacement.\n\n# Outline of the procedure\n\nThe aim of arthroscopic femoro–acetabular surgery for hip impingement syndrome is to reduce pain and improve the hip-joint range of movement.\n\nThe procedure is carried out with the patient under general anaesthesia. The hip is distracted using leg traction and an arthroscope and surgical instruments are inserted into the joint. Non-spherical sections of the femoral head, and prominent sections of the anterior femoral neck and acetabular rim, are resected. Labral lesions are debrided using a shaver or radiothermal device, and the labrum may be repaired.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/365/overview\n\n# Efficacy\n\nIn a non-randomised controlled study comparing arthroscopic femoro–acetabular impingement surgery with labral refixation (36 hips) versus arthroscopic femoro–acetabular impingement surgery with labral debridement (39 hips), mean Harris hip score (HHS) (on a scale 0–100; higher scores better) was 94.3 points and 88.9 points respectively at 1-year follow-up (p = 0.029; both groups improved from baseline but these figures were not reported).\n\nA case series of 200 patients (207 hips) reported a mean improvement in HHS of 20 points from baseline at a mean follow-up of 16 months (significance not stated); 1 patient required total hip arthroplasty after 8 months due to persistent pain.\n\nThe case series of 112 patients reported improvement in mean activities of daily living score (scoring system not described) from 70.0 points at baseline to 87.8 points at 2.3-year follow-up (p\xa0<\xa00.001). Mean sport activity score (scoring system not described) improved from 43.0 points at baseline to 69.0\xa0points at 2.3-year follow-up (p\xa0<\xa00.001).\n\nA case series of 110 patients reported that 77% (85/110) of patients were satisfied or very satisfied with their treatment at 10-month follow up.\n\nThe case series of 110 patients reported a significant improvement in femoral head–neck offset angle from 64.6° at baseline to 50.6° at 10-month follow up (p\xa0<\xa00.001).\n\nThe Specialist Advisers listed key efficacy outcomes as pain relief and delayed progression to osteoarthritis.\n\n# Safety\n\nA case series of 183 patients (194 hips) reported pathological fracture in 1% (2/183) of patients. A case series of 97 patients (100 hips) reported femoral neck fracture (healed without surgery) in 1 patient.\n\nA case series of 97 patients (100 hips) reported no occurrence of avascular necrosis following the procedure. A case report described femoral head osteonecrosis following arthroscopic femoro–acetabular surgery for pincer impingement, which required arthroscopic decompression and bone marrow graft.\n\nThe case series of 200 patients reported neurapraxia of the lateral femoral cutaneous nerve (resolved at 1-month follow-up) in 1 out of 207 hips. The case series of 110 patients reported 1 case of femoral neurapraxia which resolved 'within a few months'.\n\nThe non-randomised controlled study of 75 hips reported heterotopic ossification in 8% (3/36) of patients treated with labral debridement and in 0% (0/39) of patients undergoing labral refixation at a mean 19-month follow-up (significance not stated). Heterotopic ossification was reported in 1 out of 207 hips in the case series of 200 patients with a mean follow-up of 16 months.\n\nThe Specialist Advisers listed adverse events seen or reported in the literature as genital and perineal trauma from the traction post, neurological damage (sometimes related to traction), infection, postoperative hip dislocation, haemorrhage and instrument breakage. They considered theoretical adverse events to include iatrogenic articular cartilage damage.\n\n# Other comments\n\nThe Committee noted that the available evidence was from observational studies. While this was considered adequate for the present recommendation, further studies would be useful. The Committee recognised the difficulties of comparative research and acquisition of long-term data on this procedure.\n\nThis guidance relates to the use of arthroscopic hip surgery for femoro–acetabular impingement syndrome and not other indications.", 'Further information': "For related NICE guidance see www.nice.org.uk\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG408/publicinfo"}
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https://www.nice.org.uk/guidance/ipg408
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4cb4547ff53110f925c766e1677fd705b21475f4
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nice
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Laparoscopic cryotherapy for renal cancer
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Laparoscopic cryotherapy for renal cancer
# Guidance
This document replaces previous guidance on cryotherapy for renal cancers (interventional procedure guidance 207).
Current evidence on the efficacy and safety of laparoscopic cryotherapy for renal cancer is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.
This procedure should only be offered after assessment by a specialist urological cancer multidisciplinary team.
NICE encourages collection and publication of data on the long-term outcomes of this procedure.# The procedure
# Indications and current treatments
The most common type of renal cancer in adults is renal cell carcinoma. Symptoms and signs may include pain and haematuria. Some tumours are identified when symptomatic, through imaging. Establishing the diagnosis and assessing the prognosis of some renal tumours may be difficult.
Treatment options include partial or total nephrectomy (laparoscopic or open) and ablation techniques, including radiofrequency ablation (RFA).
# Outline of the procedure
Laparoscopic cryotherapy for renal cancer is carried out with the patient under general anaesthesia. A transperitoneal or retroperitoneal approach can be used. A biopsy of the tumour may be carried out. Under laparoscopic visualisation, a probe is inserted into the tumour to deliver a coolant at subfreezing temperatures, creating an ice ball around the probe's tip, which destroys the surrounding tissue. Each freeze cycle is followed by a heat (thaw) cycle, allowing removal of the probe. Two freeze–thaw cycles are usually performed to ablate the tumour (additional cycles may also be performed if necessary), with the aim of extending the ice ball approximately 1 cm beyond tumour margins. More than 1 probe can be used.
The maximum renal tumour size for which cryotherapy is recommended is approximately 4 cm (small, stage I tumours).
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/344/overview
# Efficacy
A non-randomised study of 101 patients reported cancer-specific survival to be 89%, 100% and 84% among 36, 36 and 29 patients treated by cryoablation, laparoscopic partial nephrectomy (LPN) and RFA respectively at 2 years (significance not stated).
A meta-analysis of non-randomised comparative studies and case series, including a total of 1375 patients, reported that repeat ablations were required in fewer patients treated by cryotherapy than RFA (1% vs 9% , p < 0.0001). Furthermore, 5% (31/600) of cryotherapy-treated patients had local tumour progression (defined as radiographic or pathological evidence of residual disease after initial treatment) compared with 13% (100/775) treated by RFA during a mean follow-up of 18.7 months (p < 0.0001).
In a non-randomised comparative study of 264 patients treated by laparoscopic cryotherapy (139 lesions) or by percutaneous RFA (73 lesions), radiographic success (no evidence of central or nodular enhancement) was reported in 90% (125/139) and 85% (62/73) of lesions respectively at 6-month follow-up (p = 0.62).
In the non-randomised study of 93 patients comparing laparoscopic cryotherapy versus percutaneous cryotherapy versus RFA, patients returned to work within 18, 6 and 4 days respectively (significant for comparison between percutaneous RFA and laparoscopic cryotherapy, p < 0.05). Patient satisfaction (not otherwise described) did not differ significantly between the groups.
Specialist Advisers listed key efficacy outcomes as successful ablation based on radiological criteria, retreatment rates, tumour recurrence, disease-specific survival and overall survival.
# Safety
Haemorrhage requiring transfusion occurred in 26% (5/19) of patients treated by laparoscopic cryotherapy compared with 11% (2/18) treated by percutaneous cryotherapy in a non-randomised study of 37 patients; in 10% (2/20) of patients treated by laparoscopic cryotherapy in a non-randomised study of 66 patients; and in 2% (3/123) and 11% (4/37) in 2 case series of 123 and 37 patients, respectively.
A non-randomised comparative study comparing 29 patients treated by laparoscopic cryoablation, 20 by laparoscopic radical nephrectomy and 17 by LPN reported that conversion to open surgery because of intraoperative complications (including splenic haemorrhage, mesenteric artery haemorrhage and inability to progress due to retroperitoneal scarring) was required in 1 patient in each group.
The non-randomised study of 101 patients reported intraoperative pleural injury in 1 patient among 36 in the cryotherapy treatment group. Other postoperative complications in patients in the cryotherapy group included urine leak, haemothorax and atelectasis in 1 patient each.
A case report described acute obstruction and anuria caused by a blood clot in the renal pelvis in a patient with a single kidney and chronic renal insufficiency, successfully treated by temporary ureteric stent insertion.
Another case report described a patient with a single kidney presenting with left flank pain and fever due to obstruction by urothelial slough 3 months after the procedure. This resolved by ureteroscopic removal of the necrotic tissue and a temporary stent placement.
Specialist Advisers stated that ureteric (including pelviureteric junction), bowel and pancreatic injury have occurred but are rare. They considered theoretical adverse events to include the inherent risks of laparoscopic surgery, such as trocar injury, neurapraxia, port site hernia and CO2 embolism.
# Other comments
The Committee noted that most reports of laparoscopic cryotherapy for renal cancer included both malignant and benign lesions, and that histology was unknown for many of the lesions treated by the procedure. This made interpretation of the data difficult.
The Committee was advised that the diagnosis of malignancy is typically made by imaging and that histology may not be available to confirm the diagnosis. This contrasts with treatment by any kind of nephrectomy which provides tissue for histological diagnosis.
The Committee noted the paucity of comparative evidence on the management of localised renal cancer. It considered that further research into the comparative efficacy and safety of different surgical and ablative treatments would be useful.# Further information
For related NICE guidance see www.nice.org.uk
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG405/publicinfo
|
{'Guidance': 'This document replaces previous guidance on cryotherapy for renal cancers (interventional procedure guidance 207).\n\nCurrent evidence on the efficacy and safety of laparoscopic cryotherapy for renal cancer is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nThis procedure should only be offered after assessment by a specialist urological cancer multidisciplinary team.\n\nNICE encourages collection and publication of data on the long-term outcomes of this procedure.', 'The procedure': "# Indications and current treatments\n\nThe most common type of renal cancer in adults is renal cell carcinoma. Symptoms and signs may include pain and haematuria. Some tumours are identified when symptomatic, through imaging. Establishing the diagnosis and assessing the prognosis of some renal tumours may be difficult.\n\nTreatment options include partial or total nephrectomy (laparoscopic or open) and ablation techniques, including radiofrequency ablation (RFA).\n\n# Outline of the procedure\n\nLaparoscopic cryotherapy for renal cancer is carried out with the patient under general anaesthesia. A transperitoneal or retroperitoneal approach can be used. A biopsy of the tumour may be carried out. Under laparoscopic visualisation, a probe is inserted into the tumour to deliver a coolant at subfreezing temperatures, creating an ice ball around the probe's tip, which destroys the surrounding tissue. Each freeze cycle is followed by a heat (thaw) cycle, allowing removal of the probe. Two freeze–thaw cycles are usually performed to ablate the tumour (additional cycles may also be performed if necessary), with the aim of extending the ice ball approximately 1\xa0cm beyond tumour margins. More than 1 probe can be used.\n\nThe maximum renal tumour size for which cryotherapy is recommended is approximately 4\xa0cm (small, stage I tumours).\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/344/overview\n\n# Efficacy\n\nA non-randomised study of 101 patients reported cancer-specific survival to be 89%, 100% and 84% among 36, 36 and 29 patients treated by cryoablation, laparoscopic partial nephrectomy (LPN) and RFA respectively at 2 years (significance not stated).\n\nA meta-analysis of non-randomised comparative studies and case series, including a total of 1375 patients, reported that repeat ablations were required in fewer patients treated by cryotherapy than RFA (1% [8/600] vs 9% [66/775], p\xa0<\xa00.0001). Furthermore, 5% (31/600) of cryotherapy-treated patients had local tumour progression (defined as radiographic or pathological evidence of residual disease after initial treatment) compared with 13% (100/775) treated by RFA during a mean follow-up of 18.7 months (p < 0.0001).\n\nIn a non-randomised comparative study of 264 patients treated by laparoscopic cryotherapy (139 lesions) or by percutaneous RFA (73 lesions), radiographic success (no evidence of central or nodular enhancement) was reported in 90% (125/139) and 85% (62/73) of lesions respectively at 6-month follow-up (p = 0.62).\n\nIn the non-randomised study of 93 patients comparing laparoscopic cryotherapy versus percutaneous cryotherapy versus RFA, patients returned to work within 18, 6 and 4 days respectively (significant for comparison between percutaneous RFA and laparoscopic cryotherapy, p\xa0<\xa00.05). Patient satisfaction (not otherwise described) did not differ significantly between the groups.\n\nSpecialist Advisers listed key efficacy outcomes as successful ablation based on radiological criteria, retreatment rates, tumour recurrence, disease-specific survival and overall survival.\n\n# Safety\n\nHaemorrhage requiring transfusion occurred in 26% (5/19) of patients treated by laparoscopic cryotherapy compared with 11% (2/18) treated by percutaneous cryotherapy in a non-randomised study of 37 patients; in 10% (2/20) of patients treated by laparoscopic cryotherapy in a non-randomised study of 66 patients; and in 2% (3/123) and 11% (4/37) in 2 case series of 123 and 37 patients, respectively.\n\nA non-randomised comparative study comparing 29 patients treated by laparoscopic cryoablation, 20 by laparoscopic radical nephrectomy and 17 by LPN reported that conversion to open surgery because of intraoperative complications (including splenic haemorrhage, mesenteric artery haemorrhage and inability to progress due to retroperitoneal scarring) was required in 1 patient in each group.\n\nThe non-randomised study of 101 patients reported intraoperative pleural injury in 1 patient among 36 in the cryotherapy treatment group. Other postoperative complications in patients in the cryotherapy group included urine leak, haemothorax and atelectasis in 1 patient each.\n\nA case report described acute obstruction and anuria caused by a blood clot in the renal pelvis in a patient with a single kidney and chronic renal insufficiency, successfully treated by temporary ureteric stent insertion.\n\nAnother case report described a patient with a single kidney presenting with left flank pain and fever due to obstruction by urothelial slough 3 months after the procedure. This resolved by ureteroscopic removal of the necrotic tissue and a temporary stent placement.\n\nSpecialist Advisers stated that ureteric (including pelviureteric junction), bowel and pancreatic injury have occurred but are rare. They considered theoretical adverse events to include the inherent risks of laparoscopic surgery, such as trocar injury, neurapraxia, port site hernia and CO2 embolism.\n\n# Other comments\n\nThe Committee noted that most reports of laparoscopic cryotherapy for renal cancer included both malignant and benign lesions, and that histology was unknown for many of the lesions treated by the procedure. This made interpretation of the data difficult.\n\nThe Committee was advised that the diagnosis of malignancy is typically made by imaging and that histology may not be available to confirm the diagnosis. This contrasts with treatment by any kind of nephrectomy which provides tissue for histological diagnosis.\n\nThe Committee noted the paucity of comparative evidence on the management of localised renal cancer. It considered that further research into the comparative efficacy and safety of different surgical and ablative treatments would be useful.", 'Further information': "For related NICE guidance see www.nice.org.uk\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG405/publicinfo"}
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https://www.nice.org.uk/guidance/ipg405
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08aaccea9da9e896ec8b4ed014c1f6344860d069
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nice
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Bortezomib and thalidomide for the first‑line treatment of multiple myeloma
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Bortezomib and thalidomide for the first‑line treatment of multiple myeloma
Evidence-based recommendations on bortezomib (Velcade) and thalidomide (Thalidomide Celgene) for treating multiple myeloma in adults.
# Guidance
Thalidomide in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate.
Bortezomib in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma if:
high-dose chemotherapy with stem cell transplantation is considered inappropriate and
the person is unable to tolerate or has contraindications to thalidomide.# Clinical need and practice
Multiple myeloma is a cancer of a type of white blood cell (plasma cell) in the bone marrow. In people with multiple myeloma, a single plasma cell becomes cancerous to form a myeloma cell, which begins to multiply. These abnormal plasma cells, or myeloma cells, build up in the bone marrow, reducing the space available for making normal white cells, red cells and platelets. Normal blood cells are responsible for fighting infections, carrying oxygen around the body and blood clotting. Myeloma cells produce large amounts of one type of abnormal antibody, which does not work properly and is not able to fight infection. Symptoms and clinical features of multiple myeloma include fatigue, bone pain and/or fracture, anaemia, infections, M-protein in serum and/or urine, and hypercalcaemia. The origin of multiple myeloma is unknown and malignant cells display a variety of cytogenetic abnormalities. Multiple myeloma is the second most common haematological cancer in the UK. In England and Wales there are approximately 3600 new diagnoses recorded annually. In 2007, most diagnoses were recorded in people aged 75–79 years. Multiple myeloma is about 1.5 times more common in men than in women, and twice as common in people of African or Caribbean descent. In the UK, the estimated lifetime risk of developing multiple myeloma is 1 in 148 for men and 1 in 186 for women. There are currently between 10,000 and 15,000 people living with multiple myeloma in the UK.
Multiple myeloma remains an incurable disease, with an average survival of 4–6 years, but it can be treated with a combination of supportive measures and chemotherapy. The aim of treatment is to extend the length and quality of life by alleviating symptoms, controlling disease and minimising adverse effects. Survival after diagnosis can vary from months to more than 10 years. Factors affecting survival and outcome include burden of disease, type of cytogenetic abnormality, age and performance status, and response to treatment.
In England and Wales the choice of first-line treatment (that is, treatment for treatment-naïve patients) depends on a combination of factors. Most people with multiple myeloma are not able to withstand intensive treatment, such as high-dose chemotherapy with stem cell transplantation, because of their age, other health problems or poor performance status. These people are offered single-agent or combination chemotherapy, which is less intensive. Typically, combination therapies include chemotherapy with an alkylating agent (such as melphalan or cyclophosphamide) and a corticosteroid (such as prednisolone or dexamethasone). More recent treatment options include drugs such as thalidomide and bortezomib. The main objective of first-line therapy is to achieve a period of stable disease (termed the plateau phase) for as long as possible, thereby prolonging survival and maximising quality of life. After initial treatment, most people usually experience a period of remission, but almost all relapse eventually, and some have disease that does not respond (is refractory) to treatment.# The technologies
Bortezomib
Bortezomib (Velcade, Janssen) is an anticancer drug that works by reversible proteasome inhibition. This inhibition leads to arrest of the cell cycle and apoptosis (cell death), which reduces tumour growth. Myeloma cells are more sensitive to the action of bortezomib than normal cells.
Bortezomib, in combination with melphalan and prednisone, is licensed for the treatment of patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with bone marrow transplant. Bortezomib is administered as an intravenous injection. Bortezomib is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles. In cycles 1–4, bortezomib is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In cycles 5–9, bortezomib is administered once weekly (days 1, 8, 22 and 29). Melphalan and prednisone should both be given orally on days 1, 2, 3 and 4 of the first week of each cycle.
Bortezomib treatment is associated with peripheral neuropathy, thrombocytopenia, gastrointestinal effects (diarrhoea, nausea, vomiting and constipation) and other side effects. For full details of side effects and contraindications, see the summary of product characteristics (SPC).
The cost for a 3.5-mg vial of bortezomib is £762.38 (British national formulary edition 61). Costs may vary in different settings because of negotiated procurement discounts.
Thalidomide
Thalidomide (Thalidomide Celgene, Celgene) is an immunomodulatory agent. Its precise mechanism of action is under investigation and is currently unknown, but it is thought to have multiple actions, including anti-inflammatory activity and the ability to inhibit the growth and survival of myeloma cells and the growth of new blood vessels. It is also a non-barbiturate hypnotic sedative with central action.
Thalidomide in combination with melphalan and prednisone is licensed 'as first-line treatment of patients with untreated multiple myeloma, aged ≥ 65 years or ineligible for high dose chemotherapy'. The recommended dose is 200 mg daily, taken orally. A maximum number of 12 cycles of 6 weeks should be used. Thalidomide is prescribed and dispensed according to the Thalidomide Celgene Pregnancy Prevention Programme.
Thalidomide treatment is associated with thromboembolic events, peripheral neuropathy, rash/skin reactions, bradycardia, syncope and somnolence. Section 4.2 of the SPC outlines how to manage comorbidities such as risk of thromboembolic events, peripheral neuropathy or hepatic or renal impairment. For full details of side effects and contraindications, see the SPC.
The cost for a 28-capsule pack of 50-mg thalidomide capsules is £298.48 (BNF edition 61). Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
# Clinical effectiveness
In addition to the licensed indications of bortezomib and thalidomide, the remit of the scope allowed for inclusion of evidence from the ongoing UK-wide, Medical Research Council-sponsored Multiple Myeloma IX (MMIX) trial. This trial included thalidomide in combination with cyclosphosphamide and attenuated dexamethasone, which is not a licensed indication for thalidomide. The appraisal investigated the following treatment strategies:
thalidomide, melphalan and prednisolone/prednisone (MPT)
thalidomide, cyclosphosphamide and attenuated dexamethasone (CTDa)
bortezomib, melphalan and prednisolone/prednisone (VMP).
Each was compared with melphalan or cyclosphosphamide plus prednisolone/prednisone or dexamethasone.
The Assessment Group and manufacturers identified evidence on the clinical effectiveness of bortezomib and thalidomide against the relevant comparators within the licensed indications for each drug, and according to the appraisal scope.
## MPT versus melphalan plus prednisolone/prednisone (MP)
The Assessment Group identified three randomised controlled trials (RCTs) (Intergroupe Francophone du Myélome 99/06, IFM 01/01 and GIMEMA) that compared MPT with MP. The numbers of participants recruited to the studies were 447, 232 and 331 respectively. The two IFM studies differed in the target age range of participants: IFM 01/01 included people aged at least 75 years, whereas IFM 99/06 mainly included people aged between 65 and 75 years, with younger people being eligible for inclusion providing they were not eligible for high-dose chemotherapy. The GIMEMA study included people older than 65 years without specifying any upper age limit, but also included participants younger than 65 years providing they were unable to undergo high-dose chemotherapy with stem cell transplantation. The quality of the RCTs was variable and was difficult to determine in some cases because details needed for quality assessment were incompletely reported. The intention-to-treat analyses and the methods used to account for missing data were in general poorly described.
Overall survival was the primary outcome for IFM 99/06 and IFM 01/01. The secondary outcomes of these studies included response rates, progression-free survival and adverse events. The primary outcome measures for the GIMEMA study were response rates and progression-free survival. The secondary outcomes included overall survival and adverse events.
IFM 99/06 and IFM 01/01 reported a statistically significant increase in progression-free survival (p = 0.001) in the MPT group compared with the MP group. The IFM 99/06 study reported median progression-free survival of 27.5 months (standard error = 2.1) for the MPT group compared with 17.8 months (SE = 1.4) for the MP group at a median follow-up of 51.5 months (difference of 9.7 months). The IFM 01/01 study reported median progression-free survival of 24.1 months (95% confidence interval 19.4 to 29.0) for the MPT group compared with 18.5 months (95% CI 14.6 to 23.1) for the MP group after a median follow-up of 47.5 months (difference of 5.6 months). Meta-analysis of the data on progression-free survival confirmed that MPT was superior to MP for this outcome. The hazard ratio (HR) for progression-free survival from the meta-analysis was 0.56 (95% CI 0.46 to 0.67) in favour of MPT. The meta-analysis suggested that there was little or no heterogeneity between the two trials for this outcome.
The GIMEMA study included maintenance therapy with thalidomide after first-line treatment (that is, patients received six cycles of first-line treatment and if they responded and their condition did not progress, they received maintenance treatment continuously until relapse or the development of refractory disease). Because patients received maintenance therapy, overall survival, which was a secondary outcome in this study, was not eligible for inclusion in the Assessment Group's systematic review. IFM 99/06 and IFM 01/01 reported a statistically significant difference in overall survival in favour of the group receiving MPT. The IFM 99/06 study reported a median overall survival of 51.6 months (interquartile range 26.6 to not reached) for the MPT group compared with 33.2 months (IQR 13.8 to 54.8) for the MP group after a median follow-up of 51.5 months. The IFM 01/01 study reported a median survival of 44 months (95% CI 33.4 to 58.7) in the group receiving MPT compared with 29.1 months (95% CI 26.4 to 34.9) in the group receiving MP. Meta-analysis of the data on overall survival from the two studies confirmed the superiority of MPT over MP. The HR for overall survival from the meta-analysis was 0.62 (95% CI 0.50 to 0.77) and showed that there was little or no heterogeneity between the two trials for this outcome.
Response to treatment (at 6 months) was a primary outcome of the GIMEMA study and a secondary outcome in IFM 99/06 and IFM 01/01. At 6 months, more participants in the MPT group had a complete response or a partial response or better (according to European Group for Blood and Marrow Transplantation criteria). At 12 months, IFM 99/06 and IFM 01/01 reported that a statistically significantly greater proportion of participants had a complete response or at least a partial response. Complete response outcomes from the three studies were combined by meta-analysis, and this confirmed that MPT was superior to MP in terms of the proportion of patients achieving a complete response (relative risk 5.49, 95% CI 2.55 to 11.83).
Adverse events were difficult to summarise across the three studies because they were reported differently. Because the GIMEMA study included maintenance therapy with thalidomide, few data on adverse events from this study could be included in the Assessment Group's systematic review. Adverse events that occurred statistically significantly more often in the MPT arms of IFM 99/06 and IFM 01/01 included neutropenia and peripheral neuropathy. The IFM 99/06 study found that non-haematological adverse events of grade 3 or more were statistically significantly more likely in the MPT group (p 0.0001). For thrombosis or embolism, somnolence and constipation, the results were inconsistent between IFM 99/06 and IFM 01/01, with no significant difference in incidence in the IFM 01/01 study and statistically significantly more of these events in the MPT group in the IFM 99/06 study. This inconsistency may be a result of the different methods of reporting adverse events.
The IFM 99/06 and IFM 01/01 studies provided data on second-line treatment that could be included in the Assessment Group's systematic review. In the IFM 99/06 study, 65% of the MP group received second-line treatment compared with 44% of the MPT group. The IFM 01/01 study reported disease progression in 156 participants overall, with more participants with disease progression in the MP group than the MPT group (72% versus 64%). Second-line treatment was received by a similar proportion of participants with disease progression in each arm. In both IFM 99/06 and IFM 01/01, thalidomide (alone or in combination with another agent) was the most common second-line treatment in the MP group, with about a fifth of participants in the MPT groups receiving thalidomide again as second-line therapy. In the IFM 99/06 study, the most common second-line treatment in the MPT group was a combination of vincristine, doxorubicin, and dexamethasone. Only 13% of participants in the MPT group received bortezomib. In contrast, IFM 01/01 reported that 31% of participants in the MPT group received bortezomib as a second-line treatment. Because the GIMEMA study included maintenance therapy with thalidomide after first-line treatment, data on second-line treatment were not eligible for inclusion in the Assessment Group's systematic review.
## CTDa versus MP
The Assessment Group acknowledged an ongoing RCT, the MMIX trial, which compared CTDa with MP. People were eligible to participate if they had newly diagnosed symptomatic or non-secretory multiple myeloma and had not received previous treatment for myeloma (other than local radiotherapy). The non-intensive pathway of the MMIX study was designed for older (generally 70 years of age or older) or less fit participants (who could be younger than 70), but strict age restrictions were not in place. The primary outcomes were overall survival, progression-free survival and response. Secondary outcomes included quality of life and adverse events.
Some data from the MMIX study on overall survival, progression-free survival, adverse events and health-related quality of life were not eligible for inclusion in the Assessment Group's systematic review because participants were randomised to receive either maintenance therapy with thalidomide or no maintenance therapy after they had completed first-line treatment. In response to a request from the Assessment Group, the MMIX trial management group provided data on overall survival, progression-free survival and response to treatment for participants who were excluded from the maintenance randomisation and for those randomised to receive no maintenance (that is, all people who received first-line only treatment were considered). The Assessment Group concluded that these additional data did not substantially alter the outcomes for the whole trial population because the data were immature and for a small number of patients. Although the data for participants receiving maintenance therapy were not included, the Committee considered very carefully data from the small number of participants who were randomised to receive no maintenance therapy.
Data on response rates from the MMIX study were eligible for inclusion in the Assessment Group's systematic review. Response was measured as complete, very good or partial. The principal investigators of the MMIX study identified data on response and adverse events as unpublished academic in confidence and therefore these data cannot be reported.
## VMP versus MP
The Assessment Group identified one RCT (VISTA) comparing VMP with MP. People were eligible to participate if they had newly diagnosed, untreated, symptomatic, measurable myeloma and were not candidates for high-dose chemotherapy with stem cell transplantation because of their age (65 years or older) or coexisting conditions. Most, but not all, analyses had followed intention-to-treat principles, but the methods used to account for any missing data were not described.
The primary outcome was time to disease progression. Secondary outcomes included overall survival, progression-free survival, response, adverse events and health-related quality of life. Median time to subsequent myeloma therapy and treatment-free interval were 20.8 months and 9.4 months respectively in the group receiving MP; these were not reached in the group receiving VMP. Median time to disease progression was significantly longer in the VMP group than in the MP group (20.7 and 15 months respectively; HR = 0.54, p < 0.001). An advantage in terms of overall survival was reported for VMP compared with MP. A statistically significant survival benefit for VMP was reported after a median follow-up of 25.9 months (HR = 0.64, p = 0.0032). After a median follow-up of 36.7 months, 3-year survival rates were 68.5% versus 54% respectively. The most recent analyses showed a median overall survival of 43.1 months for participants receiving MP; it was not possible to estimate overall survival in the group receiving VMP because median overall survival had not been reached for VMP. After a median follow-up of 16.3 months, median progression-free survival was 21.7 months for the group receiving VMP compared with 15.2 months for the group receiving MP (HR = 0.56, p < 0.001). A number of response-to-treatment rates (including partial response and complete response) were reported as secondary outcomes. The time at which response was assessed was not reported. The proportion of participants with at least a partial response was 71% in the VMP group and 35% in the MP group (p < 0.001). The proportions with a complete response were 30% and 4% respectively (p < 0.001). The proportion with a partial response was 40% in the VMP group and 31% in the MP group, and the proportions with a minimal response were 9% and 22% respectively. The proportion with stable disease was 18% in the VMP group and 40% in the MP group, and the progressive disease rates were 1% and 2% respectively.
Participants in both arms of the VISTA trial experienced adverse events. Although the occurrence of any adverse event and any grade 4 adverse event was similar in the two groups, there was a statistically significant increase in grade 3 adverse events in the group receiving VMP (53% versus 44%, p = 0.02). Haematological events were the most frequently reported and were similar in the two groups. Peripheral sensory neuropathy was reported more frequently in the group receiving VMP, but at the time of the last analysis, 74% of peripheral neuropathy events had either resolved (56%) or decreased by at least one toxicity grade (18%) within a median of 2 months. All grade 3 and grade 4 gastrointestinal events were more frequent in the group receiving VMP (19% versus 5%, no p value given). The incidence of deep vein thrombosis was low and similar in the two groups.
Limited data on health-related quality of life were available. After best response, participants treated with VMP had a higher sustained improvement in 14 of the 15 European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C‑30 (EORTC QLQ-C30) scores than participants treated with MP.
Data on second-line treatment indicated that in the MP group 57% of participants started second-line treatment within 2 years compared with 38% in the VMP group. Over half of the participants in each group received either thalidomide or lenalidomide as a second-line treatment.
## Summary of the clinical effectiveness
The Assessment Group concluded that the evidence from two studies (IFM 99/06 and IFM 01/01) indicated that MPT was more effective than MP in terms of increasing overall survival (HR = 0.62, 95% CI 0.50 to 0.77) and the secondary outcome of progression-free survival (HR = 0.56, 95% CI 0.46 to 0.67). Three studies (IFM 99/06, IFM 01/01 and GIMEMA) provided evidence of a complete response in a statistically significantly greater proportion of participants receiving MPT (RR = 5.49, 95% CI 2.55 to 11.83). Adverse events occurred in both trial arms, but peripheral neuropathy and neutropenia were most consistently, and statistically significantly, associated with the use of thalidomide.
Data from the MMIX trial (CTDa versus MP) on response rates were eligible for inclusion in the Assessment Group's systematic review; however, overall survival and progression-free survival were not eligible for inclusion (see section 4.1.10).
The Assessment Group concluded that the evidence from one study (VISTA) indicated that combination chemotherapy with VMP was more effective than MP in terms of a longer time to disease progression, increasing overall survival and increasing the proportion of participants achieving a complete response. Adverse events occurred in both trial arms. Bortezomib was associated with a statistically significant increase in grade 3 adverse events.
Following consultation, the manufacturer of bortezomib submitted evidence of the effect on overall survival of the inclusion of studies with participants who had received maintenance therapy with thalidomide (GIMEMA, MMIX and two additional studies HOVON and NORDIC). For each study, the manufacturer plotted the HR of overall survival at cumulative time periods (3-month intervals). The HR was derived using all deaths up to that point but excluded further follow-up. The manufacturer stated that in all studies except IFM 99/06, the HR improved as follow-up increased, regardless of whether the studies included maintenance treatment or not. The Assessment Group commented on the additional evidence and stated that it was not possible to make conclusions about the relative effects of maintenance versus first-line treatment from the evidence submitted.
# Cost effectiveness
The two manufacturers submitted cost-effectiveness models. The Assessment Group developed its own economic model and critiqued the economic models submitted by the manufacturers.
## The Celgene economic model
The manufacturer of thalidomide developed a Markov model to compare the costs and benefits of MPT with those of VMP and MP in people with multiple myeloma who are older than 65 years or are 'ineligible for high-dose chemotherapy'. The model had four health states that were defined by the stage of disease progression or the occurrence of adverse events. The four health states were: pre-progression without adverse events, pre-progression with adverse events, post-progression and death. The analysis was undertaken over a lifetime horizon (that is, 30 years). Treatment effects were calculated from a mixed-treatment comparison of data from three RCTs (VISTA, IFM 99/06, IFM 01/01), using measures of survival time before and after progression as the primary outcomes. Resources and costs were obtained from several sources, including an unpublished survey of UK haematologists by the manufacturer of thalidomide, NHS reference costs, and BNF edition 57 with costs inflated to 2008 values.
The manufacturer's model included the following assumptions:
Post-progression survival was modelled to be the same across different treatment strategies, with the different arms assumed to receive the same alternative treatment after progression (that is, second- and third-line treatments).
Patients were assumed to discontinue first-line treatment on disease progression.
No costs for second- and third-line treatments were included.
Deaths occurred at or after progression and were assumed to be because of disease-related deterioration.
Adverse events included in the model incorporated a utility decrement at the time of the event and the additional cost of treating them. They were assumed not to affect the rates of disease progression or overall survival, or treatment duration, efficacy or dose.
Data on health-related quality of life were obtained from an RCT (HOVON 24) of intensive chemotherapy followed by myeloablative therapy with autologous stem cell rescue compared with intensive chemotherapy alone. The utility values used were 0.64 for people not responding to treatment and 0.81 for people who did respond (using the utility value for the general population of the same age). A utility value of 0.77 at 24 months was used for people who continue to respond to intensive chemotherapy and whose disease has not progressed.
The base-case cost-effectiveness results were as follows:
MPT compared with MP was associated with an incremental cost-effectiveness ratio (ICER) of £23,381 per quality-adjusted life year (QALY) gained based on an incremental effect of 0.85 QALYs and an incremental cost of £19,768.
VMP compared with MPT was associated with an ICER of £303,845 per QALY gained based on an incremental effect of 0.07 QALYs and an incremental cost of £21,483.
One-way deterministic sensitivity analyses showed that the parameters with the greatest effect on the model results were changes in treatment efficacy, with a range of £16,586 to £33,275 per QALY gained for MPT versus MP and a range of £148,873 to £1,000,435 per QALY gained for VMP versus MPT. Probabilistic sensitivity analysis was not conducted because the manufacturer considered the efficacy of MPT and VMP to be essentially the same and therefore the cost difference would be the key factor in the model.
## The Janssen economic model
The manufacturer of bortezomib developed a decision-analytic cost–utility model to compare the costs and benefits for VMP with those of MPT, CTDa and MP in people with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with stem cell transplantation. The model included four health states: before response to treatment; response to treatment without progression; post-progression; and death. The times to response or death were estimated from life tables constructed directly from data from the VISTA trial. Progression-free survival at 6, 12, 18 and 24 months for MP was estimated from a meta-analysis of the MP arms of included RCTs. Progression-free survival was extrapolated beyond 24 months. Utility values for health-related quality of life were assigned to each of the states: 0.77 for before response to treatment; 0.81 for response to treatment without progression; and 0.64 for post-progression. The model used a cohort of people newly diagnosed with multiple myeloma, with MP as the baseline treatment. Treatment effects for VMP, MPT and CTDa were then modelled over time by adjusting the baseline results via HRs. HRs were estimated at 48 months for overall survival for each of the RCTs, except the VISTA trial, which had a follow-up of only 36 months. Overall survival for patients receiving thalidomide was estimated from five RCTs, some of which included thalidomide maintenance.
The manufacturer's model made the following assumptions:
The resource use cost for the first-line management of multiple myeloma was the same for all regimens.
Seven cycles of treatment with MP were used (as in the VISTA trial).
For bortezomib, 31.5 vials were used per patient (as in the VISTA trial).
A dose of thalidomide of 150 mg/day was used for the MPT regimen and 167 mg/day was used for the CTDa regimen.
The costs of treating adverse events were included in the model; the incidence of adverse events does not influence the treatment duration, efficacy or patient utility.
Costs were included for second- and third-line treatments. On disease progression, it was assumed that second-line treatment would consist of bortezomib plus high-dose dexamethasone, CTDa or high-dose dexamethasone. Most people received CTDa after first-line VMP. People on other first-line therapies usually received bortezomib and high-dose dexamethasone as second-line treatment. All patients received lenalidomide plus dexamethasone as third-line treatment. Most people receiving bortezomib as first‑line treatment would not receive it as second-line treatment.
The manufacturer's base-case cost-effectiveness results were as follows:
MPT compared with MP was associated with an ICER of £8912 per QALY gained based on an incremental effect of 0.55 QALYs and an incremental cost of £4888.
CTDa compared with MP was associated with an ICER of £10,905 per QALY gained based on an incremental effect of 0.21 QALYs and an incremental cost of £2234.
VMP compared with MP was associated with an ICER of £10,498 per QALY gained based on an incremental effect of 1.17 QALYs and an incremental cost of £12,242.
One-way sensitivity analysis showed the model was most sensitive to the following parameters: underlying MP survival hazard, HRs for overall survival, dose of thalidomide, and duration of treatment with thalidomide in the MPT arm. A probabilistic sensitivity analysis showed that at the £20,000 and £30,000 thresholds, VMP has the highest probability of being cost effective (64% and 75% respectively).
Two scenario analyses were conducted. The first excluded the costs of subsequent therapy after first-line treatment. In this scenario, the cost-effectiveness results were less favourable for each of the treatments and the ICERs increased to £48,437, £16,956 and £21,099 per QALY gained for CTDa, MPT, and VMP respectively, compared with MP. The second scenario assumed the same second-line treatments as for people treated with MP in the VISTA trial. For this scenario, the results were similar to the base-case analyses.
## The Assessment Group model
The Assessment Group's survival model was developed to estimate the costs, benefits and cost effectiveness of MPT, VMP and CTDa compared with MP, in people with newly diagnosed multiple myeloma who are 'ineligible' for high-dose chemotherapy with stem cell transplantation. The model consisted of cycles of 6 weeks in length to be consistent with the cycle lengths used for chemotherapy treatment. A lifetime horizon of 30 years was modelled. Survival was classified into three health states: treatment (defined as the time patients are treated with first-line therapy); post-treatment (defined as the mean time from the end of first-line treatment until disease progression) and post-progression (defined as the mean time from disease progression until death).
The Assessment Group constructed a survival curve for overall survival and a curve for progression-free survival for each of the alternative treatments (MPT, MP, VMP) included in its systematic review (see sections 4.1.4, 4.1.5 and 4.1.13). These curves were used to derive the time spent in the three health states. For each treatment option, the relative risk for complete response compared with MP was derived from the outcome data for complete response from the RCTs included in the Assessment Group's systematic review (see sections 4.1.6, 4.1.11 and 4.1.13).
Health-related quality of life data were from a systematic review of studies of health-related quality of life. The Assessment Group did not identify any generic preference-based studies of people with untreated multiple myeloma who were not eligible for high-dose chemotherapy with stem cell transplantation, but did identify a study not identified by the manufacturers that assessed health-related quality of life in this group using the EORTC QLQ-C30. The Assessment Group mapped the EORTC QLQ-C30 to the EQ-5D using a validated mapping algorithm. The utility estimates used were 0.58 for the treatment health state and 0.68 for the post-treatment state.
Costs were derived from a number of sources including the BNF, RCTs included in the Assessment Group's systematic review and clinical and expert clinical opinion. The Assessment Group's model included the following assumptions:
For bortezomib, each person receives one vial per administration.
Patients receive second-line treatment following disease progression after first-line therapy. The model assumed that most people who received VMP as first-line treatment received CTDa as second-line treatment and most who did not receive bortezomib as first-line treatment received it as second-line treatment.
Costs were included for second-line treatment. The effect of second-line treatment on health outcomes was not included in the model because second-line treatments varied among the RCTs included in the Assessment Group's systematic review (see sections 4.1.8 and 4.1.16).
Cost and outcomes of third-line and subsequent treatments were assumed to be the same between arms.
People discontinued first-line treatment on disease progression.
Health-related quality of life was better for those with complete response than those with less than complete response and was assumed to improve when people stop treatment.
Adverse events were not modelled explicitly, but additional costs for treating the adverse events were included.
The base-case cost-effectiveness results were as follows:
MPT compared with MP was associated with an ICER of £9174 per QALY gained based on an incremental effect of 1.22 QALYs and an incremental cost of £11,207.
CTDa compared with MP was associated with an ICER of £33,216 per QALY gained based on an incremental effect of 0.26 QALYs and an incremental cost of £8592.
VMP compared with MP was associated with an ICER of £29,837 per QALY gained based on an incremental effect of 1.20 QALYs and an incremental cost of £35,749.
The incremental cost-effectiveness analysis suggested that CTDa is extendedly dominated by MPT and MP, and that MPT dominates VMP because it is more effective and cheaper. The incremental baseline cost-effectiveness results were as follows: CTDa compared with MP was associated with an ICER of £33,216 per QALY gained; and VMP compared with CTDa was associated with an ICER of £28,907 per QALY gained. The comparison of VMP versus MPT suggested that VMP and CTDa were unlikely to be cost-effective treatment options at the thresholds of £20,000 to £30,000 per QALY gained.
Sensitivity analyses showed the effects of a range of parameter values in the economic model. For each of the treatments the model results were most sensitive to the HRs for overall survival, cost and dosage of the treatment and the overall baseline survival curve used for MP. The deterministic sensitivity results for MPT versus MP varied between £6470 and £22,855 per QALY gained. The deterministic sensitivity analysis for VMP versus MP gave ICERs between £20,451 and £87,716 per QALY gained. VMP was dominated by MPT in all analyses apart from that investigating sensitivity to changes in overall survival. The deterministic sensitivity analysis for CTDa versus MP gave ICERs between −£29,388 (dominant, that is CTDa is more effective and less costly than MP) and £16,989 per QALY gained.
In addition to the sensitivity analyses, five alternative scenarios were explored to investigate the uncertainty around structural assumptions. In scenario A (no subsequent therapies), the ICERs for MPT, CTDa and VMP versus MP increased from £9174, £33,216 and £29,837, to £9738, £34,013 and £37,727 per QALY gained respectively.
Scenario B (vial sharing/fewer vials) investigated the cost effectiveness when patients share vials of bortezomib. With vial sharing and no wastage, the ICERs for MPT and CTDa versus MP increased from £9174 and £33,216 to £9369 and £33,492 per QALY gained respectively. The ICER for VMP versus MP decreased from £29,837 to £22,549 per QALY gained. Following comments received from consultees on the draft assessment report, the Assessment Group undertook an additional scenario analysis in which it was assumed that four cycles or 31 vials of bortezomib were used, with no loss of efficacy. In this scenario, the ICER for VMP versus MP decreased from £29,837 (no vial sharing) to £18,996 per QALY gained. The ICER for VMP versus MPT decreased from −£1,000,000 (that is, MPT dominates VMP) to £319,923 per QALY gained.
Scenario C (inclusion of thalidomide maintenance trials) investigated the cost effectiveness using the estimate of efficacy for MPT from a meta-analysis that included trials with thalidomide maintenance. The manufacturer of bortezomib conducted a mixed-treatment comparison for MPT versus MP with trials that included thalidomide maintenance. Using the HR from this analysis the ICER for MPT versus MP increased from £9174 to £24,390 per QALY gained. The ICERs for CTDa and VMP remained the same as in the base-case analysis (£33,216 and £29,837 per QALY gained respectively). In addition, MPT no longer dominated VMP, with an ICER of £32,739 for VMP versus MPT.
Scenario D (treatment effectiveness beyond the end of trial) investigated an alternative assumption whereby there is no treatment benefit for the three drug combinations over MP (that is, the event rates for these treatments are the same as for MP) after the end of the trial. This assumption had a large effect on the model results and all treatments were less cost effective than MP. The ICERs for each of the treatment options more than doubled to £20,698 (MPT), £71,264 (VMP) and £80,840 (CTDa) per QALY gained versus MP.
The probabilistic sensitivity analysis estimated the probability of each of the treatments being cost effective at the £20,000 and £30,000 thresholds. MPT had the highest probability (0.95 at both thresholds) of being cost effective. The baseline probabilistic sensitivity analysis showed that MPT was cost effective compared with MP, with an ICER of £9124. The comparisons of VMP versus MP and CTDa versus MP produced ICERs of £29,102 and £31,612 respectively.
## Comparison of the manufacturer and Assessment Group models
The cost-effectiveness estimates differed between the manufacturers and the Assessment Group. This was a result of differences in incremental costs for MPT versus MP, differences in incremental QALY estimates for MPT versus MP (depending on whether trials with maintenance treatment were included), differences in the modelling of adverse events and inclusion of costs for second- and third-line treatments.
The incremental costs for MPT versus MP varied between £4888 (the manufacturer of bortezomib) and £19,768 (manufacturer of thalidomide). The manufacturer of thalidomide used higher dosages of thalidomide (238 mg/day) for longer periods (11 cycles) than the other two analyses. The incremental costs for VMP versus MP varied between £12,242 (manufacturer of bortezomib) and £41,251 (manufacturer of thalidomide). These differences were largely a result of the assumptions around the number of vials of bortezomib used, with the manufacturer of bortezomib assuming a mean of 31.5 vials per person, and the Assessment Group and manufacturer of thalidomide assuming over 40 vials. The incremental costs for CTDa versus MP varied between £2234 (manufacturer of bortezomib) and £8592 (Assessment Group). These differences were because of an error in the cost calculation for third-line therapy for CTDa by the manufacturer of bortezomib.
The total QALY estimates used by the manufacturers and the Assessment Group were similar, with estimates for all treatment arms varying between 2.42 and 4.03. The incremental QALY estimates for MPT versus MP varied from 0.55 (manufacturer of bortezomib) to 1.22 (Assessment Group). These differences resulted from the estimates chosen for the HR for overall survival compared with MP. Estimates used by the manufacturer of bortezomib included studies with maintenance treatment whereas those used by the Assessment Group excluded studies with maintenance treatment.
There were differences in the way adverse events were modelled. The manufacturer of bortezomib included adverse events in the model as the cost of treating them. The manufacturer of thalidomide included adverse events in the model as a utility decrement at the time of the event and as the cost of treating them. The Assessment Group did not explicitly model adverse events for patient outcomes (that is, overall survival and progression-free survival), but included an additional cost for treating the adverse events in the model.
There were also differences in inclusion of costs after first-line treatment:
The manufacturer of bortezomib included costs for second- and third-line treatments. Most people who received VMP as first-line treatment received CTDa as second-line treatment and most who did not receive VMP as first-line treatment received it as second-line.
The manufacturer of thalidomide assumed that patients discontinued first-line treatment on disease progression and did not include costs for second- and third-line treatments.
The Assessment Group included costs for second-line treatments. Most people who received VMP as first-line treatment received CTDa as second-line treatment and most who did not receive bortezomib as first-line treatment received it as second-line.
## Extra analyses post-consultation
Following consultation on the appraisal consultation document, the manufacturer of bortezomib submitted additional cost-effectiveness estimates using their model and applying different assumptions used by the Assessment Group, including evidence from studies including maintenance therapy, use of 31.5 vials of bortezomib and varying second-line therapies. The five scenarios were as follows:
Scenario 1 investigated the use of 52 vials of bortezomib, with evidence of MPT efficacy from IFM 99/06 and IFM 01/01 studies and second-line therapies as in the Assessment Group model (see section 4.2.16).
Scenario 2 investigated use of 52 vials of bortezomib, with evidence of MPT efficacy from a meta-analysis that included five trials with maintenance therapy, and second-line therapies as in the Assessment Group model (see section 4.2.16).
Scenario 3 investigated use of 31.5 vials of bortezomib, with evidence of MPT efficacy from IFM 99/06 and IFM 01/01 studies and second-line therapies as in the Assessment Group model (see section 4.2.16).
Scenario 4 investigated use of 31.5 vials of bortezomib, with evidence of MPT efficacy from a meta-analysis that included five trials with maintenance therapy, and second-line therapies as in the Assessment Group model (see section 4.2.16).
Scenario 5 investigated use of 31.5 vials of bortezomib, with evidence of MPT efficacy from a meta-analysis that included five trials with maintenance therapy, and second-line therapies as in the VISTA trial (see section 4.1.16).
For MPT versus MP, the ICERs for the five scenarios varied between £9138 (scenarios 1 and 3) and £17,337 (scenario 5) per QALY gained. The incremental costs varied between £8706 (scenarios 2 and 4), £9509 (scenario 5) and £12,104 (scenarios 1 and 3), and the incremental QALYs from 0.55 (scenarios 2, 4 and 5) to 1.32 (scenarios 1 and 3). That is, the QALY was reduced from 1.32 for those scenarios in which only two MPT studies (IFM 99/06 and IFM 01/01) were included to 0.55 when studies with maintenance therapy (5 studies) were included.
For VMP versus MP, the ICERs varied from £15,107 (scenarios 3 and 4) to £28,510 (scenarios 1 and 2) per QALY gained. The incremental costs varied from £17,615 (scenarios 3 and 4) to £33,244 (scenarios 1 and 2). The incremental QALYs for all scenarios were 1.17.
For VMP versus MPT, the ICERs varied between £14,426 (scenario 4), £21,565 (scenario 5) and £39,733 (scenario 2) per QALY gained. VMP was dominated by MPT in scenarios 1 and 3. The incremental costs varied from £5512 (scenario 3) to £24,538 (scenario 2) and the incremental QALYs varied from −0.16 (scenarios 1 and 3) to 0.62 (scenarios 2, 4 and 5).
The Assessment Group reviewed the additional scenarios presented by the manufacturer of bortezomib. It confirmed that there was close agreement between the two models when using the same assumptions and data for both models. However, the Assessment Group did not agree with the assumptions and the data used in the manufacturer's additional scenarios.
## Extra analyses post-appeal
Following an Appeal Panel request, the Assessment Group's economic model, which had previously not been released because it contained confidential information, was released for consultation. Only the manufacturer of bortezomib (Janssen) submitted comments on the Assessment Group's economic model. The manufacturer of bortezomib incorporated a number of their proposed amendments to the Assessment Group's economic model and submitted revised cost-effectiveness estimates. These amendments related to the cost of managing adverse events, treatment duration of thalidomide based on mean duration observed in IFM99-06, IFM01-01 and VISTA trials, method for estimating QALYs, cost of second-line treatment and inclusion of three additional maintenance studies for thalidomide (GIMEMA, HOVON and NORDIC). The manufacturer of bortezomib presented three alternative scenarios for each of the comparisons (MPT versus MP, VMP versus MP and CTDa versus MP), in which the amendments were incorporated into the Assessment Group's economic model:
Scenario 1 corrected for the cost of managing adverse events, treatment duration of thalidomide, QALYs estimated using Markov trace and cost of second-line treatment.
Scenario 2 corrected for the inclusion of data from the pre-maintenance phase of maintenance studies (GIMEMA, HOVON, NORDIC) for the first 6-month period, in addition to the corrections listed in scenario 1.
Scenario 3 corrected for the inclusion of data from the pre-maintenance phase of maintenance studies for the first 12-month period, in addition to the corrections listed in scenario 1.
For MPT versus MP the ICERs for the three scenarios varied from £11,511 (scenario 1) to £13,722 (scenario 3) per QALY gained. For VMP versus MP the ICER was £19,505 per QALY gained for all three scenarios. For CTDa versus MP the ICERs varied between £11,890 (scenario 2) and £34,014 (scenario 1) per QALY gained. For VMP versus MPT, the ICERs varied between £36,794 (scenario 3) and £211,508 (scenario 1).
The Assessment Group commented on the proposed amendments and the revised cost-effectiveness estimates submitted by the manufacturer of bortezomib. The Assessment Group accepted that the model contained an error in the calculation of the adverse events costs, and that the use of a Markov trace may possibly provide a more accurate method for estimating the QALYs. The Assessment Group therefore provided revised cost-effectiveness results based on a revision to the adverse events costs and the use of a Markov trace to estimate the QALYs. The revised cost-effectiveness results were as follows:
MPT compared with MP was associated with an ICER of £9189 per QALY gained based on an incremental effect of 1.21 QALYs and an incremental cost of £11,159.
CTDa compared with MP was associated with an ICER of £33,703 per QALY gained based on an incremental effect of 0.25 QALYs and an incremental cost of £8544.
VMP compared with MP was associated with an ICER of £29,930 per QALY gained based on an incremental effect of 1.19 QALYs and an incremental cost of £35,729.
The Assessment Group's incremental analysis showed that MPT continues to dominate VMP.
## Summary of the cost effectiveness
The different assumptions and methodology used (see sections 4.2.25 to 4.2.37) resulted in a range of ICERs for the options for first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate. The Assessment Group and manufacturers' base-case cost-effectiveness results for MPT versus MP varied between £8912 (manufacturer of bortezomib) and £23,381 (manufacturer of thalidomide) per QALY gained. The Assessment Group and manufacturers' base-case cost-effectiveness results for VMP versus MP varied between £10,498 (manufacturer of bortezomib) and £29,837 (Assessment Group) per QALY gained. The Assessment Group and manufacturers' base-case cost-effectiveness results for CTDa versus MP varied between £10,905 (manufacturer of bortezomib) and £33,216 (Assessment Group) per QALY gained. The Assessment Group and manufacturers' base-case cost-effectiveness results for MPT versus VMP were £303,845 (manufacturer of thalidomide), and £319,923 (when the Assessment Group used the scenario of 31 vials of bortezomib) per QALY gained. The Assessment Group's incremental analysis of its base-case cost-effectiveness results suggested MPT dominates VMP because it is more effective and cheaper. The additional scenarios presented by the manufacturer of bortezomib following consultation on the appraisal consultation document (May 2010) resulted in ICERs for VMP versus MPT of £39,733 per QALY gained (scenario 2), £14,426 per QALY gained (scenario 4) and £21,565 (scenario 5). VMP was dominated by MPT in scenarios 1 and 3. The revised ICERs presented by the manufacturer of bortezomib and the Assessment Group following the release of the economic model for MPT versus MP varied between £9189 (Assessment Group) and £13,722 (manufacturer of bortezomib, scenario 3) per QALY gained, for VMP versus MP varied between £19,505 (manufacturer of bortezomib, all three scenarios) and £29,930 (Assessment Group) per QALY gained and for CTDa versus MP varied between £11,890 (manufacturer of bortezomib, scenario 2) and £34,014 (manufacturer of bortezomib, scenario 1) per QALY gained. The Assessment Group's incremental analysis of its revised cost-effectiveness results suggested that MPT continued to dominate VMP.
# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bortezomib and thalidomide, having considered evidence on the nature of multiple myeloma and the value placed on the benefits of bortezomib and thalidomide by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee acknowledged the history of thalidomide as a teratogenic compound and noted that it is now prescribed and dispensed according to the Thalidomide Celgene Pregnancy Prevention Programme.
The Committee discussed the pathway of care for people with multiple myeloma for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate. The Committee heard from the clinical specialists that in UK clinical practice before the advent of thalidomide and bortezomib, first-line treatment consisted of an alkylating agent (melphalan or cyclophosphamide) and a corticosteroid (attenuated dexamethasone or prednisolone). Since thalidomide and bortezomib had become available, one of these, according to patient preference, comorbidities and adverse events, was normally added to first-line treatment. The Committee heard from the clinical specialists and patient experts that although both the thalidomide and bortezomib regimens were well tolerated, administration of the bortezomib regimen took longer and was less convenient than thalidomide (because it involved intravenous infusion rather than oral administration). The clinical specialists stated that a thalidomide regimen would be considered more appropriate for 70–75% of patients and that their preferred choice of regimen was thalidomide in combination with cyclophosphamide and attenuated dexamethasone (because of the mode of oral administration). The clinical specialists stated that they considered the two thalidomide regimens (CTDa and MPT), which both included an alkylating agent and a steroid, to be equivalent in terms of safety and efficacy. Past studies of the two regimens before the addition of thalidomide had shown equivalent safety and efficacy and the clinical specialists did not consider that the addition of thalidomide would have a differential effect. The Committee heard that for those people who were intolerant of thalidomide or had clotting disorders or impaired renal function, bortezomib in combination with melphalan and prednisolone was considered the most appropriate treatment. The Committee was not persuaded that comorbidities such as clotting disorders or renal impairment prevented a person from receiving thalidomide because they could be managed as outlined in the SPC for thalidomide. The Committee accepted that clinicians considered the three treatment regimens to be equivalent in terms of clinical efficacy, but that the choice of treatment for an individual patient will depend on the comorbidities present and the different mechanisms of action and adverse events associated with the treatments.
## Clinical effectiveness
The Committee considered the estimates for the clinical effectiveness of MPT and CTDa. It noted that the Assessment Group had derived HRs for overall survival for thalidomide from two studies without maintenance treatment and had excluded studies in which participants received maintenance with thalidomide after first-line treatment. The Committee noted that maintenance with thalidomide monotherapy after first-line treatment with a combination regimen did not fall within the appraisal scope. It also noted that, if possible (that is, when available for first-line treatment without maintenance), outcome data (for example, complete response) had been included in the Assessment Group's systematic review of clinical effectiveness. The Committee also heard from the clinical specialists and the manufacturer of thalidomide that not all participants in the maintenance studies benefited from maintenance treatment and that some people on thalidomide maintenance had a shorter overall survival, possibly because the prolonged thalidomide treatment induced disease resistance. The Committee concluded (see section 4.3.10) that to assign studies (published and ongoing) in which the results were confounded by treatment outside the appraisal scope equivalent weight to the two key studies without maintenance treatment was not justified. Nevertheless it was prepared to bear in mind these data without overemphasising them. Similarly the Committee considered the estimates of overall survival for CTDa and noted that the evidence came from preliminary results of the MMIX trial which included participants who had received maintenance treatment with thalidomide. The Committee noted these results but considered that the main conclusions on the clinical effectiveness of thalidomide should be derived from the MPT data. Based on these data, the Committee concluded that thalidomide in combination with an alkylating agent and a corticosteroid improved outcomes when compared with an alkylating agent and a corticosteroid in people with multiple myeloma for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate.
The Committee discussed the relative effectiveness of bortezomib in combination with an alkylating agent and a corticosteroid as presented by the Assessment Group. It noted that the evidence for the effectiveness of bortezomib in combination with an alkylating agent and a corticosteroid was derived from a single study (VISTA). This study showed that bortezomib was more effective than melphalan in combination with prednisolone in terms of overall survival and progression-free survival. It noted that survival rates with bortezomib were similar to those for thalidomide but that the two regimens were not compared head-to-head because of differences in participants' characteristics, delivery of the comparator and length of follow-up. The Committee concluded that it was likely that bortezomib in combination with an alkylating agent and corticosteroid improved outcomes to a similar degree to thalidomide in combination with an alkylating agent and corticosteroid.
## Cost effectiveness
The Committee considered the base-case ICERs for thalidomide in combination with an alkylating agent and a corticosteroid from the Assessment Group's economic analyses. The Assessment Group calculated an ICER of £9170 per QALY gained for the MPT combination compared with MP and £33,200 per QALY gained for the CTDa combination compared with MP. The Committee accepted that if the safety and efficacy of the two thalidomide regimens were considered equivalent (see section 4.3.3), the ICER of £9170 for MPT was likely to be the more robust estimate because it was based on studies without thalidomide maintenance treatment.
The Committee also noted the variation in the ICERs presented by the manufacturers for MPT compared with MP (£8910 to £23,400). The highest of these, £23,400, was from the manufacturer of thalidomide and assumed higher dosages of thalidomide and a greater number of cycles of treatment than the analyses from the manufacturer of bortezomib and the Assessment Group. The dosage of thalidomide used by the manufacturer of thalidomide was the maximum specified in the SPC but was higher than would be used in clinical practice (most patients are not able to tolerate such a high dose). The Committee considered that the ICER was likely to be lower than the estimate from the manufacturer of thalidomide and that the most plausible ICERs for the two thalidomide regimens would fall within the range considered a cost-effective use of NHS resources (below £20,000 to £30,000). The Committee therefore concluded that thalidomide in combination with an alkylating agent and a corticosteroid is a cost-effective option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate.
The Committee then considered the Assessment Group's ICERs for VMP compared with MP and with the thalidomide regimens. The Committee heard from the Assessment Group that the maximum dose of bortezomib specified in the SPC is eight cycles, which the manufacturer agreed would amount to 48 vials. The manufacturer of bortezomib stated, however, that on average only 31.5 vials were used in the VISTA trial. The manufacturer accounted for this difference on the grounds of dose reduction and dose delay. At the first Appraisal Committee meeting, the Committee accepted the concern raised by the manufacturer of bortezomib that the Assessment Group had assumed too many vials of bortezomib. Following consultation comments from the Assessment Group and on further discussion with both the manufacturer and the Assessment Group at the second meeting, the Committee considered that the costs of delayed doses might still reflect clinical practice and need to be considered. It therefore agreed that the manufacturer's preference for modelling 31.5 vials should be considered the most optimistic estimate for clinical practice. The Committee noted that the Assessment Group's scenario that assumed four cycles (equivalent to 31 vials used) gave an ICER of £19,000 per QALY gained for VMP compared with MP and £320,000 per QALY gained for VMP compared with MPT.
The Committee noted the differences in the ICERs presented by the Assessment Group and the manufacturer of bortezomib for VMP compared with MPT. Apart from the fewer vials of bortezomib assumed by the manufacturer, the manufacturer of bortezomib also included costs for second-and third-line treatments in its model. This involved adding the cost of thalidomide to the bortezomib regimen, and of bortezomib to the thalidomide regimen, neutralising the approximately four-fold cost advantage of thalidomide, and greatly increasing the cost of MP. The Committee agreed that some accounting for second-line treatments was plausible, but not such that the cost of thalidomide in effect carried the cost of bortezomib, and certainly no more than the distribution of second-line treatments noted in the VISTA trial.
The Committee then considered the use by the manufacturer of bortezomib of a HR for overall survival for thalidomide which was derived from a meta-analysis that included RCTs with thalidomide maintenance. The Committee heard a strong case from the manufacturer of bortezomib that the maintenance studies should be included in the economic analysis, along with 31.5 vials and their estimate of the distribution of second-line treatments. The Committee was aware of the testimonies from the clinical specialists and the manufacturer of thalidomide (see section 4.3.4) that it was appropriate to exclude all the maintenance studies. However, the Committee took the view that it was appropriate to consider the maintenance studies, but did not accept that results from these studies (which were confounded by treatment outside the appraisal scope) should be considered equivalent to the key studies without maintenance treatment. The Committee concluded that the most plausible ICER for bortezomib versus thalidomide could be less than the Assessment Group's base case of £320,000 per QALY gained, but would be considerably greater than those from the two most optimistic scenarios (£14,400, scenario 4 and £21,600, scenario 5) presented by the manufacturer of bortezomib (see section 4.2.30). The Committee therefore did not accept the manufacturer of bortezomib's assertion that the bortezomib regimen (VMP) was cost effective compared with the thalidomide regimen (MPT).
The Committee considered the revised cost-effectiveness estimates submitted by the manufacturer of bortezomib and the responses by the Assessment Group following release of the Assessment Group's economic model. It noted that the revised ICERs for MPT compared with MP presented by the Assessment Group and manufacturer of bortezomib were similar and slightly higher than their respective original base-case cost-effectiveness results (see sections 4.2.10 and 4.2.17). The Committee also discussed the revised ICERs for CTDa compared with MP presented by the Assessment Group and manufacturer of bortezomib. It noted that the Assessment Group's revised ICERs were similar and slightly higher to their base-case cost-effectiveness results, and the Committee reconfirmed its conclusion that the thalidomide evidence should be principally drawn from the MPT data. The Committee also noted that the revised ICERs presented by the manufacturer of bortezomib ranged from £11,900 to £34,000 and these were higher than its original base-case cost-effectiveness results (see sections 4.2.10 and 4.2.36). The Committee noted that the lowest estimate (£11,900) included data from the maintenance studies which it had previously agreed should not be considered equivalent to the studies without maintenance treatment (see section 4.3.10). The Committee agreed that the manufacturer of bortezomib's revised ICERs for the two thalidomide regimens did not change the original decision that thalidomide in combination with an alkylating agent and a corticosteroid is a cost-effective option for the first-line treatment of multiple myeloma in people for who high-dose chemotherapy with stem cell transplantation is considered in appropriate. The Committee then discussed the revised cost-effectiveness estimates presented for VMP compared with MPT. It noted that the ICERs presented by the Assessment Group showed that MPT continued to dominate VMP and that the ICERs presented by the manufacturer of bortezomib exceeded £30,000 per QALY (£36,800 to £211,500 per QALY gained), despite the more optimistic estimate including the maintenance trial data. The Committee therefore concluded that these revised ICERs did not change their original assertion that VMP was not cost-effective compared with MPT.
However, the Committee did consider that bortezomib regimens could be cost effective for people who are unable to tolerate or have a contraindication to thalidomide. The Committee was aware that the contraindications specified in the SPC for thalidomide are pregnancy and hypersensitivity. It was mindful of the testimonies from the clinical specialists that people who are intolerant of thalidomide, or who had previous thrombosis or impaired renal function, are offered the bortezomib regimen (VMP). The Committee noted that comorbidities such as risk of thromoboembolic events and renal impairment are highlighted in the posology section of the SPC for thalidomide, which describes that low molecular weight heparin or warfarin should be recommended in patients at risk of thromboembolic events, and patients with renal or hepatic impairment should be monitored for adverse events. The Committee again considered the argument that the wording of the guidance around the contraindications to thalidomide should include people with comorbidities such as risk of thrombosis and impaired renal function. The Committee understood that thalidomide could be prescribed to people with renal impairment and risk of thromboembolic events if it is administered as outlined in section 4.2 (posology and method of administration) of the SPC for thalidomide. The Committee agreed that the SPC for thalidomide covered the safety risks adequately. The Committee concluded that since it had accepted the Assessment Group's ICER of £19,000 per QALY gained for VMP compared with MP (see section 4.3.8), bortezomib in combination with an alkylating agent and a corticosteroid is likely to be a cost-effective option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate and who are intolerant of or have contraindications to thalidomide.
In summary, the Committee considered that the combination of thalidomide plus an alkylating agent and steroid was both clinically effective and cost effective for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate. The Committee considered that bortezomib plus an alkylating agent and steroid was not cost effective when compared with both thalidomide combinations, but was likely to be cost effective for the first-line treatment of multiple myeloma for people who are intolerant to or have contraindications to thalidomide.
# Summary of Appraisal Committee's key conclusions
TA228 (MTA)
Appraisal title: Bortezomib and thalidomide for the first-line treatment of multiple myeloma
FAD section
Key conclusion
Thalidomide in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma in people for whom high dose chemotherapy with stem cell transplantation is considered inappropriate.
Bortezomib in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma if:
high-dose chemotherapy with stem cell transplantation is considered inappropriate and
the person is unable to tolerate or has contraindications to thalidomide.
The Committee concluded that thalidomide in combination with an alkylating agent and a corticosteroid improved outcomes when compared with an alkylating agent and a corticosteroid in people with multiple myeloma for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate.
The Committee concluded that it was likely that bortezomib in combination with an alkylating agent and corticosteroid improved outcomes to a similar degree to thalidomide in combination with an alkylating agent and corticosteroid.
The Committee concluded that thalidomide in combination with an alkylating agent and a corticosteroid is a cost-effective option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate.
The Committee did not accept the manufacturer of bortezomib's assertion that the bortezomib regimen (VMP) was cost effective compared with the thalidomide regimen (MPT). However, the Committee did consider that bortezomib regimens could be cost effective for people who are unable to tolerate or have a contraindication to thalidomide.
Current practice
Clinical need, including the availability of alternative treatments
Multiple myeloma remains an incurable disease, with an average survival of 4–6 years, but it can be treated with a combination of supportive measures and chemotherapy.
The Committee discussed the pathway of care for people with multiple myeloma for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate. The Committee heard from the clinical specialists that in UK clinical practice before the advent of thalidomide and bortezomib, first-line treatment consisted of an alkylating agent (melphalan or cyclophosphamide) and a corticosteroid (attenuated dexamethasone or prednisolone). Since thalidomide and bortezomib had become available, one of these, according to patient preference, comorbidities and adverse events, was normally added to first-line treatment.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
Thalidomide is an immunomodulatory agent. Its precise mechanism of action is under investigation and is currently unknown, but it is thought to have multiple actions, including anti-inflammatory activity and the ability to inhibit the growth and survival of myeloma cells and the growth of new blood vessels. It is also a non-barbiturate hypnotic sedative with central action.
Bortezomib is an anticancer drug that works by reversible proteasome inhibition. This inhibition leads to arrest of the cell cycle and apoptosis (cell death), which reduces tumour growth. Myeloma cells are more sensitive to the action of bortezomib than normal cells.
What is the position of the treatment in the pathway of care for the condition?
The Committee heard from the clinical specialist that in UK clinical practice before the advent of thalidomide and bortezomib, first-line treatment consisted of an alkylating agent (melphalan or cyclophosphamide) and a corticosteroid (attenuated dexamethasone or prednisolone). Since thalidomide and bortezomib had become available, one of these, according to patient preference, comorbidities and adverse events, was normally added to first-line treatment. The Committee accepted that clinicians considered the three treatment regimens to be equivalent in terms of clinical efficacy but that the choice of treatment for an individual patient will depend on the comorbidities present and the different mechanisms of action and adverse events associated with the treatments.
Adverse effects
Adverse events were not a key driver in the economic evaluation; however, see section 4.2.3, 4.2.8 and 4.2.16 for details of how adverse events were modelled by the manufacturers and the Assessment Group.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee noted that Assessment Group had derived hazard ratios for overall survival for thalidomide from two studies without maintenance treatment. The Committee accepted that it was appropriate for the Assessment Group to exclude from its analysis survival data from studies which included participants who had received maintenance therapy.
The Committee noted that the evidence for the effectiveness of bortezomib in combination with an alkylating agent and a corticosteroid was derived from a single study (the VISTA trial).
Relevance to general clinical practice in the NHS
Both thalidomide regimens and the bortezomib regimen are used in clinical practice for the first-line treatment of multiple myeloma. The clinical specialists stated that a thalidomide regimen would be considered more appropriate for 70–75% of patients and that their preferred choice of regimen was thalidomide in combination with cyclophosphamide and attenuated dexamethasone (because of the mode of oral administration). They stated that they considered the two thalidomide regimens (CTDa and MPT) to be equivalent in terms of safety and efficacy. The Committee heard that for those people who were intolerant of or had contraindications to thalidomide, the bortezomib regimen (VMP) was considered the most appropriate treatment.
Uncertainties generated by the evidence
The Committee was persuaded by advice from the clinical specialists that the two thalidomide regimens (CTDa and MPT), which both included an alkylating agent and a steroid, were equivalent in terms of safety and efficacy. The evidence for the clinical effectiveness of bortezomib in combination with an alkylating agent and a corticosteroid was derived from a single study (VISTA). The Committee noted survival rates with bortezomib were similar to those for thalidomide. However, the two regimens were not compared head to head. The Committee concluded that it was likely that bortezomib in combination with an alkylating agent and corticosteroid improved outcomes to a similar degree to thalidomide in combination with an alkylating agent and corticosteroid.
to 4.3.5
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness
The Committee was mindful of the testimonies from the clinical specialists that people who are intolerant of thalidomide, or who had previous thrombosis or impaired renal function, are offered the bortezomib regimen (VMP). It noted that comorbidities such as risk of thromoboembolic events and renal impairment are highlighted in the posology section of the SPC for thalidomide. It therefore concluded that bortezomib in combination with an alkylating agent and a corticosteroid is likely to be a cost-effective option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate and who are intolerant of or have contraindications to thalidomide.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that thalidomide in combination with an alkylating agent and a corticosteroid improved outcomes when compared with an alkylating agent and a corticosteroid in people with multiple myeloma for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate.
It noted that survival rates with bortezomib were similar to those for thalidomide but that the two regimens had not been compared head to head because there were differences in participants' characteristics, delivery of the comparator and length of follow-up. The Committee concluded that it was likely that bortezomib in combination with an alkylating agent and corticosteroid improved outcomes to a similar degree to thalidomide in combination with an alkylating agent and corticosteroid.
Evidence for cost effectiveness
Availability and nature of evidence
The two manufacturers submitted cost-effectiveness models. The Assessment Group developed their own economic model and critiqued the economic models submitted by the manufacturers.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted the variation in the ICERs presented by the manufacturers and the Assessment Group for MPT, CTDa and VMP compared with MP and MPT compared with VMP. The Committee accepted that the variation was a result of the following factors:
Dosage and number of cycles of thalidomide
Number of vials of bortezomib
The inclusion of studies with thalidomide maintenance in the estimate of overall survival hazard ratio for thalidomide
costs for second-and third-line treatments.
Incorporation of health-related quality of life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
No health-related benefits were identified that were not included in the economic models.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee was mindful of the testimonies from the clinical specialists that people who are intolerant of thalidomide, or who had previous thrombosis or impaired renal function, are offered the bortezomib regimen (VMP). It noted that comorbidities such as risk of thromoboembolic events and renal impairment are highlighted in the posology section of the SPC for thalidomide. It therefore concluded that bortezomib in combination with an alkylating agent and a corticosteroid is likely to be a cost-effective option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate and who are intolerant of or have contraindications to thalidomide.
What are the key drivers of cost effectiveness?
The key drivers of cost effectiveness of VMP compared with MPT were the inclusion of data from studies with maintenance treatment and the number of vials of bortezomib used.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee considered the base-case ICERs for thalidomide in combination with an alkylating agent and a corticosteroid from the Assessment Group's economic analyses. The Assessment Group calculated an ICER of £9170 per QALY gained for the MPT combination compared with MP and £33,200 per QALY gained for the CTDa combination compared with MP. The Committee accepted that if the safety and efficacy of the two thalidomide regimens were considered equivalent (see section 4.3.3), the ICER of £9170 for MPT was likely to be the more robust estimate because it was based on studies without thalidomide maintenance treatment.
The Committee agreed that the manufacturer's preference for modelling 31.5 vials should be considered the most optimistic estimate for clinical practice. The Committee noted that the Assessment Group's scenario that assumed four cycles (equivalent to 31 vials used) gave an ICER of £19,000 per QALY gained for VMP compared with MP and £320,000 per QALY gained for VMP compared with MPT.
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable.
End-of-life considerations
Not applicable.
Equalities considerations
Not applicable.
# Related NICE guidance
Published
Lenalidomide for the treatment of multiple myeloma in people who have received at least one prior therapy. NICE technology appraisal guidance 171 (2009). Available from www.nice.org.uk/guidance/TA171
Bortezomib monotherapy for relapsed multiple myeloma. NICE technology appraisal guidance 129 (2007). Available from www.nice.org.uk/guidance/TA129
Under development
NICE is developing the following guidance (details available from www.nice.org.uk):
Denosumab for the treatment of bone metastases from solid tumours and multiple myeloma. NICE technology appraisal guidance (publication expected June 2012).# Review of guidance
The guidance on this technology will be considered for review by the Guidance Executive in July 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew Dillon
Chief Executive
July 2011# Changes after publication
February 2014: implementation section updated to clarify that bortezomib and thalidomide are recommended as options for treating multiple myeloma. Additional minor maintenance update also carried out.# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your
responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Thalidomide in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate.\n\nBortezomib in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma if:\n\nhigh-dose chemotherapy with stem cell transplantation is considered inappropriate and\n\nthe person is unable to tolerate or has contraindications to thalidomide.', 'Clinical need and practice': 'Multiple myeloma is a cancer of a type of white blood cell (plasma cell) in the bone marrow. In people with multiple myeloma, a single plasma cell becomes cancerous to form a myeloma cell, which begins to multiply. These abnormal plasma cells, or myeloma cells, build up in the bone marrow, reducing the space available for making normal white cells, red cells and platelets. Normal blood cells are responsible for fighting infections, carrying oxygen around the body and blood clotting. Myeloma cells produce large amounts of one type of abnormal antibody, which does not work properly and is not able to fight infection. Symptoms and clinical features of multiple myeloma include fatigue, bone pain and/or fracture, anaemia, infections, M-protein in serum and/or urine, and hypercalcaemia. The origin of multiple myeloma is unknown and malignant cells display a variety of cytogenetic abnormalities. Multiple myeloma is the second most common haematological cancer in the UK. In England and Wales there are approximately 3600 new diagnoses recorded annually. In 2007, most diagnoses were recorded in people aged 75–79\xa0years. Multiple myeloma is about 1.5 times more common in men than in women, and twice as common in people of African or Caribbean descent. In the UK, the estimated lifetime risk of developing multiple myeloma is 1 in 148 for men and 1 in 186 for women. There are currently between 10,000 and 15,000 people living with multiple myeloma in the UK.\n\nMultiple myeloma remains an incurable disease, with an average survival of 4–6\xa0years, but it can be treated with a combination of supportive measures and chemotherapy. The aim of treatment is to extend the length and quality of life by alleviating symptoms, controlling disease and minimising adverse effects. Survival after diagnosis can vary from months to more than 10\xa0years. Factors affecting survival and outcome include burden of disease, type of cytogenetic abnormality, age and performance status, and response to treatment.\n\nIn England and Wales the choice of first-line treatment (that is, treatment for treatment-naïve patients) depends on a combination of factors. Most people with multiple myeloma are not able to withstand intensive treatment, such as high-dose chemotherapy with stem cell transplantation, because of their age, other health problems or poor performance status. These people are offered single-agent or combination chemotherapy, which is less intensive. Typically, combination therapies include chemotherapy with an alkylating agent (such as melphalan or cyclophosphamide) and a corticosteroid (such as prednisolone or dexamethasone). More recent treatment options include drugs such as thalidomide and bortezomib. The main objective of first-line therapy is to achieve a period of stable disease (termed the plateau phase) for as long as possible, thereby prolonging survival and maximising quality of life. After initial treatment, most people usually experience a period of remission, but almost all relapse eventually, and some have disease that does not respond (is refractory) to treatment.', 'The technologies ': "Bortezomib\n\nBortezomib (Velcade, Janssen) is an anticancer drug that works by reversible proteasome inhibition. This inhibition leads to arrest of the cell cycle and apoptosis (cell death), which reduces tumour growth. Myeloma cells are more sensitive to the action of bortezomib than normal cells.\n\nBortezomib, in combination with melphalan and prednisone, is licensed for the treatment of patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with bone marrow transplant. Bortezomib is administered as an intravenous injection. Bortezomib is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles. In cycles 1–4, bortezomib is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In cycles 5–9, bortezomib is administered once weekly (days 1, 8, 22 and 29). Melphalan and prednisone should both be given orally on days 1, 2, 3 and 4 of the first week of each cycle.\n\nBortezomib treatment is associated with peripheral neuropathy, thrombocytopenia, gastrointestinal effects (diarrhoea, nausea, vomiting and constipation) and other side effects. For full details of side effects and contraindications, see the summary of product characteristics (SPC).\n\nThe cost for a 3.5-mg vial of bortezomib is £762.38 (British national formulary [BNF] edition 61). Costs may vary in different settings because of negotiated procurement discounts.\n\nThalidomide\n\nThalidomide (Thalidomide Celgene, Celgene) is an immunomodulatory agent. Its precise mechanism of action is under investigation and is currently unknown, but it is thought to have multiple actions, including anti-inflammatory activity and the ability to inhibit the growth and survival of myeloma cells and the growth of new blood vessels. It is also a non-barbiturate hypnotic sedative with central action.\n\nThalidomide in combination with melphalan and prednisone is licensed 'as first-line treatment of patients with untreated multiple myeloma, aged ≥\xa065\xa0years or ineligible for high dose chemotherapy'. The recommended dose is 200\xa0mg daily, taken orally. A maximum number of 12 cycles of 6 weeks should be used. Thalidomide is prescribed and dispensed according to the Thalidomide Celgene Pregnancy Prevention Programme.\n\nThalidomide treatment is associated with thromboembolic events, peripheral neuropathy, rash/skin reactions, bradycardia, syncope and somnolence. Section 4.2 of the SPC outlines how to manage comorbidities such as risk of thromboembolic events, peripheral neuropathy or hepatic or renal impairment. For full details of side effects and contraindications, see the SPC.\n\nThe cost for a 28-capsule pack of 50-mg thalidomide capsules is £298.48 (BNF edition 61). Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nIn addition to the licensed indications of bortezomib and thalidomide, the remit of the scope allowed for inclusion of evidence from the ongoing UK-wide, Medical Research Council-sponsored Multiple Myeloma IX (MMIX) trial. This trial included thalidomide in combination with cyclosphosphamide and attenuated dexamethasone, which is not a licensed indication for thalidomide. The appraisal investigated the following treatment strategies:\n\nthalidomide, melphalan and prednisolone/prednisone (MPT)\n\nthalidomide, cyclosphosphamide and attenuated dexamethasone (CTDa)\n\nbortezomib, melphalan and prednisolone/prednisone (VMP).\n\nEach was compared with melphalan or cyclosphosphamide plus prednisolone/prednisone or dexamethasone.\n\nThe Assessment Group and manufacturers identified evidence on the clinical effectiveness of bortezomib and thalidomide against the relevant comparators within the licensed indications for each drug, and according to the appraisal scope.\n\n## MPT versus melphalan plus prednisolone/prednisone (MP)\n\nThe Assessment Group identified three randomised controlled trials (RCTs) (Intergroupe Francophone du Myélome [IFM] 99/06, IFM\xa001/01 and GIMEMA) that compared MPT with MP. The numbers of participants recruited to the studies were 447, 232 and 331 respectively. The two IFM studies differed in the target age range of participants: IFM\xa001/01 included people aged at least 75 years, whereas IFM\xa099/06 mainly included people aged between 65 and 75 years, with younger people being eligible for inclusion providing they were not eligible for high-dose chemotherapy. The GIMEMA study included people older than 65\xa0years without specifying any upper age limit, but also included participants younger than 65\xa0years providing they were unable to undergo high-dose chemotherapy with stem cell transplantation. The quality of the RCTs was variable and was difficult to determine in some cases because details needed for quality assessment were incompletely reported. The intention-to-treat analyses and the methods used to account for missing data were in general poorly described.\n\nOverall survival was the primary outcome for IFM\xa099/06 and IFM\xa001/01. The secondary outcomes of these studies included response rates, progression-free survival and adverse events. The primary outcome measures for the GIMEMA study were response rates and progression-free survival. The secondary outcomes included overall survival and adverse events.\n\nIFM\xa099/06 and IFM\xa001/01 reported a statistically significant increase in progression-free survival (p\xa0=\xa00.001) in the MPT group compared with the MP group. The IFM\xa099/06 study reported median progression-free survival of 27.5\xa0months (standard error [SE]\xa0=\xa02.1) for the MPT group compared with 17.8\xa0months (SE\xa0=\xa01.4) for the MP group at a median follow-up of 51.5\xa0months (difference of 9.7\xa0months). The IFM\xa001/01 study reported median progression-free survival of 24.1\xa0months (95% confidence interval [CI] 19.4 to 29.0) for the MPT group compared with 18.5\xa0months (95% CI 14.6 to 23.1) for the MP group after a median follow-up of 47.5\xa0months (difference of 5.6\xa0months). Meta-analysis of the data on progression-free survival confirmed that MPT was superior to MP for this outcome. The hazard ratio (HR) for progression-free survival from the meta-analysis was 0.56 (95% CI 0.46 to 0.67) in favour of MPT. The meta-analysis suggested that there was little or no heterogeneity between the two trials for this outcome.\n\nThe GIMEMA study included maintenance therapy with thalidomide after first-line treatment (that is, patients received six cycles of first-line treatment and if they responded and their condition did not progress, they received maintenance treatment continuously until relapse or the development of refractory disease). Because patients received maintenance therapy, overall survival, which was a secondary outcome in this study, was not eligible for inclusion in the Assessment Group's systematic review. IFM\xa099/06 and IFM\xa001/01 reported a statistically significant difference in overall survival in favour of the group receiving MPT. The IFM\xa099/06 study reported a median overall survival of 51.6\xa0months (interquartile range [IQR] 26.6 to not reached) for the MPT group compared with 33.2\xa0months (IQR 13.8 to 54.8) for the MP group after a median follow-up of 51.5\xa0months. The IFM\xa001/01 study reported a median survival of 44\xa0months (95% CI 33.4 to 58.7) in the group receiving MPT compared with 29.1\xa0months (95% CI 26.4 to 34.9) in the group receiving MP. Meta-analysis of the data on overall survival from the two studies confirmed the superiority of MPT over MP. The HR for overall survival from the meta-analysis was 0.62 (95% CI 0.50 to 0.77) and showed that there was little or no heterogeneity between the two trials for this outcome.\n\nResponse to treatment (at 6\xa0months) was a primary outcome of the GIMEMA study and a secondary outcome in IFM\xa099/06 and IFM\xa001/01. At 6\xa0months, more participants in the MPT group had a complete response or a partial response or better (according to European Group for Blood and Marrow Transplantation criteria). At 12\xa0months, IFM\xa099/06 and IFM\xa001/01 reported that a statistically significantly greater proportion of participants had a complete response or at least a partial response. Complete response outcomes from the three studies were combined by meta-analysis, and this confirmed that MPT was superior to MP in terms of the proportion of patients achieving a complete response (relative risk [RR] 5.49, 95% CI 2.55 to 11.83).\n\nAdverse events were difficult to summarise across the three studies because they were reported differently. Because the GIMEMA study included maintenance therapy with thalidomide, few data on adverse events from this study could be included in the Assessment Group's systematic review. Adverse events that occurred statistically significantly more often in the MPT arms of IFM\xa099/06 and IFM\xa001/01 included neutropenia and peripheral neuropathy. The IFM\xa099/06 study found that non-haematological adverse events of grade 3 or more were statistically significantly more likely in the MPT group (p\xa0\xa00.0001). For thrombosis or embolism, somnolence and constipation, the results were inconsistent between IFM\xa099/06 and IFM\xa001/01, with no significant difference in incidence in the IFM\xa001/01 study and statistically significantly more of these events in the MPT group in the IFM\xa099/06 study. This inconsistency may be a result of the different methods of reporting adverse events.\n\nThe IFM\xa099/06 and IFM\xa001/01 studies provided data on second-line treatment that could be included in the Assessment Group's systematic review. In the IFM\xa099/06 study, 65% of the MP group received second-line treatment compared with 44% of the MPT group. The IFM\xa001/01 study reported disease progression in 156\xa0participants overall, with more participants with disease progression in the MP group than the MPT group (72% versus 64%). Second-line treatment was received by a similar proportion of participants with disease progression in each arm. In both IFM\xa099/06 and IFM\xa001/01, thalidomide (alone or in combination with another agent) was the most common second-line treatment in the MP group, with about a fifth of participants in the MPT groups receiving thalidomide again as second-line therapy. In the IFM\xa099/06 study, the most common second-line treatment in the MPT group was a combination of vincristine, doxorubicin, and dexamethasone. Only 13% of participants in the MPT group received bortezomib. In contrast, IFM\xa001/01 reported that 31% of participants in the MPT group received bortezomib as a second-line treatment. Because the GIMEMA study included maintenance therapy with thalidomide after first-line treatment, data on second-line treatment were not eligible for inclusion in the Assessment Group's systematic review.\n\n## CTDa versus MP\n\nThe Assessment Group acknowledged an ongoing RCT, the MMIX trial, which compared CTDa with MP. People were eligible to participate if they had newly diagnosed symptomatic or non-secretory multiple myeloma and had not received previous treatment for myeloma (other than local radiotherapy). The non-intensive pathway of the MMIX study was designed for older (generally 70\xa0years of age or older) or less fit participants (who could be younger than 70), but strict age restrictions were not in place. The primary outcomes were overall survival, progression-free survival and response. Secondary outcomes included quality of life and adverse events.\n\nSome data from the MMIX study on overall survival, progression-free survival, adverse events and health-related quality of life were not eligible for inclusion in the Assessment Group's systematic review because participants were randomised to receive either maintenance therapy with thalidomide or no maintenance therapy after they had completed first-line treatment. In response to a request from the Assessment Group, the MMIX trial management group provided data on overall survival, progression-free survival and response to treatment for participants who were excluded from the maintenance randomisation and for those randomised to receive no maintenance (that is, all people who received first-line only treatment were considered). The Assessment Group concluded that these additional data did not substantially alter the outcomes for the whole trial population because the data were immature and for a small number of patients. Although the data for participants receiving maintenance therapy were not included, the Committee considered very carefully data from the small number of participants who were randomised to receive no maintenance therapy.\n\nData on response rates from the MMIX study were eligible for inclusion in the Assessment Group's systematic review. Response was measured as complete, very good or partial. The principal investigators of the MMIX study identified data on response and adverse events as unpublished academic in confidence and therefore these data cannot be reported.\n\n## VMP versus MP\n\nThe Assessment Group identified one RCT (VISTA) comparing VMP with MP. People were eligible to participate if they had newly diagnosed, untreated, symptomatic, measurable myeloma and were not candidates for high-dose chemotherapy with stem cell transplantation because of their age (65\xa0years or older) or coexisting conditions. Most, but not all, analyses had followed intention-to-treat principles, but the methods used to account for any missing data were not described.\n\nThe primary outcome was time to disease progression. Secondary outcomes included overall survival, progression-free survival, response, adverse events and health-related quality of life. Median time to subsequent myeloma therapy and treatment-free interval were 20.8\xa0months and 9.4\xa0months respectively in the group receiving MP; these were not reached in the group receiving VMP. Median time to disease progression was significantly longer in the VMP group than in the MP group (20.7 and 15\xa0months respectively; HR\xa0=\xa00.54, p\xa0<\xa00.001). An advantage in terms of overall survival was reported for VMP compared with MP. A statistically significant survival benefit for VMP was reported after a median follow-up of 25.9\xa0months (HR\xa0=\xa00.64, p\xa0=\xa00.0032). After a median follow-up of 36.7\xa0months, 3-year survival rates were 68.5% versus 54% respectively. The most recent analyses showed a median overall survival of 43.1\xa0months for participants receiving MP; it was not possible to estimate overall survival in the group receiving VMP because median overall survival had not been reached for VMP. After a median follow-up of 16.3\xa0months, median progression-free survival was 21.7\xa0months for the group receiving VMP compared with 15.2\xa0months for the group receiving MP (HR\xa0=\xa00.56, p\xa0<\xa00.001). A number of response-to-treatment rates (including partial response and complete response) were reported as secondary outcomes. The time at which response was assessed was not reported. The proportion of participants with at least a partial response was 71% in the VMP group and 35% in the MP group (p\xa0<\xa00.001). The proportions with a complete response were 30% and 4% respectively (p\xa0<\xa00.001). The proportion with a partial response was 40% in the VMP group and 31% in the MP group, and the proportions with a minimal response were 9% and 22% respectively. The proportion with stable disease was 18% in the VMP group and 40% in the MP group, and the progressive disease rates were 1% and 2% respectively.\n\nParticipants in both arms of the VISTA trial experienced adverse events. Although the occurrence of any adverse event and any grade 4 adverse event was similar in the two groups, there was a statistically significant increase in grade 3 adverse events in the group receiving VMP (53% versus 44%, p\xa0=\xa00.02). Haematological events were the most frequently reported and were similar in the two groups. Peripheral sensory neuropathy was reported more frequently in the group receiving VMP, but at the time of the last analysis, 74% of peripheral neuropathy events had either resolved (56%) or decreased by at least one toxicity grade (18%) within a median of 2\xa0months. All grade 3 and grade 4 gastrointestinal events were more frequent in the group receiving VMP (19% versus 5%, no p value given). The incidence of deep vein thrombosis was low and similar in the two groups.\n\nLimited data on health-related quality of life were available. After best response, participants treated with VMP had a higher sustained improvement in 14 of the 15 European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C‑30 (EORTC QLQ-C30) scores than participants treated with MP.\n\nData on second-line treatment indicated that in the MP group 57% of participants started second-line treatment within 2\xa0years compared with 38% in the VMP group. Over half of the participants in each group received either thalidomide or lenalidomide as a second-line treatment.\n\n## Summary of the clinical effectiveness\n\nThe Assessment Group concluded that the evidence from two studies (IFM\xa099/06 and IFM\xa001/01) indicated that MPT was more effective than MP in terms of increasing overall survival (HR\xa0=\xa00.62, 95% CI 0.50 to 0.77) and the secondary outcome of progression-free survival (HR\xa0=\xa00.56, 95% CI 0.46 to 0.67). Three studies (IFM\xa099/06, IFM\xa001/01 and GIMEMA) provided evidence of a complete response in a statistically significantly greater proportion of participants receiving MPT (RR\xa0=\xa05.49, 95% CI 2.55 to 11.83). Adverse events occurred in both trial arms, but peripheral neuropathy and neutropenia were most consistently, and statistically significantly, associated with the use of thalidomide.\n\nData from the MMIX trial (CTDa versus MP) on response rates were eligible for inclusion in the Assessment Group's systematic review; however, overall survival and progression-free survival were not eligible for inclusion (see section 4.1.10).\n\nThe Assessment Group concluded that the evidence from one study (VISTA) indicated that combination chemotherapy with VMP was more effective than MP in terms of a longer time to disease progression, increasing overall survival and increasing the proportion of participants achieving a complete response. Adverse events occurred in both trial arms. Bortezomib was associated with a statistically significant increase in grade 3 adverse events.\n\nFollowing consultation, the manufacturer of bortezomib submitted evidence of the effect on overall survival of the inclusion of studies with participants who had received maintenance therapy with thalidomide (GIMEMA, MMIX and two additional studies HOVON and NORDIC). For each study, the manufacturer plotted the HR of overall survival at cumulative time periods (3-month intervals). The HR was derived using all deaths up to that point but excluded further follow-up. The manufacturer stated that in all studies except IFM\xa099/06, the HR improved as follow-up increased, regardless of whether the studies included maintenance treatment or not. The Assessment Group commented on the additional evidence and stated that it was not possible to make conclusions about the relative effects of maintenance versus first-line treatment from the evidence submitted.\n\n# Cost effectiveness\n\nThe two manufacturers submitted cost-effectiveness models. The Assessment Group developed its own economic model and critiqued the economic models submitted by the manufacturers.\n\n## The Celgene economic model\n\nThe manufacturer of thalidomide developed a Markov model to compare the costs and benefits of MPT with those of VMP and MP in people with multiple myeloma who are older than 65\xa0years or are 'ineligible for high-dose chemotherapy'. The model had four health states that were defined by the stage of disease progression or the occurrence of adverse events. The four health states were: pre-progression without adverse events, pre-progression with adverse events, post-progression and death. The analysis was undertaken over a lifetime horizon (that is, 30\xa0years). Treatment effects were calculated from a mixed-treatment comparison of data from three RCTs (VISTA, IFM\xa099/06, IFM\xa001/01), using measures of survival time before and after progression as the primary outcomes. Resources and costs were obtained from several sources, including an unpublished survey of UK haematologists by the manufacturer of thalidomide, NHS reference costs, and BNF edition 57 with costs inflated to 2008 values.\n\nThe manufacturer's model included the following assumptions:\n\nPost-progression survival was modelled to be the same across different treatment strategies, with the different arms assumed to receive the same alternative treatment after progression (that is, second- and third-line treatments).\n\nPatients were assumed to discontinue first-line treatment on disease progression.\n\nNo costs for second- and third-line treatments were included.\n\nDeaths occurred at or after progression and were assumed to be because of disease-related deterioration.\n\nAdverse events included in the model incorporated a utility decrement at the time of the event and the additional cost of treating them. They were assumed not to affect the rates of disease progression or overall survival, or treatment duration, efficacy or dose.\n\nData on health-related quality of life were obtained from an RCT (HOVON 24) of intensive chemotherapy followed by myeloablative therapy with autologous stem cell rescue compared with intensive chemotherapy alone. The utility values used were 0.64 for people not responding to treatment and 0.81 for people who did respond (using the utility value for the general population of the same age). A utility value of 0.77 at 24\xa0months was used for people who continue to respond to intensive chemotherapy and whose disease has not progressed.\n\nThe base-case cost-effectiveness results were as follows:\n\nMPT compared with MP was associated with an incremental cost-effectiveness ratio (ICER) of £23,381 per quality-adjusted life year (QALY) gained based on an incremental effect of 0.85 QALYs and an incremental cost of £19,768.\n\nVMP compared with MPT was associated with an ICER of £303,845 per QALY gained based on an incremental effect of 0.07 QALYs and an incremental cost of £21,483.\n\nOne-way deterministic sensitivity analyses showed that the parameters with the greatest effect on the model results were changes in treatment efficacy, with a range of £16,586 to £33,275 per QALY gained for MPT versus MP and a range of £148,873 to £1,000,435 per QALY gained for VMP versus MPT. Probabilistic sensitivity analysis was not conducted because the manufacturer considered the efficacy of MPT and VMP to be essentially the same and therefore the cost difference would be the key factor in the model.\n\n## The Janssen economic model\n\nThe manufacturer of bortezomib developed a decision-analytic cost–utility model to compare the costs and benefits for VMP with those of MPT, CTDa and MP in people with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with stem cell transplantation. The model included four health states: before response to treatment; response to treatment without progression; post-progression; and death. The times to response or death were estimated from life tables constructed directly from data from the VISTA trial. Progression-free survival at 6, 12, 18 and 24\xa0months for MP was estimated from a meta-analysis of the MP arms of included RCTs. Progression-free survival was extrapolated beyond 24\xa0months. Utility values for health-related quality of life were assigned to each of the states: 0.77 for before response to treatment; 0.81 for response to treatment without progression; and 0.64 for post-progression. The model used a cohort of people newly diagnosed with multiple myeloma, with MP as the baseline treatment. Treatment effects for VMP, MPT and CTDa were then modelled over time by adjusting the baseline results via HRs. HRs were estimated at 48\xa0months for overall survival for each of the RCTs, except the VISTA trial, which had a follow-up of only 36\xa0months. Overall survival for patients receiving thalidomide was estimated from five RCTs, some of which included thalidomide maintenance.\n\nThe manufacturer's model made the following assumptions:\n\nThe resource use cost for the first-line management of multiple myeloma was the same for all regimens.\n\nSeven cycles of treatment with MP were used (as in the VISTA trial).\n\nFor bortezomib, 31.5 vials were used per patient (as in the VISTA trial).\n\nA dose of thalidomide of 150\xa0mg/day was used for the MPT regimen and 167\xa0mg/day was used for the CTDa regimen.\n\nThe costs of treating adverse events were included in the model; the incidence of adverse events does not influence the treatment duration, efficacy or patient utility.\n\nCosts were included for second- and third-line treatments. On disease progression, it was assumed that second-line treatment would consist of bortezomib plus high-dose dexamethasone, CTDa or high-dose dexamethasone. Most people received CTDa after first-line VMP. People on other first-line therapies usually received bortezomib and high-dose dexamethasone as second-line treatment. All patients received lenalidomide plus dexamethasone as third-line treatment. Most people receiving bortezomib as first‑line treatment would not receive it as second-line treatment.\n\nThe manufacturer's base-case cost-effectiveness results were as follows:\n\nMPT compared with MP was associated with an ICER of £8912 per QALY gained based on an incremental effect of 0.55 QALYs and an incremental cost of £4888.\n\nCTDa compared with MP was associated with an ICER of £10,905 per QALY gained based on an incremental effect of 0.21 QALYs and an incremental cost of £2234.\n\nVMP compared with MP was associated with an ICER of £10,498 per QALY gained based on an incremental effect of 1.17 QALYs and an incremental cost of £12,242.\n\nOne-way sensitivity analysis showed the model was most sensitive to the following parameters: underlying MP survival hazard, HRs for overall survival, dose of thalidomide, and duration of treatment with thalidomide in the MPT arm. A probabilistic sensitivity analysis showed that at the £20,000 and £30,000 thresholds, VMP has the highest probability of being cost effective (64% and 75% respectively).\n\nTwo scenario analyses were conducted. The first excluded the costs of subsequent therapy after first-line treatment. In this scenario, the cost-effectiveness results were less favourable for each of the treatments and the ICERs increased to £48,437, £16,956 and £21,099 per QALY gained for CTDa, MPT, and VMP respectively, compared with MP. The second scenario assumed the same second-line treatments as for people treated with MP in the VISTA trial. For this scenario, the results were similar to the base-case analyses.\n\n## The Assessment Group model\n\nThe Assessment Group's survival model was developed to estimate the costs, benefits and cost effectiveness of MPT, VMP and CTDa compared with MP, in people with newly diagnosed multiple myeloma who are 'ineligible' for high-dose chemotherapy with stem cell transplantation. The model consisted of cycles of 6\xa0weeks in length to be consistent with the cycle lengths used for chemotherapy treatment. A lifetime horizon of 30\xa0years was modelled. Survival was classified into three health states: treatment (defined as the time patients are treated with first-line therapy); post-treatment (defined as the mean time from the end of first-line treatment until disease progression) and post-progression (defined as the mean time from disease progression until death).\n\nThe Assessment Group constructed a survival curve for overall survival and a curve for progression-free survival for each of the alternative treatments (MPT, MP, VMP) included in its systematic review (see sections 4.1.4, 4.1.5 and 4.1.13). These curves were used to derive the time spent in the three health states. For each treatment option, the relative risk for complete response compared with MP was derived from the outcome data for complete response from the RCTs included in the Assessment Group's systematic review (see sections 4.1.6, 4.1.11 and 4.1.13).\n\nHealth-related quality of life data were from a systematic review of studies of health-related quality of life. The Assessment Group did not identify any generic preference-based studies of people with untreated multiple myeloma who were not eligible for high-dose chemotherapy with stem cell transplantation, but did identify a study not identified by the manufacturers that assessed health-related quality of life in this group using the EORTC QLQ-C30. The Assessment Group mapped the EORTC QLQ-C30 to the EQ-5D using a validated mapping algorithm. The utility estimates used were 0.58 for the treatment health state and 0.68 for the post-treatment state.\n\nCosts were derived from a number of sources including the BNF, RCTs included in the Assessment Group's systematic review and clinical and expert clinical opinion. The Assessment Group's model included the following assumptions:\n\nFor bortezomib, each person receives one vial per administration.\n\nPatients receive second-line treatment following disease progression after first-line therapy. The model assumed that most people who received VMP as first-line treatment received CTDa as second-line treatment and most who did not receive bortezomib as first-line treatment received it as second-line treatment.\n\nCosts were included for second-line treatment. The effect of second-line treatment on health outcomes was not included in the model because second-line treatments varied among the RCTs included in the Assessment Group's systematic review (see sections 4.1.8 and 4.1.16).\n\nCost and outcomes of third-line and subsequent treatments were assumed to be the same between arms.\n\nPeople discontinued first-line treatment on disease progression.\n\nHealth-related quality of life was better for those with complete response than those with less than complete response and was assumed to improve when people stop treatment.\n\nAdverse events were not modelled explicitly, but additional costs for treating the adverse events were included.\n\nThe base-case cost-effectiveness results were as follows:\n\nMPT compared with MP was associated with an ICER of £9174 per QALY gained based on an incremental effect of 1.22 QALYs and an incremental cost of £11,207.\n\nCTDa compared with MP was associated with an ICER of £33,216 per QALY gained based on an incremental effect of 0.26 QALYs and an incremental cost of £8592.\n\nVMP compared with MP was associated with an ICER of £29,837 per QALY gained based on an incremental effect of 1.20 QALYs and an incremental cost of £35,749.\n\nThe incremental cost-effectiveness analysis suggested that CTDa is extendedly dominated by MPT and MP, and that MPT dominates VMP because it is more effective and cheaper. The incremental baseline cost-effectiveness results were as follows: CTDa compared with MP was associated with an ICER of £33,216 per QALY gained; and VMP compared with CTDa was associated with an ICER of £28,907 per QALY gained. The comparison of VMP versus MPT suggested that VMP and CTDa were unlikely to be cost-effective treatment options at the thresholds of £20,000 to £30,000 per QALY gained.\n\nSensitivity analyses showed the effects of a range of parameter values in the economic model. For each of the treatments the model results were most sensitive to the HRs for overall survival, cost and dosage of the treatment and the overall baseline survival curve used for MP. The deterministic sensitivity results for MPT versus MP varied between £6470 and £22,855 per QALY gained. The deterministic sensitivity analysis for VMP versus MP gave ICERs between £20,451 and £87,716 per QALY gained. VMP was dominated by MPT in all analyses apart from that investigating sensitivity to changes in overall survival. The deterministic sensitivity analysis for CTDa versus MP gave ICERs between −£29,388 (dominant, that is CTDa is more effective and less costly than MP) and £16,989 per QALY gained.\n\nIn addition to the sensitivity analyses, five alternative scenarios were explored to investigate the uncertainty around structural assumptions. In scenario A (no subsequent therapies), the ICERs for MPT, CTDa and VMP versus MP increased from £9174, £33,216 and £29,837, to £9738, £34,013 and £37,727 per QALY gained respectively.\n\nScenario B (vial sharing/fewer vials) investigated the cost effectiveness when patients share vials of bortezomib. With vial sharing and no wastage, the ICERs for MPT and CTDa versus MP increased from £9174 and £33,216 to £9369 and £33,492 per QALY gained respectively. The ICER for VMP versus MP decreased from £29,837 to £22,549 per QALY gained. Following comments received from consultees on the draft assessment report, the Assessment Group undertook an additional scenario analysis in which it was assumed that four cycles or 31 vials of bortezomib were used, with no loss of efficacy. In this scenario, the ICER for VMP versus MP decreased from £29,837 (no vial sharing) to £18,996 per QALY gained. The ICER for VMP versus MPT decreased from −£1,000,000 (that is, MPT dominates VMP) to £319,923 per QALY gained.\n\nScenario C (inclusion of thalidomide maintenance trials) investigated the cost effectiveness using the estimate of efficacy for MPT from a meta-analysis that included trials with thalidomide maintenance. The manufacturer of bortezomib conducted a mixed-treatment comparison for MPT versus MP with trials that included thalidomide maintenance. Using the HR from this analysis the ICER for MPT versus MP increased from £9174 to £24,390 per QALY gained. The ICERs for CTDa and VMP remained the same as in the base-case analysis (£33,216 and £29,837 per QALY gained respectively). In addition, MPT no longer dominated VMP, with an ICER of £32,739 for VMP versus MPT.\n\nScenario D (treatment effectiveness beyond the end of trial) investigated an alternative assumption whereby there is no treatment benefit for the three drug combinations over MP (that is, the event rates for these treatments are the same as for MP) after the end of the trial. This assumption had a large effect on the model results and all treatments were less cost effective than MP. The ICERs for each of the treatment options more than doubled to £20,698 (MPT), £71,264 (VMP) and £80,840 (CTDa) per QALY gained versus MP.\n\nThe probabilistic sensitivity analysis estimated the probability of each of the treatments being cost effective at the £20,000 and £30,000 thresholds. MPT had the highest probability (0.95 at both thresholds) of being cost effective. The baseline probabilistic sensitivity analysis showed that MPT was cost effective compared with MP, with an ICER of £9124. The comparisons of VMP versus MP and CTDa versus MP produced ICERs of £29,102 and £31,612 respectively.\n\n## Comparison of the manufacturer and Assessment Group models\n\nThe cost-effectiveness estimates differed between the manufacturers and the Assessment Group. This was a result of differences in incremental costs for MPT versus MP, differences in incremental QALY estimates for MPT versus MP (depending on whether trials with maintenance treatment were included), differences in the modelling of adverse events and inclusion of costs for second- and third-line treatments.\n\nThe incremental costs for MPT versus MP varied between £4888 (the manufacturer of bortezomib) and £19,768 (manufacturer of thalidomide). The manufacturer of thalidomide used higher dosages of thalidomide (238\xa0mg/day) for longer periods (11\xa0cycles) than the other two analyses. The incremental costs for VMP versus MP varied between £12,242 (manufacturer of bortezomib) and £41,251 (manufacturer of thalidomide). These differences were largely a result of the assumptions around the number of vials of bortezomib used, with the manufacturer of bortezomib assuming a mean of 31.5 vials per person, and the Assessment Group and manufacturer of thalidomide assuming over 40 vials. The incremental costs for CTDa versus MP varied between £2234 (manufacturer of bortezomib) and £8592 (Assessment Group). These differences were because of an error in the cost calculation for third-line therapy for CTDa by the manufacturer of bortezomib.\n\nThe total QALY estimates used by the manufacturers and the Assessment Group were similar, with estimates for all treatment arms varying between 2.42 and 4.03. The incremental QALY estimates for MPT versus MP varied from 0.55 (manufacturer of bortezomib) to 1.22 (Assessment Group). These differences resulted from the estimates chosen for the HR for overall survival compared with MP. Estimates used by the manufacturer of bortezomib included studies with maintenance treatment whereas those used by the Assessment Group excluded studies with maintenance treatment.\n\nThere were differences in the way adverse events were modelled. The manufacturer of bortezomib included adverse events in the model as the cost of treating them. The manufacturer of thalidomide included adverse events in the model as a utility decrement at the time of the event and as the cost of treating them. The Assessment Group did not explicitly model adverse events for patient outcomes (that is, overall survival and progression-free survival), but included an additional cost for treating the adverse events in the model.\n\nThere were also differences in inclusion of costs after first-line treatment:\n\nThe manufacturer of bortezomib included costs for second- and third-line treatments. Most people who received VMP as first-line treatment received CTDa as second-line treatment and most who did not receive VMP as first-line treatment received it as second-line.\n\nThe manufacturer of thalidomide assumed that patients discontinued first-line treatment on disease progression and did not include costs for second- and third-line treatments.\n\nThe Assessment Group included costs for second-line treatments. Most people who received VMP as first-line treatment received CTDa as second-line treatment and most who did not receive bortezomib as first-line treatment received it as second-line.\n\n## Extra analyses post-consultation\n\nFollowing consultation on the appraisal consultation document, the manufacturer of bortezomib submitted additional cost-effectiveness estimates using their model and applying different assumptions used by the Assessment Group, including evidence from studies including maintenance therapy, use of 31.5 vials of bortezomib and varying second-line therapies. The five scenarios were as follows:\n\nScenario 1 investigated the use of 52 vials of bortezomib, with evidence of MPT efficacy from IFM\xa099/06 and IFM\xa001/01 studies and second-line therapies as in the Assessment Group model (see section 4.2.16).\n\nScenario 2 investigated use of 52 vials of bortezomib, with evidence of MPT efficacy from a meta-analysis that included five trials with maintenance therapy, and second-line therapies as in the Assessment Group model (see section 4.2.16).\n\nScenario 3 investigated use of 31.5 vials of bortezomib, with evidence of MPT efficacy from IFM\xa099/06 and IFM\xa001/01 studies and second-line therapies as in the Assessment Group model (see section 4.2.16).\n\nScenario 4 investigated use of 31.5 vials of bortezomib, with evidence of MPT efficacy from a meta-analysis that included five trials with maintenance therapy, and second-line therapies as in the Assessment Group model (see section 4.2.16).\n\nScenario 5 investigated use of 31.5 vials of bortezomib, with evidence of MPT efficacy from a meta-analysis that included five trials with maintenance therapy, and second-line therapies as in the VISTA trial (see section 4.1.16).\n\nFor MPT versus MP, the ICERs for the five scenarios varied between £9138 (scenarios 1 and 3) and £17,337 (scenario 5) per QALY gained. The incremental costs varied between £8706 (scenarios 2 and 4), £9509 (scenario 5) and £12,104 (scenarios 1 and 3), and the incremental QALYs from 0.55 (scenarios 2, 4 and 5) to 1.32 (scenarios 1 and 3). That is, the QALY was reduced from 1.32 for those scenarios in which only two MPT studies (IFM\xa099/06 and IFM\xa001/01) were included to 0.55 when studies with maintenance therapy (5 studies) were included.\n\nFor VMP versus MP, the ICERs varied from £15,107 (scenarios 3 and 4) to £28,510 (scenarios 1 and 2) per QALY gained. The incremental costs varied from £17,615 (scenarios 3 and 4) to £33,244 (scenarios 1 and 2). The incremental QALYs for all scenarios were 1.17.\n\nFor VMP versus MPT, the ICERs varied between £14,426 (scenario 4), £21,565 (scenario 5) and £39,733 (scenario 2) per QALY gained. VMP was dominated by MPT in scenarios 1 and 3. The incremental costs varied from £5512 (scenario 3) to £24,538 (scenario 2) and the incremental QALYs varied from −0.16 (scenarios 1 and 3) to 0.62 (scenarios 2, 4 and 5).\n\nThe Assessment Group reviewed the additional scenarios presented by the manufacturer of bortezomib. It confirmed that there was close agreement between the two models when using the same assumptions and data for both models. However, the Assessment Group did not agree with the assumptions and the data used in the manufacturer's additional scenarios.\n\n## Extra analyses post-appeal\n\nFollowing an Appeal Panel request, the Assessment Group's economic model, which had previously not been released because it contained confidential information, was released for consultation. Only the manufacturer of bortezomib (Janssen) submitted comments on the Assessment Group's economic model. The manufacturer of bortezomib incorporated a number of their proposed amendments to the Assessment Group's economic model and submitted revised cost-effectiveness estimates. These amendments related to the cost of managing adverse events, treatment duration of thalidomide based on mean duration observed in IFM99-06, IFM01-01 and VISTA trials, method for estimating QALYs, cost of second-line treatment and inclusion of three additional maintenance studies for thalidomide (GIMEMA, HOVON and NORDIC). The manufacturer of bortezomib presented three alternative scenarios for each of the comparisons (MPT versus MP, VMP versus MP and CTDa versus MP), in which the amendments were incorporated into the Assessment Group's economic model:\n\nScenario 1 corrected for the cost of managing adverse events, treatment duration of thalidomide, QALYs estimated using Markov trace and cost of second-line treatment.\n\nScenario 2 corrected for the inclusion of data from the pre-maintenance phase of maintenance studies (GIMEMA, HOVON, NORDIC) for the first 6-month period, in addition to the corrections listed in scenario 1.\n\nScenario 3 corrected for the inclusion of data from the pre-maintenance phase of maintenance studies for the first 12-month period, in addition to the corrections listed in scenario\xa01.\n\nFor MPT versus MP the ICERs for the three scenarios varied from £11,511 (scenario 1) to £13,722 (scenario 3) per QALY gained. For VMP versus MP the ICER was £19,505 per QALY gained for all three scenarios. For CTDa versus MP the ICERs varied between £11,890 (scenario 2) and £34,014 (scenario 1) per QALY gained. For VMP versus MPT, the ICERs varied between £36,794 (scenario 3) and £211,508 (scenario 1).\n\nThe Assessment Group commented on the proposed amendments and the revised cost-effectiveness estimates submitted by the manufacturer of bortezomib. The Assessment Group accepted that the model contained an error in the calculation of the adverse events costs, and that the use of a Markov trace may possibly provide a more accurate method for estimating the QALYs. The Assessment Group therefore provided revised cost-effectiveness results based on a revision to the adverse events costs and the use of a Markov trace to estimate the QALYs. The revised cost-effectiveness results were as follows:\n\nMPT compared with MP was associated with an ICER of £9189 per QALY gained based on an incremental effect of 1.21 QALYs and an incremental cost of £11,159.\n\nCTDa compared with MP was associated with an ICER of £33,703 per QALY gained based on an incremental effect of 0.25 QALYs and an incremental cost of £8544.\n\nVMP compared with MP was associated with an ICER of £29,930 per QALY gained based on an incremental effect of 1.19 QALYs and an incremental cost of £35,729.\n\nThe Assessment Group's incremental analysis showed that MPT continues to dominate VMP.\n\n## Summary of the cost effectiveness\n\nThe different assumptions and methodology used (see sections 4.2.25 to 4.2.37) resulted in a range of ICERs for the options for first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate. The Assessment Group and manufacturers' base-case cost-effectiveness results for MPT versus MP varied between £8912 (manufacturer of bortezomib) and £23,381 (manufacturer of thalidomide) per QALY gained. The Assessment Group and manufacturers' base-case cost-effectiveness results for VMP versus MP varied between £10,498 (manufacturer of bortezomib) and £29,837 (Assessment Group) per QALY gained. The Assessment Group and manufacturers' base-case cost-effectiveness results for CTDa versus MP varied between £10,905 (manufacturer of bortezomib) and £33,216 (Assessment Group) per QALY gained. The Assessment Group and manufacturers' base-case cost-effectiveness results for MPT versus VMP were £303,845 (manufacturer of thalidomide), and £319,923 (when the Assessment Group used the scenario of 31 vials of bortezomib) per QALY gained. The Assessment Group's incremental analysis of its base-case cost-effectiveness results suggested MPT dominates VMP because it is more effective and cheaper. The additional scenarios presented by the manufacturer of bortezomib following consultation on the appraisal consultation document (May 2010) resulted in ICERs for VMP versus MPT of £39,733 per QALY gained (scenario 2), £14,426 per QALY gained (scenario 4) and £21,565 (scenario 5). VMP was dominated by MPT in scenarios 1 and 3. The revised ICERs presented by the manufacturer of bortezomib and the Assessment Group following the release of the economic model for MPT versus MP varied between £9189 (Assessment Group) and £13,722 (manufacturer of bortezomib, scenario 3) per QALY gained, for VMP versus MP varied between £19,505 (manufacturer of bortezomib, all three scenarios) and £29,930 (Assessment Group) per QALY gained and for CTDa versus MP varied between £11,890 (manufacturer of bortezomib, scenario 2) and £34,014 (manufacturer of bortezomib, scenario 1) per QALY gained. The Assessment Group's incremental analysis of its revised cost-effectiveness results suggested that MPT continued to dominate VMP.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bortezomib and thalidomide, having considered evidence on the nature of multiple myeloma and the value placed on the benefits of bortezomib and thalidomide by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee acknowledged the history of thalidomide as a teratogenic compound and noted that it is now prescribed and dispensed according to the Thalidomide Celgene Pregnancy Prevention Programme.\n\nThe Committee discussed the pathway of care for people with multiple myeloma for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate. The Committee heard from the clinical specialists that in UK clinical practice before the advent of thalidomide and bortezomib, first-line treatment consisted of an alkylating agent (melphalan or cyclophosphamide) and a corticosteroid (attenuated dexamethasone or prednisolone). Since thalidomide and bortezomib had become available, one of these, according to patient preference, comorbidities and adverse events, was normally added to first-line treatment. The Committee heard from the clinical specialists and patient experts that although both the thalidomide and bortezomib regimens were well tolerated, administration of the bortezomib regimen took longer and was less convenient than thalidomide (because it involved intravenous infusion rather than oral administration). The clinical specialists stated that a thalidomide regimen would be considered more appropriate for 70–75% of patients and that their preferred choice of regimen was thalidomide in combination with cyclophosphamide and attenuated dexamethasone (because of the mode of oral administration). The clinical specialists stated that they considered the two thalidomide regimens (CTDa and MPT), which both included an alkylating agent and a steroid, to be equivalent in terms of safety and efficacy. Past studies of the two regimens before the addition of thalidomide had shown equivalent safety and efficacy and the clinical specialists did not consider that the addition of thalidomide would have a differential effect. The Committee heard that for those people who were intolerant of thalidomide or had clotting disorders or impaired renal function, bortezomib in combination with melphalan and prednisolone was considered the most appropriate treatment. The Committee was not persuaded that comorbidities such as clotting disorders or renal impairment prevented a person from receiving thalidomide because they could be managed as outlined in the SPC for thalidomide. The Committee accepted that clinicians considered the three treatment regimens to be equivalent in terms of clinical efficacy, but that the choice of treatment for an individual patient will depend on the comorbidities present and the different mechanisms of action and adverse events associated with the treatments.\n\n## Clinical effectiveness\n\nThe Committee considered the estimates for the clinical effectiveness of MPT and CTDa. It noted that the Assessment Group had derived HRs for overall survival for thalidomide from two studies without maintenance treatment and had excluded studies in which participants received maintenance with thalidomide after first-line treatment. The Committee noted that maintenance with thalidomide monotherapy after first-line treatment with a combination regimen did not fall within the appraisal scope. It also noted that, if possible (that is, when available for first-line treatment without maintenance), outcome data (for example, complete response) had been included in the Assessment Group's systematic review of clinical effectiveness. The Committee also heard from the clinical specialists and the manufacturer of thalidomide that not all participants in the maintenance studies benefited from maintenance treatment and that some people on thalidomide maintenance had a shorter overall survival, possibly because the prolonged thalidomide treatment induced disease resistance. The Committee concluded (see section 4.3.10) that to assign studies (published and ongoing) in which the results were confounded by treatment outside the appraisal scope equivalent weight to the two key studies without maintenance treatment was not justified. Nevertheless it was prepared to bear in mind these data without overemphasising them. Similarly the Committee considered the estimates of overall survival for CTDa and noted that the evidence came from preliminary results of the MMIX trial which included participants who had received maintenance treatment with thalidomide. The Committee noted these results but considered that the main conclusions on the clinical effectiveness of thalidomide should be derived from the MPT data. Based on these data, the Committee concluded that thalidomide in combination with an alkylating agent and a corticosteroid improved outcomes when compared with an alkylating agent and a corticosteroid in people with multiple myeloma for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate.\n\nThe Committee discussed the relative effectiveness of bortezomib in combination with an alkylating agent and a corticosteroid as presented by the Assessment Group. It noted that the evidence for the effectiveness of bortezomib in combination with an alkylating agent and a corticosteroid was derived from a single study (VISTA). This study showed that bortezomib was more effective than melphalan in combination with prednisolone in terms of overall survival and progression-free survival. It noted that survival rates with bortezomib were similar to those for thalidomide but that the two regimens were not compared head-to-head because of differences in participants' characteristics, delivery of the comparator and length of follow-up. The Committee concluded that it was likely that bortezomib in combination with an alkylating agent and corticosteroid improved outcomes to a similar degree to thalidomide in combination with an alkylating agent and corticosteroid.\n\n## Cost effectiveness\n\nThe Committee considered the base-case ICERs for thalidomide in combination with an alkylating agent and a corticosteroid from the Assessment Group's economic analyses. The Assessment Group calculated an ICER of £9170 per QALY gained for the MPT combination compared with MP and £33,200 per QALY gained for the CTDa combination compared with MP. The Committee accepted that if the safety and efficacy of the two thalidomide regimens were considered equivalent (see section 4.3.3), the ICER of £9170 for MPT was likely to be the more robust estimate because it was based on studies without thalidomide maintenance treatment.\n\nThe Committee also noted the variation in the ICERs presented by the manufacturers for MPT compared with MP (£8910 to £23,400). The highest of these, £23,400, was from the manufacturer of thalidomide and assumed higher dosages of thalidomide and a greater number of cycles of treatment than the analyses from the manufacturer of bortezomib and the Assessment Group. The dosage of thalidomide used by the manufacturer of thalidomide was the maximum specified in the SPC but was higher than would be used in clinical practice (most patients are not able to tolerate such a high dose). The Committee considered that the ICER was likely to be lower than the estimate from the manufacturer of thalidomide and that the most plausible ICERs for the two thalidomide regimens would fall within the range considered a cost-effective use of NHS resources (below £20,000 to £30,000). The Committee therefore concluded that thalidomide in combination with an alkylating agent and a corticosteroid is a cost-effective option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate.\n\nThe Committee then considered the Assessment Group's ICERs for VMP compared with MP and with the thalidomide regimens. The Committee heard from the Assessment Group that the maximum dose of bortezomib specified in the SPC is eight cycles, which the manufacturer agreed would amount to 48 vials. The manufacturer of bortezomib stated, however, that on average only 31.5 vials were used in the VISTA trial. The manufacturer accounted for this difference on the grounds of dose reduction and dose delay. At the first Appraisal Committee meeting, the Committee accepted the concern raised by the manufacturer of bortezomib that the Assessment Group had assumed too many vials of bortezomib. Following consultation comments from the Assessment Group and on further discussion with both the manufacturer and the Assessment Group at the second meeting, the Committee considered that the costs of delayed doses might still reflect clinical practice and need to be considered. It therefore agreed that the manufacturer's preference for modelling 31.5 vials should be considered the most optimistic estimate for clinical practice. The Committee noted that the Assessment Group's scenario that assumed four cycles (equivalent to 31 vials used) gave an ICER of £19,000 per QALY gained for VMP compared with MP and £320,000 per QALY gained for VMP compared with MPT.\n\nThe Committee noted the differences in the ICERs presented by the Assessment Group and the manufacturer of bortezomib for VMP compared with MPT. Apart from the fewer vials of bortezomib assumed by the manufacturer, the manufacturer of bortezomib also included costs for second-and third-line treatments in its model. This involved adding the cost of thalidomide to the bortezomib regimen, and of bortezomib to the thalidomide regimen, neutralising the approximately four-fold cost advantage of thalidomide, and greatly increasing the cost of MP. The Committee agreed that some accounting for second-line treatments was plausible, but not such that the cost of thalidomide in effect carried the cost of bortezomib, and certainly no more than the distribution of second-line treatments noted in the VISTA trial.\n\nThe Committee then considered the use by the manufacturer of bortezomib of a HR for overall survival for thalidomide which was derived from a meta-analysis that included RCTs with thalidomide maintenance. The Committee heard a strong case from the manufacturer of bortezomib that the maintenance studies should be included in the economic analysis, along with 31.5 vials and their estimate of the distribution of second-line treatments. The Committee was aware of the testimonies from the clinical specialists and the manufacturer of thalidomide (see section 4.3.4) that it was appropriate to exclude all the maintenance studies. However, the Committee took the view that it was appropriate to consider the maintenance studies, but did not accept that results from these studies (which were confounded by treatment outside the appraisal scope) should be considered equivalent to the key studies without maintenance treatment. The Committee concluded that the most plausible ICER for bortezomib versus thalidomide could be less than the Assessment Group's base case of £320,000 per QALY gained, but would be considerably greater than those from the two most optimistic scenarios (£14,400, scenario 4 and £21,600, scenario 5) presented by the manufacturer of bortezomib (see section 4.2.30). The Committee therefore did not accept the manufacturer of bortezomib's assertion that the bortezomib regimen (VMP) was cost effective compared with the thalidomide regimen (MPT).\n\nThe Committee considered the revised cost-effectiveness estimates submitted by the manufacturer of bortezomib and the responses by the Assessment Group following release of the Assessment Group's economic model. It noted that the revised ICERs for MPT compared with MP presented by the Assessment Group and manufacturer of bortezomib were similar and slightly higher than their respective original base-case cost-effectiveness results (see sections 4.2.10 and 4.2.17). The Committee also discussed the revised ICERs for CTDa compared with MP presented by the Assessment Group and manufacturer of bortezomib. It noted that the Assessment Group's revised ICERs were similar and slightly higher to their base-case cost-effectiveness results, and the Committee reconfirmed its conclusion that the thalidomide evidence should be principally drawn from the MPT data. The Committee also noted that the revised ICERs presented by the manufacturer of bortezomib ranged from £11,900 to £34,000 and these were higher than its original base-case cost-effectiveness results (see sections 4.2.10 and 4.2.36). The Committee noted that the lowest estimate (£11,900) included data from the maintenance studies which it had previously agreed should not be considered equivalent to the studies without maintenance treatment (see section 4.3.10). The Committee agreed that the manufacturer of bortezomib's revised ICERs for the two thalidomide regimens did not change the original decision that thalidomide in combination with an alkylating agent and a corticosteroid is a cost-effective option for the first-line treatment of multiple myeloma in people for who high-dose chemotherapy with stem cell transplantation is considered in appropriate. The Committee then discussed the revised cost-effectiveness estimates presented for VMP compared with MPT. It noted that the ICERs presented by the Assessment Group showed that MPT continued to dominate VMP and that the ICERs presented by the manufacturer of bortezomib exceeded £30,000 per QALY (£36,800 to £211,500 per QALY gained), despite the more optimistic estimate including the maintenance trial data. The Committee therefore concluded that these revised ICERs did not change their original assertion that VMP was not cost-effective compared with MPT.\n\nHowever, the Committee did consider that bortezomib regimens could be cost effective for people who are unable to tolerate or have a contraindication to thalidomide. The Committee was aware that the contraindications specified in the SPC for thalidomide are pregnancy and hypersensitivity. It was mindful of the testimonies from the clinical specialists that people who are intolerant of thalidomide, or who had previous thrombosis or impaired renal function, are offered the bortezomib regimen (VMP). The Committee noted that comorbidities such as risk of thromoboembolic events and renal impairment are highlighted in the posology section of the SPC for thalidomide, which describes that low molecular weight heparin or warfarin should be recommended in patients at risk of thromboembolic events, and patients with renal or hepatic impairment should be monitored for adverse events. The Committee again considered the argument that the wording of the guidance around the contraindications to thalidomide should include people with comorbidities such as risk of thrombosis and impaired renal function. The Committee understood that thalidomide could be prescribed to people with renal impairment and risk of thromboembolic events if it is administered as outlined in section 4.2 (posology and method of administration) of the SPC for thalidomide. The Committee agreed that the SPC for thalidomide covered the safety risks adequately. The Committee concluded that since it had accepted the Assessment Group's ICER of £19,000 per QALY gained for VMP compared with MP (see section 4.3.8), bortezomib in combination with an alkylating agent and a corticosteroid is likely to be a cost-effective option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate and who are intolerant of or have contraindications to thalidomide.\n\nIn summary, the Committee considered that the combination of thalidomide plus an alkylating agent and steroid was both clinically effective and cost effective for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate. The Committee considered that bortezomib plus an alkylating agent and steroid was not cost effective when compared with both thalidomide combinations, but was likely to be cost effective for the first-line treatment of multiple myeloma for people who are intolerant to or have contraindications to thalidomide.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA228 (MTA)\n\n\n\nAppraisal title: Bortezomib and thalidomide for the first-line treatment of multiple myeloma\n\nFAD section\n\nKey conclusion\n\nThalidomide in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma in people for whom high dose chemotherapy with stem cell transplantation is considered inappropriate.\n\nBortezomib in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma if:\n\nhigh-dose chemotherapy with stem cell transplantation is considered inappropriate and\n\nthe person is unable to tolerate or has contraindications to thalidomide.\n\nThe Committee concluded that thalidomide in combination with an alkylating agent and a corticosteroid improved outcomes when compared with an alkylating agent and a corticosteroid in people with multiple myeloma for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate.\n\nThe Committee concluded that it was likely that bortezomib in combination with an alkylating agent and corticosteroid improved outcomes to a similar degree to thalidomide in combination with an alkylating agent and corticosteroid.\n\nThe Committee concluded that thalidomide in combination with an alkylating agent and a corticosteroid is a cost-effective option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate.\n\nThe Committee did not accept the manufacturer of bortezomib's assertion that the bortezomib regimen (VMP) was cost effective compared with the thalidomide regimen (MPT). However, the Committee did consider that bortezomib regimens could be cost effective for people who are unable to tolerate or have a contraindication to thalidomide.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n,\n\n\n\nCurrent practice\n\nClinical need, including the availability of alternative treatments\n\n\n\nMultiple myeloma remains an incurable disease, with an average survival of 4–6 years, but it can be treated with a combination of supportive measures and chemotherapy.\n\nThe Committee discussed the pathway of care for people with multiple myeloma for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate. The Committee heard from the clinical specialists that in UK clinical practice before the advent of thalidomide and bortezomib, first-line treatment consisted of an alkylating agent (melphalan or cyclophosphamide) and a corticosteroid (attenuated dexamethasone or prednisolone). Since thalidomide and bortezomib had become available, one of these, according to patient preference, comorbidities and adverse events, was normally added to first-line treatment.\n\n\n\n\n\n\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\n\n\nThalidomide is an immunomodulatory agent. Its precise mechanism of action is under investigation and is currently unknown, but it is thought to have multiple actions, including anti-inflammatory activity and the ability to inhibit the growth and survival of myeloma cells and the growth of new blood vessels. It is also a non-barbiturate hypnotic sedative with central action.\n\nBortezomib is an anticancer drug that works by reversible proteasome inhibition. This inhibition leads to arrest of the cell cycle and apoptosis (cell death), which reduces tumour growth. Myeloma cells are more sensitive to the action of bortezomib than normal cells.\n\n\n\n\n\n\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\n\n\nThe Committee heard from the clinical specialist that in UK clinical practice before the advent of thalidomide and bortezomib, first-line treatment consisted of an alkylating agent (melphalan or cyclophosphamide) and a corticosteroid (attenuated dexamethasone or prednisolone). Since thalidomide and bortezomib had become available, one of these, according to patient preference, comorbidities and adverse events, was normally added to first-line treatment. The Committee accepted that clinicians considered the three treatment regimens to be equivalent in terms of clinical efficacy but that the choice of treatment for an individual patient will depend on the comorbidities present and the different mechanisms of action and adverse events associated with the treatments.\n\n\n\nAdverse effects\n\n\n\nAdverse events were not a key driver in the economic evaluation; however, see section 4.2.3, 4.2.8 and 4.2.16 for details of how adverse events were modelled by the manufacturers and the Assessment Group.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\n\n\nThe Committee noted that Assessment Group had derived hazard ratios for overall survival for thalidomide from two studies without maintenance treatment. The Committee accepted that it was appropriate for the Assessment Group to exclude from its analysis survival data from studies which included participants who had received maintenance therapy.\n\nThe Committee noted that the evidence for the effectiveness of bortezomib in combination with an alkylating agent and a corticosteroid was derived from a single study (the VISTA trial).\n\n\n\n\n\n\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\n\n\nBoth thalidomide regimens and the bortezomib regimen are used in clinical practice for the first-line treatment of multiple myeloma. The clinical specialists stated that a thalidomide regimen would be considered more appropriate for 70–75% of patients and that their preferred choice of regimen was thalidomide in combination with cyclophosphamide and attenuated dexamethasone (because of the mode of oral administration). They stated that they considered the two thalidomide regimens (CTDa and MPT) to be equivalent in terms of safety and efficacy. The Committee heard that for those people who were intolerant of or had contraindications to thalidomide, the bortezomib regimen (VMP) was considered the most appropriate treatment.\n\n\n\n\n\nUncertainties generated by the evidence\n\n\n\nThe Committee was persuaded by advice from the clinical specialists that the two thalidomide regimens (CTDa and MPT), which both included an alkylating agent and a steroid, were equivalent in terms of safety and efficacy. The evidence for the clinical effectiveness of bortezomib in combination with an alkylating agent and a corticosteroid was derived from a single study (VISTA). The Committee noted survival rates with bortezomib were similar to those for thalidomide. However, the two regimens were not compared head to head. The Committee concluded that it was likely that bortezomib in combination with an alkylating agent and corticosteroid improved outcomes to a similar degree to thalidomide in combination with an alkylating agent and corticosteroid.\n\nto 4.3.5\n\n\n\n\n\n\n\n\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness\n\n\n\nThe Committee was mindful of the testimonies from the clinical specialists that people who are intolerant of thalidomide, or who had previous thrombosis or impaired renal function, are offered the bortezomib regimen (VMP). It noted that comorbidities such as risk of thromoboembolic events and renal impairment are highlighted in the posology section of the SPC for thalidomide. It therefore concluded that bortezomib in combination with an alkylating agent and a corticosteroid is likely to be a cost-effective option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate and who are intolerant of or have contraindications to thalidomide.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\n\n\nThe Committee concluded that thalidomide in combination with an alkylating agent and a corticosteroid improved outcomes when compared with an alkylating agent and a corticosteroid in people with multiple myeloma for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate.\n\nIt noted that survival rates with bortezomib were similar to those for thalidomide but that the two regimens had not been compared head to head because there were differences in participants' characteristics, delivery of the comparator and length of follow-up. The Committee concluded that it was likely that bortezomib in combination with an alkylating agent and corticosteroid improved outcomes to a similar degree to thalidomide in combination with an alkylating agent and corticosteroid.\n\n\n\n\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nThe two manufacturers submitted cost-effectiveness models. The Assessment Group developed their own economic model and critiqued the economic models submitted by the manufacturers.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\n\n\nThe Committee noted the variation in the ICERs presented by the manufacturers and the Assessment Group for MPT, CTDa and VMP compared with MP and MPT compared with VMP. The Committee accepted that the variation was a result of the following factors:\n\nDosage and number of cycles of thalidomide\n\nNumber of vials of bortezomib\n\nThe inclusion of studies with thalidomide maintenance in the estimate of overall survival hazard ratio for thalidomide\n\ncosts for second-and third-line treatments.\n\n\n\n\n\n\n\n\n\n4.3.10\n\n\n\nIncorporation of health-related quality of life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nNo health-related benefits were identified that were not included in the economic models.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\n\n\nThe Committee was mindful of the testimonies from the clinical specialists that people who are intolerant of thalidomide, or who had previous thrombosis or impaired renal function, are offered the bortezomib regimen (VMP). It noted that comorbidities such as risk of thromoboembolic events and renal impairment are highlighted in the posology section of the SPC for thalidomide. It therefore concluded that bortezomib in combination with an alkylating agent and a corticosteroid is likely to be a cost-effective option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate and who are intolerant of or have contraindications to thalidomide.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\n\n\nThe key drivers of cost effectiveness of VMP compared with MPT were the inclusion of data from studies with maintenance treatment and the number of vials of bortezomib used.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nThe Committee considered the base-case ICERs for thalidomide in combination with an alkylating agent and a corticosteroid from the Assessment Group's economic analyses. The Assessment Group calculated an ICER of £9170 per QALY gained for the MPT combination compared with MP and £33,200 per QALY gained for the CTDa combination compared with MP. The Committee accepted that if the safety and efficacy of the two thalidomide regimens were considered equivalent (see section 4.3.3), the ICER of £9170 for MPT was likely to be the more robust estimate because it was based on studies without thalidomide maintenance treatment.\n\nThe Committee agreed that the manufacturer's preference for modelling 31.5 vials should be considered the most optimistic estimate for clinical practice. The Committee noted that the Assessment Group's scenario that assumed four cycles (equivalent to 31 vials used) gave an ICER of £19,000 per QALY gained for VMP compared with MP and £320,000 per QALY gained for VMP compared with MPT.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n\n\nEnd-of-life considerations\n\nNot applicable.\n\n\n\nEqualities considerations\n\nNot applicable.\n\n", 'Related NICE guidance': 'Published\n\nLenalidomide for the treatment of multiple myeloma in people who have received at least one prior therapy. NICE technology appraisal guidance 171 (2009). Available from www.nice.org.uk/guidance/TA171\n\nBortezomib monotherapy for relapsed multiple myeloma. NICE technology appraisal guidance 129 (2007). Available from www.nice.org.uk/guidance/TA129\n\nUnder development\n\nNICE is developing the following guidance (details available from www.nice.org.uk):\n\nDenosumab for the treatment of bone metastases from solid tumours and multiple myeloma. NICE technology appraisal guidance (publication expected June 2012).', 'Review of guidance': 'The guidance on this technology will be considered for review by the Guidance Executive in July 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew Dillon\n\nChief Executive\n\nJuly 2011', 'Changes after publication': 'February 2014: implementation section updated to clarify that bortezomib and thalidomide are recommended as options for treating multiple myeloma. Additional minor maintenance update also carried out.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour\n responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta228
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Evidence-based recommendations on bortezomib (Velcade) and thalidomide (Thalidomide Celgene) for treating multiple myeloma in adults.
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34468452c1282f8f2e70fe2ff49e14fd913c9c76
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nice
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Agomelatine for the treatment of major depressive episodes (terminated appraisal)
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Agomelatine for the treatment of major depressive episodes (terminated appraisal)
NICE is unable to recommend the use in the NHS of agomelatine for the treatment of major depressive episodes because no evidence submission was received from the manufacturer or sponsor of the technology.
# Background
The manufacturer of agomelatine (Servier) has informed NICE that it would not be making an evidence submission for the appraisal of agomelatine for the treatment of major depressive episodes. Servier drew attention to the fact that NICE guidelines for England and Wales recommend generic selective serotonin reuptake inhibitors (SSRIs) as first-line treatment followed by a different SSRI or a better tolerated newer-generation agent as second-line treatment. The manufacturer noted that the majority of the clinical trial evidence for agomelatine was as a first-line treatment and furthermore was not against the full range of comparators in the scope. The manufacturer stated that this precluded the development of an economic case that would address the NICE decision problem and maintain the requisite level of certainty.
NICE has therefore terminated this single technology appraisal.# Information
NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use of agomelatine for the treatment of major depressive episodes in adults. If, after doing this, organisations still wish to consider the use of agomelatine for the treatment of major depressive episodes in adults, they should follow the advice set out in 'Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance' (www.dh.gov.uk/en/DH_064983), which outlines the approach that should be adopted in circumstances where NICE guidance is unavailable.
NICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission.
# Related NICE guidance
For information about NICE guidance that has been issued or is in development, see the website (www.nice.org.uk)
## Published
Common mental health disorders. NICE clinical guideline 123 (2011). Available from www.nice.org.uk/guidance/CG123
Depression with chronic physical health problems. NICE clinical guideline 91 (2009). Available from www.nice.org.uk/guidance/CG91
Depression in adults (update). NICE clinical guideline 90 (2009). Available from www.nice.org.uk/guidance/CG90
Vagus nerve stimulation for treatment-resistant depression. NICE interventional procedure guidance 330 (2009). Available from www.nice.org.uk/guidance/IPG330
Transcranial magnetic stimulation for severe depression. NICE interventional procedure guidance 242 (2007). Available from www.nice.org.uk/guidance/IPG242
Bipolar disorder. NICE clinical guideline 38 (2006). Available from www.nice.org.uk/guidance/CG38
Depression in children and young people. NICE clinical guideline 28 (2005). Available from www.nice.org.uk/guidance/CG28
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{'Background': 'The manufacturer of agomelatine (Servier) has informed NICE that it would not be making an evidence submission for the appraisal of agomelatine for the treatment of major depressive episodes. Servier drew attention to the fact that NICE guidelines for England and Wales recommend generic selective serotonin reuptake inhibitors (SSRIs) as first-line treatment followed by a different SSRI or a better tolerated newer-generation agent as second-line treatment. The manufacturer noted that the majority of the clinical trial evidence for agomelatine was as a first-line treatment and furthermore was not against the full range of comparators in the scope. The manufacturer stated that this precluded the development of an economic case that would address the NICE decision problem and maintain the requisite level of certainty.\n\nNICE has therefore terminated this single technology appraisal.', 'Information': "NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use of agomelatine for the treatment of major depressive episodes in adults. If, after doing this, organisations still wish to consider the use of agomelatine for the treatment of major depressive episodes in adults, they should follow the advice set out in 'Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance' (www.dh.gov.uk/en/DH_064983), which outlines the approach that should be adopted in circumstances where NICE guidance is unavailable.\n\nNICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission.\n\n# Related NICE guidance\n\nFor information about NICE guidance that has been issued or is in development, see the website (www.nice.org.uk)\n\n## Published\n\nCommon mental health disorders. NICE clinical guideline 123 (2011). Available from www.nice.org.uk/guidance/CG123\n\nDepression with chronic physical health problems. NICE clinical guideline 91 (2009). Available from www.nice.org.uk/guidance/CG91\n\nDepression in adults (update). NICE clinical guideline 90 (2009). Available from www.nice.org.uk/guidance/CG90\n\nVagus nerve stimulation for treatment-resistant depression. NICE interventional procedure guidance 330 (2009). Available from www.nice.org.uk/guidance/IPG330\n\nTranscranial magnetic stimulation for severe depression. NICE interventional procedure guidance 242 (2007). Available from www.nice.org.uk/guidance/IPG242\n\nBipolar disorder. NICE clinical guideline 38 (2006). Available from www.nice.org.uk/guidance/CG38\n\nDepression in children and young people. NICE clinical guideline 28 (2005). Available from www.nice.org.uk/guidance/CG28"}
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https://www.nice.org.uk/guidance/ta231
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NICE is unable to recommend the use in the NHS of agomelatine for the treatment of major depressive episodes because no evidence submission was received from the manufacturer or sponsor of the technology.
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9d049c92cf3cff7c425ef06181543af26e7f8b40
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nice
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Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion
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Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion
Evidence-based recommendations on dexamethasone intravitreal implant (Ozurdex) for treating macular oedema following retinal vein occlusion in adults.
# Guidance
Dexamethasone intravitreal implant is recommended as an option for the treatment of macular oedema following central retinal vein occlusion.
Dexamethasone intravitreal implant is recommended as an option for the treatment of macular oedema following branch retinal vein occlusion when:
treatment with laser photocoagulation has not been beneficial, or
treatment with laser photocoagulation is not considered suitable because of the extent of macular haemorrhage.
People currently receiving dexamethasone intravitreal implant for the treatment of macular oedema secondary to branch retinal vein occlusion who do not meet the criteria specified in 1.2 above should have the option to continue treatment until they and their clinicians consider it appropriate to stop.# The technology
Dexamethasone intravitreal implant (Ozurdex, Allergan) incorporates a potent corticosteroid that suppresses inflammation in the eye by inhibiting oedema, fibrin deposition, capillary leakage and phagocytic migration. Corticosteroids inhibit the expression of vascular endothelial growth factor (VEGF), a cytokine that is expressed at increased concentrations in macular oedema and is a potent promoter of vascular permeability. Corticosteroids also prevent the release of prostaglandins, some of which are mediators of cystoid macular oedema.
Dexamethasone intravitreal implant has a marketing authorisation for the treatment of adult patients with macular oedema following either branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).
The most common adverse reactions are increased intraocular pressure and conjunctival haemorrhage. Conjunctival haemorrhage is related to the intravitreous injection procedure rather than the dexamethasone implant. Other common adverse events include ocular hypertension, vitreous detachment, cataract, subcapsular cataract, vitreous haemorrhage, visual disturbance, vitreous opacities, eye pain, photopsia, conjunctival oedema, and conjunctival hyperaemia. For full details of side effects and contraindications, see the summary of product characteristics.
The cost of a 700-microgram implant and applicator is £870.00 (British National Formulary edition 61), excluding VAT. One dexamethasone intravitreal implant is administered usually every 6 months in the affected eye and up to six implants may be given. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of dexamethasone and a review of this submission by the Evidence Review Group (ERG; appendix B).
The manufacturer originally submitted evidence of clinical and cost effectiveness for dexamethasone versus best supportive care (observation). Following the consultation after the first Appraisal Committee meeting, the manufacturer submitted a comparison versus bevacizumab. No comparison was made with triamcinolone (Kenalog formulation), which was defined in the scope as a comparator for the treatment of macular oedema following both BRVO and CRVO. Similarly, dexamethasone was not compared with grid laser photocoagulation for non-ischaemic BRVO.
In the manufacturer's original submission, evidence of clinical effectiveness versus observation was based on two identical randomised, sham-controlled, three-arm parallel-group studies of dexamethasone intravitreal implant in people with macular oedema secondary to BRVO or CRVO. Both studies (GENEVA 008 and GENEVA 009) had an initial 6-month treatment period followed by a 6-month open-label extension in which all patients in both arms of the study who met the re-treatment criteria received a dexamethasone implant. Patients were re-treated if best corrected visual acuity (BCVA) was less than 84 letters or the retinal thickness by optical coherence tomography was more than 250 µm in the central 1 mm macular subfield and, in the investigators' opinion, the procedure would not put the patient at significant risk. All participants had macular oedema for 6 weeks to 12 months before study entry. Participants were allocated in a 1:1:1 ratio to receive a 700-microgram dexamethasone intravitreal implant (n = 427), a sham implant (n = 426) or a 350-microgram dexamethasone implant (n = 414). This appraisal considered the 700-microgram dose which is the only dose which has a UK marketing authorisation. The sham group had a needleless applicator pressed against the conjunctiva actuated with a click. Investigators were masked to study treatment. The results were presented separately for people with retinal vein occlusion (RVO) and the subgroups of people with macular oedema secondary to CRVO, BRVO, BRVO with macular haemorrhage and BRVO with previous laser treatment. People with BRVO who are eligible for laser therapy were not included as a subgroup. The results from the two studies (GENEVA 008 and GENEVA 009) were pooled and this formed the basis of the evidence considered by the Committee, although the data were also available separately for each study in the manufacturer's submission.
The results of the pooled analysis showed that for the total RVO population 21.3% of the 427 patients in the intention-to-treat population receiving dexamethasone had an improvement in BCVA from baseline of at least 15 letters at day 30 compared with 7.5% of 426 patients in the sham group. This rose to 29.3% at day 60 (compared with 11.3% in the sham group) but returned to 21.8% and 21.5% at day 90 and day 180 respectively (compared with 13.1% and 17.6% in the sham group). The differences were statistically significant at day 30 (p 0.05). The results for patients who were re-treated at day 180 were presented as academic-in-confidence information and are therefore not presented here.
For the CRVO subgroup, 21.3% of patients in the dexamethasone group had an improvement in BCVA from baseline of at least 15 letters compared with 6.8% in the sham group at day 30 (p < 0.001). At day 60, 28.7% in the dexamethasone group had an improvement in BCVA of at least 15 letters compared with 8.8% in the sham group (p < 0.001). There was no statistically significant difference between the groups at days 90 and 180.
In the subgroup with BRVO, 21.3% of patients receiving dexamethasone had an improvement in BCVA from baseline of at least 15 letters at day 30 compared with 7.9% in the sham group (p 0.001). The corresponding figures for the subgroup with BRVO with macular haemorrhage were 22.0 % and 8.8 % respectively (p ≤ 0.001). Both subgroups had statistically significant differences between patients treated with dexamethasone and the sham group at days 60 and 90, but not at day 180. In the subgroup with BRVO and previous laser therapy 22.2% had an improvement in BCVA from baseline of at least 15 letters at day 30 compared with 2.8% in the sham group (p = 0.028). Differences between the dexamethasone and sham groups were also statistically significant at days 60 (p < 0.001), 90 (p = 0.011) and 180 (p = 0.022).
The cumulative response rate for time to achieve an improvement in BCVA of at least 15 letters from baseline in the study eye was statistically significant for dexamethasone versus sham. The difference in mean change from baseline BCVA, the categorical change from baseline BCVA and proportion of patients with an improvement in BCVA of at least 10 letters from baseline in the study eye were statistically significantly higher for dexamethasone versus sham at days 30, 60, 90 and 180 in the pooled analysis. For all RVO at 180 days, the most common adverse events were raised intraocular pressure, eye pain and ocular hypertension. Intraocular pressure was raised in 25.2 % of patients treated with dexamethasone compared with 1.2 % in the sham group. Of patients treated with dexamethasone, 7.4% had eye pain compared with 3.8% in the sham group. Ocular hypertension was experienced by 4% of patients in the treated group compared with 0.7% in the sham group. Presence of anterior chamber cells and retinal neovascularisation were also reported. Other reported adverse events were retinal detachment, retinal tears and cataract. Safety data for the re-treated population (receiving a second implant by day 180) were presented as academic-in-confidence information and are therefore not presented here.
Following the consultation after the first Appraisal Committee meeting, the manufacturer submitted a mixed-treatment comparison of dexamethasone versus bevacizumab. The network of evidence from a systematic review was for BRVO only and included the BRVO data from the GENEVA trials, a non-randomised study by the Branch Vein Occlusion Study group comparing laser with sham treatment (n = 78) and a randomised study by Russo et al. comparing laser with bevacizumab (n = 30). The outcome was improvement in BCVA using standard effect sizes and a fixed-effects model. Dexamethasone was less effective than bevacizumab with a difference in BCVA of 1.74 letters (95% confidence interval 9.57 to 6.19) when assessed at day 180. However dexamethasone was more effective than bevacizumab when assessed at day 60, with a gain of 2.55 letters (95% CI 5.28 to 10.48).
For evidence of cost effectiveness, the manufacturer submitted a de novo Markov model that compared treatment with dexamethasone with sham injection in people with macular oedema and vision loss following CRVO or BRVO. Treatment was modelled over a lifetime horizon based on the transition of people between five health states based on the Early Treatment Diabetic Retinopathy Study (EDTRS) measurement of BCVA in the affected eye and death. The worst health state represented visual acuity less than or equal to 38 letters, which equated to severe visual impairment. The best health state was visual acuity of 69 letters or over. The mean BCVA of people in the model was 54 letters, which equates to the second best health state. The patient population was based on data from the GENEVA trials. The model assumed that 90% of people would present with macular oedema in the 'worse-seeing' eye. The model had a cycle length of 1 month for the first 3 months following presentation with RVO, followed by a 3-month cycle in months 4–6 and 6-monthly cycles thereafter. Patients entering the model received dexamethasone or observation. Up to 12 months, transition probabilities were based on pooled patient-level data from the GENEVA studies, including the open-label extension. Beyond 12 months, data were extrapolated from 6- to 12-month data for treatment and re‑treatment and 3- to 6-month data for sham. Treatment duration was assumed to last for 2.5 years in people with BRVO and 3 years in people with CRVO; thereafter visual acuity was assumed to be stable.
The data inputs for the manufacturer's model included utility values estimated using the Visual Function Questionnaire Utility Index (VFQ-UI) and mapped onto the health states using an algorithm from a study eliciting preferences from the general population. Resource use was identified from a systematic review of the literature and input from clinical specialists. Costs included drug cost and medical resource use (hospital visits, monitoring, costs associated with blindness and the cost of treating adverse events, including raised intraocular pressure, cataracts, retinal tears/detachment). Costs associated with treating adverse events were assumed to increase with the third and fourth treatment.
Key assumptions of the economic model included:
% of people treated would have macular oedema in the 'worse-seeing' eye
the stabilisation of visual acuity for 2.5 years in people with BRVO and 3 years in people with CRVO
re-treatment at 6-monthly intervals with a maximum of five injections for BRVO and six injections for CRVO (with assumptions over the number of treatments received)
a risk of involvement of the other eye of 6.5% in the first year (for those with initial RVO in their 'worse-seeing' eye)
blindness and an excess mortality hazard of 1.54 associated with a BCVA in the 'better-seeing' eye of 38 or fewer letters (measured by the EDTRS).
Sensitivity analyses included varying utility estimates, costs, stabilisation of visual acuity at day 360, extrapolation assumptions, mortality, involvement of the other eye, discounting, re-treatment, and people with a worse BCVA on entering the model. Results were presented for the entire RVO population and the subgroups of CRVO, BRVO with macular haemorrhage, BRVO with previous laser therapy, BRVO with a diagnosis of 90 days or less at the time of treatment, and BRVO with a diagnosis of more than 90 days at the time of treatment. In the original sensitivity analyses (manufacturer original submission), the factors having the largest impact on estimates of cost effectiveness for the total population were costs associated with vision loss (costs of residential care and the uptake of residential care), affected eye (proportion of people treated for macular oedema in the 'worse-seeing' eye) and rates of discount.
Following the consultation after the first Appraisal Committee meeting, the model was amended by the manufacturer, resulting in a revised base-case ICER. The revised base case used a ratio of 25% outpatient versus 75% day case procedures for administration and an adjustment to the way that the costs of vision loss were applied to the 'better-seeing' eye in patients whose BCVA in the affected eye falls below < 20/200. An adjustment of 25% plus a further 10% uplift applied every 6 months was made to the average annual costs associated with severe visual impairment. The model continued to use only the last 3 months of observation data from the GENEVA studies.
In the revised base case for all RVO, the total incremental cost was £3698 for dexamethasone compared with observation and the incremental QALYs were 0.21. The incremental cost-effectiveness ratio (ICER) was £17,558 per QALY gained for dexamethasone intravitreal implant compared with observation in all RVO. In the revised base case for CRVO, the total incremental cost was £4732 and the incremental QALYs were 0.29. The cost per QALY gained was £16,522 for dexamethasone compared with observation. In the revised base case for BRVO with macular haemorrhage, the total incremental cost was £3119 and the incremental QALYs were 0.18. The incremental cost per QALY gained was £17,741. In the revised base case for BRVO with previous laser therapy, the total incremental cost was £1857 and the incremental QALYs were 0.29. The incremental cost per QALY was £6361 for dexamethasone compared with observation for BRVO with previous laser treatment.
In addition, the manufacturer also provided additional scenario analyses in response to requests in the appraisal consultation document. Alternative scenario analyses for the re-treatment rate included scenarios in which proportions re-treated were as at day 180 for the five injections after the first injection in people with CRVO, proportions re-treated were as at day 180 for the four injections after the first injection in people with BRVO and proportions re-treated were varied between the two extremes of the base case and the GENEVA studies. When proportions re-treated were as at day 180, the ICERs for CRVO, BRVO with macular haemorrhage and BRVO with previous laser treatment increased from £16,522, £17,741 and £6361 to £22,083, £45,878 and £16,548 per QALY gained respectively. When the mid-point was used, the ICERs for CRVO, BRVO with macular haemorrhage and BRVO with previous laser treatment increased from £16,522, £17,741 and £6361 to £20,257, £31,123 and £10,876 per QALY gained respectively.
Following the consultation after the first Appraisal Committee meeting, the manufacturer submitted an additional cost–utility analysis versus bevacizumab for BRVO. This used the mixed-treatment analysis to obtain treatment effects for bevacizumab compared with dexamethasone (a non-significant mean gain of 1.74 letters for bevacizumab compared with dexamethasone at 6 months). Compared with bevacizumab, in the base case for all RVO, the net marginal benefit for dexamethasone (where net marginal benefit is larger than zero and treatment with dexamethasone considered cost effective) was £1927 at £30,000 per QALY gained. The manufacturer submitted a cost-minimisation analysis for dexamethasone versus bevacizumab in CRVO assuming equivalent efficacy for bevacizumab and dexamethasone in CRVO. This was associated with a cost saving of £4463 with dexamethasone which was mainly a result of a lower frequency of injections with dexamethasone compared with bevacizumab and fewer subsequent follow-up visits.
The manufacturer also submitted a second exploratory cost-minimisation analysis for BRVO and a comparison using ranibizumab as a substitute for bevacizumab. This analysis was submitted as commercial in confidence because of its exploratory nature and so is not presented here.
The manufacturer also provided more information about the location and extent of macular haemorrhage in the subgroup of patients for whom laser treatment was not considered appropriate because of macular haemorrhage. In the GENEVA trials, the location and extent was assessed by standardised fundus photographs evaluated by trained graders using a standardised grading protocol (the ETDRS macular oedema grading protocol) and masked to patient group. Retinal haemorrhage in the macula was defined when the grader was at least 90% certain that the retinal haemorrhage was present in the grid (macular area).
The ERG considered the GENEVA trials to be of high quality. Although there was a statistically significant increase in the BCVA based on the mean letter score with the dexamethasone implant, the ERG did not consider this to be clinically significant because most patients did not achieve a 15-letter improvement from baseline. However, a higher proportion had an improvement of at least 10 letters. The effectiveness of the dexamethasone implant appeared to peak at around 60 days. The ERG highlighted that the trial protocol did not allow for early re-treatment and during the trial and open-label follow-on patients received only two injections of dexamethasone. The ERG noted that the main benefit from re-treatment was in patients whose condition had responded during the initial 180-day trial period. The ERG also commented that the number of treatments needed in practice is not known and that clinical opinion estimated a maximum of six.
The ERG also highlighted that because the trial included a maximum of two dexamethasone treatments, the impact of up to six treatments on the incidence of adverse events was not known. The ERG also expressed concern over the size of the needle which is larger for dexamethasone intravitreal implant than for other treatments. The ERG stated that the main weaknesses in the evidence were lack of long-term follow-up data and data on earlier re-treatment before 180 days.
The ERG considered the robustness of the manufacturer's original model. It highlighted cost inputs (particularly the cost of dexamethasone administration and the cost of severe visual impairment), structural assumptions in the model (such as the duration of trial data on which to base extrapolation of health states in the treatment and observation arms, assumptions related to the stability of visual acuity in 'resolved' patients, the proportion of people who will present with RVO in their 'worse-seeing' eye and the modelling of fellow eye involvement).
The ERG considered that a number of the unit costs applied in the model had been overestimated. For example, the cost of administering the dexamethasone intravitreal implant might have been overestimated because the implant could be given on an outpatient basis (£150) but costs were based on day-case (£648) care in the manufacturer's submission. The ERG also estimated that the cost of residential care was £16,999 instead of £23,972 as used in the base case, and the cost of cataract extraction was £789 rather than £965 as in the base-case model.
The ERG conducted a sensitivity analysis on the unit costs applied in the manufacturer's model and other assumptions related to the extrapolation of effectiveness data beyond the trial. According to the ERG, key uncertainties related to the extrapolation of data remain in the evaluation of cost effectiveness. The likely maximum number of dexamethasone administrations and frequency of re-treatment, the likelihood of resolution, the likelihood of cataract development and extraction, the likelihood of involvement of the other eye and the likelihood of the RVO leading to macular oedema are all important aspects of this uncertainty.
The ERG highlighted factors in the manufacturer's original sensitivity analyses that appeared to have a particular impact on cost effectiveness. When visual acuity was assumed to be stable after a year with no further dexamethasone treatments (rather than at 2.5 years with BRVO and 3 years with CRVO) the base-case ICER increased from £7368 to £10,764 per QALY gained for the RVO population. When those not treated were all assumed to have the observation transition probabilities applied up to 2.5 years for BRVO and 3 years for CRVO (rather than transition probabilities weighted by proportion of people who were not treated who resolved at day 180 and those who discontinued treatment for other reasons), the base-case ICER increased from £7368 to £24,924 per QALY gained for the RVO population. When the proportions re‑treated were based on the re-treatment rate in the trial (day 180) for the five injections after the first in CRVO (85.7%) and the four injections after the first in BRVO (78.8%), this increased the base-case ICER from £7368 to £19,100 per QALY gained for the RVO population. When there was a decline in vision in 1.5% of patients in each health state, worsening by one health state every 6 months was assumed (compared with visual stability from 2.5 years for BRVO and 3 years for CRVO in the base case). This had a small effect on the base-case ICER, which increased from £7368 to £7685 per QALY gained for the RVO population.
The ERG also conducted its own additional exploratory analyses on the manufacturer's original economic model which updated the modelling of fellow eye involvement. The ERG compared the manufacturer's model, which included the Weibull function for fellow eye involvement, with the same model with no fellow eye involvement. At the same time, the ERG also varied the proportion of people entering the model with macular oedema in the 'worse-seeing' eye from 90% (as in the manufacturer's model) to 97% (based on the proportion treated in the 'worse-seeing' eye in the trials). The alternative assumption of no fellow eye involvement changed the base-case ICERs for CRVO, BRVO with macular haemorrhage and BRVO with previous laser from £6041, £7987 and dominant to £17,279, £34,277 and £11,905 per QALY gained respectively. The alternative assumption of 97% with macular oedema in the 'worse-seeing' eye changed the base-case ICER for CRVO, BRVO with macular haemorrhage and BRVO with previous laser from £6041, £7987 and dominant to £15,800, £10,206 and dominant per QALY gained respectively.
In addition, the ERG questioned the way in which 6-month data from the open-label phase were used for the extrapolation of results with dexamethasone treatment and the use of 3- to 6-month data from the trial phase for extrapolation in the observation arm of the original model. After the first Committee meeting the Committee had requested that all data be included in a revised model. When extrapolation was based on 6- to 12-month data from the open-label phase of the trial for dexamethasone treatment and 0- to 6-month data for the observation arm (with 90% of people being treated in the 'worse-seeing' eye) the base-case ICER increased from £6041 to £15,395 per QALY gained for the RVO population.
The manufacturer submitted two additional original base-case models: one involving structural changes in the modelling of fellow eye involvement, and another which also included lower costs of dexamethasone administration. The revised modelling of fellow eye involvement took account of age with differential survival by collapsing the model into two health states. Without inclusion of lower costs for dexamethasone administration, the revised model was associated with higher ICERs for dexamethasone versus observation of £10,271 per QALY gained for all RVO, £8165 for CRVO, £11,403 for BRVO with macular haemorrhage, and dominance for dexamethasone over observation for BRVO with previous laser treatment. With revised cost assumptions (outpatient appointments rather than day-case costs, reduced costs of residential care and reduced costs of cataract removal), ICERs were reduced to £7616 per QALY gained for all RVO, £6221 for CRVO, £8848 for all BRVO, £8313 for BRVO with macular haemorrhage, and dominance for dexamethasone over observation for BRVO with previous laser treatment.
The ERG noted that the manufacturer's model applied the cost associated with severe visual impairment to people with visual acuity less than or equal to 38 letters in the 'worse-seeing' eye. The ERG noted that the cost of severe visual impairment should only be applied when both eyes have visual acuity less than 38 letters. The ERG conducted a sensitivity analysis in which the cost of severe visual impairment was applied when both eyes entered the worse state (visual acuity less than 38 letters) and assumed perfect correlation in the BCVA of both eyes and no correlation between the eyes. This increased the base-case ICER for CRVO from £6221 to £15,956 per QALY gained when there was perfect correlation and to £18,091 per QALY gained when there was no correlation between eyes. The corresponding base-case ICERs for BRVO with macular haemorrhage increased from £8313 to £9674 and £21,443 per QALY gained respectively.
Following the consultation after the first Appraisal Committee meeting, the ERG noted that the manufacturer's revised analysis of cost effectiveness included several deviations from the analysis requested by the Committee at its first meeting. The manufacturer included administration costs for 75:25 day-case to outpatient procedures whereas the Committee had requested day-case costs for all patients. No bevacizumab vial sharing was included in the base case. Extrapolation from data for the last 3 months of observation in the GENEVA studies was used although the Committee requested that all 6 months of data be used. In addition, severe visual impairment was not modelled as requiring bilateral involvement. Cost of reduction of severe visual impairment was reduced by 25% as a proxy with 10% applied every 6 months. The ERG noted that the 10% was not applied annually and it was unclear from where the 10% figure was derived. When the ERG removed this 10% uplift per cycle, the manufacturer's estimated ICERs for CRVO, BRVO with macular haemorrhage and BRVO with previous laser treatment increased from £16,522, £17,741 and £6361 to £22,831, £23,847 and £12,857 per QALY gained respectively. When the ERG included all 6 months of observational data from the GENEVA studies, the manufacturer's estimated ICERs for CRVO, BRVO with macular haemorrhage and BRVO with previous laser treatment increased from £16,522, £17,741 and £6361 to £25,336, £38,489 and £11,650 per QALY gained respectively.
The ERG considered that a number of the unit costs applied in the revised model had been overestimated for bevacizumab and the costs used favoured dexamethasone. For example, administration costs were used for 25% outpatient and 75% day-case procedures, there was uncertainty over the calculation of the administration costs for outpatients, a high bevacizumab cost was used and a large number of bevacizumab administrations included. Also, the ERG stated that the frequency of cataracts with steroids was underestimated. When the ERG made adjustments for these costs (a cost of bevacizumab of £50, less frequent bevacizumab administration and follow-up based on the Pan American Collaborative Retina Study group data, and 100% outpatient procedures), the base-case cost minimisation for CRVO, which estimated a cost saving of £4463 with dexamethasone versus bevacizumab, became a cost saving for bevacizumab of £2127 versus dexamethasone.
The ERG highlighted that there was a considerable amount of data on bevacizumab treatment from trials including bevacizumab, laser therapy and triamcinolone in RVO (992 observed patient-years) and agreed that this type of observational and uncontrolled data generates uncertainty. The ERG concluded that more data could have been included in the network model by using data on triamcinolone treatment.
Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA229# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dexamethasone, having considered evidence on the nature of macular oedema secondary to RVO and the value placed on the benefits of dexamethasone by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee considered the impact of macular oedema on the everyday life of patients. It heard from patient experts about the problems associated with macular oedema and related vision loss, including difficulties with driving in the dark, taking part in hobbies such as craftwork, picking up small things, reading, using computers and distinguishing objects in crowded places. The patient experts also noted the negative impact of macular oedema on social activities. The patient experts acknowledged that although people may be worried about having an injection in the eye, this is preferable to loss of vision. They also noted that the injections were administered from the side and so could not be seen. The Committee concluded that loss of vision caused by macular oedema secondary to RVO had a negative impact on health-related quality of life and that there was a need for appropriate treatment.
The Committee considered the decision problem submitted by the manufacturer. It noted that the manufacturer's initial submission compared dexamethasone with best supportive care (observation) alone. This was not consistent with the scope, which defined the comparators for both BRVO and CRVO as triamcinolone acetonide (IVTA; Kenalog formulation or equivalent), bevacizumab and best supportive care, and for non-ischaemic BRVO as grid pattern photocoagulation.
The Committee considered the use of triamcinolone to treat RVO in UK clinical practice. It heard from clinical specialists that the triamcinolone formulation available in the UK is contraindicated for ocular use (Kenalog formulation); it also heard from the manufacturer of the intraocular formulation of triamcinolone (Trivaris) that it is not available in the UK and would not be marketed anywhere in the world. The Committee concluded that triamcinolone is not available and would not be a relevant comparator for dexamethasone.
The Committee considered the use of bevacizumab to treat RVO in UK clinical practice. It noted that bevacizumab does not have a UK marketing authorisation for the treatment of RVO and heard from patient experts that they were concerned about the use of any unlicensed treatments for which there was no formal post-marketing surveillance, particularly if there were alternatives that had a UK marketing authorisation. The Committee understood that licensing is not a prerequisite for consideration of a comparator in a NICE appraisal as long as it is in routine use or best practice. It heard from clinical specialists that bevacizumab is currently reasonably widely used in the NHS, being routinely used in some centres, for some RVO cases only in others, and not at all in other centres. It heard from the experts that some clinicians and patients want more information about its long-term efficacy and safety. It also noted consultee comments following consultation confirming the use of bevacizumab by many ophthalmologists in the UK The Committee considered the results of the independent survey supplied by the manufacturer which indicated that a proportion of consultant ophthalmologists use bevacizumab for RVO either regularly or occasionally. It acknowledged that the sample size for the survey was small and could be subject to some selection bias. The Committee concluded that bevacizumab is in routine use to treat RVO in some parts of the UK; and it is therefore relevant for consideration as a comparator to dexamethasone.
The Committee considered laser photocoagulation as a treatment for BRVO. It noted that the manufacturer restricted the analysed population to those people with BRVO who cannot receive or have already tried and not benefited from laser photocoagulation. The Committee noted that the manufacturer defined those who cannot receive laser photocoagulation as people with macular haemorrhage. It noted comments from clinical specialists and consultees that all cases of RVO have a degree of macular haemorrhage and the decision to treat using laser photocoagulation is relatively subjective. Therefore, the Committee recognised that for a subgroup of people with BRVO with a lesser extent of macular haemorrhage, laser photocoagulation would be a treatment option and that this subgroup is within the licensed indication for dexamethasone. The Committee concluded that because no evidence had been provided for this subgroup, any recommendation for dexamethasone would be optimised to those subgroups of people with BRVO who cannot receive or have already tried and not benefited from laser photocoagulation.
# Clinical effectiveness
The Committee considered the potential of dexamethasone to offer additional health-related benefits compared with currently available treatment options. It heard from the patient experts about the impact of dexamethasone on their quality of life. Patients advised that after the administration of dexamethasone their sight improved and they were able to resume normal daily activities.
The Committee considered the evidence for the efficacy of dexamethasone intravitreal implant compared with best supportive care from the GENEVA trials. It noted that the primary outcome was the percentage of patients with an improvement of BCVA of 15 letters or more, which represented a gain of three lines on the EDTRS chart (this enables patients to see letters half the height of those they could see before). The Committee heard from clinical specialists that this represented the gold standard for assessing the effect of treatment on visual acuity, although a gain of 10 letters is also considered to be clinically significant.
The Committee considered the results from the trials. It first considered the pooled primary outcome data from the GENEVA trials for the entire population with macular oedema following RVO. The Committee noted that dexamethasone is associated with a statistically significant improvement in visual acuity (based on percentage of patients with an improvement of BCVA of 15 letters or more) compared with sham treatment at day 30, 60 and 90, but there was no statistically significant improvement at day 180. The Committee also noted that dexamethasone was associated with a statistically significant improvement in mean change in BCVA at day 30, 60, 90 and 180 for all people with macular oedema following RVO. The Committee also considered the pooled primary outcome data from the GENEVA trials for the CRVO and BRVO subgroups. It noted that dexamethasone was associated with a statistically significantly higher proportion of people gaining BCVA of 15 letters or more compared with sham treatment for CRVO (day 30 and 60), BRVO (day 30, 60 and 90), BRVO with macular haemorrhage (day 30, 60 and 90) and at all time points for BRVO with previous laser treatment. These results for the subgroups were similar to those obtained for the combined population with RVO. The Committee concluded that treatment with dexamethasone is clinically effective when compared with best supportive care.
The Committee considered the evidence for adverse events associated with dexamethasone. These included cataracts, raised intraocular pressure and infection. The Committee noted that evidence was limited by trial duration to adverse events after two treatments with data collected up to 360 days. The Committee discussed the impact of dexamethasone in causing cataracts and the potential issues for people with diabetes, who have a higher risk of developing glaucoma and cataracts. The Committee heard from the clinical specialist that a similar infection risk to that of its comparators would be expected. It also heard that the incidence of raised intraocular pressure was 25% with dexamethasone but that this is usually well managed with eye drops and that 1% of people required laser or surgical procedures for management of elevated intraocular pressure. A higher percentage was likely to need surgery for cataracts according to the number of dexamethasone injections given. The Committee concluded that there were some concerns about the long term safety of dexamethasone treatment because the marketing authorisation is based on a evidence base trial with two re-treatments over 360 days and the manufacturer assumed that up to six treatments would be given and there are limited data on long-term treatment and multiple re-treatment (see section 3.6).
The Committee considered the evidence for re-treatment from the open-label extension of the GENEVA trials (which was submitted as academic-in-confidence information, as described in section 3.6, and is therefore not presented here). The Committee noted that for the whole population the proportion of patients with an improvement in BCVA of at least 15 letters was higher in the group that received dexamethasone at day 0 and day 180 compared with those who received sham at day 0 and dexamethasone at day 180. The Committee also considered the expected frequency of treatment with dexamethasone at day 180. The Committee heard from the clinical specialist that the criteria for re-treatment were based on the patient's experience with previous treatment (whether their vision had initially improved with treatment but had started to deteriorate), deterioration in visual acuity as assessed by BCVA and the persistence of macular oedema. The Committee was further advised that it is difficult to use a cut-off value for visual acuity that would indicate re-treatment, but that with a loss of five letters it would be appropriate to consider re-treatment. The Committee agreed with the clinical specialist that although the safety data relate to 6-monthly treatment, it is expected that clinicians may re-treat at 4 months in clinical practice, but may not treat more frequently because of the risk of adverse events from the accumulation of dexamethasone in the eye.
The Committee then considered the clinical effectiveness of dexamethasone compared with bevacizumab. It heard from the clinical specialist that bevacizumab is generally considered by ophthalmologists to be efficacious and safe, although there is some uncertainty as to the optimal dosing schedule, relative effectiveness versus dexamethasone and frequency of treatments. The Committee considered the results of the mixed-treatment comparison provided by the manufacturer in response to requests made at the first Appraisal Committee meeting. It noted that the difference in BCVA was marginally favourable for dexamethasone over bevacizumab at day 60, but that at day 180 the difference in BCVA was marginally favourable for bevacizumab over dexamethasone. However, at both time points the confidence intervals were wide and therefore little certainty could be placed in either of the findings. The Committee noted the ERG's misgivings about the lack of completeness of the mixed-treatment comparison and also that the two cost–utility analyses provided by the manufacturer favoured bevacizumab in terms of efficacy. Nevertheless the Committee considered that a clinical efficacy advantage for dexamethasone over bevacizumab could not be concluded with certainty based on current evidence.
The Committee considered the mode of delivery and adverse events associated with dexamethasone and bevacizumab, including infection and needle phobia. The clinical specialist informed the Committee that dexamethasone was administered with a larger needle than existing treatments and that dexamethasone was associated with increased intraocular pressure and cataracts. However, more injections of bevacizumab were needed and this presented a greater infection risk. The clinical specialist also informed the Committee that with bevacizumab, which had no agreed protocol for use, sterile endophthalmitis had been reported, but was rare. The Committee concluded that the adverse events associated with dexamethasone were expected to be more severe and more difficult to treat than those associated with bevacizumab.
# Cost effectiveness
The Committee considered the cost effectiveness of dexamethasone relative to best supportive care. It noted the manufacturer's revised base-case estimate of the ICER for all people with RVO of £17,600 per QALY gained. It understood that this estimate incorporated an assumption that 90% of people would be treated for macular oedema in their 'worst-seeing eye'. It heard from clinical specialists that in practice this proportion would be between 90% and 97%. It further heard from clinical specialists that the manufacturer's estimate of the percentage (6.5%) of people who require treatment for the other eye (fellow eye involvement) was plausible. Patient experts had highlighted the importance of treating the first eye affected, even though overall acuity depends mostly on the 'better-seeing' eye, because RVO and other eye conditions may later affect the critical second eye. The Committee concluded that in this instance it was appropriate to treat the first eye affected.
The Committee considered the manufacturer's response to requests made at the first Appraisal Committee meeting. It understood that the revised base-case estimate of the ICER incorporated revised assumptions for the setting for the administration of dexamethasone and the cost of care for people with blindness. It further understood that the manufacturer had provided scenario analyses to demonstrate the effect of different re-treatment rates. The Committee noted that the revised base-case ICER did not incorporate the Committee's request that the extrapolation of data for the observation arm should be based on those trial data between 0 and 6 months rather than 3–6 months. The Committee discussed each of these assumptions, and the results of the sensitivity analyses for re-treatment rates, in turn.
The Committee considered the setting for the administration of dexamethasone. It noted that the revised base case was based on an assumption of 75% of procedures being performed in a day-case unit and 25% in an outpatient clinic, instead of 100% in an outpatient clinic as requested by the Committee at the first Appraisal Committee meeting. The Committee noted comments from consultees that it was reasonable to expect a higher proportion to be performed in a day-case unit while ophthalmologists are gaining familiarity with dexamethasone administration, but that in time it would be expected that most would be performed in an outpatient clinic. The Committee therefore accepted the proportions used by the manufacturer in the revised base case for the setting for the administration of dexamethasone.
The Committee considered the revised assumption for the cost associated with blindness in the revised base case. It understood that the manufacturer had accepted the rationale for applying this cost to only those people who have both eyes in the worst health state. However, the Committee noted that in the revised base-case estimate, the cost associated with blindness was reduced as a proxy for adjusting the proportion of people who fall into this health state of severe visual impairment in both eyes. The manufacturer adjusted the cost associated with blindness to 25% of the full cost (that is, £1490 instead of £5963), and increased this every 6 months by 10% of the reduced cost (that is, an increase of £149 for each cycle). The Committee accepted this to be a reasonable reduction and concluded that although it would have been preferable to have adjusted the assumptions around the number of people with severe visual impairment in both eyes, the manufacturer's adjustment went some way towards meeting the Committee's request and was considered acceptable.
The Committee considered the extrapolation of health-state data beyond the trial for the observation arm. It noted the manufacturer's assertion that it was inappropriate to include 0- to 3-month data for BRVO because spontaneous resolution occurs in approximately a quarter of people during that period. The Committee also heard from the manufacturer that although it may be appropriate to include 0- to 3-month data for CRVO, the ERG's exploratory analysis used aggregate data rather than transition probabilities based on individual patient data. The manufacturer stated that this had led to an overestimation of the ICER for CRVO by the ERG. The Committee accepted that spontaneous resolution occurs in BRVO and therefore it was not appropriate to include the first 3 months of data for this subgroup. It further concluded that using individual patient data for the first 6 months may have been relevant for CRVO, but that the increased ICER for CRVO from the ERG's analysis (from £16,500 to £25,300 per QALY gained including a decrease from 0.29 to 0.22 of net total QALYs and an increase in total cost from £4732 to £5469) may be an overestimate. The Committee concluded that 0- to 3-month data for the observation arm of the GENEVA trials for people with CRVO would not have a substantial impact on the overall ICER and therefore accepted the manufacturer's use of 0- to 3-month data in the revised base case.
The Committee considered the sensitivity analyses around re‑treatment rates provided by the manufacturer in response to requests made by the Committee at the first meeting. The Committee understood that the manufacturer had combined the revised assumptions relating to the setting for administering dexamethasone (see section 4.16) and the costs associated with blindness (see section 4.17) with three scenario analyses for different re-treatment rates. The Committee noted that the re‑treatment scenarios covered the extreme positions of both the base-case estimates (in which re-treatment rates were based on clinical opinion) and those re-treated at day 180 in the GENEVA trials. The Committee noted that for all people with RVO, the ICER varied between £17,600 (including incremental costs of £3698 and incremental QALYs of 0.40) and £34,700 (including incremental costs of £8041 and incremental QALYs of 0.44) per QALY gained for these scenarios respectively. The Committee further noted the manufacturer's scenario analysis in which the re-treatment rates were at the mid-points between the two extremes. With this assumption the ICER for all people with RVO was £26,300 per QALY gained. The Committee accepted the assumption of mid‑point re-treatment rates.
On the basis of previous discussions (see sections 4.17 to 4.21), the Committee accepted the revised manufacturer's base-case estimate using the mid-point re-treatment rates from the manufacturer's scenario analysis as the most appropriate estimate of the ICER for its consideration. It therefore concluded that the decision regarding the cost effectiveness of dexamethasone compared with best supportive care should be based on the manufacturer's ICER of £26,300 per QALY gained for all people with RVO. The Committee further concluded that this represented an acceptable level of cost effectiveness in this case and that dexamethasone intravitreal implant for the treatment of RVO represents a cost-effective use of NHS resources when compared with best supportive care.
The Committee considered the cost effectiveness of dexamethasone relative to bevacizumab. It understood that the manufacturer had presented a cost-minimisation approach for CRVO and that the cost assumptions from this approach had been used in both cost–utility analyses (that is, the mixed-treatment comparison, and the indirect comparison using a different anti-VEGF treatment as a proxy for bevacizumab) (see sections 3.14 and 3.15). The Committee therefore considered that its discussion on the relative cost effectiveness of dexamethasone compared with bevacizumab should focus on the assumptions within the manufacturer's cost-minimisation analysis.
The Committee considered the assumptions in the manufacturer's cost-minimisation analysis between dexamethasone and bevacizumab. It noted comments from the ERG that the cost of bevacizumab had been modelled on the higher of the two estimates from the two suppliers of bevacizumab for eye treatment (that is, £150 per vial rather than £50 per vial). The ERG further highlighted that the manufacturer's estimate of the average number of doses of bevacizumab was 13.75 in the first 2 years, but that the Pan American Collaborative Retina Study Group had found an average of 7 doses over this time period. The Committee heard from the manufacturer that this study was a small cohort follow-up study and may not be representative of UK clinical practice. In addition the manufacturer highlighted to the Committee that the recently reported HORIZON study found that 3.8 injections per year of ranibizumab were insufficient to maintain the clinical effects seen in the first year (ranibizumab, another anti-VEGF, was given monthly in the CRUISE study). Therefore the manufacturer considered 7 doses of bevacizumab over 2 years to be lower than UK clinical practice. The Committee understood that the cost-minimisation analysis also assumed that the setting for the administration of both bevacizumab and dexamethasone would be the same (that is, 75% of procedures would be carried out in a day-case unit and 25% would be carried out in an outpatient clinic). The Committee noted the ERG's view that all anti-VEGF injections are currently administered in an outpatient clinic. The Committee concluded, on the one hand, that the cost of bevacizumab may have been overestimated, and on the other, that there was uncertainty around the number of injections of bevacizumab. The Committee concluded that the assumptions used in the manufacturer's cost-minimisation analysis between dexamethasone and bevacizumab may overestimate the cost of bevacizumab, but considered the cost may not be as low as suggested by the ERG.
The Committee considered the results of the cost-minimisation analysis. It noted that the manufacturer estimated the cost of dexamethasone treatment to be approximately £4500 less per patient than bevacizumab, but that with the ERG's amendments, dexamethasone could cost up to £2100 more per patient than bevacizumab. On the basis of previous discussion (see section 4.22) the Committee accepted that there was some uncertainty around the assumptions used to calculate the cost of bevacizumab and concluded that it was as likely that dexamethasone might cost more than bevacizumab as it was that dexamethasone might cost less. The Committee therefore concluded that a cost advantage of dexamethasone compared with bevacizumab had not been conclusively demonstrated.
In summary, the Committee considered the costs and clinical effectiveness of dexamethasone. It considered that comparisons with best supportive care and bevacizumab were both relevant to the NHS. It acknowledged that an incremental analysis in which dexamethasone, bevacizumab and best supportive care were simultaneously assessed was not available. The Committee recognised the difficulties within the evidence base for bevacizumab and commended the manufacturer's attempts to provide a comparison of the relative clinical and cost effectiveness of bevacizumab and dexamethasone. It considered that a clinical efficacy advantage for dexamethasone over bevacizumab could not be concluded with certainty based on presently available evidence and that the adverse events associated with dexamethasone were expected to be more severe and more difficult to treat than those associated with bevacizumab. It also accepted that there was uncertainty around the assumptions used in the cost minimisation comparing dexamethasone with bevacizumab. Based on the manufacturer's revised ICER of £26,300 per QALY gained compared with best supportive care for all people with RVO, the Committee concluded that dexamethasone intravitreal implant represents a cost-effective use of NHS resources and should be offered as an option for the treatment of macular oedema secondary to RVO.
The Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal that required addressing in the guidance.
# Summary of Appraisal Committee's key conclusions
TA229
Appraisal title: Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion
Section
Key conclusion
Dexamethasone intravitreal implant is recommended as an option for the treatment of macular oedema following central retinal vein occlusion.
Dexamethasone intravitreal implant is recommended as an option for the treatment of macular oedema following branch retinal vein occlusion when:
treatment with laser photocoagulation has not been beneficial, or
treatment with laser photocoagulation is not considered suitable because of the extent of macular haemorrhage.
People currently receiving dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion should have the option to continue treatment until they and their clinicians consider it appropriate to stop.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee concluded that triamcinolone (Kenalog formulation) is not available and is not a relevant comparator for dexamethasone.
The Committee concluded that bevacizumab is in routine use in some parts of the UK to treat macular oedema secondary to retinal vein occlusion (RVO) and is therefore relevant for consideration as a comparator for dexamethasone.
The Committee recognised that for a subgroup of people with branch retinal vein occlusion (BRVO) with a lesser extent of macular haemorrhage, laser photocoagulation would be a treatment option and that this subgroup is within the licensed indication for dexamethasone. The Committee concluded that because no evidence had been provided for this subgroup, any recommendation for dexamethasone would be restricted to those subgroups of people with BRVO who cannot receive or have already tried and not benefited from laser photocoagulation.
The Committee concluded that loss of vision caused by macular oedema secondary to RVO had a negative impact on health-related quality of life and that there was a need for appropriate treatment.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
Dexamethasone intravitreal implant incorporates a potent corticosteroid that suppresses inflammation in the eye by inhibiting oedema, fibrin deposition, capillary leakage and phagocytic migration.
What is the position of the treatment in the pathway of care for the condition?
Dexamethasone intravitreal implant has a marketing authorisation for the treatment of adult patients with macular oedema following either BRVO or central retinal vein occlusion (CRVO).
Comparator treatments include best supportive care (observation), bevacizumab, triamcinolone (Kenalog formulation) and laser therapy (BRVO only).
Adverse effects
The Committee concluded that there were some concerns about long-term safety of dexamethasone treatment because the marketing authorisation is based on an evidence base trial with two re-treatments over 360 days and the manufacturer assumed that up to six treatments would be given and there are limited data on long-term treatment and multiple re-treatment.
The Committee concluded that the adverse events associated with dexamethasone were expected to be more severe and more difficult to treat than those associated with bevacizumab.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Evidence Review Group (ERG) considered the GENEVA trials, RCTs of dexamethasone versus sham treatment, to be of high quality.
The ERG highlighted that there was a considerable amount of data on bevacizumab treatment from trials including bevacizumab, laser therapy and triamcinolone in RVO (992 observed patient-years) and agreed that this type of observational and uncontrolled data generates uncertainty. The Committee recognised the difficulties within the evidence base for bevacizumab and commended the manufacturer's attempts to provide a comparison of the relative clinical and cost effectiveness of bevacizumab and dexamethasone.
Relevance to general clinical practice in the NHS
The Committee noted that the primary outcome in the GENEVA trials was the percentage of patients with an improvement of BCVA of 15 letters or more. The Committee heard from clinical specialists that this represented the gold standard for assessing the effect of treatment on visual acuity, although a gain of 10 letters is also considered to be clinically significant.
Uncertainties generated by the evidence
The Committee considered that a clinical efficacy advantage for dexamethasone over bevacizumab could not be concluded with certainty based on current evidence.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee noted that dexamethasone was associated with a statistically significantly higher proportion of people gaining BCVA of 15 letters or more compared with sham treatment for CRVO (day 30 and 60), BRVO (day 30, 60 and 90), BRVO with macular haemorrhage (day 30, 60 and 90) and at all time points for BRVO with previous laser treatment. These results for the subgroups were similar to those obtained for the combined population with RVO.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
Of the 427 patients in the intention-to-treat population receiving dexamethasone, 21.3% had an improvement in BCVA from baseline of at least 15 letters at day 30 compared with 7.5% of 426 patients in the sham group.
The Committee also noted that dexamethasone was associated with a statistically significant improvement in mean change in BCVA at day 30, 60, 90 and 180 for all people with macular oedema following RVO compared with sham.
The Committee noted that the difference in BCVA was marginally favourable for dexamethasone over bevacizumab at day 60, but that at day 180 the difference in BCVA was marginally favourable for bevacizumab over dexamethasone. However, at both time points the confidence intervals were wide and therefore little certainty could be placed in either of the findings. The Committee considered that a clinical efficacy advantage for bevacizumab over dexamethasone could not be concluded with certainty based on current evidence.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee acknowledged that an incremental analysis in which dexamethasone, bevacizumab and best supportive care were simultaneously assessed was not available. The Committee recognised the difficulties within the evidence base for bevacizumab and commended the manufacturer's attempts to provide a comparison of the relative clinical and cost effectiveness of bevacizumab and dexamethasone.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee considered the setting for the administration of dexamethasone. It noted that the revised base case was based on an assumption of 75% of procedures being performed in a day-case unit and 25% in an outpatient clinic. The Committee accepted the proportions used by the manufacturer in the revised base case.
The Committee considered the revised assumption for the cost associated with blindness in the revised base case. The manufacturer adjusted the cost associated with blindness to 25% of the full cost (that is, £1490 instead of £5963), and increased this every 6 months by 10% of the reduced cost (that is, an increase of £149 for each cycle). The Committee accepted this to be a reasonable reduction and concluded that although it would have been preferable to have adjusted the assumptions around the number of people with severe visual impairment in both eyes, the manufacturer's adjustment went some way towards meeting the Committee's request as best they could given the data available and was therefore considered acceptable.
The Committee considered the extrapolation of health-state data beyond the trial for the observation arm. The Committee accepted that spontaneous resolution occurs in BRVO and therefore it was not appropriate to include the first 3 months of data for this subgroup. The Committee concluded that 0- to 3-month data for the observation arm of the GENEVA trials for people with CRVO would not have a substantial impact on the overall ICER and therefore accepted the manufacturer's use of 0- to 3-month data in the revised base case.
The Committee considered the sensitivity analyses around re-treatment rates provided by the manufacturer in response to requests made by the Committee at the first meeting. The Committee accepted the assumption of mid-point re-treatment rates.
The Committee considered the assumptions in the manufacturer's cost-minimisation analysis between dexamethasone and bevacizumab. The Committee concluded that the cost of bevacizumab may have been overestimated, but that there was uncertainty around the number of injections of bevacizumab. The Committee concluded that the assumptions used in the manufacturer's cost-minimisation analysis between dexamethasone and bevacizumab may overestimate the cost of bevacizumab, but the cost may not be as low as suggested by the ERG.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The data inputs for the manufacturer's model included utility values estimated using the Visual Function Questionnaire Utility Index (VFQ-UI) and mapped onto the health states using an algorithm from a study eliciting preferences from the general population.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee recognised that for a subgroup of people with BRVO with a lesser extent of macular haemorrhage, laser photocoagulation would be a treatment option and that this subgroup is within the licensed indication for dexamethasone. The Committee concluded that because no evidence had been provided for this subgroup, any recommendation for dexamethasone would be restricted to those subgroups of people with BRVO who cannot receive or have already tried and not benefited from laser photocoagulation.
What are the key drivers of cost effectiveness?
The cost effectiveness of dexamethasone compared with best supportive care was affected by assumptions around re-treatment.
The Committee considered that its discussion on the relative cost effectiveness of dexamethasone compared with bevacizumab should focus on the assumptions within the manufacturer's cost-minimisation analysis.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee concluded that the decision regarding the cost effectiveness of dexamethasone compared with best supportive care should be based on the manufacturer's revised ICER of £26,300 per QALY gained (including an incremental costs of £5937 and incremental QALYs of 0.23) for all people with RVO. The Committee further concluded that this represented an acceptable level of cost effectiveness in this case and that dexamethasone intravitreal implant for the treatment of RVO represents a cost-effective use of NHS resources when compared with best supportive care.
Additional factors taken into account
Patient access schemes (PPRS)
None
End-of-life considerations
None
Equalities considerations and social value judgements
The Committee concluded that there were no equality issues relating to this appraisal that required addressing in the guidance.
# Related NICE guidance
Published
Ranibizumab and pegaptanib for the treatment of age-related macular degeneration. NICE technology appraisal guidance 155 (2008). Available from www.nice.org.uk/guidance/TA155
Guidance on the use of photodynamic therapy for age-related macular degeneration. NICE technology appraisal guidance 68 (2003). Available from www.nice.org.uk/guidance/TA68
Under development
NICE is developing the following guidance (details available from www.nice.org.uk):
Ranibizumab for the treatment of macular oedema caused by retinal vein occlusion. NICE technology appraisal (publication date to be confirmed).
Ranibizumab for the treatment of diabetic macular oedema. NICE technology appraisal (publication date to be confirmed).
Pegaptanib sodium for the treatment of diabetic macular oedema. NICE technology appraisal (publication date to be confirmed).# Proposed date for review of guidance
NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in 2014. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew Dillon
Chief Executive
July 2011# Changes after publication
February 2014: implementation section updated to clarify that dexamethasone intravitreal implant is recommended as an option for treating macular oedema secondary to retinal vein occlusion. Additional minor maintenance update also carried out.# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your
responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Dexamethasone intravitreal implant is recommended as an option for the treatment of macular oedema following central retinal vein occlusion.\n\nDexamethasone intravitreal implant is recommended as an option for the treatment of macular oedema following branch retinal vein occlusion when:\n\ntreatment with laser photocoagulation has not been beneficial, or\n\ntreatment with laser photocoagulation is not considered suitable because of the extent of macular haemorrhage.\n\nPeople currently receiving dexamethasone intravitreal implant for the treatment of macular oedema secondary to branch retinal vein occlusion who do not meet the criteria specified in 1.2 above should have the option to continue treatment until they and their clinicians consider it appropriate to stop.', 'The technology ': 'Dexamethasone intravitreal implant (Ozurdex, Allergan) incorporates a potent corticosteroid that suppresses inflammation in the eye by inhibiting oedema, fibrin deposition, capillary leakage and phagocytic migration. Corticosteroids inhibit the expression of vascular endothelial growth factor (VEGF), a cytokine that is expressed at increased concentrations in macular oedema and is a potent promoter of vascular permeability. Corticosteroids also prevent the release of prostaglandins, some of which are mediators of cystoid macular oedema.\n\nDexamethasone intravitreal implant has a marketing authorisation for the treatment of adult patients with macular oedema following either branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).\n\nThe most common adverse reactions are increased intraocular pressure and conjunctival haemorrhage. Conjunctival haemorrhage is related to the intravitreous injection procedure rather than the dexamethasone implant. Other common adverse events include ocular hypertension, vitreous detachment, cataract, subcapsular cataract, vitreous haemorrhage, visual disturbance, vitreous opacities, eye pain, photopsia, conjunctival oedema, and conjunctival hyperaemia. For full details of side effects and contraindications, see the summary of product characteristics.\n\nThe cost of a 700-microgram implant and applicator is £870.00 (British National Formulary [BNF] edition 61), excluding VAT. One dexamethasone intravitreal implant is administered usually every 6\xa0months in the affected eye and up to six implants may be given. Costs may vary in different settings because of negotiated procurement discounts.', "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of dexamethasone and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer originally submitted evidence of clinical and cost effectiveness for dexamethasone versus best supportive care (observation). Following the consultation after the first Appraisal Committee meeting, the manufacturer submitted a comparison versus bevacizumab. No comparison was made with triamcinolone (Kenalog formulation), which was defined in the scope as a comparator for the treatment of macular oedema following both BRVO and CRVO. Similarly, dexamethasone was not compared with grid laser photocoagulation for non-ischaemic BRVO.\n\nIn the manufacturer's original submission, evidence of clinical effectiveness versus observation was based on two identical randomised, sham-controlled, three-arm parallel-group studies of dexamethasone intravitreal implant in people with macular oedema secondary to BRVO or CRVO. Both studies (GENEVA 008 and GENEVA 009) had an initial 6-month treatment period followed by a 6-month open-label extension in which all patients in both arms of the study who met the re-treatment criteria received a dexamethasone implant. Patients were re-treated if best corrected visual acuity (BCVA) was less than 84 letters or the retinal thickness by optical coherence tomography was more than 250\xa0µm in the central 1\xa0mm macular subfield and, in the investigators' opinion, the procedure would not put the patient at significant risk. All participants had macular oedema for 6\xa0weeks to 12\xa0months before study entry. Participants were allocated in a 1:1:1 ratio to receive a 700-microgram dexamethasone intravitreal implant (n\xa0=\xa0427), a sham implant (n\xa0=\xa0426) or a 350-microgram dexamethasone implant (n\xa0=\xa0414). This appraisal considered the 700-microgram dose which is the only dose which has a UK marketing authorisation. The sham group had a needleless applicator pressed against the conjunctiva actuated with a click. Investigators were masked to study treatment. The results were presented separately for people with retinal vein occlusion (RVO) and the subgroups of people with macular oedema secondary to CRVO, BRVO, BRVO with macular haemorrhage and BRVO with previous laser treatment. People with BRVO who are eligible for laser therapy were not included as a subgroup. The results from the two studies (GENEVA 008 and GENEVA 009) were pooled and this formed the basis of the evidence considered by the Committee, although the data were also available separately for each study in the manufacturer's submission.\n\nThe results of the pooled analysis showed that for the total RVO population 21.3% of the 427 patients in the intention-to-treat population receiving dexamethasone had an improvement in BCVA from baseline of at least 15 letters at day 30 compared with 7.5% of 426 patients in the sham group. This rose to 29.3% at day 60 (compared with 11.3% in the sham group) but returned to 21.8% and 21.5% at day 90 and day 180 respectively (compared with 13.1% and 17.6% in the sham group). The differences were statistically significant at day 30 (p\xa0<\xa00.001), 60 (p\xa0<\xa00.001) and 90 (p\xa0=\xa00.008) but not at day 180 (p\xa0>\xa00.05). The results for patients who were re-treated at day 180 were presented as academic-in-confidence information and are therefore not presented here.\n\nFor the CRVO subgroup, 21.3% of patients in the dexamethasone group had an improvement in BCVA from baseline of at least 15 letters compared with 6.8% in the sham group at day 30 (p\xa0<\xa00.001). At day 60, 28.7% in the dexamethasone group had an improvement in BCVA of at least 15 letters compared with 8.8% in the sham group (p\xa0<\xa00.001). There was no statistically significant difference between the groups at days 90 and 180.\n\nIn the subgroup with BRVO, 21.3% of patients receiving dexamethasone had an improvement in BCVA from baseline of at least 15 letters at day 30 compared with 7.9% in the sham group (p\xa0\xa00.001). The corresponding figures for the subgroup with BRVO with macular haemorrhage were 22.0 % and 8.8 % respectively (p\xa0≤\xa00.001). Both subgroups had statistically significant differences between patients treated with dexamethasone and the sham group at days 60 and 90, but not at day 180. In the subgroup with BRVO and previous laser therapy 22.2% had an improvement in BCVA from baseline of at least 15 letters at day 30 compared with 2.8% in the sham group (p\xa0=\xa00.028). Differences between the dexamethasone and sham groups were also statistically significant at days 60 (p\xa0<\xa00.001), 90 (p\xa0=\xa00.011) and 180 (p\xa0=\xa00.022).\n\nThe cumulative response rate for time to achieve an improvement in BCVA of at least 15 letters from baseline in the study eye was statistically significant for dexamethasone versus sham. The difference in mean change from baseline BCVA, the categorical change from baseline BCVA and proportion of patients with an improvement in BCVA of at least 10 letters from baseline in the study eye were statistically significantly higher for dexamethasone versus sham at days 30, 60, 90 and 180 in the pooled analysis. For all RVO at 180 days, the most common adverse events were raised intraocular pressure, eye pain and ocular hypertension. Intraocular pressure was raised in 25.2 % of patients treated with dexamethasone compared with 1.2 % in the sham group. Of patients treated with dexamethasone, 7.4% had eye pain compared with 3.8% in the sham group. Ocular hypertension was experienced by 4% of patients in the treated group compared with 0.7% in the sham group. Presence of anterior chamber cells and retinal neovascularisation were also reported. Other reported adverse events were retinal detachment, retinal tears and cataract. Safety data for the re-treated population (receiving a second implant by day 180) were presented as academic-in-confidence information and are therefore not presented here.\n\nFollowing the consultation after the first Appraisal Committee meeting, the manufacturer submitted a mixed-treatment comparison of dexamethasone versus bevacizumab. The network of evidence from a systematic review was for BRVO only and included the BRVO data from the GENEVA trials, a non-randomised study by the Branch Vein Occlusion Study group comparing laser with sham treatment (n\xa0=\xa078) and a randomised study by Russo et al. comparing laser with bevacizumab (n\xa0=\xa030). The outcome was improvement in BCVA using standard effect sizes and a fixed-effects model. Dexamethasone was less effective than bevacizumab with a difference in BCVA of 1.74 letters (95% confidence interval [CI] 9.57 to 6.19) when assessed at day 180. However dexamethasone was more effective than bevacizumab when assessed at day 60, with a gain of 2.55 letters (95% CI 5.28 to 10.48).\n\nFor evidence of cost effectiveness, the manufacturer submitted a de novo Markov model that compared treatment with dexamethasone with sham injection in people with macular oedema and vision loss following CRVO or BRVO. Treatment was modelled over a lifetime horizon based on the transition of people between five health states based on the Early Treatment Diabetic Retinopathy Study (EDTRS) measurement of BCVA in the affected eye and death. The worst health state represented visual acuity less than or equal to 38 letters, which equated to severe visual impairment. The best health state was visual acuity of 69 letters or over. The mean BCVA of people in the model was 54 letters, which equates to the second best health state. The patient population was based on data from the GENEVA trials. The model assumed that 90% of people would present with macular oedema in the 'worse-seeing' eye. The model had a cycle length of 1\xa0month for the first 3\xa0months following presentation with RVO, followed by a 3-month cycle in months 4–6 and 6-monthly cycles thereafter. Patients entering the model received dexamethasone or observation. Up to 12 months, transition probabilities were based on pooled patient-level data from the GENEVA studies, including the open-label extension. Beyond 12\xa0months, data were extrapolated from 6- to 12-month data for treatment and re‑treatment and 3- to 6-month data for sham. Treatment duration was assumed to last for 2.5\xa0years in people with BRVO and 3\xa0years in people with CRVO; thereafter visual acuity was assumed to be stable.\n\nThe data inputs for the manufacturer's model included utility values estimated using the Visual Function Questionnaire Utility Index (VFQ-UI) and mapped onto the health states using an algorithm from a study eliciting preferences from the general population. Resource use was identified from a systematic review of the literature and input from clinical specialists. Costs included drug cost and medical resource use (hospital visits, monitoring, costs associated with blindness and the cost of treating adverse events, including raised intraocular pressure, cataracts, retinal tears/detachment). Costs associated with treating adverse events were assumed to increase with the third and fourth treatment.\n\nKey assumptions of the economic model included:\n\n% of people treated would have macular oedema in the 'worse-seeing' eye\n\nthe stabilisation of visual acuity for 2.5\xa0years in people with BRVO and 3\xa0years in people with CRVO\n\nre-treatment at 6-monthly intervals with a maximum of five injections for BRVO and six injections for CRVO (with assumptions over the number of treatments received)\n\na risk of involvement of the other eye of 6.5% in the first year (for those with initial RVO in their 'worse-seeing' eye)\n\nblindness and an excess mortality hazard of 1.54 associated with a BCVA in the 'better-seeing' eye of 38 or fewer letters (measured by the EDTRS).\n\nSensitivity analyses included varying utility estimates, costs, stabilisation of visual acuity at day 360, extrapolation assumptions, mortality, involvement of the other eye, discounting, re-treatment, and people with a worse BCVA on entering the model. Results were presented for the entire RVO population and the subgroups of CRVO, BRVO with macular haemorrhage, BRVO with previous laser therapy, BRVO with a diagnosis of 90 days or less at the time of treatment, and BRVO with a diagnosis of more than 90 days at the time of treatment. In the original sensitivity analyses (manufacturer original submission), the factors having the largest impact on estimates of cost effectiveness for the total population were costs associated with vision loss (costs of residential care and the uptake of residential care), affected eye (proportion of people treated for macular oedema in the 'worse-seeing' eye) and rates of discount.\n\nFollowing the consultation after the first Appraisal Committee meeting, the model was amended by the manufacturer, resulting in a revised base-case ICER. The revised base case used a ratio of 25% outpatient versus 75% day case procedures for administration and an adjustment to the way that the costs of vision loss were applied to the 'better-seeing' eye in patients whose BCVA in the affected eye falls below <\xa020/200. An adjustment of 25% plus a further 10% uplift applied every 6\xa0months was made to the average annual costs associated with severe visual impairment. The model continued to use only the last 3\xa0months of observation data from the GENEVA studies.\n\nIn the revised base case for all RVO, the total incremental cost was £3698 for dexamethasone compared with observation and the incremental QALYs were 0.21. The incremental cost-effectiveness ratio (ICER) was £17,558 per QALY gained for dexamethasone intravitreal implant compared with observation in all RVO. In the revised base case for CRVO, the total incremental cost was £4732 and the incremental QALYs were 0.29. The cost per QALY gained was £16,522 for dexamethasone compared with observation. In the revised base case for BRVO with macular haemorrhage, the total incremental cost was £3119 and the incremental QALYs were 0.18. The incremental cost per QALY gained was £17,741. In the revised base case for BRVO with previous laser therapy, the total incremental cost was £1857 and the incremental QALYs were 0.29. The incremental cost per QALY was £6361 for dexamethasone compared with observation for BRVO with previous laser treatment.\n\nIn addition, the manufacturer also provided additional scenario analyses in response to requests in the appraisal consultation document. Alternative scenario analyses for the re-treatment rate included scenarios in which proportions re-treated were as at day 180 for the five injections after the first injection in people with CRVO, proportions re-treated were as at day 180 for the four injections after the first injection in people with BRVO and proportions re-treated were varied between the two extremes of the base case and the GENEVA studies. When proportions re-treated were as at day 180, the ICERs for CRVO, BRVO with macular haemorrhage and BRVO with previous laser treatment increased from £16,522, £17,741 and £6361 to £22,083, £45,878 and £16,548 per QALY gained respectively. When the mid-point was used, the ICERs for CRVO, BRVO with macular haemorrhage and BRVO with previous laser treatment increased from £16,522, £17,741 and £6361 to £20,257, £31,123 and £10,876 per QALY gained respectively.\n\nFollowing the consultation after the first Appraisal Committee meeting, the manufacturer submitted an additional cost–utility analysis versus bevacizumab for BRVO. This used the mixed-treatment analysis to obtain treatment effects for bevacizumab compared with dexamethasone (a non-significant mean gain of 1.74 letters for bevacizumab compared with dexamethasone at 6\xa0months). Compared with bevacizumab, in the base case for all RVO, the net marginal benefit for dexamethasone (where net marginal benefit is larger than zero and treatment with dexamethasone considered cost effective) was £1927 at £30,000 per QALY gained. The manufacturer submitted a cost-minimisation analysis for dexamethasone versus bevacizumab in CRVO assuming equivalent efficacy for bevacizumab and dexamethasone in CRVO. This was associated with a cost saving of £4463 with dexamethasone which was mainly a result of a lower frequency of injections with dexamethasone compared with bevacizumab and fewer subsequent follow-up visits.\n\nThe manufacturer also submitted a second exploratory cost-minimisation analysis for BRVO and a comparison using ranibizumab as a substitute for bevacizumab. This analysis was submitted as commercial in confidence because of its exploratory nature and so is not presented here.\n\nThe manufacturer also provided more information about the location and extent of macular haemorrhage in the subgroup of patients for whom laser treatment was not considered appropriate because of macular haemorrhage. In the GENEVA trials, the location and extent was assessed by standardised fundus photographs evaluated by trained graders using a standardised grading protocol (the ETDRS macular oedema grading protocol) and masked to patient group. Retinal haemorrhage in the macula was defined when the grader was at least 90% certain that the retinal haemorrhage was present in the grid (macular area).\n\nThe ERG considered the GENEVA trials to be of high quality. Although there was a statistically significant increase in the BCVA based on the mean letter score with the dexamethasone implant, the ERG did not consider this to be clinically significant because most patients did not achieve a 15-letter improvement from baseline. However, a higher proportion had an improvement of at least 10 letters. The effectiveness of the dexamethasone implant appeared to peak at around 60 days. The ERG highlighted that the trial protocol did not allow for early re-treatment and during the trial and open-label follow-on patients received only two injections of dexamethasone. The ERG noted that the main benefit from re-treatment was in patients whose condition had responded during the initial 180-day trial period. The ERG also commented that the number of treatments needed in practice is not known and that clinical opinion estimated a maximum of six.\n\nThe ERG also highlighted that because the trial included a maximum of two dexamethasone treatments, the impact of up to six treatments on the incidence of adverse events was not known. The ERG also expressed concern over the size of the needle which is larger for dexamethasone intravitreal implant than for other treatments. The ERG stated that the main weaknesses in the evidence were lack of long-term follow-up data and data on earlier re-treatment before 180 days.\n\nThe ERG considered the robustness of the manufacturer's original model. It highlighted cost inputs (particularly the cost of dexamethasone administration and the cost of severe visual impairment), structural assumptions in the model (such as the duration of trial data on which to base extrapolation of health states in the treatment and observation arms, assumptions related to the stability of visual acuity in 'resolved' patients, the proportion of people who will present with RVO in their 'worse-seeing' eye and the modelling of fellow eye involvement).\n\nThe ERG considered that a number of the unit costs applied in the model had been overestimated. For example, the cost of administering the dexamethasone intravitreal implant might have been overestimated because the implant could be given on an outpatient basis (£150) but costs were based on day-case (£648) care in the manufacturer's submission. The ERG also estimated that the cost of residential care was £16,999 instead of £23,972 as used in the base case, and the cost of cataract extraction was £789 rather than £965 as in the base-case model.\n\nThe ERG conducted a sensitivity analysis on the unit costs applied in the manufacturer's model and other assumptions related to the extrapolation of effectiveness data beyond the trial. According to the ERG, key uncertainties related to the extrapolation of data remain in the evaluation of cost effectiveness. The likely maximum number of dexamethasone administrations and frequency of re-treatment, the likelihood of resolution, the likelihood of cataract development and extraction, the likelihood of involvement of the other eye and the likelihood of the RVO leading to macular oedema are all important aspects of this uncertainty.\n\nThe ERG highlighted factors in the manufacturer's original sensitivity analyses that appeared to have a particular impact on cost effectiveness. When visual acuity was assumed to be stable after a year with no further dexamethasone treatments (rather than at 2.5\xa0years with BRVO and 3\xa0years with CRVO) the base-case ICER increased from £7368 to £10,764 per QALY gained for the RVO population. When those not treated were all assumed to have the observation transition probabilities applied up to 2.5\xa0years for BRVO and 3\xa0years for CRVO (rather than transition probabilities weighted by proportion of people who were not treated who resolved at day 180 and those who discontinued treatment for other reasons), the base-case ICER increased from £7368 to £24,924 per QALY gained for the RVO population. When the proportions re‑treated were based on the re-treatment rate in the trial (day 180) for the five injections after the first in CRVO (85.7%) and the four injections after the first in BRVO (78.8%), this increased the base-case ICER from £7368 to £19,100 per QALY gained for the RVO population. When there was a decline in vision in 1.5% of patients in each health state, worsening by one health state every 6\xa0months was assumed (compared with visual stability from 2.5\xa0years for BRVO and 3\xa0years for CRVO in the base case). This had a small effect on the base-case ICER, which increased from £7368 to £7685 per QALY gained for the RVO population.\n\nThe ERG also conducted its own additional exploratory analyses on the manufacturer's original economic model which updated the modelling of fellow eye involvement. The ERG compared the manufacturer's model, which included the Weibull function for fellow eye involvement, with the same model with no fellow eye involvement. At the same time, the ERG also varied the proportion of people entering the model with macular oedema in the 'worse-seeing' eye from 90% (as in the manufacturer's model) to 97% (based on the proportion treated in the 'worse-seeing' eye in the trials). The alternative assumption of no fellow eye involvement changed the base-case ICERs for CRVO, BRVO with macular haemorrhage and BRVO with previous laser from £6041, £7987 and dominant to £17,279, £34,277 and £11,905 per QALY gained respectively. The alternative assumption of 97% with macular oedema in the 'worse-seeing' eye changed the base-case ICER for CRVO, BRVO with macular haemorrhage and BRVO with previous laser from £6041, £7987 and dominant to £15,800, £10,206 and dominant per QALY gained respectively.\n\nIn addition, the ERG questioned the way in which 6-month data from the open-label phase were used for the extrapolation of results with dexamethasone treatment and the use of 3- to 6-month data from the trial phase for extrapolation in the observation arm of the original model. After the first Committee meeting the Committee had requested that all data be included in a revised model. When extrapolation was based on 6- to 12-month data from the open-label phase of the trial for dexamethasone treatment and 0- to 6-month data for the observation arm (with 90% of people being treated in the 'worse-seeing' eye) the base-case ICER increased from £6041 to £15,395 per QALY gained for the RVO population.\n\nThe manufacturer submitted two additional original base-case models: one involving structural changes in the modelling of fellow eye involvement, and another which also included lower costs of dexamethasone administration. The revised modelling of fellow eye involvement took account of age with differential survival by collapsing the model into two health states. Without inclusion of lower costs for dexamethasone administration, the revised model was associated with higher ICERs for dexamethasone versus observation of £10,271 per QALY gained for all RVO, £8165 for CRVO, £11,403 for BRVO with macular haemorrhage, and dominance for dexamethasone over observation for BRVO with previous laser treatment. With revised cost assumptions (outpatient appointments rather than day-case costs, reduced costs of residential care and reduced costs of cataract removal), ICERs were reduced to £7616 per QALY gained for all RVO, £6221 for CRVO, £8848 for all BRVO, £8313 for BRVO with macular haemorrhage, and dominance for dexamethasone over observation for BRVO with previous laser treatment.\n\nThe ERG noted that the manufacturer's model applied the cost associated with severe visual impairment to people with visual acuity less than or equal to 38 letters in the 'worse-seeing' eye. The ERG noted that the cost of severe visual impairment should only be applied when both eyes have visual acuity less than 38 letters. The ERG conducted a sensitivity analysis in which the cost of severe visual impairment was applied when both eyes entered the worse state (visual acuity less than 38 letters) and assumed perfect correlation in the BCVA of both eyes and no correlation between the eyes. This increased the base-case ICER for CRVO from £6221 to £15,956 per QALY gained when there was perfect correlation and to £18,091 per QALY gained when there was no correlation between eyes. The corresponding base-case ICERs for BRVO with macular haemorrhage increased from £8313 to £9674 and £21,443 per QALY gained respectively.\n\nFollowing the consultation after the first Appraisal Committee meeting, the ERG noted that the manufacturer's revised analysis of cost effectiveness included several deviations from the analysis requested by the Committee at its first meeting. The manufacturer included administration costs for 75:25 day-case to outpatient procedures whereas the Committee had requested day-case costs for all patients. No bevacizumab vial sharing was included in the base case. Extrapolation from data for the last 3\xa0months of observation in the GENEVA studies was used although the Committee requested that all 6\xa0months of data be used. In addition, severe visual impairment was not modelled as requiring bilateral involvement. Cost of reduction of severe visual impairment was reduced by 25% as a proxy with 10% applied every 6 months. The ERG noted that the 10% was not applied annually and it was unclear from where the 10% figure was derived. When the ERG removed this 10% uplift per cycle, the manufacturer's estimated ICERs for CRVO, BRVO with macular haemorrhage and BRVO with previous laser treatment increased from £16,522, £17,741 and £6361 to £22,831, £23,847 and £12,857 per QALY gained respectively. When the ERG included all 6\xa0months of observational data from the GENEVA studies, the manufacturer's estimated ICERs for CRVO, BRVO with macular haemorrhage and BRVO with previous laser treatment increased from £16,522, £17,741 and £6361 to £25,336, £38,489 and £11,650 per QALY gained respectively.\n\nThe ERG considered that a number of the unit costs applied in the revised model had been overestimated for bevacizumab and the costs used favoured dexamethasone. For example, administration costs were used for 25% outpatient and 75% day-case procedures, there was uncertainty over the calculation of the administration costs for outpatients, a high bevacizumab cost was used and a large number of bevacizumab administrations included. Also, the ERG stated that the frequency of cataracts with steroids was underestimated. When the ERG made adjustments for these costs (a cost of bevacizumab of £50, less frequent bevacizumab administration and follow-up based on the Pan American Collaborative Retina Study group data, and 100% outpatient procedures), the base-case cost minimisation for CRVO, which estimated a cost saving of £4463 with dexamethasone versus bevacizumab, became a cost saving for bevacizumab of £2127 versus dexamethasone.\n\nThe ERG highlighted that there was a considerable amount of data on bevacizumab treatment from trials including bevacizumab, laser therapy and triamcinolone in RVO (992 observed patient-years) and agreed that this type of observational and uncontrolled data generates uncertainty. The ERG concluded that more data could have been included in the network model by using data on triamcinolone treatment.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA229", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dexamethasone, having considered evidence on the nature of macular oedema secondary to RVO and the value placed on the benefits of dexamethasone by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee considered the impact of macular oedema on the everyday life of patients. It heard from patient experts about the problems associated with macular oedema and related vision loss, including difficulties with driving in the dark, taking part in hobbies such as craftwork, picking up small things, reading, using computers and distinguishing objects in crowded places. The patient experts also noted the negative impact of macular oedema on social activities. The patient experts acknowledged that although people may be worried about having an injection in the eye, this is preferable to loss of vision. They also noted that the injections were administered from the side and so could not be seen. The Committee concluded that loss of vision caused by macular oedema secondary to RVO had a negative impact on health-related quality of life and that there was a need for appropriate treatment.\n\nThe Committee considered the decision problem submitted by the manufacturer. It noted that the manufacturer's initial submission compared dexamethasone with best supportive care (observation) alone. This was not consistent with the scope, which defined the comparators for both BRVO and CRVO as triamcinolone acetonide (IVTA; Kenalog formulation or equivalent), bevacizumab and best supportive care, and for non-ischaemic BRVO as grid pattern photocoagulation.\n\nThe Committee considered the use of triamcinolone to treat RVO in UK clinical practice. It heard from clinical specialists that the triamcinolone formulation available in the UK is contraindicated for ocular use (Kenalog formulation); it also heard from the manufacturer of the intraocular formulation of triamcinolone (Trivaris) that it is not available in the UK and would not be marketed anywhere in the world. The Committee concluded that triamcinolone is not available and would not be a relevant comparator for dexamethasone.\n\nThe Committee considered the use of bevacizumab to treat RVO in UK clinical practice. It noted that bevacizumab does not have a UK marketing authorisation for the treatment of RVO and heard from patient experts that they were concerned about the use of any unlicensed treatments for which there was no formal post-marketing surveillance, particularly if there were alternatives that had a UK marketing authorisation. The Committee understood that licensing is not a prerequisite for consideration of a comparator in a NICE appraisal as long as it is in routine use or best practice. It heard from clinical specialists that bevacizumab is currently reasonably widely used in the NHS, being routinely used in some centres, for some RVO cases only in others, and not at all in other centres. It heard from the experts that some clinicians and patients want more information about its long-term efficacy and safety. It also noted consultee comments following consultation confirming the use of bevacizumab by many ophthalmologists in the UK The Committee considered the results of the independent survey supplied by the manufacturer which indicated that a proportion of consultant ophthalmologists use bevacizumab for RVO either regularly or occasionally. It acknowledged that the sample size for the survey was small and could be subject to some selection bias. The Committee concluded that bevacizumab is in routine use to treat RVO in some parts of the UK; and it is therefore relevant for consideration as a comparator to dexamethasone.\n\nThe Committee considered laser photocoagulation as a treatment for BRVO. It noted that the manufacturer restricted the analysed population to those people with BRVO who cannot receive or have already tried and not benefited from laser photocoagulation. The Committee noted that the manufacturer defined those who cannot receive laser photocoagulation as people with macular haemorrhage. It noted comments from clinical specialists and consultees that all cases of RVO have a degree of macular haemorrhage and the decision to treat using laser photocoagulation is relatively subjective. Therefore, the Committee recognised that for a subgroup of people with BRVO with a lesser extent of macular haemorrhage, laser photocoagulation would be a treatment option and that this subgroup is within the licensed indication for dexamethasone. The Committee concluded that because no evidence had been provided for this subgroup, any recommendation for dexamethasone would be optimised to those subgroups of people with BRVO who cannot receive or have already tried and not benefited from laser photocoagulation.\n\n# Clinical effectiveness\n\nThe Committee considered the potential of dexamethasone to offer additional health-related benefits compared with currently available treatment options. It heard from the patient experts about the impact of dexamethasone on their quality of life. Patients advised that after the administration of dexamethasone their sight improved and they were able to resume normal daily activities.\n\nThe Committee considered the evidence for the efficacy of dexamethasone intravitreal implant compared with best supportive care from the GENEVA trials. It noted that the primary outcome was the percentage of patients with an improvement of BCVA of 15 letters or more, which represented a gain of three lines on the EDTRS chart (this enables patients to see letters half the height of those they could see before). The Committee heard from clinical specialists that this represented the gold standard for assessing the effect of treatment on visual acuity, although a gain of 10 letters is also considered to be clinically significant.\n\nThe Committee considered the results from the trials. It first considered the pooled primary outcome data from the GENEVA trials for the entire population with macular oedema following RVO. The Committee noted that dexamethasone is associated with a statistically significant improvement in visual acuity (based on percentage of patients with an improvement of BCVA of 15 letters or more) compared with sham treatment at day 30, 60 and 90, but there was no statistically significant improvement at day 180. The Committee also noted that dexamethasone was associated with a statistically significant improvement in mean change in BCVA at day 30, 60, 90 and 180 for all people with macular oedema following RVO. The Committee also considered the pooled primary outcome data from the GENEVA trials for the CRVO and BRVO subgroups. It noted that dexamethasone was associated with a statistically significantly higher proportion of people gaining BCVA of 15 letters or more compared with sham treatment for CRVO (day\xa030 and 60), BRVO (day 30, 60 and 90), BRVO with macular haemorrhage (day 30, 60 and 90) and at all time points for BRVO with previous laser treatment. These results for the subgroups were similar to those obtained for the combined population with RVO. The Committee concluded that treatment with dexamethasone is clinically effective when compared with best supportive care.\n\nThe Committee considered the evidence for adverse events associated with dexamethasone. These included cataracts, raised intraocular pressure and infection. The Committee noted that evidence was limited by trial duration to adverse events after two treatments with data collected up to 360 days. The Committee discussed the impact of dexamethasone in causing cataracts and the potential issues for people with diabetes, who have a higher risk of developing glaucoma and cataracts. The Committee heard from the clinical specialist that a similar infection risk to that of its comparators would be expected. It also heard that the incidence of raised intraocular pressure was 25% with dexamethasone but that this is usually well managed with eye drops and that 1% of people required laser or surgical procedures for management of elevated intraocular pressure. A higher percentage was likely to need surgery for cataracts according to the number of dexamethasone injections given. The Committee concluded that there were some concerns about the long term safety of dexamethasone treatment because the marketing authorisation is based on a evidence base trial with two re-treatments over 360 days and the manufacturer assumed that up to six treatments would be given and there are limited data on long-term treatment and multiple re-treatment (see section 3.6).\n\nThe Committee considered the evidence for re-treatment from the open-label extension of the GENEVA trials (which was submitted as academic-in-confidence information, as described in section 3.6, and is therefore not presented here). The Committee noted that for the whole population the proportion of patients with an improvement in BCVA of at least 15 letters was higher in the group that received dexamethasone at day 0 and day 180 compared with those who received sham at day 0 and dexamethasone at day 180. The Committee also considered the expected frequency of treatment with dexamethasone at day 180. The Committee heard from the clinical specialist that the criteria for re-treatment were based on the patient's experience with previous treatment (whether their vision had initially improved with treatment but had started to deteriorate), deterioration in visual acuity as assessed by BCVA and the persistence of macular oedema. The Committee was further advised that it is difficult to use a cut-off value for visual acuity that would indicate re-treatment, but that with a loss of five letters it would be appropriate to consider re-treatment. The Committee agreed with the clinical specialist that although the safety data relate to 6-monthly treatment, it is expected that clinicians may re-treat at 4\xa0months in clinical practice, but may not treat more frequently because of the risk of adverse events from the accumulation of dexamethasone in the eye.\n\nThe Committee then considered the clinical effectiveness of dexamethasone compared with bevacizumab. It heard from the clinical specialist that bevacizumab is generally considered by ophthalmologists to be efficacious and safe, although there is some uncertainty as to the optimal dosing schedule, relative effectiveness versus dexamethasone and frequency of treatments. The Committee considered the results of the mixed-treatment comparison provided by the manufacturer in response to requests made at the first Appraisal Committee meeting. It noted that the difference in BCVA was marginally favourable for dexamethasone over bevacizumab at day 60, but that at day 180 the difference in BCVA was marginally favourable for bevacizumab over dexamethasone. However, at both time points the confidence intervals were wide and therefore little certainty could be placed in either of the findings. The Committee noted the ERG's misgivings about the lack of completeness of the mixed-treatment comparison and also that the two cost–utility analyses provided by the manufacturer favoured bevacizumab in terms of efficacy. Nevertheless the Committee considered that a clinical efficacy advantage for dexamethasone over bevacizumab could not be concluded with certainty based on current evidence.\n\nThe Committee considered the mode of delivery and adverse events associated with dexamethasone and bevacizumab, including infection and needle phobia. The clinical specialist informed the Committee that dexamethasone was administered with a larger needle than existing treatments and that dexamethasone was associated with increased intraocular pressure and cataracts. However, more injections of bevacizumab were needed and this presented a greater infection risk. The clinical specialist also informed the Committee that with bevacizumab, which had no agreed protocol for use, sterile endophthalmitis had been reported, but was rare. The Committee concluded that the adverse events associated with dexamethasone were expected to be more severe and more difficult to treat than those associated with bevacizumab.\n\n# Cost effectiveness\n\nThe Committee considered the cost effectiveness of dexamethasone relative to best supportive care. It noted the manufacturer's revised base-case estimate of the ICER for all people with RVO of £17,600 per QALY gained. It understood that this estimate incorporated an assumption that 90% of people would be treated for macular oedema in their 'worst-seeing eye'. It heard from clinical specialists that in practice this proportion would be between 90% and 97%. It further heard from clinical specialists that the manufacturer's estimate of the percentage (6.5%) of people who require treatment for the other eye (fellow eye involvement) was plausible. Patient experts had highlighted the importance of treating the first eye affected, even though overall acuity depends mostly on the 'better-seeing' eye, because RVO and other eye conditions may later affect the critical second eye. The Committee concluded that in this instance it was appropriate to treat the first eye affected.\n\nThe Committee considered the manufacturer's response to requests made at the first Appraisal Committee meeting. It understood that the revised base-case estimate of the ICER incorporated revised assumptions for the setting for the administration of dexamethasone and the cost of care for people with blindness. It further understood that the manufacturer had provided scenario analyses to demonstrate the effect of different re-treatment rates. The Committee noted that the revised base-case ICER did not incorporate the Committee's request that the extrapolation of data for the observation arm should be based on those trial data between 0 and 6\xa0months rather than 3–6\xa0months. The Committee discussed each of these assumptions, and the results of the sensitivity analyses for re-treatment rates, in turn.\n\nThe Committee considered the setting for the administration of dexamethasone. It noted that the revised base case was based on an assumption of 75% of procedures being performed in a day-case unit and 25% in an outpatient clinic, instead of 100% in an outpatient clinic as requested by the Committee at the first Appraisal Committee meeting. The Committee noted comments from consultees that it was reasonable to expect a higher proportion to be performed in a day-case unit while ophthalmologists are gaining familiarity with dexamethasone administration, but that in time it would be expected that most would be performed in an outpatient clinic. The Committee therefore accepted the proportions used by the manufacturer in the revised base case for the setting for the administration of dexamethasone.\n\nThe Committee considered the revised assumption for the cost associated with blindness in the revised base case. It understood that the manufacturer had accepted the rationale for applying this cost to only those people who have both eyes in the worst health state. However, the Committee noted that in the revised base-case estimate, the cost associated with blindness was reduced as a proxy for adjusting the proportion of people who fall into this health state of severe visual impairment in both eyes. The manufacturer adjusted the cost associated with blindness to 25% of the full cost (that is, £1490 instead of £5963), and increased this every 6\xa0months by 10% of the reduced cost (that is, an increase of £149 for each cycle). The Committee accepted this to be a reasonable reduction and concluded that although it would have been preferable to have adjusted the assumptions around the number of people with severe visual impairment in both eyes, the manufacturer's adjustment went some way towards meeting the Committee's request and was considered acceptable.\n\nThe Committee considered the extrapolation of health-state data beyond the trial for the observation arm. It noted the manufacturer's assertion that it was inappropriate to include 0- to 3-month data for BRVO because spontaneous resolution occurs in approximately a quarter of people during that period. The Committee also heard from the manufacturer that although it may be appropriate to include 0- to 3-month data for CRVO, the ERG's exploratory analysis used aggregate data rather than transition probabilities based on individual patient data. The manufacturer stated that this had led to an overestimation of the ICER for CRVO by the ERG. The Committee accepted that spontaneous resolution occurs in BRVO and therefore it was not appropriate to include the first 3\xa0months of data for this subgroup. It further concluded that using individual patient data for the first 6\xa0months may have been relevant for CRVO, but that the increased ICER for CRVO from the ERG's analysis (from £16,500 to £25,300 per QALY gained including a decrease from 0.29 to 0.22 of net total QALYs and an increase in total cost from £4732 to £5469) may be an overestimate. The Committee concluded that 0- to 3-month data for the observation arm of the GENEVA trials for people with CRVO would not have a substantial impact on the overall ICER and therefore accepted the manufacturer's use of 0- to 3-month data in the revised base case.\n\nThe Committee considered the sensitivity analyses around re‑treatment rates provided by the manufacturer in response to requests made by the Committee at the first meeting. The Committee understood that the manufacturer had combined the revised assumptions relating to the setting for administering dexamethasone (see section 4.16) and the costs associated with blindness (see section 4.17) with three scenario analyses for different re-treatment rates. The Committee noted that the re‑treatment scenarios covered the extreme positions of both the base-case estimates (in which re-treatment rates were based on clinical opinion) and those re-treated at day 180 in the GENEVA trials. The Committee noted that for all people with RVO, the ICER varied between £17,600 (including incremental costs of £3698 and incremental QALYs of 0.40) and £34,700 (including incremental costs of £8041 and incremental QALYs of 0.44) per QALY gained for these scenarios respectively. The Committee further noted the manufacturer's scenario analysis in which the re-treatment rates were at the mid-points between the two extremes. With this assumption the ICER for all people with RVO was £26,300 per QALY gained. The Committee accepted the assumption of mid‑point re-treatment rates.\n\nOn the basis of previous discussions (see sections 4.17 to 4.21), the Committee accepted the revised manufacturer's base-case estimate using the mid-point re-treatment rates from the manufacturer's scenario analysis as the most appropriate estimate of the ICER for its consideration. It therefore concluded that the decision regarding the cost effectiveness of dexamethasone compared with best supportive care should be based on the manufacturer's ICER of £26,300 per QALY gained for all people with RVO. The Committee further concluded that this represented an acceptable level of cost effectiveness in this case and that dexamethasone intravitreal implant for the treatment of RVO represents a cost-effective use of NHS resources when compared with best supportive care.\n\nThe Committee considered the cost effectiveness of dexamethasone relative to bevacizumab. It understood that the manufacturer had presented a cost-minimisation approach for CRVO and that the cost assumptions from this approach had been used in both cost–utility analyses (that is, the mixed-treatment comparison, and the indirect comparison using a different anti-VEGF treatment as a proxy for bevacizumab) (see sections 3.14 and 3.15). The Committee therefore considered that its discussion on the relative cost effectiveness of dexamethasone compared with bevacizumab should focus on the assumptions within the manufacturer's cost-minimisation analysis.\n\nThe Committee considered the assumptions in the manufacturer's cost-minimisation analysis between dexamethasone and bevacizumab. It noted comments from the ERG that the cost of bevacizumab had been modelled on the higher of the two estimates from the two suppliers of bevacizumab for eye treatment (that is, £150 per vial rather than £50 per vial). The ERG further highlighted that the manufacturer's estimate of the average number of doses of bevacizumab was 13.75 in the first 2\xa0years, but that the Pan American Collaborative Retina Study Group had found an average of 7 doses over this time period. The Committee heard from the manufacturer that this study was a small cohort follow-up study and may not be representative of UK clinical practice. In addition the manufacturer highlighted to the Committee that the recently reported HORIZON study found that 3.8 injections per year of ranibizumab were insufficient to maintain the clinical effects seen in the first year (ranibizumab, another anti-VEGF, was given monthly in the CRUISE study). Therefore the manufacturer considered 7 doses of bevacizumab over 2\xa0years to be lower than UK clinical practice. The Committee understood that the cost-minimisation analysis also assumed that the setting for the administration of both bevacizumab and dexamethasone would be the same (that is, 75% of procedures would be carried out in a day-case unit and 25% would be carried out in an outpatient clinic). The Committee noted the ERG's view that all anti-VEGF injections are currently administered in an outpatient clinic. The Committee concluded, on the one hand, that the cost of bevacizumab may have been overestimated, and on the other, that there was uncertainty around the number of injections of bevacizumab. The Committee concluded that the assumptions used in the manufacturer's cost-minimisation analysis between dexamethasone and bevacizumab may overestimate the cost of bevacizumab, but considered the cost may not be as low as suggested by the ERG.\n\nThe Committee considered the results of the cost-minimisation analysis. It noted that the manufacturer estimated the cost of dexamethasone treatment to be approximately £4500 less per patient than bevacizumab, but that with the ERG's amendments, dexamethasone could cost up to £2100 more per patient than bevacizumab. On the basis of previous discussion (see section 4.22) the Committee accepted that there was some uncertainty around the assumptions used to calculate the cost of bevacizumab and concluded that it was as likely that dexamethasone might cost more than bevacizumab as it was that dexamethasone might cost less. The Committee therefore concluded that a cost advantage of dexamethasone compared with bevacizumab had not been conclusively demonstrated.\n\nIn summary, the Committee considered the costs and clinical effectiveness of dexamethasone. It considered that comparisons with best supportive care and bevacizumab were both relevant to the NHS. It acknowledged that an incremental analysis in which dexamethasone, bevacizumab and best supportive care were simultaneously assessed was not available. The Committee recognised the difficulties within the evidence base for bevacizumab and commended the manufacturer's attempts to provide a comparison of the relative clinical and cost effectiveness of bevacizumab and dexamethasone. It considered that a clinical efficacy advantage for dexamethasone over bevacizumab could not be concluded with certainty based on presently available evidence and that the adverse events associated with dexamethasone were expected to be more severe and more difficult to treat than those associated with bevacizumab. It also accepted that there was uncertainty around the assumptions used in the cost minimisation comparing dexamethasone with bevacizumab. Based on the manufacturer's revised ICER of £26,300 per QALY gained compared with best supportive care for all people with RVO, the Committee concluded that dexamethasone intravitreal implant represents a cost-effective use of NHS resources and should be offered as an option for the treatment of macular oedema secondary to RVO.\n\nThe Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal that required addressing in the guidance.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA229\n\nAppraisal title: Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion\n\nSection\n\nKey conclusion\n\nDexamethasone intravitreal implant is recommended as an option for the treatment of macular oedema following central retinal vein occlusion.\n\nDexamethasone intravitreal implant is recommended as an option for the treatment of macular oedema following branch retinal vein occlusion when:\n\ntreatment with laser photocoagulation has not been beneficial, or\n\ntreatment with laser photocoagulation is not considered suitable because of the extent of macular haemorrhage.\n\nPeople currently receiving dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion should have the option to continue treatment until they and their clinicians consider it appropriate to stop.\n\n\n\n\n\n\n\n\n\n\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee concluded that triamcinolone (Kenalog formulation) is not available and is not a relevant comparator for dexamethasone.\n\nThe Committee concluded that bevacizumab is in routine use in some parts of the UK to treat macular oedema secondary to retinal vein occlusion (RVO) and is therefore relevant for consideration as a comparator for dexamethasone.\n\nThe Committee recognised that for a subgroup of people with branch retinal vein occlusion (BRVO) with a lesser extent of macular haemorrhage, laser photocoagulation would be a treatment option and that this subgroup is within the licensed indication for dexamethasone. The Committee concluded that because no evidence had been provided for this subgroup, any recommendation for dexamethasone would be restricted to those subgroups of people with BRVO who cannot receive or have already tried and not benefited from laser photocoagulation.\n\nThe Committee concluded that loss of vision caused by macular oedema secondary to RVO had a negative impact on health-related quality of life and that there was a need for appropriate treatment.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nDexamethasone intravitreal implant incorporates a potent corticosteroid that suppresses inflammation in the eye by inhibiting oedema, fibrin deposition, capillary leakage and phagocytic migration.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nDexamethasone intravitreal implant has a marketing authorisation for the treatment of adult patients with macular oedema following either BRVO or central retinal vein occlusion (CRVO).\n\nComparator treatments include best supportive care (observation), bevacizumab, triamcinolone (Kenalog formulation) and laser therapy (BRVO only).\n\n\n\n\n\n\n\n\n\nAdverse effects\n\nThe Committee concluded that there were some concerns about long-term safety of dexamethasone treatment because the marketing authorisation is based on an evidence base trial with two re-treatments over 360 days and the manufacturer assumed that up to six treatments would be given and there are limited data on long-term treatment and multiple re-treatment.\n\nThe Committee concluded that the adverse events associated with dexamethasone were expected to be more severe and more difficult to treat than those associated with bevacizumab.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Evidence Review Group (ERG) considered the GENEVA trials, RCTs of dexamethasone versus sham treatment, to be of high quality.\n\nThe ERG highlighted that there was a considerable amount of data on bevacizumab treatment from trials including bevacizumab, laser therapy and triamcinolone in RVO (992 observed patient-years) and agreed that this type of observational and uncontrolled data generates uncertainty. The Committee recognised the difficulties within the evidence base for bevacizumab and commended the manufacturer's attempts to provide a comparison of the relative clinical and cost effectiveness of bevacizumab and dexamethasone.\n\n\n\n\n\n\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee noted that the primary outcome in the GENEVA trials was the percentage of patients with an improvement of BCVA of 15 letters or more. The Committee heard from clinical specialists that this represented the gold standard for assessing the effect of treatment on visual acuity, although a gain of 10 letters is also considered to be clinically significant.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee considered that a clinical efficacy advantage for dexamethasone over bevacizumab could not be concluded with certainty based on current evidence.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee noted that dexamethasone was associated with a statistically significantly higher proportion of people gaining BCVA of 15 letters or more compared with sham treatment for CRVO (day 30 and 60), BRVO (day 30, 60 and 90), BRVO with macular haemorrhage (day 30, 60 and 90) and at all time points for BRVO with previous laser treatment. These results for the subgroups were similar to those obtained for the combined population with RVO.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nOf the 427 patients in the intention-to-treat population receiving dexamethasone, 21.3% had an improvement in BCVA from baseline of at least 15 letters at day 30 compared with 7.5% of 426 patients in the sham group.\n\nThe Committee also noted that dexamethasone was associated with a statistically significant improvement in mean change in BCVA at day 30, 60, 90 and 180 for all people with macular oedema following RVO compared with sham.\n\nThe Committee noted that the difference in BCVA was marginally favourable for dexamethasone over bevacizumab at day 60, but that at day 180 the difference in BCVA was marginally favourable for bevacizumab over dexamethasone. However, at both time points the confidence intervals were wide and therefore little certainty could be placed in either of the findings. The Committee considered that a clinical efficacy advantage for bevacizumab over dexamethasone could not be concluded with certainty based on current evidence.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee acknowledged that an incremental analysis in which dexamethasone, bevacizumab and best supportive care were simultaneously assessed was not available. The Committee recognised the difficulties within the evidence base for bevacizumab and commended the manufacturer's attempts to provide a comparison of the relative clinical and cost effectiveness of bevacizumab and dexamethasone.\n\n\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee considered the setting for the administration of dexamethasone. It noted that the revised base case was based on an assumption of 75% of procedures being performed in a day-case unit and 25% in an outpatient clinic. The Committee accepted the proportions used by the manufacturer in the revised base case.\n\nThe Committee considered the revised assumption for the cost associated with blindness in the revised base case. The manufacturer adjusted the cost associated with blindness to 25% of the full cost (that is, £1490 instead of £5963), and increased this every 6 months by 10% of the reduced cost (that is, an increase of £149 for each cycle). The Committee accepted this to be a reasonable reduction and concluded that although it would have been preferable to have adjusted the assumptions around the number of people with severe visual impairment in both eyes, the manufacturer's adjustment went some way towards meeting the Committee's request as best they could given the data available and was therefore considered acceptable.\n\nThe Committee considered the extrapolation of health-state data beyond the trial for the observation arm. The Committee accepted that spontaneous resolution occurs in BRVO and therefore it was not appropriate to include the first 3 months of data for this subgroup. The Committee concluded that 0- to 3-month data for the observation arm of the GENEVA trials for people with CRVO would not have a substantial impact on the overall ICER and therefore accepted the manufacturer's use of 0- to 3-month data in the revised base case.\n\nThe Committee considered the sensitivity analyses around re-treatment rates provided by the manufacturer in response to requests made by the Committee at the first meeting. The Committee accepted the assumption of mid-point re-treatment rates.\n\nThe Committee considered the assumptions in the manufacturer's cost-minimisation analysis between dexamethasone and bevacizumab. The Committee concluded that the cost of bevacizumab may have been overestimated, but that there was uncertainty around the number of injections of bevacizumab. The Committee concluded that the assumptions used in the manufacturer's cost-minimisation analysis between dexamethasone and bevacizumab may overestimate the cost of bevacizumab, but the cost may not be as low as suggested by the ERG.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe data inputs for the manufacturer's model included utility values estimated using the Visual Function Questionnaire Utility Index (VFQ-UI) and mapped onto the health states using an algorithm from a study eliciting preferences from the general population.\n\n\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee recognised that for a subgroup of people with BRVO with a lesser extent of macular haemorrhage, laser photocoagulation would be a treatment option and that this subgroup is within the licensed indication for dexamethasone. The Committee concluded that because no evidence had been provided for this subgroup, any recommendation for dexamethasone would be restricted to those subgroups of people with BRVO who cannot receive or have already tried and not benefited from laser photocoagulation.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe cost effectiveness of dexamethasone compared with best supportive care was affected by assumptions around re-treatment.\n\nThe Committee considered that its discussion on the relative cost effectiveness of dexamethasone compared with bevacizumab should focus on the assumptions within the manufacturer's cost-minimisation analysis.\n\n\n\n\n\n\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee concluded that the decision regarding the cost effectiveness of dexamethasone compared with best supportive care should be based on the manufacturer's revised ICER of £26,300 per QALY gained (including an incremental costs of £5937 and incremental QALYs of 0.23) for all people with RVO. The Committee further concluded that this represented an acceptable level of cost effectiveness in this case and that dexamethasone intravitreal implant for the treatment of RVO represents a cost-effective use of NHS resources when compared with best supportive care.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNone\n\n\n\nEnd-of-life considerations\n\nNone\n\n\n\nEqualities considerations and social value judgements\n\nThe Committee concluded that there were no equality issues relating to this appraisal that required addressing in the guidance.\n\n", 'Related NICE guidance': 'Published\n\nRanibizumab and pegaptanib for the treatment of age-related macular degeneration. NICE technology appraisal guidance 155 (2008). Available from www.nice.org.uk/guidance/TA155\n\nGuidance on the use of photodynamic therapy for age-related macular degeneration. NICE technology appraisal guidance 68 (2003). Available from www.nice.org.uk/guidance/TA68\n\nUnder development\n\nNICE is developing the following guidance (details available from www.nice.org.uk):\n\nRanibizumab for the treatment of macular oedema caused by retinal vein occlusion. NICE technology appraisal (publication date to be confirmed).\n\nRanibizumab for the treatment of diabetic macular oedema. NICE technology appraisal (publication date to be confirmed).\n\nPegaptanib sodium for the treatment of diabetic macular oedema. NICE technology appraisal (publication date to be confirmed).', 'Proposed date for review of guidance': 'NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in 2014. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew Dillon\n\nChief Executive\n\nJuly 2011', 'Changes after publication': 'February 2014: implementation section updated to clarify that dexamethasone intravitreal implant is recommended as an option for treating macular oedema secondary to retinal vein occlusion. Additional minor maintenance update also carried out.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour\n responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta229
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Evidence-based recommendations on dexamethasone intravitreal implant (Ozurdex) for treating macular oedema following retinal vein occlusion in adults.
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badc85ccf0ec7b405334146eafc14d153bc47374
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nice
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Open femoro–acetabular surgery for hip impingement syndrome
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Open femoro–acetabular surgery for hip impingement syndrome
# Guidance
This document replaces previous guidance on open femoro–acetabular surgery for hip impingement syndrome (interventional procedure guidance 203).
Current evidence on the efficacy of open femoro–acetabular surgery for hip impingement syndrome is adequate in terms of symptom relief in the short and medium term. With regard to safety, there are well recognised complications. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit with local review of outcomes.
The British Hip Society is establishing a register for open femoro–acetabular surgery for hip impingement syndrome and clinicians should submit details of all patients undergoing this procedure to the register once it is available. One of the main purposes of the register is to provide information about long-term outcomes. It is important that both the register and other studies report details of patient selection to allow clear understanding of these outcomes.
Open femoro–acetabular surgery for hip impingement syndrome involves major surgery with the potential for serious complications and should only be undertaken by surgeons who are well-trained and highly experienced in this type of procedure.# The procedure
# Indications and current treatments
Hip or femoro–acetabular impingement results from abnormalities of the femoral head or the acetabulum. It can be caused by jamming of an abnormally shaped femoral head into the acetabulum, or by contact between the acetabular rim and the femoral head–neck junction. It is believed that it may lead to the development of osteoarthritis.
Symptoms may include restriction of hip-joint movement, pain and 'clicking' of the hip joint. Symptoms are typically exacerbated by hip flexion or prolonged sitting.
The management of hip impingement syndrome includes conservative measures, such as modification of activity and non-steroidal anti-inflammatory medication. Surgical treatment options include arthroscopic hip impingement surgery. Patients with advanced osteoarthritic degeneration may require a total hip replacement.
# Outline of the procedure
The aim of open femoro–acetabular surgery for hip impingement syndrome is to reduce pain and improve the hip-joint range of movement.
The procedure is carried out with the patient under general or regional anaesthesia using an incision on the outer side of the thigh. The hip is dislocated to expose the femoral head and acetabulum, using a method that preserves the blood supply to the femoral head. Non-spherical sections of the femoral head, prominent sections of the anterior femoral neck and excessive acetabular rim are removed. After femoral and acetabular osteoplasty are completed, the hip is relocated, residual impingement is evaluated and further surgery performed as necessary. If impingement is due to a retroverted acetabulum, periacetabular osteotomy may also be performed.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at guidance.nice.org.uk/IPG403/Overview_Final
# Efficacy
In a non-randomised controlled study of 52 patients comparing open femoro–acetabular impingement surgery with labral refixation (35 hips) versus open femoro–acetabular impingement surgery with labral resection (25 hips), mean Merle d'Aubigné pain scores improved compared with baseline in both groups, but significantly more so in the refixation group (73%) compared with the resection group (59%) at a median 2-year follow-up (absolute figures not stated, p = 0.0009). 'Clinical status' based on mean Merle d'Aubigné score (a scale of 4–18 points; higher score indicates better hip function) improved from 12 at baseline in both groups to 17 and 15 for the refixation versus removal, respectively at 2-year follow-up.
A case series of 46 patients (48 hips) reported that group mean Merle d'Aubigné score improved from 13.0 points at baseline to 16.8 points at 38-month follow-up (p < 0.001).
A case series of 94 patients (96 hips) reported that group mean Harris hip score (0–100 scale; higher scores better) improved from 67 points at baseline to 91 points at a mean 26-month follow-up (p < 0.0001).
A case series of 34 patients (37 hips) reported that group mean University of California, Los Angeles activity score (1–10 scale; higher scores better) improved from 4.8 points at baseline to 7.5 points at a mean 3.1-year follow-up (p < 0.001).
The case series of 46 patients reported radiographic restoration of normal hip offset in 100% (46/46) of patients.
The Specialist Advisers listed key efficacy outcomes as pain relief and delayed progression to osteoarthritis.
# Safety
The case series of 213 hips reported no clinical or radiographic evidence of avascular necrosis of the femoral head at a minimum 2-year follow-up. A case series of 94 patients (96 hips) reported no femoral head osteonecrosis at a mean 26-month follow-up.
Heterotopic ossification was reported in 37% (79/213) of hips in the case series of 213 hips at a minimum follow-up of 2 years (clinical sequelae not described).
Postoperative partial neurapraxia of the sciatic nerve was found in less than 1% (2/213) of hips in a case series of 213 hips (both resolved by 6-month follow-up).
Painful internal fixation requiring screw removal occurred in 26% (9/34) of patients in the case series of 34 patients at a mean follow-up of 8 months.
In the case series of 22 patients (29 hips) subsequent surgery was required in 12% (3/26) of hips, 1 procedure each for postoperative loss of reduction, correction of posteroinferior impingement, and recurrent anterior impingement (timing of events not stated).
The Specialist Advisers listed adverse events known from reports or experience to include vascular insult to the femoral head causing necrosis (rare but serious), fracture, non-union of trochanteric fragment, trochanteric bursitis, nerve injury, infection, deep vein thrombosis and accelerated osteoarthritis. They considered theoretical adverse events to include postoperative dislocation, haemorrhage and haematoma.# Further information
For related NICE guidance see www.nice.org.uk
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG403/publicinfo
# Changes after publication
August 2013: Minor maintenance
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{'Guidance': 'This document replaces previous guidance on open femoro–acetabular surgery for hip impingement syndrome (interventional procedure guidance 203).\n\nCurrent evidence on the efficacy of open femoro–acetabular surgery for hip impingement syndrome is adequate in terms of symptom relief in the short and medium term. With regard to safety, there are well recognised complications. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit with local review of outcomes.\n\nThe British Hip Society is establishing a register for open femoro–acetabular surgery for hip impingement syndrome and clinicians should submit details of all patients undergoing this procedure to the register once it is available.\xa0One of the main purposes of the register is to provide information about long-term outcomes. It is important that both the register and other studies report details of patient selection to allow clear understanding of these outcomes.\n\nOpen femoro–acetabular surgery for hip impingement syndrome involves major surgery with the potential for serious complications and should only be undertaken by surgeons who are well-trained and highly experienced in this type of procedure.', 'The procedure': "# Indications and current treatments\n\nHip or femoro–acetabular impingement results from abnormalities of the femoral head or the acetabulum. It can be caused by jamming of an abnormally shaped femoral head into the acetabulum, or by contact between the acetabular rim and the femoral head–neck junction. It is believed that it may lead to the development of osteoarthritis.\n\nSymptoms may include restriction of hip-joint movement, pain and 'clicking' of the hip joint. Symptoms are typically exacerbated by hip flexion or prolonged sitting.\n\nThe management of hip impingement syndrome includes conservative measures, such as modification of activity and non-steroidal anti-inflammatory medication. Surgical treatment options include arthroscopic hip impingement surgery. Patients with advanced osteoarthritic degeneration may require a total hip replacement.\n\n# Outline of the procedure\n\nThe aim of open femoro–acetabular surgery for hip impingement syndrome is to reduce pain and improve the hip-joint range of movement.\n\nThe procedure is carried out with the patient under general or regional anaesthesia using an incision on the outer side of the thigh. The hip is dislocated to expose the femoral head and acetabulum, using a method that preserves the blood supply to the femoral head. Non-spherical sections of the femoral head, prominent sections of the anterior femoral neck and excessive acetabular rim are removed. After femoral and acetabular osteoplasty are completed, the hip is relocated, residual impingement is evaluated and further surgery performed as necessary. If impingement is due to a retroverted acetabulum, periacetabular osteotomy may also be performed.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at guidance.nice.org.uk/IPG403/Overview_Final\n\n# Efficacy\n\nIn a non-randomised controlled study of 52 patients comparing open femoro–acetabular impingement surgery with labral refixation (35 hips) versus open femoro–acetabular impingement surgery with labral resection (25 hips), mean Merle d'Aubigné pain scores improved compared with baseline in both groups, but significantly more so in the refixation group (73%) compared with the resection group (59%) at a median 2-year follow-up (absolute figures not stated, p = 0.0009). 'Clinical status' based on mean Merle d'Aubigné score (a scale of 4–18 points; higher score indicates better hip function) improved from 12 at baseline in both groups to 17 and 15 for the refixation versus removal, respectively at 2-year follow-up.\n\nA case series of 46 patients (48\xa0hips) reported that group mean Merle d'Aubigné score improved from 13.0\xa0points at baseline to 16.8 points at 38-month follow-up (p\xa0<\xa00.001).\n\nA case series of 94 patients (96 hips) reported that group mean Harris hip score (0–100 scale; higher scores better) improved from 67 points at baseline to 91 points at a mean 26-month follow-up (p\xa0< 0.0001).\n\nA case series of 34 patients (37 hips) reported that group mean University of California, Los Angeles activity score (1–10 scale; higher scores better) improved from 4.8 points at baseline to 7.5 points at a mean 3.1-year follow-up (p\xa0<\xa00.001).\n\nThe case series of 46 patients reported radiographic restoration of normal hip offset in 100% (46/46) of patients.\n\nThe Specialist Advisers listed key efficacy outcomes as pain relief and delayed progression to osteoarthritis.\n\n# Safety\n\nThe case series of 213 hips reported no clinical or radiographic evidence of avascular necrosis of the femoral head at a minimum 2-year follow-up. A case series of 94 patients (96 hips) reported no femoral head osteonecrosis at a mean 26-month follow-up.\n\nHeterotopic ossification was reported in 37% (79/213) of hips in the case series of 213 hips at a minimum follow-up of 2 years (clinical sequelae not described).\n\nPostoperative partial neurapraxia of the sciatic nerve was found in less than 1% (2/213) of hips in a case series of 213 hips (both resolved by 6-month follow-up).\n\nPainful internal fixation requiring screw removal occurred in 26% (9/34) of patients in the case series of 34 patients at a mean follow-up of 8 months.\n\nIn the case series of 22 patients (29 hips) subsequent surgery was required in 12% (3/26) of hips, 1 procedure each for postoperative loss of reduction, correction of posteroinferior impingement, and recurrent anterior impingement (timing of events not stated).\n\nThe Specialist Advisers listed adverse events known from reports or experience to include vascular insult to the femoral head causing necrosis (rare but serious), fracture, non-union of trochanteric fragment, trochanteric bursitis, nerve injury, infection, deep vein thrombosis and accelerated osteoarthritis. They considered theoretical adverse events to include postoperative dislocation, haemorrhage and haematoma.", 'Further information': "For related NICE guidance see www.nice.org.uk\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG403/publicinfo\n\n# Changes after publication\n\nAugust 2013: Minor maintenance"}
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https://www.nice.org.uk/guidance/ipg403
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7ac3b3cba5676dab3fc25994c98d5787def76e8a
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nice
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Percutaneous cryotherapy for renal cancer
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Percutaneous cryotherapy for renal cancer
# Guidance
This document replaces previous guidance on cryotherapy for renal cancers (interventional procedure guidance 207).
Current evidence on the efficacy and safety of percutaneous cryotherapy for renal cancer is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.
This procedure should only be offered after assessment by a specialist urological cancer multidisciplinary team.
NICE encourages collection and publication of data on the outcomes of this procedure in the long term. Further research should compare the long-term outcomes of cryotherapy with those of other treatments for renal cancer.# The procedure
# Indications and current treatments
The most common type of renal cancer in adults is renal cell carcinoma. Symptoms and signs may include pain and haematuria. Some tumours are identified when symptomatic, through imaging. Establishing the diagnosis and assessing the prognosis of some renal tumours may be difficult.
Treatment options include partial or total nephrectomy (laparoscopic or open), and ablation techniques including radiofrequency ablation (RFA).
# Outline of the procedure
Percutaneous cryotherapy for renal cancer is carried out with the patient under general anaesthesia, or local anaesthesia and sedation. A biopsy of the tumour may be carried out. With suitable imaging guidance, a probe is inserted percutaneously into the tumour to deliver a coolant at subfreezing temperatures, creating an ice ball around the probe's tip, which destroys the surrounding tissues. Each freeze cycle is followed by a heat (thaw) cycle, allowing removal of the probe. Two freeze–thaw cycles are usually performed to ablate the tumour (additional cycles may also be performed if necessary), aiming to extend the ice ball approximately 1 cm beyond tumour margins. More than 1 probe can be used.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/934/overview
# Efficacy
A non-randomised comparative study of 93 patients treated by laparoscopic or percutaneous cryotherapy reported no disease-related deaths at 22-month and 12-month follow-up respectively.
A meta-analysis of non-randomised comparative studies and case series including a total of 1375 tumours reported that significantly fewer patients treated by cryotherapy had local tumour progression (defined as radiographic or pathological evidence of residual disease after initial treatment, regardless of time to recurrence) compared with those treated by RFA at a mean follow-up of 18.7 months (5% vs 13% , p < 0.0001). Repeat ablations were required in fewer patients treated by cryotherapy than RFA (1% vs 9% , p < 0.0001). Fewer patients treated by cryotherapy had progression to metastatic disease but this was not significant (1% vs 3% , p = 0.06).
A non-randomised comparative study of 93 patients reported that 10% (2/20) of patients who had percutaneous cryoablation and 4% (2/56) of patients treated by laparoscopic cryotherapy had persistently enhancing lesions at early follow-up suggesting incomplete ablation (all patients had further treatment; 3 patients were treated by percutaneous cryotherapy and 1 by radical nephrectomy).
A non-randomised comparative study of 90 patients reported 'primary effectiveness' (complete ablation of tumour after the initial procedure) in 90% (27/30) of patients treated by percutaneous cryotherapy and 93% (56/60) of patients treated by laparoscopic cryotherapy (p = 0.68).
In a non-randomised comparative study of 66 patients treated by percutaneous or laparoscopic cryotherapy, further treatment was needed in 25% (5/20) and 4% (2/52) of patients respectively (p = 0.015).
In the non-randomised comparative study of 93 patients treated by percutaneous cryotherapy (n = 20), or laparoscopic cryotherapy (n = 59), or RFA (n = 15), patients returned to work within 6.2, 17.5 and 4.0 days respectively. The difference between the percutaneous RFA and laparoscopic cryotherapy groups was significant (p < 0.05).
The Specialist Advisers listed key efficacy outcomes as success rate of cryoablation based on radiological criteria, retreatment rates, recurrence, and disease-specific and overall survival.
# Safety
The non-randomised comparative study of 90 patients reported no major complications in patients treated by percutaneous cryotherapy and 3 major complications in patients treated by laparoscopic cryotherapy (severe respiratory distress in 1, intraoperative bowel injury in 1, and postoperative atrial fibrillation in 1).
The non-randomised comparative study of 37 patients reported that haemorrhage requiring transfusion occurred in 11% (2/18) of patients treated by percutaneous cryotherapy and 28% (5/20) of patients treated by laparoscopic cryotherapy.
The non-randomised comparative study of 93 patients reported significant postoperative prolonged neurapraxia (not otherwise described) in 2 patients treated by percutaneous cryotherapy.
The non-randomised comparative study of 90 patients reported that 4 patients treated by percutaneous cryotherapy had minor procedural complications, including symptomatic perinephric haematoma, asymptomatic and self-limited urine leak identified at imaging, self-limited flank paraesthesia and neuralgia, and intercostal neurapraxia.
The Specialist Advisers stated that the most common complication is bleeding. They stated that ureteric, bowel and pancreatic injury are rare complications. They considered theoretical adverse events to include pneumothorax and thermal injury to the skin.
# Other comments
The Committee noted that most studies of percutaneous cryotherapy for renal cancer included both malignant and benign lesions, and that histology was unknown for many of the lesions treated by the procedure. This made interpretation of the evidence difficult.
The Committee was advised that the diagnosis of malignancy is typically made by imaging, and that histology is generally not available to confirm the diagnosis; this contrasts with treatment by any kind of nephrectomy which provides tissue for histological diagnosis.
The Committee noted that the maximum renal tumour size for which cryotherapy is recommended is approximately 4 cm (small, stage I tumours) but it has been used recently in larger tumours.# Further information
For related NICE guidance see www.nice.org.uk
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG402/publicinfo
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{'Guidance': 'This document replaces previous guidance on cryotherapy for renal cancers (interventional procedure guidance 207).\n\nCurrent evidence on the efficacy and safety of percutaneous cryotherapy for renal cancer is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nThis procedure should only be offered after assessment by a specialist urological cancer multidisciplinary team.\n\nNICE encourages collection and publication of data on the outcomes of this procedure in the long term. Further research should compare the long-term outcomes of cryotherapy with those of other treatments for renal cancer.', 'The procedure': "# Indications and current treatments\n\nThe most common type of renal cancer in adults is renal cell carcinoma. Symptoms and signs may include pain and haematuria. Some tumours are identified when symptomatic, through imaging. Establishing the diagnosis and assessing the prognosis of some renal tumours may be difficult.\n\nTreatment options include partial or total nephrectomy (laparoscopic or open), and ablation techniques including radiofrequency ablation (RFA).\n\n# Outline of the procedure\n\nPercutaneous cryotherapy for renal cancer is carried out with the patient under general anaesthesia, or local anaesthesia and sedation. A biopsy of the tumour may be carried out. With suitable imaging guidance, a probe is inserted percutaneously into the tumour to deliver a coolant at subfreezing temperatures, creating an ice ball around the probe's tip, which destroys the surrounding tissues. Each freeze cycle is followed by a heat (thaw) cycle, allowing removal of the probe. Two freeze–thaw cycles are usually performed to ablate the tumour (additional cycles may also be performed if necessary), aiming to extend the ice ball approximately 1\xa0cm beyond tumour margins. More than 1 probe can be used.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/934/overview\n\n# Efficacy\n\nA non-randomised comparative study of 93 patients treated by laparoscopic or percutaneous cryotherapy reported no disease-related deaths at 22-month and 12-month follow-up respectively.\n\nA meta-analysis of non-randomised comparative studies and case series including a total of 1375 tumours reported that significantly fewer patients treated by cryotherapy had local tumour progression (defined as radiographic or pathological evidence of residual disease after initial treatment, regardless of time to recurrence) compared with those treated by RFA at a mean follow-up of 18.7 months (5% [31/600] vs 13% [100/775], p\xa0<\xa00.0001). Repeat ablations were required in fewer patients treated by cryotherapy than RFA (1% [8/600] vs 9% [66/775], p\xa0< 0.0001). Fewer patients treated by cryotherapy had progression to metastatic disease but this was not significant (1% [6/600] vs 3% [19/775], p = 0.06).\n\nA non-randomised comparative study of 93 patients reported that 10% (2/20) of patients who had percutaneous cryoablation and 4% (2/56) of patients treated by laparoscopic cryotherapy had persistently enhancing lesions at early follow-up suggesting incomplete ablation (all patients had further treatment; 3 patients were treated by percutaneous cryotherapy and 1 by radical nephrectomy).\n\nA non-randomised comparative study of 90 patients reported 'primary effectiveness' (complete ablation of tumour after the initial procedure) in 90% (27/30) of patients treated by percutaneous cryotherapy and 93% (56/60) of patients treated by laparoscopic cryotherapy (p = 0.68).\n\nIn a non-randomised comparative study of 66 patients treated by percutaneous or laparoscopic cryotherapy, further treatment was needed in 25% (5/20) and 4% (2/52) of patients respectively (p = 0.015).\n\nIn the non-randomised comparative study of 93 patients treated by percutaneous cryotherapy (n = 20), or laparoscopic cryotherapy (n = 59), or RFA (n = 15), patients returned to work within 6.2, 17.5 and 4.0 days respectively. The difference between the percutaneous RFA and laparoscopic cryotherapy groups was significant (p < 0.05).\n\nThe Specialist Advisers listed key efficacy outcomes as success rate of cryoablation based on radiological criteria, retreatment rates, recurrence, and disease-specific and overall survival.\n\n# Safety\n\nThe non-randomised comparative study of 90 patients reported no major complications in patients treated by percutaneous cryotherapy and 3 major complications in patients treated by laparoscopic cryotherapy (severe respiratory distress in 1, intraoperative bowel injury in 1, and postoperative atrial fibrillation in 1).\n\nThe non-randomised comparative study of 37 patients reported that haemorrhage requiring transfusion occurred in 11% (2/18) of patients treated by percutaneous cryotherapy and 28% (5/20) of patients treated by laparoscopic cryotherapy.\n\nThe non-randomised comparative study of 93 patients reported significant postoperative prolonged neurapraxia (not otherwise described) in 2 patients treated by percutaneous cryotherapy.\n\nThe non-randomised comparative study of 90 patients reported that 4 patients treated by percutaneous cryotherapy had minor procedural complications, including symptomatic perinephric haematoma, asymptomatic and self-limited urine leak identified at imaging, self-limited flank paraesthesia and neuralgia, and intercostal neurapraxia.\n\nThe Specialist Advisers stated that the most common complication is bleeding. They stated that ureteric, bowel and pancreatic injury are rare complications. They considered theoretical adverse events to include pneumothorax and thermal injury to the skin.\n\n# Other comments\n\nThe Committee noted that most studies of percutaneous cryotherapy for renal cancer included both malignant and benign lesions, and that histology was unknown for many of the lesions treated by the procedure. This made interpretation of the evidence difficult.\n\nThe Committee was advised that the diagnosis of malignancy is typically made by imaging, and that histology is generally not available to confirm the diagnosis; this contrasts with treatment by any kind of nephrectomy which provides tissue for histological diagnosis.\n\nThe Committee noted that the maximum renal tumour size for which cryotherapy is recommended is approximately 4\xa0cm (small, stage I tumours) but it has been used recently in larger tumours.", 'Further information': "For related NICE guidance see www.nice.org.uk\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG402/publicinfo"}
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https://www.nice.org.uk/guidance/ipg402
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nice
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Ambulight PDT for the treatment of non-melanoma skin cancer
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Ambulight PDT for the treatment of non-melanoma skin cancer
Evidence-based recommendations on Ambulight PDT for the treatment of non-melanoma skin cancer.
# Recommendations
NICE medical technologies guidance addresses specific technologies notified to NICE by manufacturers. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This 'case' is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.
Ambulight PDT offers a means of delivering photodynamic therapy (PDT) for patients with small non-melanoma skin cancers in an ambulatory care setting, including patients' homes, and its use may be associated with less pain than conventional PDT. However, the case for routine use of Ambulight PDT in achieving a more efficient service is not supported by the evidence submitted by the manufacturer. The quantity of clinical evidence on its use is limited and the cost consequences of adoption, when compared with conventional PDT, ranged from a saving (per patient) of £195 to a cost increase of £536. NHS organisations should take this into account, alongside other features of the technology, when considering whether to use Ambulight PDT.# The technology
# Description of the technology
The purpose of the Ambulight PDT device (Ambicare Health Ltd) is to deliver PDT to treat non-melanoma skin cancer in an ambulatory setting, including patients' homes in selected cases.
Ambulight PDT comprises a small single-use light-emitting device (containing its own red light source generated by a diffuser and a series of light-emitting diodes), which is connected by a lead to a pocket-sized battery. This light-emitting device sticks to the skin using a disposable plaster, 3 cm in diameter, worn directly over the treatment site. The battery can be carried in a pocket, attached to a belt or worn around the neck. The device is designed to treat single lesions that are smaller than 2.4 cm in diameter.
Before delivering Ambulight PDT, a photosensitising pro-drug is applied as a topical cream to the treatment site, where it is absorbed and metabolised to the active photosensitiser over a 3-hour period. Photodynamic therapy is then delivered for 3 hours. The light source emits the same dose and wavelength of light as in conventional PDT but the intensity is reduced and the light is administered over a longer period of time.
Depending on the indication, one or two treatments with Ambulight PDT are needed to complete a course (with separate cream applications and light-emitting devices if two treatments are needed). Each treatment lasts 6 hours (3 hours for drug absorption and 3 hours for delivering PDT). As with conventional PDT, these two treatments are carried out between 1 week and 1 month apart.
The device is worn for the full 6 hours of treatment. It is programmed so that the light source does not turn itself on until 3 hours after the battery pack is switched on, to allow for the drug absorption. A flashing light indicates, after a further 3 hours, when treatment is complete. The device switches itself off and can be removed by the patient.
Ambulight PDT is designed to enable therapy to be delivered in an ambulatory care setting, which can include the patient's home. This can avoid the need for a hospital appointment to receive the PDT, reducing travel for some patients. It is claimed that in some cases the device may allow patients to continue with their normal daily activities. It is also claimed that using Ambulight PDT may reduce pain compared with conventional PDT.
The average selling price of Ambulight PDT, as stated in the manufacturer's submission, is £200 with a price range of £180–250. The cost of Ambulight PDT may vary because of differences in purchasing contracts.
# Current management
Current practice in the management of non-melanoma skin cancer in secondary care (specifically those lesions intended for treatment with Ambulight PDT) varies substantially. For patients for whom treatment is considered suitable, options are standard hospital-based PDT, topical chemotherapy, topical immunomodulators, surgical excision, curettage, cryotherapy or radiotherapy, but the treatment of choice varies between hospitals. Some patients receive no treatment for their small low-risk skin lesions, based on clinical decisions that there is insufficient risk of progression or harm.
Conventional PDT is currently offered in some out-of-hospital settings; these may be in primary care, secondary care or in the community, but not in patients' homes.# Clinical evidence
# Summary of clinical evidence
The main clinical outcomes for the treatment of non-melanoma skin cancer with Ambulight PDT are tumour response rate (including recurrence rates or need for additional treatment), pain during treatment and adverse events. Full details of all clinical outcomes considered by the Committee are available in the assessment report.
The Committee saw data on a total of 28 patients who were treated with Ambulight PDT.
Attili et al. (2009) described a pilot study of 12 patients (8 patients with Bowen's disease and 4 patients with basal-cell carcinoma) with a median lesion diameter of 1.1 cm (range 0.6–1.9 cm) treated using a prototype of the Ambulight PDT device with 5-aminolevulinic acid as the photosensitiser. A complete response was reported in 75% (9/12) of patients at 6-month follow-up. At 12 months, 58% (7/12) of patients had complete tumour response (4 patients had peripheral margin failure; 1 had residual nodular component). In all patients for whom treatment was unsuccessful, the lesion size was greater than 1.5 cm in diameter.
Attili et al. (2009) reported pain immediately after treatment that was recorded using a numerical rating scale (1–10; higher score indicates worse pain). All 12 patients reported a pain score of 2 or less (range 0–2). No patients needed pain relief in the form of local anaesthesia or cool air treatment during therapy. One patient who reported excessive pain during previous PDT commented on the lack of discomfort with Ambulight PDT. These scores were compared retrospectively with those of 50 patients who had received conventional PDT using an inorganic light-emitting diode static lamp source (dose 75 J/cm2). The static lamp cohort had a median numerical rating scale score of 6 (range 1–10). Of the 50 patients, 11 needed local analgesia and all needed cool air treatment.
The manufacturer's submission presented data on the use of a light-emitting diode light source and methyl aminolevulinate cream (Metvix). These data included five patients with single lesions treated using Ambulight PDT and 11 patients with multiple lesions whose lesions were treated with a range of PDT treatments (at least one lesion site was treated with Ambulight PDT; other sites were treated using conventional PDT or different light-emitting diode sources). Pain immediately after treatment was recorded on a visual analogue scale (1–10; higher score indicates worse pain). For single lesions treated using Ambulight PDT the pain score ranged from 1.5 to 7. For patients with multiple lesions treated using Ambulight PDT the pain scores ranged from 0 to 8. For multiple lesions treated with other PDT, pain scores ranged from 1.5 to 10. Insufficient data were available for analysing summary statistics (mean or median) for Ambulight PDT compared with conventional PDT.
No adverse events have been reported with Ambulight PDT.
# Committee considerations
The Committee considered that there was some evidence for efficacy of Ambulight PDT but that the quantity of evidence on its use was very limited. The Committee considered that more clinical evidence is needed.
The Committee noted that the manufacturer of this technology claims that it is equivalent to, but not more effective than, conventional PDT. The Committee also noted that one of the claimed advantages over conventional PDT is that it can be used in ambulatory settings, including patients' homes in selected cases. The Committee considered that the ambulatory nature of the device offers the potential to increase convenience of treatment for patients with impaired mobility. It also noted that patients could be treated with Ambulight PDT who might otherwise have difficulty accessing PDT.
The manufacturer's submission described various techniques that have been developed to reduce pain during PDT and presented studies demonstrating that reduced irradiance is associated with reduced pain. The Committee considered that there was evidence to suggest that treatment with Ambulight PDT may cause less pain than conventional PDT in some patients.
The Committee recognised that patient preference plays a significant part in the decision to treat low-risk non-melanoma skin cancer.
Small non-melanoma skin cancers are common and most have a low risk of progression, but because of incomplete coverage of case reporting, the true incidence is unknown. The Committee was advised that practice varies substantially when deciding on treatment for these lesions and that local service configuration influences the range of treatments that can be offered. Some patients are offered one of a range of treatments including topical chemotherapy, surgical excision, radiotherapy or standard hospital-based PDT, whereas others are not offered treatment. There are no good studies comparing the range of possible treatments.
The Committee debated the usefulness of a device that treats only single lesions when many patients have multiple lesions needing treatment, and the fact that Ambulight PDT is suitable only for treating lesions of a small size. It also noted the differing views of Expert Advisers about the significance of pain as an issue with conventional PDT.
The Committee recognised that Ambulight PDT is a new device at a relatively early stage of development with a consequently small evidence base but that the manufacturer is collecting more data. The Committee considered the available clinical evidence and judged that it was insufficient to support the case for routinely adopting Ambulight PDT for treating non-melanoma skin cancers in the NHS in place of current management.
The Committee recognised that Ambulight PDT is a current treatment option for carefully selected patients.# NHS considerations
# System impact
Ambulight PDT allows PDT to be delivered in a community setting. This could reduce the demand on NHS transport services and hospital outpatient services as well as improving access to treatment and potentially reducing waiting times.
NICE cancer service guidance CSGSTIM Improving outcomes for people with skin tumours including melanoma (update): the management of low-risk basal cell carcinomas in the community states that the management of basal cell carcinomas imposes a significant workload on both primary- and secondary-care service. It recommends that treatment and care should take into account patients' needs and preferences, and recognises that there is a need to provide high-quality care close to a patient's home. A device that offers ambulatory PDT could be an attractive treatment option for some patients who express a strong desire to continue with their normal daily activities while receiving treatment.
# Committee considerations
The Committee recognised the potential for the system advantages on which the cost models described in section 5 were based.
The Committee considered that the use of Ambulight PDT might make additional staff training necessary for accurate diagnosis and treatment delivery, and need additional infrastructure set up within ambulatory care settings. Although these would have initial outlay costs, there may be cost savings once a service is established.
The Committee was advised that there is substantial variation in practice and that PDT is used much less in some hospitals than in others; this made consideration of any changes in service provision more complicated. Ambulight PDT is a current treatment option for non-melanoma skin cancer for carefully selected patients.# Cost considerations
# Cost impact evidence
The manufacturer's cost analysis evaluated the costs of service configuration in which Ambulight PDT might be used, compared with conventional hospital-based PDT using a static lamp, for a complete treatment cycle, which consists of two treatments 1 week apart. In the cost analysis it was assumed that patients had already been diagnosed with non-melanoma skin cancer, so no costs associated with the diagnostic stage of management were included. The analysis did not include any costs associated with treatment efficacy or adverse events.
Four clinical scenarios were presented in which a GP with special interest in dermatology delivered PDT in the community with Ambulight PDT. These scenarios were presented for comparison against conventional hospital-based PDT using a static lamp:
A GP operating in their own practice.
A GP operating in a specialist centre.
A GP operating in an outpatient clinic in secondary care.
A nurse hybrid service model (nurses delivering treatment in the patient's home after diagnosis by a GP with specialist interest in dermatology).
The costs of the first three of these clinical scenarios for service delivery were calculated using the analysis of the potential economic impact of the NICE cancer service guidance CSGSTIM (2006 and 2010) on skin cancer. The manufacturer did not include overheads or GP costs for the nurse hybrid service model.
The cost analysis did not include any impact on staff costs for additional training or for support for patients. Patients may need support and advice because Ambulight PDT has the potential to be used while they continue with daily activities, outside a clinical setting.
There was significant uncertainty in the costs presented in the submission so it was difficult to determine the likely cost difference in practice. The cost difference between PDT using Ambulight PDT and conventional PDT using a static lamp presented in the manufacturer's submission ranged from a cost saving of £195 to a cost increase of £536. The cost difference was dependent on the clinical scenario used for delivering PDT with Ambulight PDT and the method of calculating the cost of each scenario.
The cost analysis presented cost savings associated with Ambulight PDT in the form of removing the need for staff to administer illumination from a static machine, room hire for the illumination period, and anaesthesia, which could translate into resource savings.
# Committee considerations
The Committee considered that the cost models submitted by the manufacturer were complicated and difficult to interpret. The range of cost consequences was wide, with some showing an increase in cost to the service and others showing small savings. The Committee was therefore unable to draw firm conclusions about the cost savings associated with using Ambulight PDT in the community.
The Committee discussed the potential resource savings to the NHS from using Ambulight PDT in the community (see section 5.6). However, it is likely that the level of service provision for PDT already established in a community setting is a key factor in whether using Ambulight PDT might be associated with a cost saving or cost increase compared with conventional PDT with a static lamp. The Committee was mindful of the additional costs involved in setting up the range of facilities to deliver PDT in the community, and was not convinced that the potential resource savings would confer sufficient advantage.# Conclusions
The Committee concluded that the claimed clinical advantages of treating non-melanoma skin cancer using Ambulight PDT were not adequately supported by the limited evidence available, especially in light of the substantial variations in management of small, low-risk lesions. In addition, the pathways of care for using Ambulight PDT in ambulatory care settings are not yet established. The Committee considered that the cost models did not present a robust case for benefits to the NHS.
The Committee concluded that the case for adoption of Ambulight PDT as a routine treatment for selected patients in place of conventional PDT could not be supported at this stage. Ambulight PDT is one treatment option for people with non-melanoma skin cancer in the community. It is a novel development in the area of PDT that shows some promise, but further work is needed to support its case for adoption in the NHS.# Related NICE guidance
# Published
Skin cancer: prevention using public information, sun protection resources and changes to the environment. Public health guidance 32 (2011).
Improving outcomes for people with skin tumours including melanoma (update): the management of low-risk basal cell carcinomas in the community. Cancer service guidance CSGSTIM (2010).
Improving outcomes for people with skin tumours including melanoma. Cancer service guidance CSGSTIM (2006).
Photodynamic therapy for non-melanoma skin tumours (including premalignant and primary non-metastatic skin lesions). Interventional procedures guidance 155 (2006). Sir Andrew DillonChief ExecutiveJuly 2011# About this guidance
NICE medical technology guidance addresses specific technologies notified to NICE by manufacturers. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This 'case' is reviewed against the evidence submitted and expert advice. The medical technology guidance on 'Ambulight PDT for the treatment of non-melanoma skin cancer' recommends further research. This recommendation is not intended to preclude the use of the technology in the NHS but to identify further evidence which, after evaluation, could support a recommendation for wider adoption.
This guidance was developed using the NICE medical technologies guidance process.
We have produced a summary of this guidance for patients and carers.
Changes after publicationApril 2015: minor maintenance
February 2013: minor maintenance.
April 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence, 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
ISBN: 978-1-4731-1172-1
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{'Recommendations': "NICE medical technologies guidance addresses specific technologies notified to NICE by manufacturers. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This 'case' is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.\n\nAmbulight PDT offers a means of delivering photodynamic therapy (PDT) for patients with small non-melanoma skin cancers in an ambulatory care setting, including patients' homes, and its use may be associated with less pain than conventional PDT. However, the case for routine use of Ambulight PDT in achieving a more efficient service is not supported by the evidence submitted by the manufacturer. The quantity of clinical evidence on its use is limited and the cost consequences of adoption, when compared with conventional PDT, ranged from a saving (per patient) of £195 to a cost increase of £536. NHS organisations should take this into account, alongside other features of the technology, when considering whether to use Ambulight PDT.", 'The technology': "# Description of the technology\n\nThe purpose of the Ambulight\xa0PDT device (Ambicare Health Ltd) is to deliver PDT to treat non-melanoma skin cancer in an ambulatory setting, including patients' homes in selected cases.\n\nAmbulight\xa0PDT comprises a small single-use light-emitting device (containing its own red light source generated by a diffuser and a series of light-emitting diodes), which is connected by a lead to a pocket-sized battery. This light-emitting device sticks to the skin using a disposable plaster, 3\xa0cm in diameter, worn directly over the treatment site. The battery can be carried in a pocket, attached to a belt or worn around the neck. The device is designed to treat single lesions that are smaller than 2.4 cm in diameter.\n\nBefore delivering Ambulight PDT, a photosensitising pro-drug is applied as a topical cream to the treatment site, where it is absorbed and metabolised to the active photosensitiser over a 3-hour period. Photodynamic therapy is then delivered for 3\xa0hours. The light source emits the same dose and wavelength of light as in conventional PDT but the intensity is reduced and the light is administered over a longer period of time.\n\nDepending on the indication, one or two treatments with Ambulight\xa0PDT are needed to complete a course (with separate cream applications and light-emitting devices if two treatments are needed). Each treatment lasts 6\xa0hours (3\xa0hours for drug absorption and 3\xa0hours for delivering PDT). As with conventional PDT, these two treatments are carried out between 1\xa0week and 1\xa0month apart.\n\nThe device is worn for the full 6\xa0hours of treatment. It is programmed so that the light source does not turn itself on until 3\xa0hours after the battery pack is switched on, to allow for the drug absorption. A flashing light indicates, after a further 3\xa0hours, when treatment is complete. The device switches itself off and can be removed by the patient.\n\nAmbulight\xa0PDT is designed to enable therapy to be delivered in an ambulatory care setting, which can include the patient's home. This can avoid the need for a hospital appointment to receive the PDT, reducing travel for some patients. It is claimed that in some cases the device may allow patients to continue with their normal daily activities. It is also claimed that using Ambulight PDT may reduce pain compared with conventional PDT.\n\nThe average selling price of Ambulight\xa0PDT, as stated in the manufacturer's submission, is £200 with a price range of £180–250. The cost of Ambulight\xa0PDT may vary because of differences in purchasing contracts.\n\n# Current management\n\nCurrent practice in the management of non-melanoma skin cancer in secondary care (specifically those lesions intended for treatment with Ambulight\xa0PDT) varies substantially. For patients for whom treatment is considered suitable, options are standard hospital-based PDT, topical chemotherapy, topical immunomodulators, surgical excision, curettage, cryotherapy or radiotherapy, but the treatment of choice varies between hospitals. Some patients receive no treatment for their small low-risk skin lesions, based on clinical decisions that there is insufficient risk of progression or harm.\n\nConventional PDT is currently offered in some out-of-hospital settings; these may be in primary care, secondary care or in the community, but not in patients' homes.", 'Clinical evidence': "# Summary of clinical evidence\n\nThe main clinical outcomes for the treatment of non-melanoma skin cancer with Ambulight\xa0PDT are tumour response rate (including recurrence rates or need for additional treatment), pain during treatment and adverse events. Full details of all clinical outcomes considered by the Committee are available in the assessment report.\n\nThe Committee saw data on a total of 28 patients who were treated with Ambulight PDT.\n\nAttili et al. (2009) described a pilot study of 12\xa0patients (8\xa0patients with Bowen's disease and 4\xa0patients with basal-cell carcinoma) with a median lesion diameter of 1.1\xa0cm (range 0.6–1.9\xa0cm) treated using a prototype of the Ambulight\xa0PDT device with 5-aminolevulinic acid as the photosensitiser. A complete response was reported in 75% (9/12) of patients at 6-month follow-up. At 12\xa0months, 58% (7/12) of patients had complete tumour response (4\xa0patients had peripheral margin failure; 1 had residual nodular component). In all patients for whom treatment was unsuccessful, the lesion size was greater than\xa01.5\xa0cm in diameter.\n\nAttili et al. (2009) reported pain immediately after treatment that was recorded using a numerical rating scale (1–10; higher score indicates worse pain). All 12\xa0patients reported a pain score of\xa02 or less (range 0–2). No patients needed pain relief in the form of local anaesthesia or cool air treatment during therapy. One patient who reported excessive pain during previous PDT commented on the lack of discomfort with Ambulight\xa0PDT. These scores were compared retrospectively with those of 50\xa0patients who had received conventional PDT using an inorganic light-emitting diode static lamp source (dose 75\xa0J/cm2). The static lamp cohort had a median numerical rating scale score of 6 (range 1–10). Of the 50\xa0patients, 11 needed local analgesia and all needed cool air treatment.\n\nThe manufacturer's submission presented data on the use of a light-emitting diode light source and methyl aminolevulinate cream (Metvix). These data included five\xa0patients with single lesions treated using Ambulight\xa0PDT and 11\xa0patients with multiple lesions whose lesions were treated with a range of PDT treatments (at least one lesion site was treated with Ambulight\xa0PDT; other sites were treated using conventional PDT or different light-emitting diode sources). Pain immediately after treatment was recorded on a visual analogue scale (1–10; higher score indicates worse pain). For single lesions treated using Ambulight\xa0PDT the pain score ranged from 1.5 to 7. For patients with multiple lesions treated using Ambulight\xa0PDT the pain scores ranged from 0 to 8. For multiple lesions treated with other PDT, pain scores ranged from 1.5 to 10. Insufficient data were available for analysing summary statistics (mean or median) for Ambulight PDT compared with conventional PDT.\n\nNo adverse events have been reported with Ambulight\xa0PDT.\n\n# Committee considerations\n\nThe Committee considered that there was some evidence for efficacy of Ambulight\xa0PDT but that the quantity of evidence on its use was very limited. The Committee considered that more clinical evidence is needed.\n\nThe Committee noted that the manufacturer of this technology claims that it is equivalent to, but not more effective than, conventional PDT. The Committee also noted that one of the claimed advantages over conventional PDT is that it can be used in ambulatory settings, including patients' homes in selected cases. The Committee considered that the ambulatory nature of the device offers the potential to increase convenience of treatment for patients with impaired mobility. It also noted that patients could be treated with Ambulight PDT who might otherwise have difficulty accessing PDT.\n\nThe manufacturer's submission described various techniques that have been developed to reduce pain during PDT and presented studies demonstrating that reduced irradiance is associated with reduced pain. The Committee considered that there was evidence to suggest that treatment with Ambulight\xa0PDT may cause less pain than conventional PDT in some patients.\n\nThe Committee recognised that patient preference plays a significant part in the decision to treat low-risk non-melanoma skin cancer.\n\nSmall non-melanoma skin cancers are common and most have a low risk of progression, but because of incomplete coverage of case reporting, the true incidence is unknown. The Committee was advised that practice varies substantially when deciding on treatment for these lesions and that local service configuration influences the range of treatments that can be offered. Some patients are offered one of a range of treatments including topical chemotherapy, surgical excision, radiotherapy or standard hospital-based PDT, whereas others are not offered treatment. There are no good studies comparing the range of possible treatments.\n\nThe Committee debated the usefulness of a device that treats only single lesions when many patients have multiple lesions needing treatment, and the fact that Ambulight\xa0PDT is suitable only for treating lesions of a small size. It also noted the differing views of Expert Advisers about the significance of pain as an issue with conventional PDT.\n\nThe Committee recognised that Ambulight\xa0PDT is a new device at a relatively early stage of development with a consequently small evidence base but that the manufacturer is collecting more data. The Committee considered the available clinical evidence and judged that it was insufficient to support the case for routinely adopting Ambulight\xa0PDT for treating non-melanoma skin cancers in the NHS in place of current management.\n\nThe Committee recognised that Ambulight PDT is a current treatment option for carefully selected patients.", 'NHS considerations': "# System impact\n\nAmbulight\xa0PDT allows PDT to be delivered in a community setting. This could reduce the demand on NHS transport services and hospital outpatient services as well as improving access to treatment and potentially reducing waiting times.\n\nNICE cancer service guidance CSGSTIM Improving outcomes for people with skin tumours including melanoma (update): the management of low-risk basal cell carcinomas in the community states that the management of basal cell carcinomas imposes a significant workload on both primary- and secondary-care service. It recommends that treatment and care should take into account patients' needs and preferences, and recognises that there is a need to provide high-quality care close to a patient's home. A device that offers ambulatory PDT could be an attractive treatment option for some patients who express a strong desire to continue with their normal daily activities while receiving treatment.\n\n# Committee considerations\n\nThe Committee recognised the potential for the system advantages on which the cost models described in section\xa05 were based.\n\nThe Committee considered that the use of Ambulight\xa0PDT might make additional staff training necessary for accurate diagnosis and treatment delivery, and need additional infrastructure set up within ambulatory care settings. Although these would have initial outlay costs, there may be cost savings once a service is established.\n\nThe Committee was advised that there is substantial variation in practice and that PDT is used much less in some hospitals than in others; this made consideration of any changes in service provision more complicated. Ambulight\xa0PDT is a current treatment option for non-melanoma skin cancer for carefully selected patients.", 'Cost considerations': "# Cost impact evidence\n\nThe manufacturer's cost analysis evaluated the costs of service configuration in which Ambulight\xa0PDT might be used, compared with conventional hospital-based PDT using a static lamp, for a complete treatment cycle, which consists of two treatments 1\xa0week apart. In the cost analysis it was assumed that patients had already been diagnosed with non-melanoma skin cancer, so no costs associated with the diagnostic stage of management were included. The analysis did not include any costs associated with treatment efficacy or adverse events.\n\nFour clinical scenarios were presented in which a GP with special interest in dermatology delivered PDT in the community with Ambulight\xa0PDT. These scenarios were presented for comparison against conventional hospital-based PDT using a static lamp:\n\nA GP operating in their own practice.\n\nA GP operating in a specialist centre.\n\nA GP operating in an outpatient clinic in secondary care.\n\nA nurse hybrid service model (nurses delivering treatment in the patient's home after diagnosis by a GP with specialist interest in dermatology).\n\nThe costs of the first three of these clinical scenarios for service delivery were calculated using the analysis of the potential economic impact of the NICE cancer service guidance CSGSTIM (2006 and 2010) on skin cancer. The manufacturer did not include overheads or GP costs for the nurse hybrid service model.\n\nThe cost analysis did not include any impact on staff costs for additional training or for support for patients. Patients may need support and advice because Ambulight\xa0PDT has the potential to be used while they continue with daily activities, outside a clinical setting.\n\nThere was significant uncertainty in the costs presented in the submission so it was difficult to determine the likely cost difference in practice. The cost difference between PDT using Ambulight\xa0PDT and conventional PDT using a static lamp presented in the manufacturer's submission ranged from a cost saving of £195 to a cost increase of £536. The cost difference was dependent on the clinical scenario used for delivering PDT with Ambulight\xa0PDT and the method of calculating the cost of each scenario.\n\nThe cost analysis presented cost savings associated with Ambulight\xa0PDT in the form of removing the need for staff to administer illumination from a static machine, room hire for the illumination period, and anaesthesia, which could translate into resource savings.\n\n# Committee considerations\n\nThe Committee considered that the cost models submitted by the manufacturer were complicated and difficult to interpret. The range of cost consequences was wide, with some showing an increase in cost to the service and others showing small savings. The Committee was therefore unable to draw firm conclusions about the cost savings associated with using Ambulight\xa0PDT in the community.\n\nThe Committee discussed the potential resource savings to the NHS from using Ambulight\xa0PDT in the community (see section\xa05.6). However, it is likely that the level of service provision for PDT already established in a community setting is a key factor in whether using Ambulight PDT might be associated with a cost saving or cost increase compared with conventional PDT with a static lamp. The Committee was mindful of the additional costs involved in setting up the range of facilities to deliver PDT in the community, and was not convinced that the potential resource savings would confer sufficient advantage.", 'Conclusions': 'The Committee concluded that the claimed clinical advantages of treating non-melanoma skin cancer using Ambulight\xa0PDT were not adequately supported by the limited evidence available, especially in light of the substantial variations in management of small, low-risk lesions. In addition, the pathways of care for using Ambulight PDT in ambulatory care settings are not yet established. The Committee considered that the cost models did not present a robust case for benefits to the NHS.\n\nThe Committee concluded that the case for adoption of Ambulight\xa0PDT as a routine treatment for selected patients in place of conventional PDT could not be supported at this stage. Ambulight\xa0PDT is one treatment option for people with non-melanoma skin cancer in the community. It is a novel development in the area of PDT that shows some promise, but further work is needed to support its case for adoption in the NHS.', 'Related NICE guidance': '# Published\n\nSkin cancer: prevention using public information, sun protection resources and changes to the environment. Public health guidance 32 (2011).\n\nImproving outcomes for people with skin tumours including melanoma (update): the management of low-risk basal cell carcinomas in the community. Cancer service guidance CSGSTIM (2010).\n\nImproving outcomes for people with skin tumours including melanoma. Cancer service guidance CSGSTIM (2006).\n\nPhotodynamic therapy for non-melanoma skin tumours (including premalignant and primary non-metastatic skin lesions). Interventional procedures guidance 155 (2006). Sir Andrew DillonChief ExecutiveJuly 2011', 'About this guidance': "NICE medical technology guidance addresses specific technologies notified to NICE by manufacturers. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This 'case' is reviewed against the evidence submitted and expert advice. The medical technology guidance on 'Ambulight PDT for the treatment of non-melanoma skin cancer' recommends further research. This recommendation is not intended to preclude the use of the technology in the NHS but to identify further evidence which, after evaluation, could support a recommendation for wider adoption.\n\nThis guidance was developed using the NICE medical technologies guidance process.\n\nWe have produced a summary of this guidance for patients and carers.\n\nChanges after publicationApril 2015: minor maintenance\n\nFebruary 2013: minor maintenance.\n\nApril 2012: minor maintenance.\n\nYour responsibility\n This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n © National Institute for Health and Clinical Excellence, 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-1172-1"}
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https://www.nice.org.uk/guidance/mtg6
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Evidence-based recommendations on Ambulight PDT for the treatment of non-melanoma skin cancer.
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The MIST Therapy system for the promotion of wound healing
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The MIST Therapy system for the promotion of wound healing
Evidence-based recommendations on the MIST Therapy system for the promotion of wound healing.
# Recommendations
NICE medical technologies guidance addresses specific technologies notified to NICE by manufacturers. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. The medical technology guidance on the MIST Therapy system for the promotion of wound healing recommends further research. This recommendation is not intended to preclude the use of the technology in the NHS but to identify further evidence which, after evaluation, could support a recommendation for wider adoption.
The MIST Therapy system shows potential to enhance the healing of chronic, 'hard-to-heal', complex wounds, compared with standard methods of wound management. If this potential is substantiated then MIST could offer advantages to both patients and the NHS.
The amount and quality of published evidence on the relative effectiveness of the MIST Therapy system is not sufficient, at the time of writing, to support the case for routine adoption of the MIST Therapy system in the NHS.
Comparative research is recommended in the UK to reduce uncertainty about the outcomes of patients with chronic, 'hard-to-heal', complex wounds treated by the MIST Therapy system compared with those treated by standard methods of wound care. This research should define the types and chronicity of wounds being treated and the details of other treatments being used. It should report healing rates, durations of treatment (including debridement) needed to achieve healing, and quality of life measures (including quality of life if wounds heal only partially). It is recommended that centres using the MIST Therapy system take part in research that delivers these outcomes. Current users of the MIST Therapy system who are unable to join research studies should use NICE's audit criteria to collect further information on healing rates, duration of treatment and quality of life and publish their results.
NICE will review this guidance when new and substantive evidence becomes available.# The technology
# Description of the technology
The MIST Therapy system (Celleration) aims to promote wound healing in chronic, 'hard-to-heal' wounds and acute wounds by delivering low-energy, low-intensity ultrasound to the wound bed through a continuous saline mist. The mist is claimed to transmit the ultrasonic energy to the wound bed, to activate healing by the removal of slough, exudate and bacteria, and to stimulate tissue regeneration.
The MIST Therapy system comprises a generator, a single-use applicator and a sterile saline bottle. Wound surface area is measured and entered into the MIST Therapy system, which then calculates the appropriate treatment time. When the applicator and saline bottle are connected, the ultrasound system is activated and a continuous mist is delivered to the wound bed using a hand-held applicator. The distance between the applicator and the wound bed is 0.5 to 1.5 cm. Once the treatment is complete, the generator switches off automatically.
The MIST Therapy system is intended for use as an adjunct to standard wound care with dressings and other cleaning or debridement as necessary.
Each treatment is estimated to take 5 to 7 minutes to complete and is normally performed three times a week, at the same treatment session as the wound dressings are changed.
The annual rental price of the MIST Therapy system stated in the manufacturer's submission is £7,500.
# Current management
Standard care for chronic, 'hard-to-heal' wounds normally involves the use of advanced wound dressings, which include: alginate, capillary action, charcoal, foam, honey, hydrocolloid, hydrocolloid fibrous, hydrogel, iodine, low- or non-adherent wound contact layer, silicone and silver dressings. Venous leg ulcers are a common type of chronic wound and compression bandaging is a mainstay of treatment, provided that serious ischaemia is not present.
Standard practice in the management of chronic wounds also includes wound debridement to remove dead tissue, and systemic antibiotic therapy for patients with wounds showing clinical signs of infection.# Clinical evidence
# Summary of clinical evidence
The main outcome measures for the promotion of wound healing using the MIST Therapy system are rate of healing and percentage of wounds healed. Also relevant are wound size, wound volume, wound area, level of bacterial contamination (bioburden), treatment time, pain score, quality of life, recurrence and adverse events.
The manufacturer's submission described almost 200 reports on the clinical use of the MIST Therapy system. The External Assessment Centre considered that 10 studies (2 randomised controlled trials and 8 peer-reviewed observational studies, of which 2 were prospective) were the key sources of evidence in the evaluation of the clinical effectiveness of the MIST Therapy system.
In one randomised controlled trial, 70 patients with non-healing wounds and chronic critical limb ischaemia had standard wound care and treatment with the MIST Therapy system (intervention group, n = 35) or standard wound care alone (control group, n = 35) for 12 weeks (Kavros et al. 2007). The MIST Therapy system was used for 5 minutes per treatment, three times per week. Standard wound care included daily dressing changes and weekly wound debridement. The study reported that 63% of wounds healed (healing defined as a greater than 50% reduction in wound volume) in the intervention group compared with 29% in the control group (p < 0.01).
In the second randomised controlled trial, 133 patients with diabetes and chronic foot ulcers were treated using the MIST Therapy system (intervention group, n = 70) or a sham device (control group, n = 63) for 10 weeks (Ennis et al. 2005). Wounds were treated 3 times per week, with 4 minutes use of the active or sham device, in addition to standard wound care with dressings and weekly debridement as needed. The study reported that, based on the intention-to-treat analysis, 26% of wounds healed in the intervention group compared with 22% in the control group (not statistically significant).
The one prospective observational study of 23 patients with chronic lower-extremity wounds of any aetiology treated by the MIST Therapy system (the intervention group) reported that 69% of wounds healed with a mean healing time of 8 weeks (median 7 weeks) (Ennis et al. 2006). These were compared with 218 patients with chronic wounds treated previously by electrical stimulation or megahertz ultrasound (the historical control group) in whom 72% of wounds healed with a mean healing time of 18.7 weeks (median 10 weeks) (p = 0.0005 in favour of the MIST group). The proportion of patients in the historical control group admitted to hospital for wound treatment (including surgical procedures) was significantly higher than in the MIST group (p = 0.04). The MIST Therapy system was used for 3 to 12 minutes per treatment depending on the area of the wound, 3 times per week. All patients received standard wound care including daily dressing changes and weekly wound debridement. Patient demographics and wound aetiologies were comparable between the intervention group and the historical control group.
A retrospective analysis reviewed the medical charts of patients with chronic lower-extremity wounds of any aetiology who were treated using the MIST Therapy system and standard wound care for 90 days (intervention group, n = 163) or standard wound care alone (control group, n = 47) (Kavros et al. 2008). The MIST Therapy system was used for 3 to 12 minutes per treatment depending on the area of the wound, 3 times per week. Standard wound care included advanced wound care dressings (silver, collagens) and debridement. The study reported that 53% of wounds healed in the intervention group with a mean healing time of 147 days compared with 32% in the control group, which had a mean healing time of 134 days (p = 0.009). At the start of treatment, the median wound volume in the intervention group and the control group was 304 mm3 and 368 mm3 respectively. The median wound volume in both groups decreased during treatment to a final volume of 0 mm3 in the intervention group and 68 mm3 in the control group.
A retrospective case series analysed the medical records of 51 patients with chronic lower-extremity ulcers that had been present for 3 to 18 months. Patients had standard wound care for a mean of 9.8 ± 5.5 weeks followed by the MIST Therapy system for a mean of 5.5 ± 2.8 weeks (Kavros and Schenk 2007). Patients received treatment using the MIST Therapy system when their wounds failed to improve with standard wound care alone and were treated 3 to 5 times a week (duration of each treatment was not stated). Standard wound care comprised moist wound dressings, debridement and compression. The study reported a 94.9 ± 9.8% reduction in wound volume during the period with the MIST Therapy system compared with a 37.3 ± 18.6% reduction during the period with standard wound care alone (p < 0.0001). No wound closed using standard wound care alone compared with 26 out of 51 wounds closing (51%) during treatment with the MIST Therapy system.
One retrospective observational study reviewed the medical charts of 76 patients with non-healing wounds of any aetiology who were treated using the MIST Therapy system as an adjunct to standard wound care (Bell and Cavorsi 2008). Treatment was administered for a mean of 5.1 minutes per treatment for a mean of 2.3 times per week. The median duration of treatment was 4.3 weeks. Standard wound care included moist wound dressings, selective debridement and compression. The study reported that the median wound area was reduced by 79% (from 2.5 to 0.6 cm²) and the proportion of patients with greater than 75% healthy granulation tissue increased from 32% to 46% during treatment. The patient-reported mean pain rating (0 to 10; a higher score indicates more-intense pain) decreased by a mean of 1.8 points during treatment (p = 0.001).
Cole et al. (2009) described a retrospective observational study that reviewed the medical charts of 41 consecutive patients with non-healing wounds of any aetiology who were treated using the MIST Therapy system as an adjunct to standard wound care. Treatment was administered for a mean of 3.7 minutes per treatment for a mean of 2.5 times per week. Standard wound care included moist wound dressings, debridement and other interventions specific to wound aetiology. Mean wound area decreased by 60% (median 88%) and the proportion of patients with greater than 75% healthy granulation tissue increased from 26% (n = 12) to 80% (n = 41) during treatment. The percentage of wounds that healed completely was 38% (n = 20) with a mean healing time of 6.8 weeks. The patient-reported mean pain rating (0 to 10; a higher score indicates more-intense pain) decreased by a mean of 2.9 points during treatment (p < 0.0001).
Haan et al. (2009) described a retrospective review of medical charts from 48 consecutive patients who had a chronic wound of any aetiology treated using the MIST Therapy system and physical therapy wound management (including debridement, wound dressings, compression, negative-pressure wound therapy and pulsed lavage with suction). Treatment was administered for a mean of 4.1 minutes per treatment for a mean of 2.1 times per week. The review reported that the median wound area decreased by 92% and the proportion of patients with greater than 75% healthy granulation tissue increased from 37% (n = 18) to 89% (n = 41) during treatment (p < 0.0001). The percentage of wounds that healed completely was 24% (n = 12) with a mean healing time of 4.3 weeks. The patient-reported mean pain rating (0 to 10; a higher score indicates more-intense pain) (n = 42) decreased by a mean of 2.6 (3.6 to 0.8) points during treatment (p < 0.0001).
A retrospective case study of medical records from 15 consecutive patients with painful, chronic lower-extremity wounds of various aetiologies treated by the MIST Therapy system reported a decrease in mean pain score (0 to 10; a higher score indicates more-intense pain) of 6.4 points (8.07 ± 1.91 to 1.67 ± 1.76, p = 0.0003), which was an 80% reduction in patient-reported pain (Gehling et al. 2007). Patients reduced or stopped their use of pain killers within 2 weeks of starting treatment.
A prospective case series of 11 consecutive patients with chronic pressure ulcers reported bacterial colony counts in the chronic wounds (Serena et al. 2009). Treatment was administered for a mean duration of 4 minutes per treatment, 3 times a week. No antiseptics, antibiotics, silver or antimicrobial dressings were used during the study. The study reported that the mean wound bioburden decreased by 50% (from 4 x 107 to 2 x 107 colony-forming units per gram of tissue) during treatment. Mean wound area decreased by 26% and mean wound volume decreased by 20% during the treatment period.
# Committee considerations
The Committee considered that the evidence suggested real potential for the MIST Therapy system to enhance the healing of chronic wounds, but that overall the quality of the evidence was limited by small patient numbers and lack of appropriate comparison groups.
The Committee noted that there was only one study comparing the MIST Therapy system and a sham device for the treatment of chronic wounds and judged the study to be of low quality. In addition to more clinical studies, the Committee considered that it would be useful to have more proof-of-concept evidence to demonstrate the transmission of ultrasound energy through a saline mist.
The Committee recognised that the quality of evidence in the area of wound care is generally low and that the heterogeneity of chronic wounds poses a challenge. The Committee was advised that the evidence supporting the clinical effectiveness of the MIST Therapy system was equal to or better than evidence for many other wound care interventions in current use in the NHS.
The Committee noted that patients reported a reduction in pain and an improvement in health following MIST Therapy treatment. It was advised that even partial healing can result in reduction in pain and improvement in quality of life for some patients with chronic wounds.
The Committee noted limited evidence on the rates of recurrence of chronic ulcers after MIST Therapy treatment. Further information on this longer-term outcome would be useful.
The Committee noted that no adverse events specific to the use of the MIST Therapy system have been reported in the published literature or to the manufacturer.
The few available studies on use of the MIST Therapy system for acute wounds were small and lacking in statistical outcomes. The Committee considered there was no substantial evidence to make a judgement on the clinical effectiveness of the MIST Therapy system for the treatment of acute wounds.# NHS considerations
# System impact
NICE's guideline on pressure ulcers: prevention and management, states that the cost of treating a grade 4 pressure ulcer is estimated to be £40,000 a year (Collier 1999). If the MIST Therapy system reduced the healing time of these wounds it could potentially offer substantial cost savings to the NHS, although most chronic wounds are likely to involve less prolonged and complex treatment.
The MIST Therapy system is claimed to enhance healing and decrease bioburden in wounds and might therefore reduce the use of antimicrobial dressings and systemic antibiotics. This could result in a reduction in the expenditure on wound dressings and in the risk of antibiotic resistance.
The Committee was advised that the MIST Therapy system can be used in a community setting, where most chronic wounds are managed.
# Committee considerations
The Committee recognised that the MIST Therapy system potentially offers substantial cost savings to the NHS by reducing the length of time that chronic wounds require attention, and so decreasing costs associated with nursing time, wound dressings, hospital admissions and surgical interventions (including, occasionally, amputation).
The Committee was advised by the expert adviser that patients have reported improvements in wellbeing after treatment with the MIST Therapy system and have shown greater willingness to attend clinics for treatment two to three times a week.
The Committee noted that the use of the MIST Therapy system in a community setting could make it easier for patients with disabilities to access treatment, so promoting equality.# Cost considerations
# Cost evidence
The economic evidence for the MIST Therapy system comprised an unpublished cost-effectiveness study, a conference poster and a new cost analysis.
An unpublished study from the USA considered the economic impact of healing a foot ulcer in a patient with diabetes using the MIST Therapy system plus standard wound care compared with standard wound care alone (Driver 2010). The effectiveness of the two treatments was taken from peer-reviewed studies about foot ulcers in patients with diabetes and the primary outcome measure was defined as 'time to heal'. The study estimated that for every 1,000 patients treated for a 12-week period, the cost savings were US$2,555,620. The savings associated with the MIST Therapy system resulted from the greater proportion of ulcers that healed or progressed towards healing within 12 weeks. The assumed difference in healing rate between the 2 treatments was large, and it was not clear how the costs attributed to each treatment were derived.
The conference poster described an economic evaluation based on a case series of five patients with pressure ulcers treated using the MIST Therapy system and standard wound care for 2 months (Anaeme et al. 2009). Cost savings were estimated from the direct costs of using the MIST Therapy system compared with negative pressure wound therapy as an adjunct to standard care. The cost calculations of negative pressure wound therapy were not described. The poster reported that mean wound area decreased by 34% during treatment with the MIST Therapy system. This was claimed to offer an average saving of US$1,310, ranging from US$563 to US$2,187 per patient compared with the use of negative pressure wound therapy.
The cost model submitted by the manufacturer was based on an estimate of 600,000 leg ulcers, pressure ulcers and diabetic foot ulcers in the UK and an estimate of £2.3 to 3.1 billion as the total cost of treating chronic wounds in England and Wales in 2005 (Posnett and Franks 2008). The population-based costs and incidence were used to calculate an annual per-patient cost for each type of ulcer. These costs per patient were compared with the cost of 26 weeks of treatment with the MIST Therapy system.
In the cost analysis, it was assumed that the use of MIST Therapy would follow the current care pathway for the treatment of wounds; it would be used if standard wound care had failed to heal the wound or if the wound had not improved within 30 days. The treatment would take place at the same time as the changing of wound dressings during standard wound care so it was assumed in the cost model that there would be no additional nurse visits. The additional nurse time taken to treat a patient with the MIST Therapy system alongside standard wound care was not analysed in the cost model. This analysis of differences in nurse time could not be undertaken owing to the different approaches used to calculate the cost of treatment with the MIST Therapy system and standard wound care.
For the purposes of the cost analysis, the effectiveness of the MIST Therapy system was described as mean time to healing. This was calculated as 14 weeks from a number of studies with different study design. In the cost model, a mean healing time of 26 weeks for the MIST Therapy system was assumed compared with 52 weeks for continual standard wound care.
The costs associated with treatment included annual rental of the MIST Therapy system, administration of the therapy, MIST Therapy consumables and dressings for standard wound care. The cost of ordering, transporting, processing and storing consumables was not included in the analysis. The energy cost and the cost of disposal of consumables was also not included in the analysis.
The annual total rental cost of the MIST Therapy system is £7,500.
The treatment cost for the MIST Therapy system is £7,626 per patient for 26 weeks based on three treatments per week. Rental cost per treatment was estimated to be £6 assuming one MIST Therapy system would be used on five patients per day 5 days a week. Its consumables cost was calculated to be £35 per treatment. The treatment cost for MIST Therapy also included wound dressing costs at £7 per treatment and nursing time at £50 per visit.
The costs of standard wound care were calculated from NHS annual wound statistics for complex wounds, and estimated total wound care costs in the UK for each ulcer type, to calculate an average cost per patient ('top down' approach). The costs of the MIST Therapy system were calculated from the estimated resource use per treatment ('bottom up' approach).
The MIST Therapy cost analysis showed that the average cost per patient over 26 weeks of treatment was estimated to be £7,626 for leg, diabetic foot and pressure ulcers. The main cost saving included in the manufacturer's cost analysis related to the reduction in the time for a wound to heal compared with standard wound care alone. The annual cost savings per patient were £1,563, £2,374 and £2,925 for the treatment of leg, diabetic foot and pressure ulcers respectively.
The sensitivity analyses reported that time to heal was the most important factor for the MIST Therapy system to be cost saving to the NHS.
# Committee considerations
The Committee was concerned that the approaches used to calculate the costs of treatment with the MIST Therapy system and with standard wound care were different. The costs of standard wound care were calculated from incidence and population-based costs ('top down' approach) in contrast to the costs of the MIST Therapy system, which were calculated from the annual rental cost of the device, consumables and treatment costs ('bottom up' approach).
The Committee discussed the assumption used in the model of a healing time of 26 weeks for the MIST Therapy system compared with 52 weeks for standard wound care. It considered that a 50% reduction in healing time from using the MIST Therapy system was not adequately supported by the clinical evidence.
The Committee considered that uncertainty about the conclusions of the cost model were related primarily to uncertainty about the relative clinical effectiveness of the MIST Therapy system in promoting wound healing. This was an important consideration in determining the Committee's recommendation for further comparative research.
The Committee was advised that exclusion from the cost model of amputation and other procedures with substantial long-term cost implications meant that cost savings of the MIST Therapy system were potentially underestimated.# Conclusions
The Committee considered that the MIST Therapy system showed promise in the treatment of chronic wounds and its use was supported by expert opinion. The potential cost savings claimed for its use depend primarily on evidence of comparative effectiveness. The low quality of that evidence and consequent uncertainty about its relative effectiveness in healing wounds compared with standard care alone meant that the case for routine adoption in the NHS could not be supported at the time of writing.
The Committee concluded that good quality studies are needed to substantiate the potential of the MIST Therapy system to offer advantages to patients and the NHS. The Committee wished to give strong encouragement to further research on the use of the MIST Therapy system, compared with standard care alone, for treating chronic wounds.
ISBN: 978-1-4731-1171-4
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{'Recommendations': "NICE medical technologies guidance addresses specific technologies notified to NICE by manufacturers. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. The medical technology guidance on the MIST Therapy system for the promotion of wound healing recommends further research. This recommendation is not intended to preclude the use of the technology in the NHS but to identify further evidence which, after evaluation, could support a recommendation for wider adoption.\n\nThe MIST Therapy system shows potential to enhance the healing of chronic, 'hard-to-heal', complex wounds, compared with standard methods of wound management. If this potential is substantiated then MIST could offer advantages to both patients and the NHS.\n\nThe amount and quality of published evidence on the relative effectiveness of the MIST Therapy system is not sufficient, at the time of writing, to support the case for routine adoption of the MIST Therapy system in the NHS.\n\nComparative research is recommended in the UK to reduce uncertainty about the outcomes of patients with chronic, 'hard-to-heal', complex wounds treated by the MIST Therapy system compared with those treated by standard methods of wound care. This research should define the types and chronicity of wounds being treated and the details of other treatments being used. It should report healing rates, durations of treatment (including debridement) needed to achieve healing, and quality of life measures (including quality of life if wounds heal only partially). It is recommended that centres using the MIST Therapy system take part in research that delivers these outcomes. Current users of the MIST Therapy system who are unable to join research studies should use NICE's audit criteria to collect further information on healing rates, duration of treatment and quality of life and publish their results.\n\nNICE will review this guidance when new and substantive evidence becomes available.", 'The technology': "# Description of the technology\n\nThe MIST Therapy system (Celleration) aims to promote wound healing in chronic, 'hard-to-heal' wounds and acute wounds by delivering low-energy, low-intensity ultrasound to the wound bed through a continuous saline mist. The mist is claimed to transmit the ultrasonic energy to the wound bed, to activate healing by the removal of slough, exudate and bacteria, and to stimulate tissue regeneration.\n\nThe MIST Therapy system comprises a generator, a single-use applicator and a sterile saline bottle. Wound surface area is measured and entered into the MIST Therapy system, which then calculates the appropriate treatment time. When the applicator and saline bottle are connected, the ultrasound system is activated and a continuous mist is delivered to the wound bed using a hand-held applicator. The distance between the applicator and the wound bed is 0.5 to 1.5\xa0cm. Once the treatment is complete, the generator switches off automatically.\n\nThe MIST Therapy system is intended for use as an adjunct to standard wound care with dressings and other cleaning or debridement as necessary.\n\nEach treatment is estimated to take 5 to 7 minutes to complete and is normally performed three times a week, at the same treatment session as the wound dressings are changed.\n\nThe annual rental price of the MIST Therapy system stated in the manufacturer's submission is £7,500.\n\n# Current management\n\nStandard care for chronic, 'hard-to-heal' wounds normally involves the use of advanced wound dressings, which include: alginate, capillary action, charcoal, foam, honey, hydrocolloid, hydrocolloid fibrous, hydrogel, iodine, low- or non-adherent wound contact layer, silicone and silver dressings. Venous leg ulcers are a common type of chronic wound and compression bandaging is a mainstay of treatment, provided that serious ischaemia is not present.\n\nStandard practice in the management of chronic wounds also includes wound debridement to remove dead tissue, and systemic antibiotic therapy for patients with wounds showing clinical signs of infection.", 'Clinical evidence': "# Summary of clinical evidence\n\nThe main outcome measures for the promotion of wound healing using the MIST Therapy system are rate of healing and percentage of wounds healed. Also relevant are wound size, wound volume, wound area, level of bacterial contamination (bioburden), treatment time, pain score, quality of life, recurrence and adverse events.\n\nThe manufacturer's submission described almost 200\xa0reports on the clinical use of the MIST Therapy system. The External Assessment Centre considered that 10\xa0studies (2\xa0randomised controlled trials and 8\xa0peer-reviewed observational studies, of which 2 were prospective) were the key sources of evidence in the evaluation of the clinical effectiveness of the MIST Therapy system.\n\nIn one randomised controlled trial, 70\xa0patients with non-healing wounds and chronic critical limb ischaemia had standard wound care and treatment with the MIST Therapy system (intervention group, n\xa0=\xa035) or standard wound care alone (control group, n\xa0=\xa035) for 12\xa0weeks (Kavros et al. 2007). The MIST Therapy system was used for 5\xa0minutes per treatment, three times per week. Standard wound care included daily dressing changes and weekly wound debridement. The study reported that 63% of wounds healed (healing defined as a greater than 50% reduction in wound volume) in the intervention group compared with 29% in the control group (p\xa0<\xa00.01).\n\nIn the second randomised controlled trial, 133\xa0patients with diabetes and chronic foot ulcers were treated using the MIST Therapy system (intervention group, n\xa0=\xa070) or a sham device (control group, n\xa0=\xa063) for 10\xa0weeks (Ennis et al. 2005). Wounds were treated 3 times per week, with 4\xa0minutes use of the active or sham device, in addition to standard wound care with dressings and weekly debridement as needed. The study reported that, based on the intention-to-treat analysis, 26% of wounds healed in the intervention group compared with 22% in the control group (not statistically significant).\n\nThe one prospective observational study of 23\xa0patients with chronic lower-extremity wounds of any aetiology treated by the MIST Therapy system (the intervention group) reported that 69% of wounds healed with a mean healing time of 8\xa0weeks (median 7\xa0weeks) (Ennis et al. 2006). These were compared with 218\xa0patients with chronic wounds treated previously by electrical stimulation or megahertz ultrasound (the historical control group) in whom 72% of wounds healed with a mean healing time of 18.7\xa0weeks (median 10\xa0weeks) (p\xa0=\xa00.0005 in favour of the MIST group). The proportion of patients in the historical control group admitted to hospital for wound treatment (including surgical procedures) was significantly higher than in the MIST group (p\xa0=\xa00.04). The MIST Therapy system was used for 3 to 12\xa0minutes per treatment depending on the area of the wound, 3\xa0times per week. All patients received standard wound care including daily dressing changes and weekly wound debridement. Patient demographics and wound aetiologies were comparable between the intervention group and the historical control group.\n\nA retrospective analysis reviewed the medical charts of patients with chronic lower-extremity wounds of any aetiology who were treated using the MIST Therapy system and standard wound care for 90 days (intervention group, n\xa0=\xa0163) or standard wound care alone (control group, n\xa0=\xa047) (Kavros et al. 2008). The MIST Therapy system was used for 3 to 12\xa0minutes per treatment depending on the area of the wound, 3 times per week. Standard wound care included advanced wound care dressings (silver, collagens) and debridement. The study reported that 53% of wounds healed in the intervention group with a mean healing time of 147\xa0days compared with 32% in the control group, which had a mean healing time of 134\xa0days (p\xa0=\xa00.009). At the start of treatment, the median wound volume in the intervention group and the control group was 304\xa0mm3 and 368\xa0mm3 respectively. The median wound volume in both groups decreased during treatment to a final volume of 0\xa0mm3 in the intervention group and 68\xa0mm3 in the control group.\n\nA retrospective case series analysed the medical records of 51\xa0patients with chronic lower-extremity ulcers that had been present for 3 to 18\xa0months. Patients had standard wound care for a mean of 9.8\xa0±\xa05.5\xa0weeks followed by the MIST Therapy system for a mean of 5.5\xa0±\xa02.8\xa0weeks (Kavros and Schenk 2007). Patients received treatment using the MIST Therapy system when their wounds failed to improve with standard wound care alone and were treated 3 to 5 times a week (duration of each treatment was not stated). Standard wound care comprised moist wound dressings, debridement and compression. The study reported a 94.9\xa0±\xa09.8% reduction in wound volume during the period with the MIST Therapy system compared with a 37.3\xa0±\xa018.6% reduction during the period with standard wound care alone (p\xa0<\xa00.0001). No wound closed using standard wound care alone compared with 26 out of 51\xa0wounds closing (51%) during treatment with the MIST Therapy system.\n\nOne retrospective observational study reviewed the medical charts of 76\xa0patients with non-healing wounds of any aetiology who were treated using the MIST Therapy system as an adjunct to standard wound care (Bell and Cavorsi 2008). Treatment was administered for a mean of 5.1\xa0minutes per treatment for a mean of 2.3 times per week. The median duration of treatment was 4.3\xa0weeks. Standard wound care included moist wound dressings, selective debridement and compression. The study reported that the median wound area was reduced by 79% (from 2.5 to 0.6\xa0cm²) and the proportion of patients with greater than 75% healthy granulation tissue increased from 32% to 46% during treatment. The patient-reported mean pain rating (0 to 10; a higher score indicates more-intense pain) decreased by a mean of 1.8 points during treatment (p\xa0=\xa00.001).\n\nCole et al. (2009) described a retrospective observational study that reviewed the medical charts of 41\xa0consecutive patients with non-healing wounds of any aetiology who were treated using the MIST Therapy system as an adjunct to standard wound care. Treatment was administered for a mean of 3.7\xa0minutes per treatment for a mean of 2.5 times per week. Standard wound care included moist wound dressings, debridement and other interventions specific to wound aetiology. Mean wound area decreased by 60% (median 88%) and the proportion of patients with greater than 75% healthy granulation tissue increased from 26% (n\xa0=\xa012) to 80% (n\xa0=\xa041) during treatment. The percentage of wounds that healed completely was 38% (n\xa0=\xa020) with a mean healing time of 6.8 weeks. The patient-reported mean pain rating (0 to 10; a higher score indicates more-intense pain) decreased by a mean of 2.9\xa0points during treatment (p\xa0<\xa00.0001).\n\nHaan et al. (2009) described a retrospective review of medical charts from 48\xa0consecutive patients who had a chronic wound of any aetiology treated using the MIST Therapy system and physical therapy wound management (including debridement, wound dressings, compression, negative-pressure wound therapy and pulsed lavage with suction). Treatment was administered for a mean of 4.1\xa0minutes per treatment for a mean of 2.1 times per week. The review reported that the median wound area decreased by 92% and the proportion of patients with greater than 75% healthy granulation tissue increased from 37% (n\xa0=\xa018) to 89% (n\xa0=\xa041) during treatment (p\xa0<\xa00.0001). The percentage of wounds that healed completely was 24% (n\xa0=\xa012) with a mean healing time of 4.3\xa0weeks. The patient-reported mean pain rating (0 to 10; a higher score indicates more-intense pain) (n\xa0=\xa042) decreased by a mean of 2.6 (3.6 to 0.8) points during treatment (p\xa0<\xa00.0001).\n\nA retrospective case study of medical records from 15\xa0consecutive patients with painful, chronic lower-extremity wounds of various aetiologies treated by the MIST Therapy system reported a decrease in mean pain score (0 to 10; a higher score indicates more-intense pain) of 6.4 points (8.07\xa0±\xa01.91 to 1.67\xa0±\xa01.76, p\xa0=\xa00.0003), which was an 80% reduction in patient-reported pain (Gehling et al. 2007). Patients reduced or stopped their use of pain killers within 2\xa0weeks of starting treatment.\n\nA prospective case series of 11\xa0consecutive patients with chronic pressure ulcers reported bacterial colony counts in the chronic wounds (Serena et al. 2009). Treatment was administered for a mean duration of 4\xa0minutes per treatment, 3 times a week. No antiseptics, antibiotics, silver or antimicrobial dressings were used during the study. The study reported that the mean wound bioburden decreased by 50% (from 4\xa0x\xa0107 to 2\xa0x\xa0107 colony-forming units per gram of tissue) during treatment. Mean wound area decreased by 26% and mean wound volume decreased by 20% during the treatment period.\n\n# Committee considerations\n\nThe Committee considered that the evidence suggested real potential for the MIST Therapy system to enhance the healing of chronic wounds, but that overall the quality of the evidence was limited by small patient numbers and lack of appropriate comparison groups.\n\nThe Committee noted that there was only one study comparing the MIST Therapy system and a sham device for the treatment of chronic wounds and judged the study to be of low quality. In addition to more clinical studies, the Committee considered that it would be useful to have more proof-of-concept evidence to demonstrate the transmission of ultrasound energy through a saline mist.\n\nThe Committee recognised that the quality of evidence in the area of wound care is generally low and that the heterogeneity of chronic wounds poses a challenge. The Committee was advised that the evidence supporting the clinical effectiveness of the MIST Therapy system was equal to or better than evidence for many other wound care interventions in current use in the NHS.\n\nThe Committee noted that patients reported a reduction in pain and an improvement in health following MIST Therapy treatment. It was advised that even partial healing can result in reduction in pain and improvement in quality of life for some patients with chronic wounds.\n\nThe Committee noted limited evidence on the rates of recurrence of chronic ulcers after MIST Therapy treatment. Further information on this longer-term outcome would be useful.\n\nThe Committee noted that no adverse events specific to the use of the MIST Therapy system have been reported in the published literature or to the manufacturer.\n\nThe few available studies on use of the MIST Therapy system for acute wounds were small and lacking in statistical outcomes. The Committee considered there was no substantial evidence to make a judgement on the clinical effectiveness of the MIST Therapy system for the treatment of acute wounds.", 'NHS considerations': "# System impact\n\nNICE's guideline on pressure ulcers: prevention and management, states that the cost of treating a grade 4 pressure ulcer is estimated to be £40,000 a year (Collier 1999). If the MIST Therapy system reduced the healing time of these wounds it could potentially offer substantial cost savings to the NHS, although most chronic wounds are likely to involve less prolonged and complex treatment.\n\nThe MIST Therapy system is claimed to enhance healing and decrease bioburden in wounds and might therefore reduce the use of antimicrobial dressings and systemic antibiotics. This could result in a reduction in the expenditure on wound dressings and in the risk of antibiotic resistance.\n\nThe Committee was advised that the MIST Therapy system can be used in a community setting, where most chronic wounds are managed.\n\n# Committee considerations\n\nThe Committee recognised that the MIST Therapy system potentially offers substantial cost savings to the NHS by reducing the length of time that chronic wounds require attention, and so decreasing costs associated with nursing time, wound dressings, hospital admissions and surgical interventions (including, occasionally, amputation).\n\nThe Committee was advised by the expert adviser that patients have reported improvements in wellbeing after treatment with the MIST Therapy system and have shown greater willingness to attend clinics for treatment two to three times a week.\n\nThe Committee noted that the use of the MIST Therapy system in a community setting could make it easier for patients with disabilities to access treatment, so promoting equality.", 'Cost considerations': "# Cost evidence\n\nThe economic evidence for the MIST Therapy system comprised an unpublished cost-effectiveness study, a conference poster and a new cost analysis.\n\nAn unpublished study from the USA considered the economic impact of healing a foot ulcer in a patient with diabetes using the MIST Therapy system plus standard wound care compared with standard wound care alone (Driver 2010). The effectiveness of the two treatments was taken from peer-reviewed studies about foot ulcers in patients with diabetes and the primary outcome measure was defined as 'time to heal'. The study estimated that for every 1,000\xa0patients treated for a 12-week period, the cost savings were US$2,555,620. The savings associated with the MIST Therapy system resulted from the greater proportion of ulcers that healed or progressed towards healing within 12\xa0weeks. The assumed difference in healing rate between the 2 treatments was large, and it was not clear how the costs attributed to each treatment were derived.\n\nThe conference poster described an economic evaluation based on a case series of five patients with pressure ulcers treated using the MIST Therapy system and standard wound care for 2\xa0months (Anaeme et al. 2009). Cost savings were estimated from the direct costs of using the MIST Therapy system compared with negative pressure wound therapy as an adjunct to standard care. The cost calculations of negative pressure wound therapy were not described. The poster reported that mean wound area decreased by 34% during treatment with the MIST Therapy system. This was claimed to offer an average saving of US$1,310, ranging from US$563 to US$2,187 per patient compared with the use of negative pressure wound therapy.\n\nThe cost model submitted by the manufacturer was based on an estimate of 600,000 leg ulcers, pressure ulcers and diabetic foot ulcers in the UK and an estimate of £2.3 to 3.1\xa0billion as the total cost of treating chronic wounds in England and Wales in 2005 (Posnett and Franks 2008). The population-based costs and incidence were used to calculate an annual per-patient cost for each type of ulcer. These costs per patient were compared with the cost of 26\xa0weeks of treatment with the MIST Therapy system.\n\nIn the cost analysis, it was assumed that the use of MIST Therapy would follow the current care pathway for the treatment of wounds; it would be used if standard wound care had failed to heal the wound or if the wound had not improved within 30 days. The treatment would take place at the same time as the changing of wound dressings during standard wound care so it was assumed in the cost model that there would be no additional nurse visits. The additional nurse time taken to treat a patient with the MIST Therapy system alongside standard wound care was not analysed in the cost model. This analysis of differences in nurse time could not be undertaken owing to the different approaches used to calculate the cost of treatment with the MIST Therapy system and standard wound care.\n\nFor the purposes of the cost analysis, the effectiveness of the MIST Therapy system was described as mean time to healing. This was calculated as 14\xa0weeks from a number of studies with different study design. In the cost model, a mean healing time of 26\xa0weeks for the MIST Therapy system was assumed compared with 52\xa0weeks for continual standard wound care.\n\nThe costs associated with treatment included annual rental of the MIST Therapy system, administration of the therapy, MIST Therapy consumables and dressings for standard wound care. The cost of ordering, transporting, processing and storing consumables was not included in the analysis. The energy cost and the cost of disposal of consumables was also not included in the analysis.\n\nThe annual total rental cost of the MIST Therapy system is £7,500.\n\nThe treatment cost for the MIST Therapy system is £7,626 per patient for 26\xa0weeks based on three treatments per week. Rental cost per treatment was estimated to be £6 assuming one MIST Therapy system would be used on five patients per day 5\xa0days a week. Its consumables cost was calculated to be £35 per treatment. The treatment cost for MIST Therapy also included wound dressing costs at £7 per treatment and nursing time at £50 per visit.\n\nThe costs of standard wound care were calculated from NHS annual wound statistics for complex wounds, and estimated total wound care costs in the UK for each ulcer type, to calculate an average cost per patient ('top down' approach). The costs of the MIST Therapy system were calculated from the estimated resource use per treatment ('bottom up' approach).\n\nThe MIST Therapy cost analysis showed that the average cost per patient over 26\xa0weeks of treatment was estimated to be £7,626 for leg, diabetic foot and pressure ulcers. The main cost saving included in the manufacturer's cost analysis related to the reduction in the time for a wound to heal compared with standard wound care alone. The annual cost savings per patient were £1,563, £2,374 and £2,925 for the treatment of leg, diabetic foot and pressure ulcers respectively.\n\nThe sensitivity analyses reported that time to heal was the most important factor for the MIST Therapy system to be cost saving to the NHS.\n\n# Committee considerations\n\nThe Committee was concerned that the approaches used to calculate the costs of treatment with the MIST Therapy system and with standard wound care were different. The costs of standard wound care were calculated from incidence and population-based costs ('top down' approach) in contrast to the costs of the MIST Therapy system, which were calculated from the annual rental cost of the device, consumables and treatment costs ('bottom up' approach).\n\nThe Committee discussed the assumption used in the model of a healing time of 26\xa0weeks for the MIST Therapy system compared with 52\xa0weeks for standard wound care. It considered that a 50% reduction in healing time from using the MIST Therapy system was not adequately supported by the clinical evidence.\n\nThe Committee considered that uncertainty about the conclusions of the cost model were related primarily to uncertainty about the relative clinical effectiveness of the MIST Therapy system in promoting wound healing. This was an important consideration in determining the Committee's recommendation for further comparative research.\n\nThe Committee was advised that exclusion from the cost model of amputation and other procedures with substantial long-term cost implications meant that cost savings of the MIST Therapy system were potentially underestimated.", 'Conclusions': 'The Committee considered that the MIST Therapy system showed promise in the treatment of chronic wounds and its use was supported by expert opinion. The potential cost savings claimed for its use depend primarily on evidence of comparative effectiveness. The low quality of that evidence and consequent uncertainty about its relative effectiveness in healing wounds compared with standard care alone meant that the case for routine adoption in the NHS could not be supported at the time of writing.\n\nThe Committee concluded that good quality studies are needed to substantiate the potential of the MIST Therapy system to offer advantages to patients and the NHS. The Committee wished to give strong encouragement to further research on the use of the MIST Therapy system, compared with standard care alone, for treating chronic wounds.\n\nISBN: 978-1-4731-1171-4'}
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https://www.nice.org.uk/guidance/mtg5
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Evidence-based recommendations on the MIST Therapy system for the promotion of wound healing.
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b5adf3279e68c1117762bf2ca7f13bfb53f2eee5
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Myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction
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Myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction
Evidence-based recommendations on myocardial perfusion scintigraphy for diagnosing and managing angina and myocardial infarction in adults.
# Guidance
This guidance has been partially updated by 'Chest pain of recent onset' (NICE clinical guideline 95) and 'Stable angina' (NICE clinical guideline 126).
This appraisal covers the use of myocardial perfusion scintigraphy (MPS) using single photon emission computed tomography (SPECT) in the diagnosis and management of angina and myocardial infarction. It does not cover planar MPS or the use of MPS in the management of heart failure or in the assessment of myocardial viability. In this guidance the term coronary artery disease (CAD) is used to refer to angina and myocardial infarction.
This recommendation has been updated and replaced by recommendation 1.3.6.1 in NICE clinical guideline 95.
MPS using SPECT is recommended as part of the investigational strategy in the management of established CAD in people who remain symptomatic following myocardial infarction or reperfusion interventions.This recommendation has been partially updated by recommendations 1.5.2 and 1.5.12 in NICE clinical guideline 126.# Clinical need and practice
Coronary artery disease (CAD) is the commonest cause of death in England and Wales. It is characterised by the development of lipid-laden coronary arterial plaques, which reduce the blood supply to the heart muscle. Significant CAD is defined as a stenosis (narrowing) of more than 70% of the diameter of at least one major epicardial artery segment or more than 50% of the diameter of the left main coronary artery.
Angina (chest pain) is the most common symptom of CAD. It is usually provoked by exercise and relieved by rest. Angina of rapidly increasing frequency, or experienced at rest, is called unstable angina. CAD can also lead to heart attack (myocardial infarction, MI) and sudden cardiac death. MI is characterised by severe chest pain persisting for at least 20 minutes, a rise in cardiac enzymes in the serum, and/or an abnormal electrocardiogram (ECG).
About 2.65 million people in the UK have CAD, and of these 1.2 million have had an MI. There were an estimated 275,000 heart attacks in the UK in 2001, and 335,000 new cases of angina are diagnosed each year. CAD is more prevalent in men than in women. The prevalence of CAD increases with age, and varies across geographic regions and socioeconomic groups.
Preventative strategies for reducing the frequency of CAD include smoking cessation, diet modification, exercise, and treating conditions that exacerbate progression of the disease, such as hyperlipidaemia, hyperglycaemia, hypertension and blood hypercoagulability. Medical treatment of angina symptoms includes the use of nitrates, beta-adrenergic blockers and/or calcium channel blockers. In severe CAD, revascularisation may be required, using surgical procedures such as coronary artery bypass grafting (CABG) or via the use of percutaneous coronary intervention (PCI), commonly with the insertion of an intraluminal coronary stent.
The cost of CAD to the UK healthcare system in 1999 was estimated in the Assessment Report (see Appendix B) at £1.7 billion; the total annual cost was around £7 billion when informal care and productivity losses were included. More than 378,000 inpatients were treated for CAD in NHS hospitals in 2000/2001. Approximately 28,500 CABG and 39,000 PCI procedures are performed each year in the UK.
The individual likelihood for CAD can be estimated from age, gender, ethnic group, family history, existence of symptoms, associated comorbidities and the results of tests such as resting electrocardiography (rECG). rECG is a commonly used test because it is readily available in primary care and is inexpensive, but because it does not exclude CAD, it is of limited diagnostic value. Stress ECG (sECG) and coronary angiography (CA) are commonly used in clinical practice for the diagnosis of CAD.
sECG is normally recorded during progressive exercise on a treadmill, and so is not suitable for people for whom treadmill exercise is difficult or impossible.
CA involves manipulating a cardiac catheter into the heart from a vein or artery in a limb. A contrast medium is injected through the catheter, and its progress monitored by a rapid series of X-rays. CA provides mainly anatomical information and is used to measure the degree of stenosis. It is considered the 'gold standard' for defining the site and severity of coronary artery lesions. However, CA findings are not always a reliable indicator of the functional significance of a coronary stenosis. Routine use of CA without prior non-invasive testing is not advisable, because of its high cost and associated mortality and morbidity. Potential complications include non-fatal MI (0.1%), stroke (0.1%) and death (0.1–0.2%).
Other frequently used non-invasive techniques include myocardial perfusion scintigraphy (MPS) and echocardiography. Imaging techniques such as magnetic resonance imaging and positron emission tomography are used less frequently.# The technology
MPS involves the intravenous injection of small amounts of a radioactive tracer to evaluate perfusion of living cardiac muscle via the coronary arteries after stress and at rest. After injection, the tracer is taken up by cardiac muscle cells, and its distribution within the myocardium is imaged using a gamma camera. Three tracers are commercially available in the UK: thallium-201 thallous chloride, technetium-99m 2-methoxy-isobutyl-isonitrile, and technetium-99m 1,2-bis(bisphosphino)ethane. MPS is a non-invasive procedure which provides more detailed information about coronary function than sECG and CA. Cardiovascular stress can be induced by exercise as in sECG, but is most commonly induced by pharmacological agents.
MPS was originally developed as a planar imaging technique, but SPECT is the clinical standard in current practice. In SPECT, the camera rotates around the patient for 10–20 minutes and the raw data are processed to obtain tomographic images of the myocardium. The stress and rest images are normally separated by 3–4 hours. The total patient contact time for stress induction, injection and image acquisition is approximately 60 minutes.
Homogeneous uptake of tracer throughout the myocardium indicates the absence of clinically significant infarction or coronary stenosis. A defect in the stress images that normalises in the rest images usually corresponds to a significant coronary stenosis. A defect in both stress and rest images indicates an area with loss of viable myocardium, such as after MI.
Two technical improvements to SPECT were also considered in this appraisal. Attenuation-corrected SPECT compensates for the fact that many emitted photons never reach the detector as a result of interactions with body tissues. ECG-gated SPECT is synchronised with the patient's ECG, thereby minimising artefacts caused by cardiac motion. Also, left ventricular ejection fraction can be measured at rest with ECG-gated SPECT.
The complication rates for SPECT are no different from those of sECG, and are usually related to exercise or pharmacological stimulation given as part of the stress component in the procedure, with an associated mortality of around 0.01% and a morbidity of around 0.02%. The radiation exposure from SPECT is similar to the exposure from uncomplicated CA.
The cost of a SPECT scan is estimated to be around £265, whereas the costs for sECG and CA are £104 and £1103, respectively (2002 NHS reference costs).# Evidence and interpretation
The Appraisal Committee (Appendix A) considered evidence from a number of sources (see Appendix B).
# Clinical effectiveness
The Assessment Report and the submissions reviewed the literature and focused on two aspects separately: the diagnostic performance of SPECT, and its long-term prognostic value. Much of the evidence consisted of non-randomised open observational (both prospective and retrospective) studies, with several studies using a comparative design.
## Diagnostic performance
The diagnostic performance of SPECT was expressed as sensitivity and specificity. Sensitivity is the proportion of true-positives that are correctly identified by the test. Specificity is the proportion of true-negatives that are correctly identified by the test.
The Assessment Report reviewed 21 studies with 100 or more patients that evaluated the sensitivity and specificity of both SPECT and sECG in the diagnosis of CAD compared with CA. Median sensitivity values for SPECT were higher than those for sECG in all studies (SPECT: 81% for the largest subcategory of studies, with a range of 63–93%; sECG: 65% for the largest subcategory of studies, with a range of 42–92%). However, the results were not pooled because of the heterogeneity across the different studies. Median specificity values were similar for SPECT (65%, range 10–90%) and sECG (67%, range 41–88%).
The submission from the professional groups reviewed the diagnostic performance of SPECT only (compared with CA) from 62 studies. Because of differences in inclusion criteria, only two of these studies were also included in the Assessment Report analysis. There was considerable variation in study size, quality and design, but weighted means for sensitivity and specificity were reported to be 86% and 74%, respectively. The manufacturer's submission quoted one publication with sensitivity and specificity for SPECT reported as 91% and 89%, respectively, and the American College of Cardiologists/American Heart Association Task Force guideline, with average sensitivity and specificity reported as 89–90% and 70–76%, respectively.
## Long-term prognostic value
For the long-term prognostic value of SPECT, the Assessment Report included a systematic review of 46 observational studies.
In the 20 studies that provided general prognostic information, cardiac event rates (defined as cardiac mortality or non-fatal MI) were significantly higher for patients with abnormal SPECT scans than for those with normal scans. An abnormal SPECT result was associated with an annual cardiac event rate of 6.7%, whereas a normal scan was associated with an annual cardiac event rate of 0.7% (data from metaanalyses of 15,000 and 20,963 patients, respectively). Furthermore, the extent and size of a perfusion defect can predict the likelihood of future cardiac events.
The proportion of normal angiograms was lower in patients who were referred to CA after a positive SPECT than in patients referred directly for CA (two studies: 33% versus 43% , and 18% versus 33% , respectively).
However, the rate of subsequent revascularisations was lower for the SPECT-CA strategy (13–27%) than for the direct CA strategy (16–44%) (data from three studies with a combined total of approximately 11,000 patients).
In studies where it was possible to analyse the contribution of different clinical parameters to the prediction of clinical outcomes, it was found that SPECT provided independent prognostic information for predicting MI, and had an additional value over clinical and sECG data that was maintained at long-term follow-up.
In several studies that investigated whether an abnormal SPECT scan was a predictor of cardiac death, the relative risk or odds ratios were calculated depending on study design. In all studies an abnormal SPECT scan was described as an independent, main or statistically significant predictor of cardiac death. In four studies, with patient numbers ranging from 176 to 947, the relative risk ranged between 1.1 and 17.6. In two studies, with patient numbers of 248 and 1182, the odds ratios were reported to be 2.8 and 4.8, respectively.
SPECT also provided independent prognostic information in the following subgroups: women (five studies), patients post-MI (four studies), patients who had undergone PCI or CABG (three studies), medically treated patients with left main and/or three-vessel CAD (one study), patients hospitalised with angina who had a normal or non-diagnostic sECG (one study), and patients with diabetes (two studies).
Two studies found ECG-gated SPECT to be more sensitive than non-ECG-gated SPECT, but with slightly lower specificity. Also, ECG-gated SPECT provided incremental prognostic information in patients with known or suspected CAD that was better than perfusion data alone. One study compared SPECT with attenuation-corrected SPECT and reported that attenuation correction had a significant impact on the assessment of the severity and extent of MI.
The search strategy used in the Assessment Report did not identify any studies evaluating the role of SPECT in the context of rapid access chest pain clinics or in pre-operative risk assessment of patients undergoing major surgery who were potentially at risk of coronary events. However, the submission from the professional groups lists 20 studies on SPECT in pre-operative risk assessment, and emphasises the acknowledged role of SPECT for this indication.
In summary, as studies reviewed in the Assessment Report were carried out under a number of different clinical settings investigating different outcomes, it was not possible to summarise the effectiveness of SPECT in simple quantitative estimates. However, the evidence from the reviewed studies consistently suggested that SPECT provided valuable independent and incremental information predictive of outcome that helped to risk-stratify patients and influence the way in which their condition was managed.
The submissions from the professional groups and the manufacturer included reviews of a larger number of papers and, because of differences in the inclusion criteria, there was little overlap between the studies included in each of the three reviews. Despite the differences in the evidence base of the three reviews, similar conclusions were drawn.
# Cost effectiveness
The Assessment Group, the manufacturer and the professional group reviewed published cost-effectiveness studies. The Assessment Group and the manufacturer also provided new economic models.
The systematic review in the Assessment Report included studies that compared both costs and outcomes of SPECT with alternative diagnostic strategies. The comparison of different publications was complicated by the multitude of strategies considered, differences in study designs and populations, in treatment comparisons, in costing methods and different ways in which outcomes were measured. Overall, it was concluded that direct CA (without any prior tests) was cost effective when the prevalence of disease was high. At low levels of prevalence, strategies involving SPECT and/or sECG were considered to be a better use of resources than a strategy of direct CA. Furthermore, strategies involving SPECT were often found to be dominant or provided additional benefits that might be considered worth the additional cost compared with the sECG-CA strategy.
The new economic models provided by the Assessment Group and the manufacturer used similar designs; decision tree models were constructed for the diagnostic performance of different strategies and Markov models were used to estimate the long-term costs and benefits. They both used a hypothetical cohort of 1000 patients (to start at the age of 60), with the assumption that effectiveness of therapy (CABG, PCI, medical management) lasts for 10 years. The time horizon was 25 years with an annual cycle time.
The diagnostic strategies considered in both models were:
sECG, followed by SPECT if sECG was positive or indeterminate, followed by CA if SPECT was positive or non-diagnostic (sECG-SPECT-CA)
sECG, followed by CA if sECG was positive or non-diagnostic (sECG-CA)
SPECT, followed by CA if SPECT was positive or non-diagnostic (SPECT-CA)
direct CA (CA).
The results were presented as incremental cost per true-positive diagnosed, per accurate diagnosis, per life year gained and per quality-adjusted life year (QALY) gained, and – importantly – were calculated for different levels of prevalence of CAD.
The key results were as follows:
As prevalence of CAD increased, total cost increased and total number of QALYs gained decreased for each diagnostic strategy.
At all prevalence levels of CAD the ordering of diagnostic strategies was the same, with sECG-SPECT-CA being least costly and least effective, and having the lowest average cost per QALY. This implies that an incremental cost is paid for some incremental benefit when SPECT is not included.
CA was the most costly strategy in both models and for all prevalence levels of CAD, and (as the reference standard) was defined as the most effective strategy.
Most incremental cost-effectiveness ratios (ICERs) were less favourable in the manufacturer's model than in the Assessment Report model. However, all ICERs calculated were less than £24,000, apart from the ICER for direct CA compared with SPECT-CA at low and 30% prevalence of CAD.
When compared with sECG-CA at low prevalence of CAD, the ICER for SPECT-CA (£8723) was more favourable than the ICER for direct CA (£21,538). Conversely, at high prevalence of CAD, the more favourable strategy was direct CA with an ICER of £1962, whilst SPECT-CA had an ICER of £3242.
When direct CA was compared with the SPECT-CA strategy, a high ICER was seen at low prevalence (£42,225). However, as prevalence increased, direct CA became increasingly more cost-effective. At 80% prevalence of CAD, the move to the direct CA from SPECT-CA involved a modest extra cost per additional QALY gained (£942 in the Assessment Report and £4482 in the manufacturer's submission).
Several sensitivity analyses showed that the results varied considerably depending on the sensitivity or specificity values entered for SPECT and sECG. When the impact of the additional independent information provided by SPECT was explored by increasing the proportion of SPECT positives whose condition could be satisfactorily managed medically, ICERs generally improved. When the time horizon was less than 15 years, all ICERs became less favourable. In the subgroup analysis for women, the SPECT-CA strategy dominated both the sECG-CA and CA strategies.
In summary, when compared with sECG-CA, SPECT-CA has more favourable ICERs than direct CA at low levels of prevalence of CAD. At higher prevalence levels, the sECG-CA and CA strategies lead to more favourable ICERs than SPECT-CA.
# Consideration of the evidence
The Committee reviewed the evidence available on the clinical and cost effectiveness of MPS for the diagnosis and management of CAD, having considered evidence on the value placed by users on the benefits of MPS for the diagnosis and management of CAD, from people with CAD, those who represent them, and clinical experts. It was also mindful of the need to ensure that its advice took account of the effective use of NHS resources.
The Committee considered the evidence submitted on the diagnostic performance of SPECT indicating that, overall, it is more sensitive than sECG. However, the Committee appreciated that considerable uncertainty remains over the true values for sensitivity and specificity of SPECT. In particular, trials that assessed these values were subject to referral bias, in that only SPECT-positive cases were referred for CA, which was assumed to be the 'gold standard'. Additionally the Committee was aware that, contrary to SPECT, CA does not always provide the fullest evaluation of the patient with CAD, particularly where information relating to myocardial perfusion and function are considered important for the establishment of prognosis and management.
The Committee heard from the clinical experts that SPECT is of value at all levels of likelihood for CAD, because it provides highly accurate diagnostic and prognostic information. The experts indicated that, if SPECT and sECG were equally accessible in the NHS, there would be a case for the preferential use of SPECT in certain groups of patients. However, because of the currently limited availability of SPECT in the UK, the committee believed that its use should be particularly directed to patient groups for whom it provides the greatest additional benefit in terms of initial diagnosis of suspected CAD and in the management and prediction of prognosis in those with established CAD.
The Committee also recognised that there are circumstances where the information from sECG is important, as in the evaluation of the overall exercise performance of patients with CAD. sECG is therefore likely to remain a commonly used investigation in most circumstances.
The Committee reviewed the cost-effectiveness modelling. They noted that because the difference in QALYs derived between the different investigational strategies was small, and the disutility of CA was not included in the models, the conclusions of cost–utility differences between diagnostic strategies (see Section 4.2.4) should be interpreted with caution. However, the Committee considered that, overall, SPECT was cost effective across a wide range of clinical situations.
The Committee further considered that, in terms of both clinical effectiveness and cost effectiveness, the absolute 'value' of SPECT as an appropriate diagnostic tool depends on the likelihood of the presence of CAD in the target population under investigation. Thus the diagnostic strategy SPECT-CA is clearly preferred on cost-effectiveness grounds in individuals with a lower likelihood of CAD and consequently lower risk of future coronary events. However, as the likelihood of CAD increases, differences in the incremental cost effectiveness for the different testing strategies decrease. Thus, at higher likelihood of CAD and of possible intervention (CABG or PCI), a strategy where direct CA is preferred over SPECT-CA could be considered more appropriate.
The Committee heard from the experts that SPECT enables the redirection of patients into medical rather than surgical management. SPECT may therefore postpone or completely avert the need for CA in some clinical situations. The Committee also recognised the significance of the disutility associated with CA, which would favour SPECT and had been omitted from the economic models reviewed. It concluded that full consideration of these aspects is likely to improve the cost effectiveness of SPECT.
The Committee was advised by the experts that SPECT scanning may be particularly useful as an initial diagnostic tool in people for whom sECG poses particular problems of poor sensitivity or difficulties with interpretation. This includes women, patients with cardiac conduction defects (such as left bundle branch block) and people with diabetes. SPECT also has an important role in assessing the presence of CAD in patients for whom treadmill exercise is difficult or impossible, and in the full evaluation of patients following MI or reperfusion interventions.
The Committee considered that increased provision of SPECT within the NHS over that currently available was desirable on the basis of this evidence. However, it recognised that more widespread use of SPECT would require an implementation strategy that may take several years to fulfil and would need a significant increase in the availability of both equipment and trained staff. The Committee therefore concluded that the increased use of SPECT should initially be targeted at those groups for whom it provides the greatest benefit in terms of cost effectiveness, as expressed in Section 1.# Recommendations for further research
Further research is recommended in patients with established CAD regarding the value of SPECT relative to other tests of cardiac function such as echocardiography, magnetic resonance imaging and positron emission tomography in order to inform future assessment of the needs of the NHS.# Implications for the NHS
According to the British Nuclear Cardiology Society survey, there were about 1200 SPECT scans per million population in the UK in 2000. The average waiting time for a scan was 20 weeks. The submission prepared jointly by the professional groups estimated the optimal level of SPECT provision to be around 4000 SPECT scans per million population per year, calculated on the basis of current revascularisation and CA rates. Furthermore, it suggested that suitable waiting times would be 6 weeks for routine scans and 1 week for urgent tests.
In order to achieve these levels of both adequacy of provision and speed of accessibility, it is estimated that 73 additional gamma cameras would be needed in England and Wales, at a capital cost of around £18 million. This is based on providing 2000 scans per annum per gamma camera, and a unit cost of £250,000 per camera.
Because of the current lack of trained personnel, these levels of provision could take some years to achieve, so the total cost to the NHS is likely to be phased over several years. Once a steady state is achieved, based on the provision of 4000 SPECT tests per million population per year, the estimated annual revenue cost would be in the order of £27 million.# Related guidance
The Institute issued guidance on the use of glycoprotein IIb/IIIa inhibitors in September 2002:
National Institute for Clinical Excellence (2002) Guidance on the use of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes. NICE Technology Appraisal Guidance No. 47. London: National Institute for Clinical Excellence.
The Institute issued guidance on the use of drugs for early thrombolysis in October 2002:
National Institute for Clinical Excellence (2002) Guidance on the use of drugs for early thrombolysis in the treatment of acute myocardial infarction.NICE Technology Appraisal Guidance No. 52. London: National Institute for Clinical Excellence.
The Institute issued guidance on the use of coronary artery stents in October 2003:
National Institute for Clinical Excellence (2003) Guidance on the use of coronary artery stents.NICE Technology Appraisal Guidance No. 71. London: National Institute for Clinical Excellence.
The Institute issued a clinical guideline on prophylaxis for patients who have experienced an MI in April 2001:
National Institute for Clinical Excellence (2001) Prophylaxis for patients who have experienced a myocardial infarction. NICE Inherited Clinical Guideline A. London: National Institute for Clinical Excellence.
The Institute issued a clinical guideline on heart failure in July 2003:
National Institute for Clinical Excellence (2003) Clinical Guideline on management of chronic heart failure in adults in primary and secondary care. NICE Clinical Guideline 5. London: National Institute for Clinical Excellence. .# Review of guidance
The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review.
The guidance on this technology will be reviewed in November 2006.
Andrew DillonChief ExecutiveNovember 2003# Appendix C. Detail on criteria for audit of the use of myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction
# Possible objectives for an audit
An audit on MPS using SPECT could be carried out to ensure that the technique is used appropriately.
# Possible patients to be included in the audit
An audit could be carried out on people referred for investigation of coronary artery disease (CAD) and people who have CAD and who remain symptomatic following myocardial infarction, CABG or PCI, for a reasonable period for audit, for example, 3 or 6 months.
# Measures that could be used as a basis for audit
The measure that could be used in an audit of MPS using SPECT for people referred for investigation of CAD is as follows.
Criterion
Standard
Exception
Definition of terms
. MPS using SPECT is carried out in the following circumstances:
a. as the initial diagnostic tool for an individual with suspected CAD for whom sECG poses problems of poor sensitivity or difficulties in interpretation or for whom treadmill exercise is difficult or impossible
b. as part of an investigational strategy for the diagnosis of suspected CAD in an individual with a lower likelihood of CAD and of future cardiac events
% of people who have suspected CAD and who meet 1a or 1b
None
Clinicians will need to agree locally on how patients are identified as having suspected CAD, for audit purposes.
For 1a, people for whom there may be problems of sensitivity or interpretation include women, people with cardiac conduction defects (for example, left bundle branch block), and people with diabetes. Clinicians will need to agree locally on how a patient for whom treadmill exercise is difficult or impossible is identified, for audit purposes.
For 1b, clinicians will need to agree locally on how the likelihood of CAD and the likelihood of future cardiac events is determined to be low, for audit purposes. Risk factors include age, gender, ethnic group, family history, associated co-morbidities, clinical presentation, physical examination, and results from other investigations (for example, blood cholesterol levels or a resting electrocardiogram).
The measure that could be used in an audit of MPS using SPECT for people with established CAD who remain symptomatic following myocardial infarction, CABG or PCI is as follows.
Criterion
Standard
Exception
Definition of terms
. MPS using SPECT is carried out as part of an investigational strategy for an individual with established CAD who remains symptomatic following myocardial infarction, CABG or PCI
% of people with established CAD who remain symptomatic following myocardial infarction, CABG or PCI
None
Clinicians will need to agree locally on the definition of symptomatic for an individual patient that is documented, for audit purposes.
# Calculation of compliance
Compliance (%) with each measure described in the table above is calculated as follows.
Number of patients whose care is consistent with the criterion plus number of patients who meet any exception listed
x 100
Number of patients to whom the measure applies
Clinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.# Changes after publication
March 2014: minor maintenance
March 2012: minor maintenance
July 2011: This guidance has been partially updated by 'Chest pain of recent onset' (NICE clinical guideline 95) and 'Stable angina' (NICE clinical guideline 126).
There have been changes to the recommendations in this guidance since publication. This web version contains the current wording of the recommendations. For information about the changes, see the web summary page for the guidance.# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': "This guidance has been partially updated by 'Chest pain of recent onset' (NICE clinical guideline 95) and 'Stable angina' (NICE clinical guideline 126).\n\nThis appraisal covers the use of myocardial perfusion scintigraphy (MPS) using single photon emission computed tomography (SPECT) in the diagnosis and management of angina and myocardial infarction. It does not cover planar MPS or the use of MPS in the management of heart failure or in the assessment of myocardial viability. In this guidance the term coronary artery disease (CAD) is used to refer to angina and myocardial infarction.\n\nThis recommendation has been updated and replaced by recommendation 1.3.6.1 in NICE clinical guideline 95.\n\nMPS using SPECT is recommended as part of the investigational strategy in the management of established CAD in people who remain symptomatic following myocardial infarction or reperfusion interventions.This recommendation has been partially updated by recommendations 1.5.2 and 1.5.12 in NICE clinical guideline 126.", 'Clinical need and practice': "Coronary artery disease (CAD) is the commonest cause of death in England and Wales. It is characterised by the development of lipid-laden coronary arterial plaques, which reduce the blood supply to the heart muscle. Significant CAD is defined as a stenosis (narrowing) of more than 70% of the diameter of at least one major epicardial artery segment or more than 50% of the diameter of the left main coronary artery.\n\nAngina (chest pain) is the most common symptom of CAD. It is usually provoked by exercise and relieved by rest. Angina of rapidly increasing frequency, or experienced at rest, is called unstable angina. CAD can also lead to heart attack (myocardial infarction, MI) and sudden cardiac death. MI is characterised by severe chest pain persisting for at least 20 minutes, a rise in cardiac enzymes in the serum, and/or an abnormal electrocardiogram (ECG).\n\nAbout 2.65 million people in the UK have CAD, and of these 1.2 million have had an MI. There were an estimated 275,000 heart attacks in the UK in 2001, and 335,000 new cases of angina are diagnosed each year. CAD is more prevalent in men than in women. The prevalence of CAD increases with age, and varies across geographic regions and socioeconomic groups.\n\nPreventative strategies for reducing the frequency of CAD include smoking cessation, diet modification, exercise, and treating conditions that exacerbate progression of the disease, such as hyperlipidaemia, hyperglycaemia, hypertension and blood hypercoagulability. Medical treatment of angina symptoms includes the use of nitrates, beta-adrenergic blockers and/or calcium channel blockers. In severe CAD, revascularisation may be required, using surgical procedures such as coronary artery bypass grafting (CABG) or via the use of percutaneous coronary intervention (PCI), commonly with the insertion of an intraluminal coronary stent.\n\nThe cost of CAD to the UK healthcare system in 1999 was estimated in the Assessment Report (see Appendix B) at £1.7 billion; the total annual cost was around £7 billion when informal care and productivity losses were included. More than 378,000 inpatients were treated for CAD in NHS hospitals in 2000/2001. Approximately 28,500 CABG and 39,000 PCI procedures are performed each year in the UK.\n\nThe individual likelihood for CAD can be estimated from age, gender, ethnic group, family history, existence of symptoms, associated comorbidities and the results of tests such as resting electrocardiography (rECG). rECG is a commonly used test because it is readily available in primary care and is inexpensive, but because it does not exclude CAD, it is of limited diagnostic value. Stress ECG (sECG) and coronary angiography (CA) are commonly used in clinical practice for the diagnosis of CAD.\n\nsECG is normally recorded during progressive exercise on a treadmill, and so is not suitable for people for whom treadmill exercise is difficult or impossible.\n\nCA involves manipulating a cardiac catheter into the heart from a vein or artery in a limb. A contrast medium is injected through the catheter, and its progress monitored by a rapid series of X-rays. CA provides mainly anatomical information and is used to measure the degree of stenosis. It is considered the 'gold standard' for defining the site and severity of coronary artery lesions. However, CA findings are not always a reliable indicator of the functional significance of a coronary stenosis. Routine use of CA without prior non-invasive testing is not advisable, because of its high cost and associated mortality and morbidity. Potential complications include non-fatal MI (0.1%), stroke (0.1%) and death (0.1–0.2%).\n\nOther frequently used non-invasive techniques include myocardial perfusion scintigraphy (MPS) and echocardiography. Imaging techniques such as magnetic resonance imaging and positron emission tomography are used less frequently.", 'The technology': "MPS involves the intravenous injection of small amounts of a radioactive tracer to evaluate perfusion of living cardiac muscle via the coronary arteries after stress and at rest. After injection, the tracer is taken up by cardiac muscle cells, and its distribution within the myocardium is imaged using a gamma camera. Three tracers are commercially available in the UK: thallium-201 thallous chloride, technetium-99m 2-methoxy-isobutyl-isonitrile, and technetium-99m 1,2-bis(bis[2-ethoxyethyl]phosphino)ethane. MPS is a non-invasive procedure which provides more detailed information about coronary function than sECG and CA. Cardiovascular stress can be induced by exercise as in sECG, but is most commonly induced by pharmacological agents.\n\nMPS was originally developed as a planar imaging technique, but SPECT is the clinical standard in current practice. In SPECT, the camera rotates around the patient for 10–20 minutes and the raw data are processed to obtain tomographic images of the myocardium. The stress and rest images are normally separated by 3–4 hours. The total patient contact time for stress induction, injection and image acquisition is approximately 60 minutes.\n\nHomogeneous uptake of tracer throughout the myocardium indicates the absence of clinically significant infarction or coronary stenosis. A defect in the stress images that normalises in the rest images usually corresponds to a significant coronary stenosis. A defect in both stress and rest images indicates an area with loss of viable myocardium, such as after MI.\n\nTwo technical improvements to SPECT were also considered in this appraisal. Attenuation-corrected SPECT compensates for the fact that many emitted photons never reach the detector as a result of interactions with body tissues. ECG-gated SPECT is synchronised with the patient's ECG, thereby minimising artefacts caused by cardiac motion. Also, left ventricular ejection fraction can be measured at rest with ECG-gated SPECT.\n\nThe complication rates for SPECT are no different from those of sECG, and are usually related to exercise or pharmacological stimulation given as part of the stress component in the procedure, with an associated mortality of around 0.01% and a morbidity of around 0.02%. The radiation exposure from SPECT is similar to the exposure from uncomplicated CA.\n\nThe cost of a SPECT scan is estimated to be around £265, whereas the costs for sECG and CA are £104 and £1103, respectively (2002 NHS reference costs).", 'Evidence and interpretation': "The Appraisal Committee (Appendix A) considered evidence from a number of sources (see Appendix B).\n\n# Clinical effectiveness\n\nThe Assessment Report and the submissions reviewed the literature and focused on two aspects separately: the diagnostic performance of SPECT, and its long-term prognostic value. Much of the evidence consisted of non-randomised open observational (both prospective and retrospective) studies, with several studies using a comparative design.\n\n## Diagnostic performance\n\nThe diagnostic performance of SPECT was expressed as sensitivity and specificity. Sensitivity is the proportion of true-positives that are correctly identified by the test. Specificity is the proportion of true-negatives that are correctly identified by the test.\n\nThe Assessment Report reviewed 21 studies with 100 or more patients that evaluated the sensitivity and specificity of both SPECT and sECG in the diagnosis of CAD compared with CA. Median sensitivity values for SPECT were higher than those for sECG in all studies (SPECT: 81% for the largest subcategory of studies, with a range of 63–93%; sECG: 65% for the largest subcategory of studies, with a range of 42–92%). However, the results were not pooled because of the heterogeneity across the different studies. Median specificity values were similar for SPECT (65%, range 10–90%) and sECG (67%, range 41–88%).\n\nThe submission from the professional groups reviewed the diagnostic performance of SPECT only (compared with CA) from 62 studies. Because of differences in inclusion criteria, only two of these studies were also included in the Assessment Report analysis. There was considerable variation in study size, quality and design, but weighted means for sensitivity and specificity were reported to be 86% and 74%, respectively. The manufacturer's submission quoted one publication with sensitivity and specificity for SPECT reported as 91% and 89%, respectively, and the American College of Cardiologists/American Heart Association Task Force guideline, with average sensitivity and specificity reported as 89–90% and 70–76%, respectively.\n\n## Long-term prognostic value\n\nFor the long-term prognostic value of SPECT, the Assessment Report included a systematic review of 46 observational studies.\n\nIn the 20 studies that provided general prognostic information, cardiac event rates (defined as cardiac mortality or non-fatal MI) were significantly higher for patients with abnormal SPECT scans than for those with normal scans. An abnormal SPECT result was associated with an annual cardiac event rate of 6.7%, whereas a normal scan was associated with an annual cardiac event rate of 0.7% (data from metaanalyses of 15,000 and 20,963 patients, respectively). Furthermore, the extent and size of a perfusion defect can predict the likelihood of future cardiac events.\n\nThe proportion of normal angiograms was lower in patients who were referred to CA after a positive SPECT than in patients referred directly for CA (two studies: 33% versus 43% [4688 patients], and 18% versus 33% [6800 patients], respectively).\n\nHowever, the rate of subsequent revascularisations was lower for the SPECT-CA strategy (13–27%) than for the direct CA strategy (16–44%) (data from three studies with a combined total of approximately 11,000 patients).\n\nIn studies where it was possible to analyse the contribution of different clinical parameters to the prediction of clinical outcomes, it was found that SPECT provided independent prognostic information for predicting MI, and had an additional value over clinical and sECG data that was maintained at long-term follow-up.\n\nIn several studies that investigated whether an abnormal SPECT scan was a predictor of cardiac death, the relative risk or odds ratios were calculated depending on study design. In all studies an abnormal SPECT scan was described as an independent, main or statistically significant predictor of cardiac death. In four studies, with patient numbers ranging from 176 to 947, the relative risk ranged between 1.1 and 17.6. In two studies, with patient numbers of 248 and 1182, the odds ratios were reported to be 2.8 and 4.8, respectively.\n\nSPECT also provided independent prognostic information in the following subgroups: women (five studies), patients post-MI (four studies), patients who had undergone PCI or CABG (three studies), medically treated patients with left main and/or three-vessel CAD (one study), patients hospitalised with angina who had a normal or non-diagnostic sECG (one study), and patients with diabetes (two studies).\n\nTwo studies found ECG-gated SPECT to be more sensitive than non-ECG-gated SPECT, but with slightly lower specificity. Also, ECG-gated SPECT provided incremental prognostic information in patients with known or suspected CAD that was better than perfusion data alone. One study compared SPECT with attenuation-corrected SPECT and reported that attenuation correction had a significant impact on the assessment of the severity and extent of MI.\n\nThe search strategy used in the Assessment Report did not identify any studies evaluating the role of SPECT in the context of rapid access chest pain clinics or in pre-operative risk assessment of patients undergoing major surgery who were potentially at risk of coronary events. However, the submission from the professional groups lists 20 studies on SPECT in pre-operative risk assessment, and emphasises the acknowledged role of SPECT for this indication.\n\nIn summary, as studies reviewed in the Assessment Report were carried out under a number of different clinical settings investigating different outcomes, it was not possible to summarise the effectiveness of SPECT in simple quantitative estimates. However, the evidence from the reviewed studies consistently suggested that SPECT provided valuable independent and incremental information predictive of outcome that helped to risk-stratify patients and influence the way in which their condition was managed.\n\nThe submissions from the professional groups and the manufacturer included reviews of a larger number of papers and, because of differences in the inclusion criteria, there was little overlap between the studies included in each of the three reviews. Despite the differences in the evidence base of the three reviews, similar conclusions were drawn.\n\n# Cost effectiveness\n\nThe Assessment Group, the manufacturer and the professional group reviewed published cost-effectiveness studies. The Assessment Group and the manufacturer also provided new economic models.\n\nThe systematic review in the Assessment Report included studies that compared both costs and outcomes of SPECT with alternative diagnostic strategies. The comparison of different publications was complicated by the multitude of strategies considered, differences in study designs and populations, in treatment comparisons, in costing methods and different ways in which outcomes were measured. Overall, it was concluded that direct CA (without any prior tests) was cost effective when the prevalence of disease was high. At low levels of prevalence, strategies involving SPECT and/or sECG were considered to be a better use of resources than a strategy of direct CA. Furthermore, strategies involving SPECT were often found to be dominant or provided additional benefits that might be considered worth the additional cost compared with the sECG-CA strategy.\n\nThe new economic models provided by the Assessment Group and the manufacturer used similar designs; decision tree models were constructed for the diagnostic performance of different strategies and Markov models were used to estimate the long-term costs and benefits. They both used a hypothetical cohort of 1000 patients (to start at the age of 60), with the assumption that effectiveness of therapy (CABG, PCI, medical management) lasts for 10 years. The time horizon was 25 years with an annual cycle time.\n\nThe diagnostic strategies considered in both models were:\n\nsECG, followed by SPECT if sECG was positive or indeterminate, followed by CA if SPECT was positive or non-diagnostic (sECG-SPECT-CA)\n\nsECG, followed by CA if sECG was positive or non-diagnostic (sECG-CA)\n\nSPECT, followed by CA if SPECT was positive or non-diagnostic (SPECT-CA)\n\ndirect CA (CA).\n\nThe results were presented as incremental cost per true-positive diagnosed, per accurate diagnosis, per life year gained and per quality-adjusted life year (QALY) gained, and – importantly – were calculated for different levels of prevalence of CAD.\n\nThe key results were as follows:\n\nAs prevalence of CAD increased, total cost increased and total number of QALYs gained decreased for each diagnostic strategy.\n\nAt all prevalence levels of CAD the ordering of diagnostic strategies was the same, with sECG-SPECT-CA being least costly and least effective, and having the lowest average cost per QALY. This implies that an incremental cost is paid for some incremental benefit when SPECT is not included.\n\nCA was the most costly strategy in both models and for all prevalence levels of CAD, and (as the reference standard) was defined as the most effective strategy.\n\nMost incremental cost-effectiveness ratios (ICERs) were less favourable in the manufacturer's model than in the Assessment Report model. However, all ICERs calculated were less than £24,000, apart from the ICER for direct CA compared with SPECT-CA at low and 30% prevalence of CAD.\n\nWhen compared with sECG-CA at low prevalence of CAD, the ICER for SPECT-CA (£8723) was more favourable than the ICER for direct CA (£21,538). Conversely, at high prevalence of CAD, the more favourable strategy was direct CA with an ICER of £1962, whilst SPECT-CA had an ICER of £3242.\n\nWhen direct CA was compared with the SPECT-CA strategy, a high ICER was seen at low prevalence (£42,225). However, as prevalence increased, direct CA became increasingly more cost-effective. At 80% prevalence of CAD, the move to the direct CA from SPECT-CA involved a modest extra cost per additional QALY gained (£942 in the Assessment Report and £4482 in the manufacturer's submission).\n\nSeveral sensitivity analyses showed that the results varied considerably depending on the sensitivity or specificity values entered for SPECT and sECG. When the impact of the additional independent information provided by SPECT was explored by increasing the proportion of SPECT positives whose condition could be satisfactorily managed medically, ICERs generally improved. When the time horizon was less than 15 years, all ICERs became less favourable. In the subgroup analysis for women, the SPECT-CA strategy dominated both the sECG-CA and CA strategies.\n\nIn summary, when compared with sECG-CA, SPECT-CA has more favourable ICERs than direct CA at low levels of prevalence of CAD. At higher prevalence levels, the sECG-CA and CA strategies lead to more favourable ICERs than SPECT-CA.\n\n# Consideration of the evidence\n\nThe Committee reviewed the evidence available on the clinical and cost effectiveness of MPS for the diagnosis and management of CAD, having considered evidence on the value placed by users on the benefits of MPS for the diagnosis and management of CAD, from people with CAD, those who represent them, and clinical experts. It was also mindful of the need to ensure that its advice took account of the effective use of NHS resources.\n\nThe Committee considered the evidence submitted on the diagnostic performance of SPECT indicating that, overall, it is more sensitive than sECG. However, the Committee appreciated that considerable uncertainty remains over the true values for sensitivity and specificity of SPECT. In particular, trials that assessed these values were subject to referral bias, in that only SPECT-positive cases were referred for CA, which was assumed to be the 'gold standard'. Additionally the Committee was aware that, contrary to SPECT, CA does not always provide the fullest evaluation of the patient with CAD, particularly where information relating to myocardial perfusion and function are considered important for the establishment of prognosis and management.\n\nThe Committee heard from the clinical experts that SPECT is of value at all levels of likelihood for CAD, because it provides highly accurate diagnostic and prognostic information. The experts indicated that, if SPECT and sECG were equally accessible in the NHS, there would be a case for the preferential use of SPECT in certain groups of patients. However, because of the currently limited availability of SPECT in the UK, the committee believed that its use should be particularly directed to patient groups for whom it provides the greatest additional benefit in terms of initial diagnosis of suspected CAD and in the management and prediction of prognosis in those with established CAD.\n\nThe Committee also recognised that there are circumstances where the information from sECG is important, as in the evaluation of the overall exercise performance of patients with CAD. sECG is therefore likely to remain a commonly used investigation in most circumstances.\n\nThe Committee reviewed the cost-effectiveness modelling. They noted that because the difference in QALYs derived between the different investigational strategies was small, and the disutility of CA was not included in the models, the conclusions of cost–utility differences between diagnostic strategies (see Section 4.2.4) should be interpreted with caution. However, the Committee considered that, overall, SPECT was cost effective across a wide range of clinical situations.\n\nThe Committee further considered that, in terms of both clinical effectiveness and cost effectiveness, the absolute 'value' of SPECT as an appropriate diagnostic tool depends on the likelihood of the presence of CAD in the target population under investigation. Thus the diagnostic strategy SPECT-CA is clearly preferred on cost-effectiveness grounds in individuals with a lower likelihood of CAD and consequently lower risk of future coronary events. However, as the likelihood of CAD increases, differences in the incremental cost effectiveness for the different testing strategies decrease. Thus, at higher likelihood of CAD and of possible intervention (CABG or PCI), a strategy where direct CA is preferred over SPECT-CA could be considered more appropriate.\n\nThe Committee heard from the experts that SPECT enables the redirection of patients into medical rather than surgical management. SPECT may therefore postpone or completely avert the need for CA in some clinical situations. The Committee also recognised the significance of the disutility associated with CA, which would favour SPECT and had been omitted from the economic models reviewed. It concluded that full consideration of these aspects is likely to improve the cost effectiveness of SPECT.\n\nThe Committee was advised by the experts that SPECT scanning may be particularly useful as an initial diagnostic tool in people for whom sECG poses particular problems of poor sensitivity or difficulties with interpretation. This includes women, patients with cardiac conduction defects (such as left bundle branch block) and people with diabetes. SPECT also has an important role in assessing the presence of CAD in patients for whom treadmill exercise is difficult or impossible, and in the full evaluation of patients following MI or reperfusion interventions.\n\nThe Committee considered that increased provision of SPECT within the NHS over that currently available was desirable on the basis of this evidence. However, it recognised that more widespread use of SPECT would require an implementation strategy that may take several years to fulfil and would need a significant increase in the availability of both equipment and trained staff. The Committee therefore concluded that the increased use of SPECT should initially be targeted at those groups for whom it provides the greatest benefit in terms of cost effectiveness, as expressed in Section 1.", 'Recommendations for further research': 'Further research is recommended in patients with established CAD regarding the value of SPECT relative to other tests of cardiac function such as echocardiography, magnetic resonance imaging and positron emission tomography in order to inform future assessment of the needs of the NHS.', 'Implications for the NHS': 'According to the British Nuclear Cardiology Society survey, there were about 1200 SPECT scans per million population in the UK in 2000. The average waiting time for a scan was 20 weeks. The submission prepared jointly by the professional groups estimated the optimal level of SPECT provision to be around 4000 SPECT scans per million population per year, calculated on the basis of current revascularisation and CA rates. Furthermore, it suggested that suitable waiting times would be 6 weeks for routine scans and 1 week for urgent tests.\n\nIn order to achieve these levels of both adequacy of provision and speed of accessibility, it is estimated that 73 additional gamma cameras would be needed in England and Wales, at a capital cost of around £18 million. This is based on providing 2000 scans per annum per gamma camera, and a unit cost of £250,000 per camera.\n\nBecause of the current lack of trained personnel, these levels of provision could take some years to achieve, so the total cost to the NHS is likely to be phased over several years. Once a steady state is achieved, based on the provision of 4000 SPECT tests per million population per year, the estimated annual revenue cost would be in the order of £27 million.', 'Related guidance': 'The Institute issued guidance on the use of glycoprotein IIb/IIIa inhibitors in September 2002:\n\nNational Institute for Clinical Excellence (2002) Guidance on the use of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes. NICE Technology Appraisal Guidance No. 47. London: National Institute for Clinical Excellence.\n\nThe Institute issued guidance on the use of drugs for early thrombolysis in October 2002:\n\nNational Institute for Clinical Excellence (2002) Guidance on the use of drugs for early thrombolysis in the treatment of acute myocardial infarction.NICE Technology Appraisal Guidance No. 52. London: National Institute for Clinical Excellence.\n\nThe Institute issued guidance on the use of coronary artery stents in October 2003:\n\nNational Institute for Clinical Excellence (2003) Guidance on the use of coronary artery stents.NICE Technology Appraisal Guidance No. 71. London: National Institute for Clinical Excellence.\n\nThe Institute issued a clinical guideline on prophylaxis for patients who have experienced an MI in April 2001:\n\nNational Institute for Clinical Excellence (2001) Prophylaxis for patients who have experienced a myocardial infarction. NICE Inherited Clinical Guideline A. London: National Institute for Clinical Excellence. [replaced by NICE clinical guideline 48]\n\nThe Institute issued a clinical guideline on heart failure in July 2003:\n\nNational Institute for Clinical Excellence (2003) Clinical Guideline on management of chronic heart failure in adults in primary and secondary care. NICE Clinical Guideline 5. London: National Institute for Clinical Excellence. [Replaced by NICE clinical guideline 108].', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review.\n\nThe guidance on this technology will be reviewed in November 2006.\n\nAndrew DillonChief ExecutiveNovember 2003', 'Appendix C. Detail on criteria for audit of the use of myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction': '# Possible objectives for an audit\n\nAn audit on MPS using SPECT could be carried out to ensure that the technique is used appropriately.\n\n# Possible patients to be included in the audit\n\nAn audit could be carried out on people referred for investigation of coronary artery disease (CAD) and people who have CAD and who remain symptomatic following myocardial infarction, CABG or PCI, for a reasonable period for audit, for example, 3 or 6 months.\n\n# Measures that could be used as a basis for audit\n\nThe measure that could be used in an audit of MPS using SPECT for people referred for investigation of CAD is as follows.\n\nCriterion\n\nStandard\n\nException\n\nDefinition of terms\n\n. MPS using SPECT is carried out in the following circumstances:\n\na. as the initial diagnostic tool for an individual with suspected CAD for whom sECG poses problems of poor sensitivity or difficulties in interpretation or for whom treadmill exercise is difficult or impossible\n\nb. as part of an investigational strategy for the diagnosis of suspected CAD in an individual with a lower likelihood of CAD and of future cardiac events\n\n% of people who have suspected CAD and who meet 1a or 1b\n\n\n\nNone\n\nClinicians will need to agree locally on how patients are identified as having suspected CAD, for audit purposes.\n\nFor 1a, people for whom there may be problems of sensitivity or interpretation include women, people with cardiac conduction defects (for example, left bundle branch block), and people with diabetes. Clinicians will need to agree locally on how a patient for whom treadmill exercise is difficult or impossible is identified, for audit purposes.\n\nFor 1b, clinicians will need to agree locally on how the likelihood of CAD and the likelihood of future cardiac events is determined to be low, for audit purposes. Risk factors include age, gender, ethnic group, family history, associated co-morbidities, clinical presentation, physical examination, and results from other investigations (for example, blood cholesterol levels or a resting electrocardiogram).\n\nThe measure that could be used in an audit of MPS using SPECT for people with established CAD who remain symptomatic following myocardial infarction, CABG or PCI is as follows.\n\nCriterion\n\nStandard\n\nException\n\nDefinition of terms\n\n. MPS using SPECT is carried out as part of an investigational strategy for an individual with established CAD who remains symptomatic following myocardial infarction, CABG or PCI\n\n% of people with established CAD who remain symptomatic following myocardial infarction, CABG or PCI\n\nNone\n\nClinicians will need to agree locally on the definition of symptomatic for an individual patient that is documented, for audit purposes.\n\n# Calculation of compliance\n\nCompliance (%) with each measure described in the table above is calculated as follows.\n\nNumber of patients whose care is consistent with the criterion plus number of patients who meet any exception listed\n\nx 100\n\nNumber of patients to whom the measure applies\n\nClinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.', 'Changes after publication': "March 2014: minor maintenance\n\nMarch 2012: minor maintenance\n\nJuly 2011: This guidance has been partially updated by 'Chest pain of recent onset' (NICE clinical guideline 95) and 'Stable angina' (NICE clinical guideline 126).\n\nThere have been changes to the recommendations in this guidance since publication. This web version contains the current wording of the recommendations. For information about the changes, see the web summary page for the guidance.", 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta73
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Evidence-based recommendations on myocardial perfusion scintigraphy for diagnosing and managing angina and myocardial infarction in adults.
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Erlotinib monotherapy for maintenance treatment of non-small-cell lung cancer
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Erlotinib monotherapy for maintenance treatment of non-small-cell lung cancer
Evidence-based recommendations on erlotinib (Tarceva) for the maintenance treatment of non-small-cell lung cancer in adults.
# Guidance
Erlotinib monotherapy is not recommended for maintenance treatment in people with locally advanced or metastatic non-small-cell lung cancer who have stable disease after platinum-based first-line chemotherapy.
People currently receiving erlotinib monotherapy for maintenance treatment of locally advanced or metastatic non-small-cell lung cancer who have stable disease after platinum-based first-line chemotherapy should have the option to continue treatment until they and their clinician consider it appropriate to stop.# The technology
Erlotinib (Tarceva, Roche Products) is an orally active inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. It has a UK marketing authorisation 'as monotherapy for maintenance treatment in patients with locally advanced or metastatic non-small cell lung cancer with stable disease after four cycles of standard platinum-based first-line chemotherapy'. For further information see the summary of product characteristics.
Undesirable effects of erlotinib treatment include diarrhoea, rash, anorexia, gastrointestinal bleeding, liver function test abnormalities and keratitis. For full details of side effects and contraindications, see the summary of product characteristics.
Erlotinib is given orally at a recommended dose of 150 mg/day. The normal acquisition cost of a pack of 30 tablets (150 mg) is £1631.53 (excluding VAT; 'British national formulary' edition 60). The manufacturer of erlotinib has agreed a patient access scheme with the Department of Health in which the acquisition cost of erlotinib is reduced by 14.5% and deducted at the time of supply to the NHS (that is, £1394.96 for a pack of 30 tablets ). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of erlotinib and a review of this submission by the Evidence Review Group (ERG; appendix B).
The manufacturer approached the decision problem by providing clinical and cost-effectiveness evidence for erlotinib maintenance monotherapy compared with best supportive care in patients with stage IIIB or stage IV squamous or non-squamous non-small-cell lung cancer who had stable disease after treatment with standard platinum-based first-line chemotherapy. Best supportive care included palliative radiotherapy, corticosteroids, analgesia and other symptomatic treatments and watchful waiting alone. In the economic evaluation the manufacturer provided combined and separate analyses for patients with squamous and non-squamous disease. The group of patients with non-squamous disease was further divided into two analyses: firstly those who were not eligible for pemetrexed maintenance therapy (that is, patients who received pemetrexed in combination with cisplatin as first-line treatment), with best supportive care as the comparator; and secondly those who were eligible for pemetrexed maintenance therapy (that is, patients who have received first-line treatment with platinum-based chemotherapy which did not include pemetrexed), with pemetrexed as the comparator. The manufacturer noted a lack of head-to-head clinical evidence comparing erlotinib with pemetrexed.
At the time of the manufacturer's original evidence submission, the marketing authorisation for erlotinib had not been granted and the population who would be covered by the marketing authorisation was unclear. Subsequently, erlotinib received a marketing authorisation for the maintenance treatment of a subgroup of patients with locally advanced or metastatic non-small-cell lung cancer, that is, patients with stable disease after standard platinum-based first-line chemotherapy. Because of this, some of the evidence included in the manufacturer's original submission was not relevant and further evidence for the population covered by the marketing authorisation was required. The manufacturer provided additional clinical and cost-effectiveness evidence for patients with stable disease after first-line chemotherapy in response to consultation on the first appraisal consultation document.
The key evidence submitted by the manufacturer for the clinical effectiveness of erlotinib came from a randomised double-blind controlled trial comparing erlotinib with placebo in patients with advanced or metastatic non-small-cell lung cancer whose disease had not progressed following platinum-based first-line chemotherapy (the SATURN trial). This population included patients whose disease was either stable after first-line chemotherapy, or had responded to first-line chemotherapy. Stable disease was defined according to the Response Evaluation Criteria in Solid Tumours (RECIST) as tumour shrinkage that is not sufficient to be classed as a partial response and tumour increase that is not sufficient to be classed as progressive disease.
Patients were included in the SATURN trial if their disease had not progressed after four cycles of a standard, platinum-based chemotherapy doublet (two chemotherapy drugs, one of which is platinum based), if they had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 and their life expectancy was at least 12 weeks. The primary outcome of the trial was progression-free survival, defined as the time between randomisation and the date of the first documented disease progression, or death from any cause. Secondary outcomes included overall survival (defined as the time between randomisation and death), time to disease progression, response rates (assessed by the RECIST criteria) and quality of life (assessed by the Functional Assessment of Cancer Therapy – Lung questionnaire). RECIST criteria were assessed by computed tomography (CT) scans every 6 weeks.
The SATURN trial included 889 patients, of whom 487 (55%) had stable disease after first-line chemotherapy. Of the patients with stable disease, approximately 30% had an ECOG performance status of 0 and 70% had an ECOG performance status of 1 at study entry, 20% had never smoked and 61% had non-squamous disease. Fifty percent of patients were tested for EGFR mutation status and of these 11% had activated EGFR mutations. The most common first-line treatments for patients in the whole trial population were gemcitabine plus carboplatin (28%), gemcitabine plus cisplatin (26%), and paclitaxel plus carboplatin (19%). None of the patients with non-squamous disease received combination chemotherapy with cisplatin and pemetrexed, now the most commonly prescribed first-line regimen in UK clinical practice for this histological subtype of non-small-cell lung cancer. Most patients (48%) were from Eastern Europe, 21% were from south-east Asia and 1% were from the UK. The mean age of patients was 60 years. The proportion of patients who had at least one post-study treatment was 72% in the placebo group and 71% in the erlotinib group, with 21% of patients in the placebo group and 11% in the erlotinib group receiving subsequent treatment with a tyrosine kinase inhibitor (such as erlotinib or gefitinib). The proportion of patients with stable disease who had further systemic therapy after the study was 63% in the placebo group and 61% in the erlotinib group, with 21% of patients in the placebo group and 9% in the erlotinib group receiving subsequent treatment with either erlotinib or gefitinib. Of the 50% of patients with stable disease who were tested, the incidence of activated EGFR mutation was 6% in both the placebo and the erlotinib groups. The manufacturer stated that there were no imbalances between treatment arms when clinical, molecular, or geographical parameters were considered or when prior radiotherapy, subsequent systemic treatments and time to start of investigational treatment were analysed.
The manufacturer did not provide separate demographic analyses for the squamous and non-squamous disease groups in response to consultation on the first appraisal consultation document. However, during consultation on the second appraisal consultation document, the manufacturer indicated that although the baseline characteristics of known prognostic significance in the stable, squamous disease group were reasonably balanced between the erlotinib and best supportive care arms, this was not the case for the non-squamous disease group. Data from the SATURN trial showed that for the population with stable non-squamous disease, 30% of patients in the erlotinib group and 38% in the placebo group had an ECOG status of 0, and 25% of patients in the erlotinib group and 31% in the placebo group had never smoked. The manufacturer stated that because of these imbalances, the true overall survival benefit from erlotinib in the non-squamous disease group is likely to be confounded in favour of the best supportive care group.
For patients with stable disease after first-line chemotherapy, median progression-free survival was 12.1 weeks in the erlotinib group compared with 11.3 weeks in the placebo group (hazard ratio 0.68; 95% confidence interval 0.56 to 0.83, p < 0.0001). Median overall survival was 11.9 months in the erlotinib group compared with 9.6 months in the placebo group, a difference of 2.3 months (HR 0.72; 95% CI 0.59 to 0.89, p = 0.0019). The increase in progression-free survival associated with erlotinib was similar in patients with squamous disease (HR 0.69; 95% CI 0.51 to 0.93, n = 190) and non-squamous disease (HR 0.69; 95% CI 0.54 to 0.87, n = 297). The gain in median overall survival associated with erlotinib for patients with squamous disease was 3.0 months (HR 0.67; 95% CI 0.48 to 0.92) and 3.1 months for patients with non-squamous disease (HR 0.76; 95% CI 0.59 to 1.00). There were no statistically significant differences between the erlotinib and placebo groups in quality of life measures. In response to consultation on the first appraisal consultation document, the manufacturer provided estimates for the mean overall survival benefit associated with erlotinib for patients with squamous and non-squamous disease (4.5 months and 4.2 months respectively). The mean overall survival estimate for the whole stable disease population was 3.3 months.
Subgroup analyses were carried out by the manufacturer in patients with stable disease after first-line chemotherapy by EGFR immunohistochemistry (IHC) status, stage of disease, first-line chemotherapy regimen received, ECOG performance status, smoking status, geographical region, age, race and gender. Erlotinib was associated with a greater median overall survival benefit for patients with EGFR IHC-positive tumours (HR 0.65; 95% CI 0.51 to 0.88, p-value not reported), for patients who had never smoked (HR 0.56; 95% CI 0.32 to 0.97, p-value not reported), and for women (HR 0.55; 95% CI 0.35 to 0.87, p-value not reported) compared with the whole stable disease population. In covariate analyses from the manufacturer of the whole stable SATURN population, south-east Asian patients had a greater progression-free survival benefit from erlotinib than white patients (covariate effect HR 0.78; p = 0.0214), as did patients who had never smoked compared with current smokers (covariate effect HR 1.46; p = 0.0003). In addition, the small subgroup of patients with activated EGFR mutations were also shown to gain substantially more benefit from erlotinib than the trial population as a whole (HR for progression-free survival 0.23; 95% CI 0.12 to 0.45).
During consultation on the second appraisal consultation document, the manufacturer provided adjusted analyses comparing erlotinib with best supportive care in patients with stable, non-squamous disease from the SATURN trial. The analysis suggested that when the data were adjusted for good ECOG performance status and smoking status (never smoked), patients with these characteristics had an improved rate of overall survival after treatment with erlotinib compared with the whole stable, non-squamous disease population (HR 0.71; 95% CI 0.54 to 0.93). The estimate of overall survival was even higher (HR 0.63; 95% CI 0.41 to 0.96) when the analysis was repeated only in patients without an EGFR mutation (that is, the patients who are likely to receive erlotinib in UK clinical practice due to the growing use of gefitinib in patients with an EGFR mutation). In light of these analyses, the manufacturer stated that the overall survival benefit from erlotinib in the non-squamous disease population may have been underestimated in the SATURN trial.
In response to the second appraisal consultation document, the manufacturer provided patient characteristics for the squamous disease group to allay the Committee's concerns that the population in the SATURN trial may not be representative of patients seen in the UK. In particular, they showed that only 0.5% of patients with squamous disease had an EGFR mutation, 6.9% had never smoked and 7.9% were Asian. Given the relatively low incidence of patients with these prognostic factors, the manufacturer stated that they would not have a large impact on the overall survival benefit observed in the SATURN trial for the squamous disease group relative to what would be achieved in UK clinical practice.
The most common adverse events associated with erlotinib for the whole SATURN population were rash (49% in the erlotinib group and 6% in the placebo group) and diarrhoea (20% in the erlotinib group and 5% in the placebo group). In the stable disease subgroup, more patients in the erlotinib group had an adverse event of any kind than in the placebo group (78% compared with 58%). There were 23 deaths in the erlotinib group and 22 in the placebo group during the active treatment phase.
In the original submission, the manufacturer carried out an indirect analysis of erlotinib and pemetrexed in patients with non-squamous disease using data from a randomised controlled trial of pemetrexed maintenance treatment versus placebo in patients with locally advanced or metastatic non-small-cell lung cancer (the JMEN trial). This analysis included patients with stable disease but also included patients whose disease had responded to first-line treatment with platinum-based chemotherapy. The latter group are not covered by the marketing authorisation for erlotinib. In the additional evidence submission, received during consultation on the first appraisal consultation document, the manufacturer stated that an indirect comparison of the SATURN and JMEN trials was not possible because no data on the efficacy of pemetrexed in patients with stable, non-squamous disease from the JMEN trial were publically available. The manufacturer also stated that an indirect analysis was not considered appropriate because of differences in the populations in the two trials.
In the original submission, the manufacturer submitted economic analyses for three different patient populations, two of which included patients who were not covered by the marketing authorisation, that is, patients whose disease had responded to treatment. The only economic analysis that reflected the population covered by the marketing authorisation was the comparison of erlotinib with best supportive care in patients with stable disease. In response to consultation on the first appraisal consultation document, the manufacturer submitted four new economic analyses that included the population covered by the marketing authorisation:
erlotinib compared with best supportive care in all patients with stable disease
erlotinib compared with best supportive care in patients with stable, squamous disease
erlotinib compared with best supportive care in patients with stable, non-squamous disease who were not eligible for pemetrexed maintenance treatment
erlotinib compared with pemetrexed in patients with stable, non-squamous disease who were eligible for pemetrexed maintenance treatment.
The manufacturer's new economic analyses used a model with a cycle length of 1 month and a 15-year time horizon. The model included three health states: progression-free survival, progressed (defined as the time from first treatment relapse until death), and death. All patients were assumed to start in the progression-free survival health state (after first-line chemotherapy). At the end of each cycle they could remain in this state, move to the progressed health state or die.
For the comparison of erlotinib with best supportive care, the risks of disease progression were taken from the SATURN trial. For the comparison of erlotinib with pemetrexed, the base case assumed equal efficacy of pemetrexed and erlotinib. Additional relative efficacy scenarios were modelled, ranging from assuming greater efficacy of pemetrexed (in progression-free survival and overall survival) to assuming greater efficacy of erlotinib.
In the new economic analyses, the manufacturer used the same utility values as those used in 'Pemetrexed for the maintenance treatment of non-small-cell lung cancer' (NICE technology appraisal guidance 190 ). The utility values for the progression-free survival health state were 0.6732 for the erlotinib group and 0.6628 for the placebo group. The utility value for the progressed health state was 0.53.
The new economic analyses included costs for treatment (erlotinib and pemetrexed), best supportive care, adverse events, and post-progression treatment. Costs for erlotinib were based on the patient access scheme (see section 2.3) and the treatment duration from the SATURN trial. Drug wastage was estimated based on when treatment stopped in the SATURN trial. The average per-patient drug costs for erlotinib were £7148 for the overall stable disease population, £6644 for patients with stable, squamous disease, and £7976 for patients with stable, non-squamous disease. Pemetrexed costs were based on the list price to the NHS (BNF 58) and doses were based on the distribution of body surface area of patients with stable, non-squamous disease in the SATURN trial. The average per-patient drug cost for pemetrexed was £13,062. Costs for best supportive care were based on the average cost of specialist palliative care per cancer death per year reported in a publication by NICE and the University of Sheffield (2004). This is the same methodology used in other NICE technology appraisals of treatments for non-small-cell lung cancer ('Pemetrexed for the first-line treatment of non-small-cell lung cancer' ) and in TA190. The best supportive care costs also included costs of regular monitoring (3-monthly hospital visits consisting of a consultant appointment and an outpatient CT scan).
The costs of adverse events associated with erlotinib were based on those used in 'Erlotinib for the treatment of non-small-cell lung cancer' (NICE technology appraisal guidance 162; TA162), and adjusted for inflation. The costs of adverse events associated with pemetrexed were the same as those used in TA181. Post-progression treatment costs were based on various sources including the BNF 58 and other NICE technology appraisal guidance (TA181 and TA190). Data on the number and type of post-progression treatments were collected in the SATURN trial. Because there was a lack of data on post-progression treatment from the JMEN trial, the manufacturer assumed that the costs associated with pemetrexed would be the same as those for the placebo group of the SATURN trial.
In the manufacturer's original submission, the incremental cost-effectiveness ratio (ICER) for the comparison of erlotinib with best supportive care in patients with stable disease was £47,743 per quality-adjusted life year (QALY) gained (incremental cost £7747 and incremental benefit 0.162 QALYs). In response to the first appraisal consultation document the manufacturer revised assumptions about how much time a patient spent on treatment in the progression-free health state and the costs attributed to post-progression best supportive care, resulting in an ICER of £39,936 per QALY gained (incremental cost £7813, incremental benefit 0.196 QALYs) for all patients with stable disease. In response to the second appraisal consultation document the manufacturer provided a revised ICER of £40,792 per QALY gained (incremental cost £7737, incremental benefit 0.190 QALYs) for the stable disease population, using survival estimates proposed by the ERG. For patients with stable, squamous disease the ICER for erlotinib was £35,491 per QALY gained compared with best supportive care (incremental cost £7339, incremental benefit 0.207 QALYs). In patients with stable, non-squamous disease the ICER for erlotinib was £40,020 per QALY gained compared with best supportive care (incremental cost £8696, incremental benefit 0.218 QALYs). For the comparison of erlotinib with pemetrexed in patients with stable, non-squamous disease, the cost of erlotinib was £7531 lower than the cost of pemetrexed. Therefore when erlotinib was assumed to have equal or better efficacy than pemetrexed, erlotinib dominated pemetrexed (that is, it had lower costs and better efficacy). In the manufacturer's various relative efficacy scenarios, the ICER for erlotinib compared with pemetrexed ranged from £77,598 saved per QALY lost (when erlotinib was assumed to have 10% better progression-free survival and 10% worse overall survival than pemetrexed) to £511,351 saved per QALY lost (when erlotinib was assumed to have 10% worse progression-free survival and the same overall survival as pemetrexed).
The manufacturer conducted a number of deterministic sensitivity analyses. The factors that had the greatest impact on the ICERs for erlotinib compared with best supportive care were assuming that a patient spent all their time on treatment in the progression-free health state (£44,942 per QALY gained for the stable population) and using the best supportive care costs from TA162, rather than those from TA181 and TA190 (£44,745 per QALY gained for the stable population). The maximum ICERs for patients with stable, squamous disease and for those with stable, non-squamous disease were £40,599 per QALY gained (compared with £35,491 in the base case) and £44,589 per QALY gained (compared with £40,020 in the base case) respectively.
The ERG reviewed the clinical evidence originally submitted by the manufacturer and the additional evidence provided during consultation. It noted that the extent to which patients and investigators were truly blind to treatment allocation throughout the SATURN trial was uncertain because patients in the erlotinib group were significantly more likely to develop a rash and suffer from diarrhoea than patients in the placebo group. The ERG queried whether the results of the SATURN trial could be generalised to the UK because the trial included very few UK patients and the population was younger and fitter than would be seen in UK clinical practice. It also commented that a greater proportion of patients had first-line treatment with paclitaxel in the trial than would occur in UK clinical practice and no patients had first-line treatment that included pemetrexed, which is now the most common first-line treatment for patients with non-squamous disease (following publication of TA181). The ERG noted inconsistencies in the reporting of post-study treatments between the manufacturer's submission and the SATURN clinical trial report. It commented that the patients in the SATURN trial received a variety of post-progression treatments, many of which are not routinely used in the UK (including pemetrexed, vinorelbine, gemcitabine and paclitaxel). Only docetaxel and erlotinib are recommended by NICE for second-line treatment of non-small-cell lung cancer. The ERG noted that this was likely to affect overall survival results. It commented that the clinical evidence for erlotinib in patients with stable disease was based on a post hoc unstratified subgroup analysis and that the evidence for patients with squamous and non-squamous disease came from a further post hoc division of this subgroup, again according to an unstratified variable. The ERG considered that the SATURN trial was not designed to perform these types of analyses and therefore the results should be interpreted with caution.
The ERG identified data on patients with stable, non-squamous disease from the JMEN trial. It was therefore able to carry out an indirect comparison of pemetrexed and erlotinib (using data from the SATURN trial) for this patient group. The results indicated a statistically significant progression-free survival benefit for pemetrexed (HR 0.64; 95% CI 0.47 to 0.89) but the difference was not statistically significant for overall survival (HR 0.93; 95% CI 0.66 to 1.30). However, the ERG considered that the results of this analysis should be interpreted with caution because of differences in the patient populations in the JMEN and SATURN studies, the limitations of using post hoc subgroup analyses, and the uncertainty about whether both studies could be generalised to patients in the UK.
The ERG reviewed the economic analyses originally submitted by the manufacturer and the additional analyses provided in response to consultation on both appraisal consultation documents. It considered that the comparison of erlotinib with best supportive care in the total population of patients with stable disease could be misleading because it could mask differences in clinical and cost effectiveness between the squamous and non-squamous disease groups. In addition the ERG considered that results from the SATURN trial suggest that following disease progression, subsequent survival rates differ between patients with squamous and non-squamous disease, as there appears to be no difference in post-progression survival in the non-squamous disease group, whereas approximately 60% of the survival benefit associated with erlotinib maintenance treatment occurs during the post-progression period in the squamous disease group. In addition, there was statistically significant heterogeneity in some of the prognostic factors of the patients with squamous and non-squamous disease in the SATURN trial. Therefore, the ERG expressed the view that it was not appropriate to combine the histological groups and hence did not conduct any sensitivity analyses on the manufacturer's estimates for the total stable disease population.
The ERG's main criticism of the models of erlotinib compared with best supportive care in the subgroups of patients with squamous and non-squamous disease was the method used to extrapolate survival beyond the trial period. It noted that the manufacturer had not used post-progression survival data directly from the trial, but instead calculated post-progression survival as the difference between overall survival and progression-free survival. The ERG commented that because all patients in the stable disease population of the SATURN trial had disease which had progressed (that is, the progression-free survival data set was complete), there was no need to model the mean duration of progression-free survival because it could be based directly on Kaplan-Meier survival estimates from the trial. The ERG estimated mean overall survival using new survival data provided by the manufacturer during consultation on the first appraisal consultation document, by adding progression-free survival to post-progression survival and adjusting the estimate to exclude patients dying at or before disease progression. For post-progression survival in the subgroup of patients with squamous disease, the ERG used Kaplan-Meier estimates up to a 20% survival figure and then modelled the remaining survival. For the subgroup of patients with non-squamous disease, data on post-progression survival were available up to 600 days, but required modelling after this point for the remaining 7% of patients; a common exponential model was used for both the intervention and the comparator. The ERG's approach to modelling survival resulted in mean overall survival gains of 3.4 months (95% CI 1.5 to 5.3 months) for patients with stable, squamous disease and 2.2 months (95% CI 0.9 to 3.5 months) for patients with stable, non-squamous disease (corresponding to a 28% and 75% decrease in QALY gains compared with those in the manufacturer's base case respectively). The ERG stressed the wide confidence intervals around these estimates of survival gain. For the population of patients with stable, squamous disease the manufacturer's base-case ICER for erlotinib compared with best supportive care increased from £35,491 to £44,812 per QALY gained (incremental cost £7129, incremental benefit 0.1591 QALYs) using the ERG's modelling approach. For the population of patients with stable, non-squamous disease the manufacturer's base-case ICER for erlotinib compared with best supportive care increased from £40,020 to £68,120 per QALY gained (incremental cost £8340, incremental benefit 0.1224 QALYs).
The ERG commented on the manufacturer's economic analysis of erlotinib compared with pemetrexed in the population of patients with stable, non-squamous disease. It noted that the manufacturer's estimate of pemetrexed costs did not account for gender differences in body surface area. It also noted that a modifying factor that reduced pemetrexed costs by 5% had been used and that no evidence had been provided to support this method. The ERG revised the manufacturer's model using their own estimation of pemetrexed costs, and used the hazard ratios from its indirect analysis (noting the previously mentioned caution about this analysis). The resulting ICER was based on the lower costs (−£8460) and lower efficacy (−0.1007 QALYs) of erlotinib compared with pemetrexed and represented a cost saving of £84,029 per QALY lost.
Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA227# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of maintenance treatment with erlotinib, having considered evidence on the nature of non-small-cell lung cancer and the value placed on the benefits of erlotinib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources and comments received during consultation on both appraisal consultation documents.
The Committee considered current UK practice for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer. It heard from clinical specialists that first-line treatment in the UK is usually with carboplatin or cisplatin plus gemcitabine or vinorelbine, or cisplatin plus pemetrexed for patients with non-squamous disease. If disease progresses, patients have the option of receiving second-line systemic treatment if they have a good performance status. In the UK, second-line treatment is normally docetaxel or erlotinib. The Committee was aware that maintenance treatment after first-line treatment is still a relatively new concept in lung cancer and that its aim is to prolong the benefits of first-line treatment and to maximise quality of life for as long as possible. It noted that best supportive care is currently the only maintenance treatment option for patients with squamous disease. However, pemetrexed is recommended in TA190 as an option for the maintenance treatment of people with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology if disease has not progressed immediately following platinum-based chemotherapy in combination with gemcitabine, paclitaxel or docetaxel. The Committee noted that patients are only eligible for maintenance treatment with pemetrexed if they have not received it as part of first-line treatment in combination with cisplatin. It heard from clinical specialists that the number of patients who would be eligible for maintenance treatment with pemetrexed is already small and would progressively decrease as more patients receive first-line treatment with pemetrexed (in line with TA181).
The Committee noted views from the clinical specialists that erlotinib is an oral drug with adverse effects that are well known and relatively well tolerated. The clinical specialists stated that a potential benefit of maintenance treatment is that it may keep some patients well enough to be able to receive subsequent treatment after first-line therapy. The clinical specialists also commented that erlotinib may provide a maintenance treatment option for patients who cannot receive pemetrexed maintenance treatment because they have squamous disease and/or they have had pemetrexed as a first-line treatment. The Committee also noted a statement from a patient group which emphasised that even relatively small improvements in survival and quality of life afforded by new treatments compared with current treatment options is of real importance to patients.
# Clinical effectiveness
The Committee discussed the evidence on the clinical effectiveness of erlotinib for the maintenance treatment of patients with stable disease. It noted that one randomised trial, the SATURN trial, was presented, which showed that maintenance treatment with erlotinib was associated with a statistically significant improvement in progression-free survival and overall survival compared with placebo for the overall population of patients with stable disease. It noted that the improvement in progression-free survival with erlotinib was similar for patients in the squamous and non-squamous disease subgroups, but a statistically significant improvement in overall survival was only demonstrated in the subgroup of patients with squamous disease (HR 0.67; 95% CI 0.48 to 0.92 compared with HR 0.76; 95% CI 0.59 to 1.00 in the non-squamous disease group). The Committee was aware that the results for patients with stable disease were based on a post hoc subgroup analysis of 55% of the SATURN trial population. Furthermore, the results for the subgroups of patients with squamous and non-squamous disease were also post hoc analyses based on a disaggregation of the stable disease population and there were relatively small numbers of patients in each subgroup (190 and 297 respectively). The Committee was aware that the SATURN trial had not been designed for such analyses. It therefore regarded that the true magnitude of the benefits of erlotinib in these patient populations was uncertain. The Committee considered that the adverse events associated with erlotinib (most commonly, rash and diarrhoea) were well known and noted that most patients in the SATURN trial did not require their treatment to be changed or stopped because of adverse events.
The Committee discussed whether the results of the SATURN trial could be generalised to UK clinical practice, noting that in the trial there were few UK patients, a high proportion of south-east Asian patients and a high proportion of patients who had never smoked. The Committee was aware that Asian patients are known to respond better to lung cancer treatments than patients of other races and patients who have never smoked respond better than those with a history of smoking. It also noted that in the SATURN trial 30% of patients with stable disease still had an ECOG performance status of 0 after four cycles of chemotherapy and this was likely to reflect a fitter group of patients than the population who would receive maintenance treatment with erlotinib in UK clinical practice. The Committee also observed that 66% of patients in the SATURN trial were under 65 years of age and represented a younger population of patients with non-small-cell lung cancer than would be seen in UK clinical practice. It also noted that a high proportion of patients went on to receive further systemic therapy after the SATURN trial, some of which is not routinely given to patients in UK clinical practice. The Committee therefore concluded that the results from the SATURN trial had limited generalisability to UK clinical practice, therefore adding further uncertainty to the true magnitude of the benefits of erlotinib that would be achieved for UK patients.
The Committee acknowledged that the manufacturer provided updated analyses for the stable, non-squamous disease group, during consultation on the appraisal consultation documents, which adjusted for some prognostic factors (ECOG status and smoking history), which the manufacturer suggested may have biased results against erlotinib in the SATURN trial. However, the Committee was concerned about the reliability of the data because of the small numbers of patients included in these further subgroup analyses. The Committee heard from the ERG that the differences in ECOG status and smoking history between the erlotinib and best supportive care groups were not statistically significant in the non-squamous disease population and that the differences in these baseline characteristics would not artificially decrease the overall survival estimate for erlotinib. The Committee also acknowledged comments from the ERG that no adjustments for other prognostic factors that could have had an impact on overall survival, such as gender and disease stage, had been made in these analyses by the manufacturer. The Committee further heard from the ERG that in a previous trial, patients with non-squamous disease experienced an additional gain in overall survival when treated with first-line pemetrexed and cisplatin compared to other chemotherapy regimens. In the light of these findings, it is unclear whether erlotinib maintenance treatment will supplement the extended survival advantage seen when patients receive pemetrexed and cisplatin first-line chemotherapy, because no patients received pemetrexed plus cisplatin before the SATURN trial. The Committee therefore concluded that the manufacturer's adjusted estimates of overall survival for erlotinib compared with best supportive care for people with stable, non-squamous disease were associated with considerable uncertainty.
The Committee observed that all of the survival benefit for erlotinib compared with best supportive care in patients with non-squamous disease occurred in the progression-free period, however only 40% of survival benefit in patients with squamous disease was assumed to occur in the progression-free period. The Committee considered that there was no convincing explanation for the fact that most of the apparent survival benefit for erlotinib in the squamous disease group came after treatment had been discontinued. The Committee therefore regarded the overall survival benefit for erlotinib in the squamous disease group with caution, agreeing that this estimate was highly uncertain.
The Committee was aware that EGFR mutation status was not recorded in half of the patients in the SATURN trial. It noted however that of the patients who were tested, a small proportion (11%) had activated EGFR mutations, and that this subgroup gained substantially more benefit from erlotinib than the trial population as a whole. It also heard from clinical specialists that these patients have a better prognosis with treatment than other patients with non-small-cell lung cancer. However, the Committee was aware that patients with EGFR mutations were unlikely to receive erlotinib maintenance treatment in UK clinical practice because NICE recommends gefitinib as an option for the first-line treatment in this group rather than chemotherapy ('Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer' ). The Committee was therefore concerned that some of the survival benefit of maintenance treatment with erlotinib demonstrated in the SATURN trial would not be seen in clinical practice because patients with EGFR mutations would usually receive gefitinib and would therefore not be eligible for maintenance treatment with erlotinib.
The Committee acknowledged that the manufacturer had provided additional information about the patient characteristics of the squamous disease population in the SATURN trial during consultation. The Committee accepted that these data showed that the number of patients with squamous disease with an activated EGFR mutation or who were of Asian origin or who had never smoked was small and therefore it agreed that these prognostic factors were unlikely to significantly bias the estimate of overall survival for this subpopulation. By implication, however, the Committee concluded that the numbers of patients with stable, non-squamous disease who had these baseline characteristics which may lead to better prognosis were even higher than previously thought.
The Committee discussed the first-line treatments received by patients in the SATURN trial. It considered that about 64% of patients received first-line chemotherapy regimens that are commonly used in the UK. The Committee noted that no one in the SATURN trial had received first-line treatment with pemetrexed and cisplatin, a regimen that is now commonly used as combination chemotherapy for patients with non-squamous disease because of its superiority to the regimens used in the SATURN trial. The Committee considered that patients in the SATURN trial were fitter than patients seen in UK clinical practice, noting that patients with stable disease after four cycles of platinum-based chemotherapy still had a good performance status and approximately 60% of patients went on to receive further systemic therapy after the SATURN trial, some of which would not be routinely used in the UK. It also observed that only a small proportion of patients in the placebo group had received erlotinib after progression. It considered that the post-progression treatments and the small proportion of patients in the placebo group who had received erlotinib after progression would affect the estimates of overall survival in the erlotinib and placebo groups. The Committee was aware that it is unclear whether patients would benefit more from receiving erlotinib as maintenance treatment or for treatment of relapsed disease. The Committee concluded that there was very considerable uncertainty that the benefit of erlotinib seen in the trial would be translated into routine practice.
The Committee discussed the RECIST criteria for determining disease response in the SATURN trial, taking into account the marketing authorisation for erlotinib, which includes patients with stable disease only. It heard from clinical specialists that some centres, particularly those involved in clinical trials, use the RECIST criteria routinely but that centres less involved in research may not use RECIST criteria on a day-to-day basis. The Committee noted that the RECIST criteria used in the SATURN trial were based on 6-weekly CT scans and considered that such frequent scans were not likely in the routine care of lung cancer patients in the UK. The Committee therefore concluded that it was likely that the duration of erlotinib maintenance treatment in clinical practice would exceed that observed in the SATURN trial as CT scans would be performed less frequently.
In summary, the Committee agreed that the benefit of maintenance treatment with erlotinib seen in the SATURN trial was likely to be lower in routine clinical practice when considering that the trial population represented patients who are likely to have a better prognosis than the average patient treated in the UK. In addition, the Committee considered that there were several factors that led to considerable uncertainty about the magnitude of overall survival gain expected from erlotinib maintenance treatment in the stable population and in the squamous and non-squamous disease subpopulations. These included the small numbers of patients in the post hoc subgroup analyses informing the survival estimates for the squamous and non-squamous disease groups and the use of post-progression treatments in the SATURN trial, which are not routinely used in the UK; and the lack of explanation as to why most of the survival benefit for erlotinib in the squamous disease group occurred after treatment was discontinued (in the post-progression period).
# Cost effectiveness
The Committee was aware that a patient access scheme had been agreed between the manufacturer and the Department of Health. It noted that this is a simple scheme in which erlotinib is supplied to the NHS at a discount of 14.5% of the list price. The Committee concluded that it was appropriate to appraise the cost effectiveness of erlotinib maintenance treatment on the basis of ICERs that include this discount.
The Committee discussed the evidence for the cost effectiveness of erlotinib compared with best supportive care derived the manufacturer's new economic analyses provided during consultation on the first appraisal consultation document. The Committee noted that the costs used in the analyses were based on those used in previous NICE technology appraisals of treatments for non-small-cell lung cancer and considered them to be appropriate. The Committee noted the manufacturer's ICERs for erlotinib compared with best supportive care of £40,800 per QALY gained for all patients with stable disease, £35,500 per QALY gained for patients with stable, squamous disease, £40,000 per QALY gained for patients with stable, non-squamous disease. The Committee noted that the manufacturer's ICER for all patients with stable disease was greater than both the ICERs presented for the squamous and non-squamous groups and acknowledged that the factors that had the greatest effect on the manufacturer's new ICERs were assumptions about how much time a patient spent on treatment in the progression-free health state, and the costs attributed to best supportive care.
The Committee considered the ERG's critique of the manufacturer's economic analysis. It noted the ERG's comment that it was more appropriate to consider the cost effectiveness of erlotinib in the subgroups of patients with squamous disease and non-squamous disease separately, rather than in the stable disease population as a whole, because of heterogeneity between the subgroups. The Committee agreed with the ERG, but was concerned about the subgroup analyses because the trial population had not been stratified by histology and analyses for these histological subgroups and for the stable disease population as a whole had not been predefined, which added uncertainty to the survival estimates and therefore also to the ICERs. Overall, the Committee concluded that it was justified in considering the squamous and non-squamous populations separately on clinical grounds.
The Committee discussed the ERG's comments on the methods used by the manufacturer to model progression-free survival and overall survival, in particular that post-progression survival had been calculated as the difference between overall survival and progression-free survival. The Committee concluded that the ERG's approach to estimating survival was more appropriate because it was based as much as possible on data directly from the trial and used modelling only when necessary. It noted that the ERG's modelling approach resulted in lower estimates of overall survival than the manufacturer's method, and that there were wide confidence intervals around these estimates, indicating a high degree of uncertainty. The Committee observed that the ERG's analyses resulted in significantly higher ICERs for erlotinib compared with best supportive care than those estimated by the manufacturer.
The Committee noted that the ERG's revisions to the manufacturer's model (including correcting the pemetrexed costs and using an alternative survival modelling method) increased the ICERs for erlotinib compared with best supportive care to £44,800 per QALY gained for treatment of stable, squamous disease and £68,100 per QALY gained for treatment of stable, non-squamous disease. The Committee considered that the most plausible ICERs would be considerably higher than those estimated by the ERG, and likely to be above £50,000 per QALY gained even for treatment of stable, non-squamous disease when taking into account the fact that the survival benefit observed in the SATURN trial was likely to be reduced in clinical practice where patients are less fit and have different prognostic characteristics from those seen in the trial population.
The Committee discussed the evidence for the cost effectiveness of erlotinib compared with pemetrexed. It noted that this was based on the manufacturer's new economic analysis submitted in response to the first appraisal consultation document, in which various relative efficacy scenarios were modelled because of the lack of data for erlotinib compared directly with pemetrexed. The Committee was aware that erlotinib was less costly than pemetrexed. The Committee was aware that the manufacturer considered that the JMEN and SATURN trials were not directly comparable and that a robust estimate of the relative effectiveness of erlotinib and pemetrexed was not possible to establish. However, it noted that the ERG's indirect analysis of the JMEN and SATURN trials showed that erlotinib was less effective than pemetrexed. The Committee also observed the ERG's concerns not only about the comparability of these two trial populations but also about their generalisability to UK practice. In the light of these issues, the Committee concluded that it had not been presented with a plausible estimate of the cost savings per QALY lost that would be associated with the use of erlotinib maintenance compared with pemetrexed and that therefore, erlotinib could not be specifically recommended compared with pemetrexed.
The Committee noted the manufacturer's claim that pemetrexed maintenance treatment had been recommended in TA190 for patients with non-squamous disease despite ICER estimates from the ERG exceeding £50,000 per QALY gained. However, the Committee understood that many considerations were taken into account by the Committee when finalising its appraisal of pemetrexed maintenance treatment, which subsequently decreased the ICER below £50,000 per QALY gained.
The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.
In addition, when taking these into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust.
The Committee noted that the median survival duration of patients in the UK with non-small-cell lung cancer who receive first-line chemotherapy is between 7 and 11 months. The Committee discussed the size of the patient population and was aware that the erlotinib marketing authorisation includes monotherapy for maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer with stable disease after four cycles of standard platinum-based first-line chemotherapy, but also the treatment of patients with locally advanced or metastatic non-small-cell lung cancer after failure of at least one prior chemotherapy regimen. During consultation, the manufacturer estimated that about 4100 patients would be suitable for treatment with erlotinib in the UK according to its current marketing authorisations. The Committee noted that the manufacturer had indicated that 6700 patients receive first-line chemotherapy in the UK. Some of these patients would receive erlotinib as maintenance treatment rather than as a second-line therapy. The Committee also noted that the erlotinib marketing authorisation includes the treatment of patients with metastatic pancreatic cancer in combination with gemcitabine. Most of the 7000 patients with pancreatic cancer present with metastatic disease and erlotinib would potentially be indicated for this population. The Committee discussed written evidence from a previous NICE technology appraisal appeal and noted that the Appeal Panel recognised that the criterion in the supplementary advice for end-of-life treatments for small patient populations indicated that 'Sufficient regard should be given to recognition of the desirability of developing new treatments in smaller disease areas and that higher prices, and therefore reduced cost effectiveness, were more likely to be justified given the need to recoup costs of development of the product from more limited licences'.The Appeal Panel had concluded that it was appropriate, according to the supplementary advice, to add together the potential patient populations covered by the marketing authorisation for different indications rather than on the basis of actual or recommended use. The Committee therefore considered that the true size of the cumulative population potentially eligible for treatment with erlotinib according to its UK marketing authorisations was not small and was considerably higher than the manufacturer's estimate.
The Committee then discussed the extension to life offered by erlotinib for patients with stable disease. It also considered whether mean or median survival was a more appropriate measure for evaluating the end-of-life criteria. The Committee agreed with comments from the ERG that the mean survival figures were more informative because they were based on all available data for all patients across the whole trial period. The Committee also heard from the clinical specialists that some patients have significantly longer responses to treatment with erlotinib, which was another reason to consider the mean rather than the median values. It noted that in the new analyses provided during consultation, the manufacturer estimated the mean overall survival benefit of erlotinib compared with best supportive care to be 3.3 months in the whole stable disease population, 4.2 months in the stable, squamous disease population and 4.5 months in the stable, non-squamous disease population. It also noted that the ERG estimated the mean overall survival benefit to be 3.4 months and 2.2 months in the populations of patients with squamous and non-squamous disease respectively. The Committee was concerned that no rationale could be provided to explain why both the manufacturer's median and mean survival estimates for each subpopulation were greater than for the whole population, which cast uncertainty over the validity of the analysis. During consultation the manufacturer explained that this was because of the different prognostic baseline characteristics of the patients in the squamous and non-squamous disease groups. Although the ERG did not provide an overall survival estimate for the whole stable disease population, the Committee heard from the ERG that this figure was likely to be closer to the mean overall survival estimate for patients in the non-squamous disease group (that is, 2.2 months) than the mean overall survival estimate for patients in the squamous disease group (that is, 3.4 months). The Committee had previously concluded that the overall survival benefit of erlotinib in clinical practice was uncertain and likely to be less than the ERG's estimates. The Committee did not consider that robust evidence had been provided to demonstrate an extension to life of at least 3 months and, taken together with the consideration on population size, therefore concluded that the end-of-life criteria were not met in this appraisal.
In summary, the Committee considered that the most plausible ICERs for erlotinib compared with best supportive care would be higher than those estimated by the ERG (£44,800 and £68,100 per QALY gained for treatment of patients with stable, squamous disease and with stable, non-squamous disease respectively) and considerably above £50,000 per QALY gained for treatment of the whole stable disease population. The Committee agreed that the end-of-life criteria were not met in this appraisal, but it noted that even if they were taken into account, the most plausible ICERs were higher than those normally considered to be associated with cost effective treatments. The Committee concluded that erlotinib was likely to be associated with cost savings per QALY lost compared with pemetrexed in patients with stable, non-squamous disease, but that it was not possible to establish a robust estimate. It therefore agreed that no specific recommendation could be made related to the use of erlotinib compared with pemetrexed. The Committee concluded that erlotinib could not be considered a cost-effective use of NHS resources when used as monotherapy for maintenance treatment in patients with locally advanced or metastatic non-small-cell lung cancer who have stable disease following platinum-based first-line chemotherapy.
The Committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its recommendations in any way. It noted that in response to the second appraisal consultation document the manufacturer stated that the preliminary recommendations mean that patients with squamous disease will not have a maintenance treatment option, whereas those with non-squamous disease currently have access to pemetrexed maintenance treatment through TA190. The manufacturer further stated that the histological mix of non-small-cell lung cancer shows a gender imbalance with squamous disease making up a substantially larger proportion of non-small-cell lung cancer in men. It was the manufacturer's view therefore that having no maintenance treatment option for people with squamous disease has a greater impact on men with non-small-cell lung cancer, and that this was particularly concerning given that men have an inherently worse prognosis than women. The Committee noted that no data on gender distribution based on histology were provided by the manufacturer and therefore this assertion was impossible to substantiate. However, the Committee noted that any possible differences in maintenance treatment access referred to by the manufacturer were related to TA190, rather than this appraisal. The Committee agreed that its decision about erlotinib maintenance treatment needed to be based on the evidence seen in this appraisal. Furthermore, the final decision not to recommend erlotinib maintenance treatment was made because erlotinib was not cost-effective in either of the squamous or non-squamous subgroups compared with best supportive care. The Committee concluded that its recommendations do not make it more difficult in practice for a specific group to access erlotinib maintenance treatment compared with other groups. In addition the Committee noted that, following the publication of TA181, the proportion of patients who would be eligible to receive pemetrexed maintenance treatment was declining quickly over time (because they are receiving pemetrexed as a first-line treatment instead) and therefore the manufacturer's concern that pemetrexed is currently only available as a maintenance option for non-squamous disease was becoming less relevant.
# Summary of Appraisal Committee's key conclusions
TA227
Appraisal title: Erlotinib monotherapy for maintenance treatment of non-small-cell lung cancer
Section
Key conclusion
Erlotinib monotherapy is not recommended for maintenance treatment in people with locally advanced or metastatic non-small-cell lung cancer with stable disease after platinum-based first-line chemotherapy.
The Committee agreed that the benefit of maintenance treatment with erlotinib seen in the SATURN trial was likely to be lower in routine clinical practice when considering that the trial population represented patients who are likely to have a better prognosis than the average patient treated in the UK. In addition, there were several factors that led to considerable uncertainty about the magnitude of overall survival gain expected from erlotinib maintenance in the stable population and in the squamous and non-squamous disease subpopulations.
The Committee considered that the most plausible ICER for erlotinib compared with best supportive care would be considerably higher than £50,000 per QALY gained for the whole stable disease population. In addition, the Committee considered that erlotinib was likely to be associated with cost savings per QALY lost compared with pemetrexed in patients with stable, non-squamous disease, but that it was not possible to establish a robust estimate. The Committee concluded that erlotinib could not be considered a cost-effective use of NHS resources when used as monotherapy for maintenance treatment in patients with locally advanced or metastatic non-small-cell lung cancer who have stable disease following platinum-based first-line chemotherapy.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee noted that pemetrexed is an option for the maintenance treatment of some people with non-squamous disease but best supportive care is currently the only option for patients with squamous disease. The Committee heard from clinical specialists that the number of patients who would be eligible for maintenance treatment with pemetrexed is already small and would progressively decrease as more patients receive first-line treatment with pemetrexed (in line with TA181).
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee was aware that maintenance treatment after first-line treatment is still a relatively new concept in lung cancer and that its aim is to prolong the benefits of first-line treatment and to maximise quality of life for as long as possible.
What is the position of the treatment in the pathway of care for the condition?
The Committee heard from the clinical specialists that erlotinib may provide a maintenance treatment option for patients who cannot receive pemetrexed maintenance treatment because they have squamous disease and/or they have had pemetrexed as a first-line treatment.
Adverse effects
The Committee noted views from clinical specialists that erlotinib is an oral drug with adverse events that are well known and relatively well tolerated.
The Committee considered that the adverse events associated with erlotinib (most commonly rash and diarrhoea) were well known and noted that most patients in the SATURN trial did not require their treatment to be changed or stopped because of adverse events.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee noted that the only evidence on the clinical effectiveness of erlotinib for maintenance treatment of patients with stable disease came from one randomised controlled trial (SATURN). The Committee was aware that the results for patients with stable disease were based on a post hoc subgroup analysis of 55% of the SATURN trial. Furthermore the results for the subgroups of patients with squamous and non-squamous disease were also post hoc analyses based on a disaggregation of the stable disease population and there were relatively small numbers of patients in each subgroup.
Relevance to general clinical practice in the NHS
The Committee discussed whether the results of the SATURN trial could be generalised to UK clinical practice, noting that in the trial there were few UK patients, a high proportion of south-east Asian patients and a high proportion of patients who had never smoked. The Committee was aware that Asian patients are known to respond better to lung cancer treatments than patients of other races and patients who have never smoked respond better than those with a history of smoking.
The Committee also noted that a small proportion of patients in the SATURN trial had activated EGFR mutations. It heard from clinical specialists that these patients have a better prognosis with treatment than other patients with non-small cell lung cancer. It was aware that patients with EGFR mutations were unlikely to receive erlotinib maintenance treatment after platinum-based chemotherapy in UK clinical practice because NICE recommends gefitinib as a first-line treatment in this group rather than chemotherapy (TA192).
The Committee noted that the RECIST criteria in the SATURN trial were based on 6-weekly CT scans and considered that such frequent scans were not likely in the routine care of lung cancer patients in the UK.
The Committee noted that no one in the SATURN trial had received first-line treatment with pemetrexed and cisplatin, a regimen that is now commonly used as combination chemotherapy for patients with non-squamous disease because of its superiority to the regimens used in the SATURN trial. The Committee concluded that there was very considerable uncertainty that the benefit of erlotinib seen in the trial would be translated into routine practice.
Uncertainties generated by the evidence
See 'Relevance to general clinical practice in the NHS'.
The Committee agreed that the benefit of erlotinib maintenance treatment seen in the SATURN trial was likely to be lower in routine clinical practice when considering that the trial population represented patients who are likely to have a better prognosis than the average patient treated in the UK, In addition, the Committee considered that there were several factors that led to considerable uncertainty about the magnitude of overall survival gain expected from erlotinib maintenance treatment in the stable population and in the squamous and non-squamous disease subpopulations. These included the small numbers of patients in the post hoc subgroup analyses informing the survival estimates for the squamous and non-squamous disease groups and the use of post-progression treatments in the SATURN trial which are not routinely used in the UK; and the lack of explanation as to why most of the survival benefit for erlotinib in the squamous disease group occurred after treatment was discontinued (in the post-progression period).
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
None considered.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee noted that the SATURN trial showed that maintenance treatment with erlotinib was associated with a statistically significant improvement in progression-free survival and overall survival compared with placebo for the overall population of patients with stable disease.
The Committee considered analyses from the manufacturer where the mean overall survival benefit of erlotinib compared with best supportive care was 3.3 months for the whole stable disease population, 4.2 months in the squamous disease group and 4.5 months in the non-squamous disease group. The Committee noted that the ERG's estimates for the mean overall survival benefit in the squamous and non-squamous groups were 3.4 months and 2.2 months respectively.
Evidence for cost effectiveness
Availability and nature of evidence
ICERs from the manufacturer for erlotinib compared with best supportive care were £40,800 per QALY gained for all patients with stable disease, £35,500 per QALY gained for patients with stable, squamous disease and £40,000 per QALY gained for patients with stable, non-squamous disease.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted that the ERG's approach to modelling progression-free survival and overall survival resulted in lower estimates of overall survival than the manufacturer's method and hence resulted in higher ICERs for erlotinib compared with best supportive care than those estimated by the manufacturer.
The Committee noted that most of the survival benefit for erlotinib came in the post-progression phase for patients with squamous disease, but not for patients with non-squamous disease. The Committee was unaware of an explanation for this and therefore considered that it added uncertainty.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The manufacturer used the same utility values as those used in 'Pemetrexed for the maintenance treatment of non-small-cell lung cancer' (NICE technology appraisal guidance 190 ).
None identified.
Are there specific groups of people for whom the technology is particularly cost effective?
None identified.
What are the key drivers of cost effectiveness?
The Committee acknowledged that the factors that had the greatest effect on the manufacturer's new ICERs were assumptions about how much time a patient spent on treatment in the progression-free health state, and the costs attributed to best supportive care.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee considered that the most plausible ICERs for erlotinib compared with best supportive care would be higher than those estimated by the ERG (£44,800 and £68,100 per QALY gained for treatment of patients with squamous and non-squamous disease respectively), and considerably higher than £50,000 per QALY gained for treatment of the whole stable disease population.
The Committee discussed evidence for the cost effectiveness of erlotinib compared with pemetrexed. It noted that this was based on the manufacturer's new economic analysis in which various relative efficacy scenarios were modelled because of the lack of data for erlotinib compared directly with pemetrexed. The Committee considered that erlotinib was likely to be associated with cost savings per QALY lost compared with pemetrexed in patients with stable, non-squamous disease, but that it was not possible to establish a robust estimate. It therefore agreed that no specific recommendation could be made related to the use of erlotinib compared with pemetrexed.
Additional factors taken into account
Patient access schemes
(PPRS)
The Committee was aware that a patient access scheme had been agreed between the manufacturer and the Department of Health in which erlotinib is supplied to the NHS at a discount of 14.5% of the list price.
End-of-life considerations
The Committee considered that the true size of the cumulative population potentially eligible for treatment with erlotinib according to its UK marketing authorisations was not small and was considerably higher than the manufacturer's estimate.
The Committee did not consider that robust evidence had been provided to demonstrate an extension to life of at least 3 months and, taken together with the consideration on population size, therefore concluded that the end-of-life criteria were not met in this appraisal.
Equalities considerations and social value judgements
No equalities issues were raised during the scoping exercise. In response to the second appraisal consultation document the manufacturer stated that the preliminary recommendations mean that patients with squamous disease will not have a maintenance treatment option, whereas those with non-squamous disease currently have access to pemetrexed maintenance treatment through TA190. The manufacturer further stated that the histological mix of non-small-cell lung cancer shows a gender imbalance with squamous disease making up a substantially larger proportion of non-small-cell lung cancer in men. It was the manufacturer's view therefore that having no maintenance treatment option for people with squamous disease has a greater impact on men with non-small-cell lung cancer, and that this was particularly concerning given that men have an inherently worse prognosis than women. The Committee noted that no data on gender distribution based on histology were provided by the manufacturer and therefore this assertion was impossible to substantiate. However, the Committee noted that any possible differences in maintenance treatment access referred to by the manufacturer were related to TA190, rather than this appraisal. The Committee agreed that its decision about erlotinib maintenance treatment needed to be based on the evidence seen in this appraisal. Furthermore, the final decision not to recommend erlotinib maintenance treatment was made because erlotinib was not cost-effective in either of the squamous or non-squamous subgroups compared with best supportive care. The Committee concluded that its recommendations do not make it more difficult in practice for a specific group to access erlotinib maintenance treatment compared with other groups.
, 4.24# Related NICE guidance
Published
Lung cancer. NICE clinical guideline 121 (2011). Available from www.nice.org.uk/guidance/CG121
Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer. NICE technology appraisal guidance 192 (2010). Available from www.nice.org.uk/guidance/TA192
Pemetrexed for the maintenance treatment of non-small-cell lung cancer. NICE technology appraisal guidance 190 (2010). Available from www.nice.org.uk/guidance/TA190
Pemetrexed for the first-line treatment of non-small-cell lung cancer. NICE technology appraisal guidance 181 (2009). Available from www.nice.org.uk/guidance/TA181
Gefitinib for the second-line treatment of locally advanced or metastatic non-small-cell lung cancer (terminated appraisal). NICE technology appraisal 175 (2009). Available from www.nice.org.uk/guidance/TA175
Erlotinib for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 162 (2008). Available from www.nice.org.uk/guidance/TA162
Bevacizumab for the treatment of non-small-cell lung cancer (terminated appraisal). NICE technology appraisal 148 (2008). Available from www.nice.org.uk/guidance/TA148
Pemetrexed for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 124 (2007). Available from www.nice.org.uk/guidance/TA124# Review of guidance
The guidance on this technology will be considered for review in April 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew Dillon
Chief Executive
June 2011# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your
responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Erlotinib monotherapy is not recommended for maintenance treatment in people with locally advanced or metastatic non-small-cell lung cancer who have stable disease after platinum-based first-line chemotherapy.\n\nPeople currently receiving erlotinib monotherapy for maintenance treatment of locally advanced or metastatic non-small-cell lung cancer who have stable disease after platinum-based first-line chemotherapy should have the option to continue treatment until they and their clinician consider it appropriate to stop.', 'The technology ': "Erlotinib (Tarceva, Roche Products) is an orally active inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. It has a UK marketing authorisation 'as monotherapy for maintenance treatment in patients with locally advanced or metastatic non-small cell lung cancer with stable disease after four cycles of standard platinum-based first-line chemotherapy'. For further information see the summary of product characteristics.\n\nUndesirable effects of erlotinib treatment include diarrhoea, rash, anorexia, gastrointestinal bleeding, liver function test abnormalities and keratitis. For full details of side effects and contraindications, see the summary of product characteristics.\n\nErlotinib is given orally at a recommended dose of 150\xa0mg/day. The normal acquisition cost of a pack of 30\xa0tablets (150\xa0mg) is £1631.53 (excluding VAT; 'British national formulary' [BNF] edition 60). The manufacturer of erlotinib has agreed a patient access scheme with the Department of Health in which the acquisition cost of erlotinib is reduced by 14.5% and deducted at the time of supply to the NHS (that is, £1394.96 for a pack of 30\xa0tablets [150\xa0mg]). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of erlotinib and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer approached the decision problem by providing clinical and cost-effectiveness evidence for erlotinib maintenance monotherapy compared with best supportive care in patients with stage IIIB or stage IV squamous or non-squamous non-small-cell lung cancer who had stable disease after treatment with standard platinum-based first-line chemotherapy. Best supportive care included palliative radiotherapy, corticosteroids, analgesia and other symptomatic treatments and watchful waiting alone. In the economic evaluation the manufacturer provided combined and separate analyses for patients with squamous and non-squamous disease. The group of patients with non-squamous disease was further divided into two analyses: firstly those who were not eligible for pemetrexed maintenance therapy (that is, patients who received pemetrexed in combination with cisplatin as first-line treatment), with best supportive care as the comparator; and secondly those who were eligible for pemetrexed maintenance therapy (that is, patients who have received first-line treatment with platinum-based chemotherapy which did not include pemetrexed), with pemetrexed as the comparator. The manufacturer noted a lack of head-to-head clinical evidence comparing erlotinib with pemetrexed.\n\nAt the time of the manufacturer's original evidence submission, the marketing authorisation for erlotinib had not been granted and the population who would be covered by the marketing authorisation was unclear. Subsequently, erlotinib received a marketing authorisation for the maintenance treatment of a subgroup of patients with locally advanced or metastatic non-small-cell lung cancer, that is, patients with stable disease after standard platinum-based first-line chemotherapy. Because of this, some of the evidence included in the manufacturer's original submission was not relevant and further evidence for the population covered by the marketing authorisation was required. The manufacturer provided additional clinical and cost-effectiveness evidence for patients with stable disease after first-line chemotherapy in response to consultation on the first appraisal consultation document.\n\nThe key evidence submitted by the manufacturer for the clinical effectiveness of erlotinib came from a randomised double-blind controlled trial comparing erlotinib with placebo in patients with advanced or metastatic non-small-cell lung cancer whose disease had not progressed following platinum-based first-line chemotherapy (the SATURN trial). This population included patients whose disease was either stable after first-line chemotherapy, or had responded to first-line chemotherapy. Stable disease was defined according to the Response Evaluation Criteria in Solid Tumours (RECIST) as tumour shrinkage that is not sufficient to be classed as a partial response and tumour increase that is not sufficient to be classed as progressive disease.\n\nPatients were included in the SATURN trial if their disease had not progressed after four cycles of a standard, platinum-based chemotherapy doublet (two chemotherapy drugs, one of which is platinum based), if they had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 and their life expectancy was at least 12\xa0weeks. The primary outcome of the trial was progression-free survival, defined as the time between randomisation and the date of the first documented disease progression, or death from any cause. Secondary outcomes included overall survival (defined as the time between randomisation and death), time to disease progression, response rates (assessed by the RECIST criteria) and quality of life (assessed by the Functional Assessment of Cancer Therapy – Lung [FACT-L] questionnaire). RECIST criteria were assessed by computed tomography (CT) scans every 6 weeks.\n\nThe SATURN trial included 889 patients, of whom 487 (55%) had stable disease after first-line chemotherapy. Of the patients with stable disease, approximately 30% had an ECOG performance status of 0 and 70% had an ECOG performance status of 1 at study entry, 20% had never smoked and 61% had non-squamous disease. Fifty percent of patients were tested for EGFR mutation status and of these 11% had activated EGFR mutations. The most common first-line treatments for patients in the whole trial population were gemcitabine plus carboplatin (28%), gemcitabine plus cisplatin (26%), and paclitaxel plus carboplatin (19%). None of the patients with non-squamous disease received combination chemotherapy with cisplatin and pemetrexed, now the most commonly prescribed first-line regimen in UK clinical practice for this histological subtype of non-small-cell lung cancer. Most patients (48%) were from Eastern Europe, 21% were from south-east Asia and 1% were from the UK. The mean age of patients was 60\xa0years. The proportion of patients who had at least one post-study treatment was 72% in the placebo group and 71% in the erlotinib group, with 21% of patients in the placebo group and 11% in the erlotinib group receiving subsequent treatment with a tyrosine kinase inhibitor (such as erlotinib or gefitinib). The proportion of patients with stable disease who had further systemic therapy after the study was 63% in the placebo group and 61% in the erlotinib group, with 21% of patients in the placebo group and 9% in the erlotinib group receiving subsequent treatment with either erlotinib or gefitinib. Of the 50% of patients with stable disease who were tested, the incidence of activated EGFR mutation was 6% in both the placebo and the erlotinib groups. The manufacturer stated that there were no imbalances between treatment arms when clinical, molecular, or geographical parameters were considered or when prior radiotherapy, subsequent systemic treatments and time to start of investigational treatment were analysed.\n\nThe manufacturer did not provide separate demographic analyses for the squamous and non-squamous disease groups in response to consultation on the first appraisal consultation document. However, during consultation on the second appraisal consultation document, the manufacturer indicated that although the baseline characteristics of known prognostic significance in the stable, squamous disease group were reasonably balanced between the erlotinib and best supportive care arms, this was not the case for the non-squamous disease group. Data from the SATURN trial showed that for the population with stable non-squamous disease, 30% of patients in the erlotinib group and 38% in the placebo group had an ECOG status of 0, and 25% of patients in the erlotinib group and 31% in the placebo group had never smoked. The manufacturer stated that because of these imbalances, the true overall survival benefit from erlotinib in the non-squamous disease group is likely to be confounded in favour of the best supportive care group.\n\nFor patients with stable disease after first-line chemotherapy, median progression-free survival was 12.1\xa0weeks in the erlotinib group compared with 11.3\xa0weeks in the placebo group (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.56 to 0.83, p\xa0<\xa00.0001). Median overall survival was 11.9\xa0months in the erlotinib group compared with 9.6\xa0months in the placebo group, a difference of 2.3 months (HR 0.72; 95% CI 0.59 to 0.89, p\xa0=\xa00.0019). The increase in progression-free survival associated with erlotinib was similar in patients with squamous disease (HR 0.69; 95% CI 0.51 to 0.93, n\xa0=\xa0190) and non-squamous disease (HR 0.69; 95% CI 0.54 to 0.87, n\xa0=\xa0297). The gain in median overall survival associated with erlotinib for patients with squamous disease was 3.0 months (HR 0.67; 95% CI 0.48 to 0.92) and 3.1 months for patients with non-squamous disease (HR 0.76; 95% CI 0.59 to 1.00). There were no statistically significant differences between the erlotinib and placebo groups in quality of life measures. In response to consultation on the first appraisal consultation document, the manufacturer provided estimates for the mean overall survival benefit associated with erlotinib for patients with squamous and non-squamous disease (4.5 months and 4.2 months respectively). The mean overall survival estimate for the whole stable disease population was 3.3 months.\n\nSubgroup analyses were carried out by the manufacturer in patients with stable disease after first-line chemotherapy by EGFR immunohistochemistry (IHC) status, stage of disease, first-line chemotherapy regimen received, ECOG performance status, smoking status, geographical region, age, race and gender. Erlotinib was associated with a greater median overall survival benefit for patients with EGFR IHC-positive tumours (HR 0.65; 95% CI 0.51 to 0.88, p-value not reported), for patients who had never smoked (HR 0.56; 95% CI 0.32 to 0.97, p-value not reported), and for women (HR 0.55; 95% CI 0.35 to 0.87, p-value not reported) compared with the whole stable disease population. In covariate analyses from the manufacturer of the whole stable SATURN population, south-east Asian patients had a greater progression-free survival benefit from erlotinib than white patients (covariate effect HR 0.78; p\xa0=\xa00.0214), as did patients who had never smoked compared with current smokers (covariate effect HR 1.46; p\xa0=\xa00.0003). In addition, the small subgroup of patients with activated EGFR mutations were also shown to gain substantially more benefit from erlotinib than the trial population as a whole (HR for progression-free survival 0.23; 95% CI 0.12 to 0.45).\n\nDuring consultation on the second appraisal consultation document, the manufacturer provided adjusted analyses comparing erlotinib with best supportive care in patients with stable, non-squamous disease from the SATURN trial. The analysis suggested that when the data were adjusted for good ECOG performance status and smoking status (never smoked), patients with these characteristics had an improved rate of overall survival after treatment with erlotinib compared with the whole stable, non-squamous disease population (HR 0.71; 95% CI 0.54 to 0.93). The estimate of overall survival was even higher (HR 0.63; 95% CI 0.41 to 0.96) when the analysis was repeated only in patients without an EGFR mutation (that is, the patients who are likely to receive erlotinib in UK clinical practice due to the growing use of gefitinib in patients with an EGFR mutation). In light of these analyses, the manufacturer stated that the overall survival benefit from erlotinib in the non-squamous disease population may have been underestimated in the SATURN trial.\n\nIn response to the second appraisal consultation document, the manufacturer provided patient characteristics for the squamous disease group to allay the Committee's concerns that the population in the SATURN trial may not be representative of patients seen in the UK. In particular, they showed that only 0.5% of patients with squamous disease had an EGFR mutation, 6.9% had never smoked and 7.9% were Asian. Given the relatively low incidence of patients with these prognostic factors, the manufacturer stated that they would not have a large impact on the overall survival benefit observed in the SATURN trial for the squamous disease group relative to what would be achieved in UK clinical practice.\n\nThe most common adverse events associated with erlotinib for the whole SATURN population were rash (49% in the erlotinib group and 6% in the placebo group) and diarrhoea (20% in the erlotinib group and 5% in the placebo group). In the stable disease subgroup, more patients in the erlotinib group had an adverse event of any kind than in the placebo group (78% compared with 58%). There were 23 deaths in the erlotinib group and 22 in the placebo group during the active treatment phase.\n\nIn the original submission, the manufacturer carried out an indirect analysis of erlotinib and pemetrexed in patients with non-squamous disease using data from a randomised controlled trial of pemetrexed maintenance treatment versus placebo in patients with locally advanced or metastatic non-small-cell lung cancer (the JMEN trial). This analysis included patients with stable disease but also included patients whose disease had responded to first-line treatment with platinum-based chemotherapy. The latter group are not covered by the marketing authorisation for erlotinib. In the additional evidence submission, received during consultation on the first appraisal consultation document, the manufacturer stated that an indirect comparison of the SATURN and JMEN trials was not possible because no data on the efficacy of pemetrexed in patients with stable, non-squamous disease from the JMEN trial were publically available. The manufacturer also stated that an indirect analysis was not considered appropriate because of differences in the populations in the two trials.\n\nIn the original submission, the manufacturer submitted economic analyses for three different patient populations, two of which included patients who were not covered by the marketing authorisation, that is, patients whose disease had responded to treatment. The only economic analysis that reflected the population covered by the marketing authorisation was the comparison of erlotinib with best supportive care in patients with stable disease. In response to consultation on the first appraisal consultation document, the manufacturer submitted four new economic analyses that included the population covered by the marketing authorisation:\n\nerlotinib compared with best supportive care in all patients with stable disease\n\nerlotinib compared with best supportive care in patients with stable, squamous disease\n\nerlotinib compared with best supportive care in patients with stable, non-squamous disease who were not eligible for pemetrexed maintenance treatment\n\nerlotinib compared with pemetrexed in patients with stable, non-squamous disease who were eligible for pemetrexed maintenance treatment.\n\nThe manufacturer's new economic analyses used a model with a cycle length of 1\xa0month and a 15-year time horizon. The model included three health states: progression-free survival, progressed (defined as the time from first treatment relapse until death), and death. All patients were assumed to start in the progression-free survival health state (after first-line chemotherapy). At the end of each cycle they could remain in this state, move to the progressed health state or die.\n\nFor the comparison of erlotinib with best supportive care, the risks of disease progression were taken from the SATURN trial. For the comparison of erlotinib with pemetrexed, the base case assumed equal efficacy of pemetrexed and erlotinib. Additional relative efficacy scenarios were modelled, ranging from assuming greater efficacy of pemetrexed (in progression-free survival and overall survival) to assuming greater efficacy of erlotinib.\n\nIn the new economic analyses, the manufacturer used the same utility values as those used in 'Pemetrexed for the maintenance treatment of non-small-cell lung cancer' (NICE technology appraisal guidance 190 [TA190]). The utility values for the progression-free survival health state were 0.6732 for the erlotinib group and 0.6628 for the placebo group. The utility value for the progressed health state was 0.53.\n\nThe new economic analyses included costs for treatment (erlotinib and pemetrexed), best supportive care, adverse events, and post-progression treatment. Costs for erlotinib were based on the patient access scheme (see section 2.3) and the treatment duration from the SATURN trial. Drug wastage was estimated based on when treatment stopped in the SATURN trial. The average per-patient drug costs for erlotinib were £7148 for the overall stable disease population, £6644 for patients with stable, squamous disease, and £7976 for patients with stable, non-squamous disease. Pemetrexed costs were based on the list price to the NHS (BNF 58) and doses were based on the distribution of body surface area of patients with stable, non-squamous disease in the SATURN trial. The average per-patient drug cost for pemetrexed was £13,062. Costs for best supportive care were based on the average cost of specialist palliative care per cancer death per year reported in a publication by NICE and the University of Sheffield (2004). This is the same methodology used in other NICE technology appraisals of treatments for non-small-cell lung cancer ('Pemetrexed for the first-line treatment of non-small-cell lung cancer' [NICE technology appraisal guidance 181; TA181]) and in TA190. The best supportive care costs also included costs of regular monitoring (3-monthly hospital visits consisting of a consultant appointment and an outpatient CT scan).\n\nThe costs of adverse events associated with erlotinib were based on those used in 'Erlotinib for the treatment of non-small-cell lung cancer' (NICE technology appraisal guidance 162; TA162), and adjusted for inflation. The costs of adverse events associated with pemetrexed were the same as those used in TA181. Post-progression treatment costs were based on various sources including the BNF 58 and other NICE technology appraisal guidance (TA181 and TA190). Data on the number and type of post-progression treatments were collected in the SATURN trial. Because there was a lack of data on post-progression treatment from the JMEN trial, the manufacturer assumed that the costs associated with pemetrexed would be the same as those for the placebo group of the SATURN trial.\n\nIn the manufacturer's original submission, the incremental cost-effectiveness ratio (ICER) for the comparison of erlotinib with best supportive care in patients with stable disease was £47,743 per quality-adjusted life year (QALY) gained (incremental cost £7747 and incremental benefit 0.162 QALYs). In response to the first appraisal consultation document the manufacturer revised assumptions about how much time a patient spent on treatment in the progression-free health state and the costs attributed to post-progression best supportive care, resulting in an ICER of £39,936 per QALY gained (incremental cost £7813, incremental benefit 0.196 QALYs) for all patients with stable disease. In response to the second appraisal consultation document the manufacturer provided a revised ICER of £40,792 per QALY gained (incremental cost £7737, incremental benefit 0.190 QALYs) for the stable disease population, using survival estimates proposed by the ERG. For patients with stable, squamous disease the ICER for erlotinib was £35,491 per QALY gained compared with best supportive care (incremental cost £7339, incremental benefit 0.207 QALYs). In patients with stable, non-squamous disease the ICER for erlotinib was £40,020 per QALY gained compared with best supportive care (incremental cost £8696, incremental benefit 0.218 QALYs). For the comparison of erlotinib with pemetrexed in patients with stable, non-squamous disease, the cost of erlotinib was £7531 lower than the cost of pemetrexed. Therefore when erlotinib was assumed to have equal or better efficacy than pemetrexed, erlotinib dominated pemetrexed (that is, it had lower costs and better efficacy). In the manufacturer's various relative efficacy scenarios, the ICER for erlotinib compared with pemetrexed ranged from £77,598 saved per QALY lost (when erlotinib was assumed to have 10% better progression-free survival and 10% worse overall survival than pemetrexed) to £511,351 saved per QALY lost (when erlotinib was assumed to have 10% worse progression-free survival and the same overall survival as pemetrexed).\n\nThe manufacturer conducted a number of deterministic sensitivity analyses. The factors that had the greatest impact on the ICERs for erlotinib compared with best supportive care were assuming that a patient spent all their time on treatment in the progression-free health state (£44,942 per QALY gained for the stable population) and using the best supportive care costs from TA162, rather than those from TA181 and TA190 (£44,745 per QALY gained for the stable population). The maximum ICERs for patients with stable, squamous disease and for those with stable, non-squamous disease were £40,599 per QALY gained (compared with £35,491 in the base case) and £44,589 per QALY gained (compared with £40,020 in the base case) respectively.\n\nThe ERG reviewed the clinical evidence originally submitted by the manufacturer and the additional evidence provided during consultation. It noted that the extent to which patients and investigators were truly blind to treatment allocation throughout the SATURN trial was uncertain because patients in the erlotinib group were significantly more likely to develop a rash and suffer from diarrhoea than patients in the placebo group. The ERG queried whether the results of the SATURN trial could be generalised to the UK because the trial included very few UK patients and the population was younger and fitter than would be seen in UK clinical practice. It also commented that a greater proportion of patients had first-line treatment with paclitaxel in the trial than would occur in UK clinical practice and no patients had first-line treatment that included pemetrexed, which is now the most common first-line treatment for patients with non-squamous disease (following publication of TA181). The ERG noted inconsistencies in the reporting of post-study treatments between the manufacturer's submission and the SATURN clinical trial report. It commented that the patients in the SATURN trial received a variety of post-progression treatments, many of which are not routinely used in the UK (including pemetrexed, vinorelbine, gemcitabine and paclitaxel). Only docetaxel and erlotinib are recommended by NICE for second-line treatment of non-small-cell lung cancer. The ERG noted that this was likely to affect overall survival results. It commented that the clinical evidence for erlotinib in patients with stable disease was based on a post hoc unstratified subgroup analysis and that the evidence for patients with squamous and non-squamous disease came from a further post hoc division of this subgroup, again according to an unstratified variable. The ERG considered that the SATURN trial was not designed to perform these types of analyses and therefore the results should be interpreted with caution.\n\nThe ERG identified data on patients with stable, non-squamous disease from the JMEN trial. It was therefore able to carry out an indirect comparison of pemetrexed and erlotinib (using data from the SATURN trial) for this patient group. The results indicated a statistically significant progression-free survival benefit for pemetrexed (HR 0.64; 95% CI 0.47 to 0.89) but the difference was not statistically significant for overall survival (HR 0.93; 95% CI 0.66 to 1.30). However, the ERG considered that the results of this analysis should be interpreted with caution because of differences in the patient populations in the JMEN and SATURN studies, the limitations of using post hoc subgroup analyses, and the uncertainty about whether both studies could be generalised to patients in the UK.\n\nThe ERG reviewed the economic analyses originally submitted by the manufacturer and the additional analyses provided in response to consultation on both appraisal consultation documents. It considered that the comparison of erlotinib with best supportive care in the total population of patients with stable disease could be misleading because it could mask differences in clinical and cost effectiveness between the squamous and non-squamous disease groups. In addition the ERG considered that results from the SATURN trial suggest that following disease progression, subsequent survival rates differ between patients with squamous and non-squamous disease, as there appears to be no difference in post-progression survival in the non-squamous disease group, whereas approximately 60% of the survival benefit associated with erlotinib maintenance treatment occurs during the post-progression period in the squamous disease group. In addition, there was statistically significant heterogeneity in some of the prognostic factors of the patients with squamous and non-squamous disease in the SATURN trial. Therefore, the ERG expressed the view that it was not appropriate to combine the histological groups and hence did not conduct any sensitivity analyses on the manufacturer's estimates for the total stable disease population.\n\nThe ERG's main criticism of the models of erlotinib compared with best supportive care in the subgroups of patients with squamous and non-squamous disease was the method used to extrapolate survival beyond the trial period. It noted that the manufacturer had not used post-progression survival data directly from the trial, but instead calculated post-progression survival as the difference between overall survival and progression-free survival. The ERG commented that because all patients in the stable disease population of the SATURN trial had disease which had progressed (that is, the progression-free survival data set was complete), there was no need to model the mean duration of progression-free survival because it could be based directly on Kaplan-Meier survival estimates from the trial. The ERG estimated mean overall survival using new survival data provided by the manufacturer during consultation on the first appraisal consultation document, by adding progression-free survival to post-progression survival and adjusting the estimate to exclude patients dying at or before disease progression. For post-progression survival in the subgroup of patients with squamous disease, the ERG used Kaplan-Meier estimates up to a 20% survival figure and then modelled the remaining survival. For the subgroup of patients with non-squamous disease, data on post-progression survival were available up to 600\xa0days, but required modelling after this point for the remaining 7% of patients; a common exponential model was used for both the intervention and the comparator. The ERG's approach to modelling survival resulted in mean overall survival gains of 3.4\xa0months (95% CI 1.5 to 5.3\xa0months) for patients with stable, squamous disease and 2.2\xa0months (95% CI 0.9 to 3.5\xa0months) for patients with stable, non-squamous disease (corresponding to a 28% and 75% decrease in QALY gains compared with those in the manufacturer's base case respectively). The ERG stressed the wide confidence intervals around these estimates of survival gain. For the population of patients with stable, squamous disease the manufacturer's base-case ICER for erlotinib compared with best supportive care increased from £35,491 to £44,812 per QALY gained (incremental cost £7129, incremental benefit 0.1591 QALYs) using the ERG's modelling approach. For the population of patients with stable, non-squamous disease the manufacturer's base-case ICER for erlotinib compared with best supportive care increased from £40,020 to £68,120 per QALY gained (incremental cost £8340, incremental benefit 0.1224 QALYs).\n\nThe ERG commented on the manufacturer's economic analysis of erlotinib compared with pemetrexed in the population of patients with stable, non-squamous disease. It noted that the manufacturer's estimate of pemetrexed costs did not account for gender differences in body surface area. It also noted that a modifying factor that reduced pemetrexed costs by 5% had been used and that no evidence had been provided to support this method. The ERG revised the manufacturer's model using their own estimation of pemetrexed costs, and used the hazard ratios from its indirect analysis (noting the previously mentioned caution about this analysis). The resulting ICER was based on the lower costs (−£8460) and lower efficacy (−0.1007 QALYs) of erlotinib compared with pemetrexed and represented a cost saving of £84,029 per QALY lost.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TA227", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of maintenance treatment with erlotinib, having considered evidence on the nature of non-small-cell lung cancer and the value placed on the benefits of erlotinib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources and comments received during consultation on both appraisal consultation documents.\n\nThe Committee considered current UK practice for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer. It heard from clinical specialists that first-line treatment in the UK is usually with carboplatin or cisplatin plus gemcitabine or vinorelbine, or cisplatin plus pemetrexed for patients with non-squamous disease. If disease progresses, patients have the option of receiving second-line systemic treatment if they have a good performance status. In the UK, second-line treatment is normally docetaxel or erlotinib. The Committee was aware that maintenance treatment after first-line treatment is still a relatively new concept in lung cancer and that its aim is to prolong the benefits of first-line treatment and to maximise quality of life for as long as possible. It noted that best supportive care is currently the only maintenance treatment option for patients with squamous disease. However, pemetrexed is recommended in TA190 as an option for the maintenance treatment of people with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology if disease has not progressed immediately following platinum-based chemotherapy in combination with gemcitabine, paclitaxel or docetaxel. The Committee noted that patients are only eligible for maintenance treatment with pemetrexed if they have not received it as part of first-line treatment in combination with cisplatin. It heard from clinical specialists that the number of patients who would be eligible for maintenance treatment with pemetrexed is already small and would progressively decrease as more patients receive first-line treatment with pemetrexed (in line with TA181).\n\nThe Committee noted views from the clinical specialists that erlotinib is an oral drug with adverse effects that are well known and relatively well tolerated. The clinical specialists stated that a potential benefit of maintenance treatment is that it may keep some patients well enough to be able to receive subsequent treatment after first-line therapy. The clinical specialists also commented that erlotinib may provide a maintenance treatment option for patients who cannot receive pemetrexed maintenance treatment because they have squamous disease and/or they have had pemetrexed as a first-line treatment. The Committee also noted a statement from a patient group which emphasised that even relatively small improvements in survival and quality of life afforded by new treatments compared with current treatment options is of real importance to patients.\n\n# Clinical effectiveness\n\nThe Committee discussed the evidence on the clinical effectiveness of erlotinib for the maintenance treatment of patients with stable disease. It noted that one randomised trial, the SATURN trial, was presented, which showed that maintenance treatment with erlotinib was associated with a statistically significant improvement in progression-free survival and overall survival compared with placebo for the overall population of patients with stable disease. It noted that the improvement in progression-free survival with erlotinib was similar for patients in the squamous and non-squamous disease subgroups, but a statistically significant improvement in overall survival was only demonstrated in the subgroup of patients with squamous disease (HR 0.67; 95% CI 0.48 to 0.92 compared with HR 0.76; 95% CI 0.59 to 1.00 in the non-squamous disease group). The Committee was aware that the results for patients with stable disease were based on a post hoc subgroup analysis of 55% of the SATURN trial population. Furthermore, the results for the subgroups of patients with squamous and non-squamous disease were also post hoc analyses based on a disaggregation of the stable disease population and there were relatively small numbers of patients in each subgroup (190 and 297 respectively). The Committee was aware that the SATURN trial had not been designed for such analyses. It therefore regarded that the true magnitude of the benefits of erlotinib in these patient populations was uncertain. The Committee considered that the adverse events associated with erlotinib (most commonly, rash and diarrhoea) were well known and noted that most patients in the SATURN trial did not require their treatment to be changed or stopped because of adverse events.\n\nThe Committee discussed whether the results of the SATURN trial could be generalised to UK clinical practice, noting that in the trial there were few UK patients, a high proportion of south-east Asian patients and a high proportion of patients who had never smoked. The Committee was aware that Asian patients are known to respond better to lung cancer treatments than patients of other races and patients who have never smoked respond better than those with a history of smoking. It also noted that in the SATURN trial 30% of patients with stable disease still had an ECOG performance status of 0 after four cycles of chemotherapy and this was likely to reflect a fitter group of patients than the population who would receive maintenance treatment with erlotinib in UK clinical practice. The Committee also observed that 66% of patients in the SATURN trial were under 65 years of age and represented a younger population of patients with non-small-cell lung cancer than would be seen in UK clinical practice. It also noted that a high proportion of patients went on to receive further systemic therapy after the SATURN trial, some of which is not routinely given to patients in UK clinical practice. The Committee therefore concluded that the results from the SATURN trial had limited generalisability to UK clinical practice, therefore adding further uncertainty to the true magnitude of the benefits of erlotinib that would be achieved for UK patients.\n\nThe Committee acknowledged that the manufacturer provided updated analyses for the stable, non-squamous disease group, during consultation on the appraisal consultation documents, which adjusted for some prognostic factors (ECOG status and smoking history), which the manufacturer suggested may have biased results against erlotinib in the SATURN trial. However, the Committee was concerned about the reliability of the data because of the small numbers of patients included in these further subgroup analyses. The Committee heard from the ERG that the differences in ECOG status and smoking history between the erlotinib and best supportive care groups were not statistically significant in the non-squamous disease population and that the differences in these baseline characteristics would not artificially decrease the overall survival estimate for erlotinib. The Committee also acknowledged comments from the ERG that no adjustments for other prognostic factors that could have had an impact on overall survival, such as gender and disease stage, had been made in these analyses by the manufacturer. The Committee further heard from the ERG that in a previous trial, patients with non-squamous disease experienced an additional gain in overall survival when treated with first-line pemetrexed and cisplatin compared to other chemotherapy regimens. In the light of these findings, it is unclear whether erlotinib maintenance treatment will supplement the extended survival advantage seen when patients receive pemetrexed and cisplatin first-line chemotherapy, because no patients received pemetrexed plus cisplatin before the SATURN trial. The Committee therefore concluded that the manufacturer's adjusted estimates of overall survival for erlotinib compared with best supportive care for people with stable, non-squamous disease were associated with considerable uncertainty.\n\nThe Committee observed that all of the survival benefit for erlotinib compared with best supportive care in patients with non-squamous disease occurred in the progression-free period, however only 40% of survival benefit in patients with squamous disease was assumed to occur in the progression-free period. The Committee considered that there was no convincing explanation for the fact that most of the apparent survival benefit for erlotinib in the squamous disease group came after treatment had been discontinued. The Committee therefore regarded the overall survival benefit for erlotinib in the squamous disease group with caution, agreeing that this estimate was highly uncertain.\n\nThe Committee was aware that EGFR mutation status was not recorded in half of the patients in the SATURN trial. It noted however that of the patients who were tested, a small proportion (11%) had activated EGFR mutations, and that this subgroup gained substantially more benefit from erlotinib than the trial population as a whole. It also heard from clinical specialists that these patients have a better prognosis with treatment than other patients with non-small-cell lung cancer. However, the Committee was aware that patients with EGFR mutations were unlikely to receive erlotinib maintenance treatment in UK clinical practice because NICE recommends gefitinib as an option for the first-line treatment in this group rather than chemotherapy ('Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer' [NICE technology appraisal guidance 192]). The Committee was therefore concerned that some of the survival benefit of maintenance treatment with erlotinib demonstrated in the SATURN trial would not be seen in clinical practice because patients with EGFR mutations would usually receive gefitinib and would therefore not be eligible for maintenance treatment with erlotinib.\n\nThe Committee acknowledged that the manufacturer had provided additional information about the patient characteristics of the squamous disease population in the SATURN trial during consultation. The Committee accepted that these data showed that the number of patients with squamous disease with an activated EGFR mutation or who were of Asian origin or who had never smoked was small and therefore it agreed that these prognostic factors were unlikely to significantly bias the estimate of overall survival for this subpopulation. By implication, however, the Committee concluded that the numbers of patients with stable, non-squamous disease who had these baseline characteristics which may lead to better prognosis were even higher than previously thought.\n\nThe Committee discussed the first-line treatments received by patients in the SATURN trial. It considered that about 64% of patients received first-line chemotherapy regimens that are commonly used in the UK. The Committee noted that no one in the SATURN trial had received first-line treatment with pemetrexed and cisplatin, a regimen that is now commonly used as combination chemotherapy for patients with non-squamous disease because of its superiority to the regimens used in the SATURN trial. The Committee considered that patients in the SATURN trial were fitter than patients seen in UK clinical practice, noting that patients with stable disease after four cycles of platinum-based chemotherapy still had a good performance status and approximately 60% of patients went on to receive further systemic therapy after the SATURN trial, some of which would not be routinely used in the UK. It also observed that only a small proportion of patients in the placebo group had received erlotinib after progression. It considered that the post-progression treatments and the small proportion of patients in the placebo group who had received erlotinib after progression would affect the estimates of overall survival in the erlotinib and placebo groups. The Committee was aware that it is unclear whether patients would benefit more from receiving erlotinib as maintenance treatment or for treatment of relapsed disease. The Committee concluded that there was very considerable uncertainty that the benefit of erlotinib seen in the trial would be translated into routine practice.\n\nThe Committee discussed the RECIST criteria for determining disease response in the SATURN trial, taking into account the marketing authorisation for erlotinib, which includes patients with stable disease only. It heard from clinical specialists that some centres, particularly those involved in clinical trials, use the RECIST criteria routinely but that centres less involved in research may not use RECIST criteria on a day-to-day basis. The Committee noted that the RECIST criteria used in the SATURN trial were based on 6-weekly CT scans and considered that such frequent scans were not likely in the routine care of lung cancer patients in the UK. The Committee therefore concluded that it was likely that the duration of erlotinib maintenance treatment in clinical practice would exceed that observed in the SATURN trial as CT scans would be performed less frequently.\n\nIn summary, the Committee agreed that the benefit of maintenance treatment with erlotinib seen in the SATURN trial was likely to be lower in routine clinical practice when considering that the trial population represented patients who are likely to have a better prognosis than the average patient treated in the UK. In addition, the Committee considered that there were several factors that led to considerable uncertainty about the magnitude of overall survival gain expected from erlotinib maintenance treatment in the stable population and in the squamous and non-squamous disease subpopulations. These included the small numbers of patients in the post hoc subgroup analyses informing the survival estimates for the squamous and non-squamous disease groups and the use of post-progression treatments in the SATURN trial, which are not routinely used in the UK; and the lack of explanation as to why most of the survival benefit for erlotinib in the squamous disease group occurred after treatment was discontinued (in the post-progression period).\n\n# Cost effectiveness\n\nThe Committee was aware that a patient access scheme had been agreed between the manufacturer and the Department of Health. It noted that this is a simple scheme in which erlotinib is supplied to the NHS at a discount of 14.5% of the list price. The Committee concluded that it was appropriate to appraise the cost effectiveness of erlotinib maintenance treatment on the basis of ICERs that include this discount.\n\nThe Committee discussed the evidence for the cost effectiveness of erlotinib compared with best supportive care derived the manufacturer's new economic analyses provided during consultation on the first appraisal consultation document. The Committee noted that the costs used in the analyses were based on those used in previous NICE technology appraisals of treatments for non-small-cell lung cancer and considered them to be appropriate. The Committee noted the manufacturer's ICERs for erlotinib compared with best supportive care of £40,800 per QALY gained for all patients with stable disease, £35,500 per QALY gained for patients with stable, squamous disease, £40,000 per QALY gained for patients with stable, non-squamous disease. The Committee noted that the manufacturer's ICER for all patients with stable disease was greater than both the ICERs presented for the squamous and non-squamous groups and acknowledged that the factors that had the greatest effect on the manufacturer's new ICERs were assumptions about how much time a patient spent on treatment in the progression-free health state, and the costs attributed to best supportive care.\n\nThe Committee considered the ERG's critique of the manufacturer's economic analysis. It noted the ERG's comment that it was more appropriate to consider the cost effectiveness of erlotinib in the subgroups of patients with squamous disease and non-squamous disease separately, rather than in the stable disease population as a whole, because of heterogeneity between the subgroups. The Committee agreed with the ERG, but was concerned about the subgroup analyses because the trial population had not been stratified by histology and analyses for these histological subgroups and for the stable disease population as a whole had not been predefined, which added uncertainty to the survival estimates and therefore also to the ICERs. Overall, the Committee concluded that it was justified in considering the squamous and non-squamous populations separately on clinical grounds.\n\nThe Committee discussed the ERG's comments on the methods used by the manufacturer to model progression-free survival and overall survival, in particular that post-progression survival had been calculated as the difference between overall survival and progression-free survival. The Committee concluded that the ERG's approach to estimating survival was more appropriate because it was based as much as possible on data directly from the trial and used modelling only when necessary. It noted that the ERG's modelling approach resulted in lower estimates of overall survival than the manufacturer's method, and that there were wide confidence intervals around these estimates, indicating a high degree of uncertainty. The Committee observed that the ERG's analyses resulted in significantly higher ICERs for erlotinib compared with best supportive care than those estimated by the manufacturer.\n\nThe Committee noted that the ERG's revisions to the manufacturer's model (including correcting the pemetrexed costs and using an alternative survival modelling method) increased the ICERs for erlotinib compared with best supportive care to £44,800 per QALY gained for treatment of stable, squamous disease and £68,100 per QALY gained for treatment of stable, non-squamous disease. The Committee considered that the most plausible ICERs would be considerably higher than those estimated by the ERG, and likely to be above £50,000 per QALY gained even for treatment of stable, non-squamous disease when taking into account the fact that the survival benefit observed in the SATURN trial was likely to be reduced in clinical practice where patients are less fit and have different prognostic characteristics from those seen in the trial population.\n\nThe Committee discussed the evidence for the cost effectiveness of erlotinib compared with pemetrexed. It noted that this was based on the manufacturer's new economic analysis submitted in response to the first appraisal consultation document, in which various relative efficacy scenarios were modelled because of the lack of data for erlotinib compared directly with pemetrexed. The Committee was aware that erlotinib was less costly than pemetrexed. The Committee was aware that the manufacturer considered that the JMEN and SATURN trials were not directly comparable and that a robust estimate of the relative effectiveness of erlotinib and pemetrexed was not possible to establish. However, it noted that the ERG's indirect analysis of the JMEN and SATURN trials showed that erlotinib was less effective than pemetrexed. The Committee also observed the ERG's concerns not only about the comparability of these two trial populations but also about their generalisability to UK practice. In the light of these issues, the Committee concluded that it had not been presented with a plausible estimate of the cost savings per QALY lost that would be associated with the use of erlotinib maintenance compared with pemetrexed and that therefore, erlotinib could not be specifically recommended compared with pemetrexed.\n\nThe Committee noted the manufacturer's claim that pemetrexed maintenance treatment had been recommended in TA190 for patients with non-squamous disease despite ICER estimates from the ERG exceeding £50,000 per QALY gained. However, the Committee understood that many considerations were taken into account by the Committee when finalising its appraisal of pemetrexed maintenance treatment, which subsequently decreased the ICER below £50,000 per QALY gained.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.\n\nIn addition, when taking these into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust.\n\nThe Committee noted that the median survival duration of patients in the UK with non-small-cell lung cancer who receive first-line chemotherapy is between 7 and 11\xa0months. The Committee discussed the size of the patient population and was aware that the erlotinib marketing authorisation includes monotherapy for maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer with stable disease after four cycles of standard platinum-based first-line chemotherapy, but also the treatment of patients with locally advanced or metastatic non-small-cell lung cancer after failure of at least one prior chemotherapy regimen. During consultation, the manufacturer estimated that about 4100\xa0patients would be suitable for treatment with erlotinib in the UK according to its current marketing authorisations. The Committee noted that the manufacturer had indicated that 6700\xa0patients receive first-line chemotherapy in the UK. Some of these patients would receive erlotinib as maintenance treatment rather than as a second-line therapy. The Committee also noted that the erlotinib marketing authorisation includes the treatment of patients with metastatic pancreatic cancer in combination with gemcitabine. Most of the 7000\xa0patients with pancreatic cancer present with metastatic disease and erlotinib would potentially be indicated for this population. The Committee discussed written evidence from a previous NICE technology appraisal appeal and noted that the Appeal Panel recognised that the criterion in the supplementary advice for end-of-life treatments for small patient populations indicated that 'Sufficient regard should be given to recognition of the desirability of developing new treatments in smaller disease areas and that higher prices, and therefore reduced cost effectiveness, were more likely to be justified given the need to recoup costs of development of the product from more limited licences'.The Appeal Panel had concluded that it was appropriate, according to the supplementary advice, to add together the potential patient populations covered by the marketing authorisation for different indications rather than on the basis of actual or recommended use. The Committee therefore considered that the true size of the cumulative population potentially eligible for treatment with erlotinib according to its UK marketing authorisations was not small and was considerably higher than the manufacturer's estimate.\n\nThe Committee then discussed the extension to life offered by erlotinib for patients with stable disease. It also considered whether mean or median survival was a more appropriate measure for evaluating the end-of-life criteria. The Committee agreed with comments from the ERG that the mean survival figures were more informative because they were based on all available data for all patients across the whole trial period. The Committee also heard from the clinical specialists that some patients have significantly longer responses to treatment with erlotinib, which was another reason to consider the mean rather than the median values. It noted that in the new analyses provided during consultation, the manufacturer estimated the mean overall survival benefit of erlotinib compared with best supportive care to be 3.3\xa0months in the whole stable disease population, 4.2\xa0months in the stable, squamous disease population and 4.5\xa0months in the stable, non-squamous disease population. It also noted that the ERG estimated the mean overall survival benefit to be 3.4\xa0months and 2.2\xa0months in the populations of patients with squamous and non-squamous disease respectively. The Committee was concerned that no rationale could be provided to explain why both the manufacturer's median and mean survival estimates for each subpopulation were greater than for the whole population, which cast uncertainty over the validity of the analysis. During consultation the manufacturer explained that this was because of the different prognostic baseline characteristics of the patients in the squamous and non-squamous disease groups. Although the ERG did not provide an overall survival estimate for the whole stable disease population, the Committee heard from the ERG that this figure was likely to be closer to the mean overall survival estimate for patients in the non-squamous disease group (that is, 2.2 months) than the mean overall survival estimate for patients in the squamous disease group (that is, 3.4 months). The Committee had previously concluded that the overall survival benefit of erlotinib in clinical practice was uncertain and likely to be less than the ERG's estimates. The Committee did not consider that robust evidence had been provided to demonstrate an extension to life of at least 3\xa0months and, taken together with the consideration on population size, therefore concluded that the end-of-life criteria were not met in this appraisal.\n\nIn summary, the Committee considered that the most plausible ICERs for erlotinib compared with best supportive care would be higher than those estimated by the ERG (£44,800 and £68,100 per QALY gained for treatment of patients with stable, squamous disease and with stable, non-squamous disease respectively) and considerably above £50,000 per QALY gained for treatment of the whole stable disease population. The Committee agreed that the end-of-life criteria were not met in this appraisal, but it noted that even if they were taken into account, the most plausible ICERs were higher than those normally considered to be associated with cost effective treatments. The Committee concluded that erlotinib was likely to be associated with cost savings per QALY lost compared with pemetrexed in patients with stable, non-squamous disease, but that it was not possible to establish a robust estimate. It therefore agreed that no specific recommendation could be made related to the use of erlotinib compared with pemetrexed. The Committee concluded that erlotinib could not be considered a cost-effective use of NHS resources when used as monotherapy for maintenance treatment in patients with locally advanced or metastatic non-small-cell lung cancer who have stable disease following platinum-based first-line chemotherapy.\n\nThe Committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its recommendations in any way. It noted that in response to the second appraisal consultation document the manufacturer stated that the preliminary recommendations mean that patients with squamous disease will not have a maintenance treatment option, whereas those with non-squamous disease currently have access to pemetrexed maintenance treatment through TA190. The manufacturer further stated that the histological mix of non-small-cell lung cancer shows a gender imbalance with squamous disease making up a substantially larger proportion of non-small-cell lung cancer in men. It was the manufacturer's view therefore that having no maintenance treatment option for people with squamous disease has a greater impact on men with non-small-cell lung cancer, and that this was particularly concerning given that men have an inherently worse prognosis than women. The Committee noted that no data on gender distribution based on histology were provided by the manufacturer and therefore this assertion was impossible to substantiate. However, the Committee noted that any possible differences in maintenance treatment access referred to by the manufacturer were related to TA190, rather than this appraisal. The Committee agreed that its decision about erlotinib maintenance treatment needed to be based on the evidence seen in this appraisal. Furthermore, the final decision not to recommend erlotinib maintenance treatment was made because erlotinib was not cost-effective in either of the squamous or non-squamous subgroups compared with best supportive care. The Committee concluded that its recommendations do not make it more difficult in practice for a specific group to access erlotinib maintenance treatment compared with other groups. In addition the Committee noted that, following the publication of TA181, the proportion of patients who would be eligible to receive pemetrexed maintenance treatment was declining quickly over time (because they are receiving pemetrexed as a first-line treatment instead) and therefore the manufacturer's concern that pemetrexed is currently only available as a maintenance option for non-squamous disease was becoming less relevant.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA227\n\n\n\nAppraisal title: Erlotinib monotherapy for maintenance treatment of non-small-cell lung cancer\n\nSection\n\nKey conclusion\n\nErlotinib monotherapy is not recommended for maintenance treatment in people with locally advanced or metastatic non-small-cell lung cancer with stable disease after platinum-based first-line chemotherapy.\n\n\n\nThe Committee agreed that the benefit of maintenance treatment with erlotinib seen in the SATURN trial was likely to be lower in routine clinical practice when considering that the trial population represented patients who are likely to have a better prognosis than the average patient treated in the UK. In addition, there were several factors that led to considerable uncertainty about the magnitude of overall survival gain expected from erlotinib maintenance in the stable population and in the squamous and non-squamous disease subpopulations.\n\n\n\nThe Committee considered that the most plausible ICER for erlotinib compared with best supportive care would be considerably higher than £50,000 per QALY gained for the whole stable disease population. In addition, the Committee considered that erlotinib was likely to be associated with cost savings per QALY lost compared with pemetrexed in patients with stable, non-squamous disease, but that it was not possible to establish a robust estimate. The Committee concluded that erlotinib could not be considered a cost-effective use of NHS resources when used as monotherapy for maintenance treatment in patients with locally advanced or metastatic non-small-cell lung cancer who have stable disease following platinum-based first-line chemotherapy.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee noted that pemetrexed is an option for the maintenance treatment of some people with non-squamous disease but best supportive care is currently the only option for patients with squamous disease. The Committee heard from clinical specialists that the number of patients who would be eligible for maintenance treatment with pemetrexed is already small and would progressively decrease as more patients receive first-line treatment with pemetrexed (in line with TA181).\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee was aware that maintenance treatment after first-line treatment is still a relatively new concept in lung cancer and that its aim is to prolong the benefits of first-line treatment and to maximise quality of life for as long as possible.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\n\n\nThe Committee heard from the clinical specialists that erlotinib may provide a maintenance treatment option for patients who cannot receive pemetrexed maintenance treatment because they have squamous disease and/or they have had pemetrexed as a first-line treatment.\n\n\n\nAdverse effects\n\n\n\nThe Committee noted views from clinical specialists that erlotinib is an oral drug with adverse events that are well known and relatively well tolerated.\n\n\n\nThe Committee considered that the adverse events associated with erlotinib (most commonly rash and diarrhoea) were well known and noted that most patients in the SATURN trial did not require their treatment to be changed or stopped because of adverse events.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\n\n\nThe Committee noted that the only evidence on the clinical effectiveness of erlotinib for maintenance treatment of patients with stable disease came from one randomised controlled trial (SATURN). The Committee was aware that the results for patients with stable disease were based on a post hoc subgroup analysis of 55% of the SATURN trial. Furthermore the results for the subgroups of patients with squamous and non-squamous disease were also post hoc analyses based on a disaggregation of the stable disease population and there were relatively small numbers of patients in each subgroup.\n\n\n\nRelevance to general clinical practice in the NHS\n\n\n\nThe Committee discussed whether the results of the SATURN trial could be generalised to UK clinical practice, noting that in the trial there were few UK patients, a high proportion of south-east Asian patients and a high proportion of patients who had never smoked. The Committee was aware that Asian patients are known to respond better to lung cancer treatments than patients of other races and patients who have never smoked respond better than those with a history of smoking.\n\n\n\nThe Committee also noted that a small proportion of patients in the SATURN trial had activated EGFR mutations. It heard from clinical specialists that these patients have a better prognosis with treatment than other patients with non-small cell lung cancer. It was aware that patients with EGFR mutations were unlikely to receive erlotinib maintenance treatment after platinum-based chemotherapy in UK clinical practice because NICE recommends gefitinib as a first-line treatment in this group rather than chemotherapy (TA192).\n\n\n\nThe Committee noted that the RECIST criteria in the SATURN trial were based on 6-weekly CT scans and considered that such frequent scans were not likely in the routine care of lung cancer patients in the UK.\n\n\n\nThe Committee noted that no one in the SATURN trial had received first-line treatment with pemetrexed and cisplatin, a regimen that is now commonly used as combination chemotherapy for patients with non-squamous disease because of its superiority to the regimens used in the SATURN trial. The Committee concluded that there was very considerable uncertainty that the benefit of erlotinib seen in the trial would be translated into routine practice.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nUncertainties generated by the evidence\n\n\n\nSee 'Relevance to general clinical practice in the NHS'.\n\n\n\nThe Committee agreed that the benefit of erlotinib maintenance treatment seen in the SATURN trial was likely to be lower in routine clinical practice when considering that the trial population represented patients who are likely to have a better prognosis than the average patient treated in the UK, In addition, the Committee considered that there were several factors that led to considerable uncertainty about the magnitude of overall survival gain expected from erlotinib maintenance treatment in the stable population and in the squamous and non-squamous disease subpopulations. These included the small numbers of patients in the post hoc subgroup analyses informing the survival estimates for the squamous and non-squamous disease groups and the use of post-progression treatments in the SATURN trial which are not routinely used in the UK; and the lack of explanation as to why most of the survival benefit for erlotinib in the squamous disease group occurred after treatment was discontinued (in the post-progression period).\n\n\n\n\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNone considered.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee noted that the SATURN trial showed that maintenance treatment with erlotinib was associated with a statistically significant improvement in progression-free survival and overall survival compared with placebo for the overall population of patients with stable disease.\n\n\n\nThe Committee considered analyses from the manufacturer where the mean overall survival benefit of erlotinib compared with best supportive care was 3.3 months for the whole stable disease population, 4.2 months in the squamous disease group and 4.5 months in the non-squamous disease group. The Committee noted that the ERG's estimates for the mean overall survival benefit in the squamous and non-squamous groups were 3.4 months and 2.2 months respectively.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nICERs from the manufacturer for erlotinib compared with best supportive care were £40,800 per QALY gained for all patients with stable disease, £35,500 per QALY gained for patients with stable, squamous disease and £40,000 per QALY gained for patients with stable, non-squamous disease.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that the ERG's approach to modelling progression-free survival and overall survival resulted in lower estimates of overall survival than the manufacturer's method and hence resulted in higher ICERs for erlotinib compared with best supportive care than those estimated by the manufacturer.\n\n\n\nThe Committee noted that most of the survival benefit for erlotinib came in the post-progression phase for patients with squamous disease, but not for patients with non-squamous disease. The Committee was unaware of an explanation for this and therefore considered that it added uncertainty.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe manufacturer used the same utility values as those used in 'Pemetrexed for the maintenance treatment of non-small-cell lung cancer' (NICE technology appraisal guidance 190 [TA190]).\n\n\n\n\n\nNone identified.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNone identified.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\n\n\nThe Committee acknowledged that the factors that had the greatest effect on the manufacturer's new ICERs were assumptions about how much time a patient spent on treatment in the progression-free health state, and the costs attributed to best supportive care.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nThe Committee considered that the most plausible ICERs for erlotinib compared with best supportive care would be higher than those estimated by the ERG (£44,800 and £68,100 per QALY gained for treatment of patients with squamous and non-squamous disease respectively), and considerably higher than £50,000 per QALY gained for treatment of the whole stable disease population.\n\n\n\nThe Committee discussed evidence for the cost effectiveness of erlotinib compared with pemetrexed. It noted that this was based on the manufacturer's new economic analysis in which various relative efficacy scenarios were modelled because of the lack of data for erlotinib compared directly with pemetrexed. The Committee considered that erlotinib was likely to be associated with cost savings per QALY lost compared with pemetrexed in patients with stable, non-squamous disease, but that it was not possible to establish a robust estimate. It therefore agreed that no specific recommendation could be made related to the use of erlotinib compared with pemetrexed.\n\n, 4.23\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAdditional factors taken into account\n\nPatient access schemes\n\n(PPRS)\n\nThe Committee was aware that a patient access scheme had been agreed between the manufacturer and the Department of Health in which erlotinib is supplied to the NHS at a discount of 14.5% of the list price.\n\n\n\nEnd-of-life considerations\n\n\n\nThe Committee considered that the true size of the cumulative population potentially eligible for treatment with erlotinib according to its UK marketing authorisations was not small and was considerably higher than the manufacturer's estimate.\n\n\n\nThe Committee did not consider that robust evidence had been provided to demonstrate an extension to life of at least 3 months and, taken together with the consideration on population size, therefore concluded that the end-of-life criteria were not met in this appraisal.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nEqualities considerations and social value judgements\n\n\n\nNo equalities issues were raised during the scoping exercise. In response to the second appraisal consultation document the manufacturer stated that the preliminary recommendations mean that patients with squamous disease will not have a maintenance treatment option, whereas those with non-squamous disease currently have access to pemetrexed maintenance treatment through TA190. The manufacturer further stated that the histological mix of non-small-cell lung cancer shows a gender imbalance with squamous disease making up a substantially larger proportion of non-small-cell lung cancer in men. It was the manufacturer's view therefore that having no maintenance treatment option for people with squamous disease has a greater impact on men with non-small-cell lung cancer, and that this was particularly concerning given that men have an inherently worse prognosis than women. The Committee noted that no data on gender distribution based on histology were provided by the manufacturer and therefore this assertion was impossible to substantiate. However, the Committee noted that any possible differences in maintenance treatment access referred to by the manufacturer were related to TA190, rather than this appraisal. The Committee agreed that its decision about erlotinib maintenance treatment needed to be based on the evidence seen in this appraisal. Furthermore, the final decision not to recommend erlotinib maintenance treatment was made because erlotinib was not cost-effective in either of the squamous or non-squamous subgroups compared with best supportive care. The Committee concluded that its recommendations do not make it more difficult in practice for a specific group to access erlotinib maintenance treatment compared with other groups.\n\n, 4.24", 'Related NICE guidance': 'Published\n\nLung cancer. NICE clinical guideline 121 (2011). Available from www.nice.org.uk/guidance/CG121\n\nGefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer. NICE technology appraisal guidance 192 (2010). Available from www.nice.org.uk/guidance/TA192\n\nPemetrexed for the maintenance treatment of non-small-cell lung cancer. NICE technology appraisal guidance 190 (2010). Available from www.nice.org.uk/guidance/TA190\n\nPemetrexed for the first-line treatment of non-small-cell lung cancer. NICE technology appraisal guidance 181 (2009). Available from www.nice.org.uk/guidance/TA181\n\nGefitinib for the second-line treatment of locally advanced or metastatic non-small-cell lung cancer (terminated appraisal). NICE technology appraisal 175 (2009). Available from www.nice.org.uk/guidance/TA175\n\nErlotinib for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 162 (2008). Available from www.nice.org.uk/guidance/TA162\n\nBevacizumab for the treatment of non-small-cell lung cancer (terminated appraisal). NICE technology appraisal 148 (2008). Available from www.nice.org.uk/guidance/TA148\n\nPemetrexed for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 124 (2007). Available from www.nice.org.uk/guidance/TA124', 'Review of guidance': 'The guidance on this technology will be considered for review in April 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew Dillon\n\nChief Executive\n\nJune 2011', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour\n responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta227
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Evidence-based recommendations on erlotinib (Tarceva) for the maintenance treatment of non-small-cell lung cancer in adults.
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8f7c0d61d186374838cee918b6523bb65eb94505
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Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs
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Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs
Evidence-based recommendations on golimumab (Simponi) for treating rheumatoid arthritis in adults.
# Guidance
This recommendation has been replaced by the recommendations in the NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed.
Golimumab in combination with methotrexate is recommended as an option for the treatment of rheumatoid arthritis in adults whose rheumatoid arthritis has responded inadequately to other DMARDs, including a TNF inhibitor, if:
it is used as described for other TNF inhibitor treatments in 'Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor' (NICE technology appraisal guidance 195), and
the manufacturer provides the 100 mg dose of golimumab at the same cost as the 50 mg dose, agreed as part of the patient access scheme.
When using the disease activity score (DAS28), healthcare professionals should take into account any physical, sensory or learning disabilities, communication difficulties, or disease characteristics that could adversely affect patient assessment and make any adjustments they consider appropriate.# The technology
Golimumab (Simponi, Schering Plough) is a human monoclonal antibody that prevents the binding of TNF to its receptors, thereby neutralising its activity. In October 2009, golimumab, in combination with methotrexate, received a marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to disease-modifying anti-rheumatic drug (DMARD) therapy including methotrexate has been inadequate. The summary of product characteristics (SPC) notes that golimumab has also been shown to improve physical function in this population. In February 2011, the marketing authorisation was amended to indicate that golimumab has also been shown to reduce the rate of progression of joint damage as measured by X‑ray when given in combination with methotrexate.
Golimumab is contraindicated in people with moderate to severe heart failure, hereditary problems of fructose intolerance, active tuberculosis and other severe infections. Before initiating therapy, physicians should evaluate people for prior evidence of hepatitis B virus infection, and both active and inactive (latent) tuberculosis infection. The SPC reports that the most common adverse reactions are upper respiratory tract infections, including nasopharyngitis, pharyngitis, laryngitis and rhinitis. For full details of adverse effects, contraindications, special warnings and precautions for use, see the SPC.
Golimumab is injected subcutaneously via a pre-filled injection pen. The recommended dosage is 50 mg given once a month, on the same date each month. The SPC states that in people who weigh more than 100 kg whose rheumatoid arthritis does not show an adequate clinical response after three or four doses, the dosage may be increased to 100 mg once a month. The cost of a syringe or pen pre-filled with 50 mg of golimumab is £774.58 ('Monthly Index of Medical Specialities' , December 2010). The annual drug cost of golimumab is £9295 (50 mg dose). Costs may vary in different settings because of negotiated procurement discounts.
The manufacturer has agreed a patient access scheme with the Department of Health, in which the 100 mg dose of golimumab will be available to the NHS at the same cost as the 50 mg dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Details of the patient access scheme are provided separately from this document as part of the evidence submitted.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of golimumab and reviews of these submissions by the Evidence Review Group (ERG; appendix B).
# Clinical effectiveness
The submission considered people who had never received a TNF inhibitor (the DMARD-experienced population) separately from people who had had previous therapy with a TNF inhibitor (the TNF inhibitor-experienced population).
## DMARD-experienced population
Two trials with DMARD-experienced participants were included in the submission – a phase III randomised controlled trial (RCT) with four groups (GO‑FORWARD) and a phase II dose-ranging trial with five groups (Kay et al. 2008). The trials investigated the efficacy and the dose effect of golimumab. The manufacturer's submission focused on the groups who had received the licensed dosage of 50 mg golimumab monthly.
GO‑FORWARD was a multicentre randomised double-blind trial that compared 50 mg golimumab every 4 weeks plus methotrexate (15 mg or more every week) (n=89) with placebo plus methotrexate (15 mg or more every week) (n=133). The trial participants had had active rheumatoid arthritis (defined as persistent disease activity with at least four swollen joints and four tender joints) for at least 3 months and had received methotrexate for at least 3 months. The trial included a controlled phase to 24 weeks and an open-label extension to 5 years. Participants whose disease was inadequately controlled in the placebo arm could cross over to the golimumab arm at week 14. All other participants in the placebo arm crossed over to the golimumab arm at week 24. Participants whose disease was inadequately controlled on 50 mg golimumab were able to cross over to the 100 mg golimumab arm.
The primary outcome measures were the proportion of participants with an ACR20 response at 14 weeks and an improvement from baseline in the Health Assessment Questionnaire – Disability Index (HAQ-DI) score at 24 weeks. Secondary outcome measures included ACR20 response at 24 weeks, ACR50 response at 14 and 24 weeks, ACR70 response at 14 and 24 weeks, Disease Activity Score (DAS) 28 at 14 and 24 weeks and improvement from baseline HAQ‑DI score at 14 weeks. Health-related quality of life was measured using the SF‑36 tool.
A significantly greater proportion of participants who received 50 mg golimumab plus methotrexate had an ACR20 response at 14 weeks compared with participants who received placebo plus methotrexate (55.1% and 33.1% respectively; p=0.001). Improvement in HAQ-DI score at 24 weeks was significantly greater in the 50 mg golimumab plus methotrexate group compared with the placebo plus methotrexate group (median 0.375 and 0.125 respectively; p<0.001).
Following consultation on the appraisal consultation document, the manufacturer provided long-term outcomes data from 52- and 104‑week follow-up on ACR responses and on the proportion of participants maintaining a HAQ improvement greater than or equal to 0.25. These data suggested that for the people who continued to receive golimumab the response to treatment was maintained.
The manufacturer also reported that for key secondary endpoints a significantly greater proportion of participants in the 50 mg golimumab plus methotrexate group had a response compared with participants in the placebo plus methotrexate group. An ACR20 response at 24 weeks was seen in 59.6% of the participants who received 50 mg golimumab plus methotrexate compared with 27.8% of the participants who received placebo plus methotrexate (p<0.001). More participants in the 50 mg golimumab plus methotrexate group had an ACR50 response at 24 weeks than in the placebo plus methotrexate group (37.1% and 13.5% respectively; p<0.001). An ACR70 response at 24 weeks was seen in 20.2% of the 50 mg golimumab plus methotrexate group compared with 5.3% of the placebo plus methotrexate group (p<0.001).
The manufacturer submitted SF‑36 data from the GO‑FORWARD trial following consultation on the appraisal consultation document. At 24 weeks there was a statistically significant improvement in the physical component summary score in people treated with golimumab compared with placebo (mean change 8.23 and 2.54 respectively, p<0.001). There were statistically significant changes in six of the eight domains, including all physical health domains, in people treated with golimumab compared with placebo. Social functioning and role–emotional domains did not show statistically significant improvements in people treated with golimumab compared with placebo. Data on golimumab from 104‑week follow-up suggested that changes in SF‑36 were maintained.
Following consultation on the appraisal consultation document, 24‑week and 52‑week radiographic progression data from the GO‑FORWARD trial were submitted. This reported no difference in the mean change from baseline in the van der Heijde modified Sharp (vdH-S) score between the 50 mg golimumab group and the placebo group (mean change 0.93 and 1.10 respectively, p=0.855). Median change was reported to be zero in both golimumab and placebo groups. Further 52‑week and 104‑week follow-up data were provided by the manufacturer. The key data were marked as academic in confidence and so cannot be reported here. The manufacturer noted a number of factors that could account for the minimal progression rates observed in both the placebo and golimumab groups in the GO‑FORWARD trial, including the use of radiographic outcomes as a secondary endpoint, the crossing over of all participants treated with placebo at week 24 and a lower baseline disease activity in the trial compared with trials of other biological therapies.
The manufacturer submitted a subgroup analysis that assessed people with moderate (DAS 28 score of between 3.2 and 5.1) and severe (DAS 28 score greater than 5.1) disease activity from the GO‑FORWARD study separately. The analysis reported relative risks for ACR20, ACR50 and ACR70 response at 24 weeks. For people with moderately active rheumatoid arthritis treated with golimumab (n=18) and placebo (n=28), the relative risks of achieving an ACR20, ACR50 and ACR70 response with golimumab compared with placebo were 2.67 (95% confidence interval 1.30 to 5.48), 1.78 (95% CI 0.78 to 4.05) and 3.89 (95% CI 0.84 to 17.95) respectively. For people with severely active rheumatoid arthritis treated with golimumab (n=71) and placebo (n=104), the relative risks of achieving an ACR20, ACR50 and ACR70 response with golimumab compared with placebo were 2.00 (95% CI 1.39 to 2.87), 3.33 (95% CI 1.75 to 6.32) and 3.81 (95% CI 1.42 to 10.21) respectively.
The manufacturer reported similar rates of adverse events at 16 weeks in the 50 mg golimumab plus methotrexate and the placebo plus methotrexate groups (68.5% and 60.9% respectively). The incidence of serious adverse events at 16 weeks was 5.6% in the 50 mg golimumab plus methotrexate group and 2.3% in the placebo plus methotrexate group. Long-term safety data were provided by the manufacturer following consultation on the appraisal consultation document. These were 52- and 104‑week safety data in trial participants with psoriatic arthritis, rheumatoid arthritis and ankylosing spondylitis who had received treatment with golimumab across all of the original phase III studies. These data were marked as confidential and therefore cannot be reported.
The second trial (Kay et al. 2008) was a multicentre randomised double-blind study, two arms of which compared 50 mg golimumab (every 4 weeks) plus methotrexate (10 mg or more every week) (n=35) with placebo plus methotrexate (10 mg or more every week) (n=35). The trial participants had had active rheumatoid arthritis (defined as persistent disease activity with at least six swollen joints and six tender joints) for at least 3 months and had been treated with methotrexate for at least 3 months. The primary outcome was the proportion of people who had an ACR20 response at 16 weeks. Secondary outcomes included ACR20, 50 and 70 responses over time until 52 weeks, numeric index of the ACR response at 16 weeks and DAS28 at 16 weeks.
Primary outcome data were not presented separately for the 50 mg golimumab group in the manufacturer's submission. However, they were available from a published paper, which showed that an ACR20 response at 16 weeks was seen in 60.0% of people who received 50 mg golimumab plus methotrexate and 37.1% of people who received placebo plus methotrexate.
An ACR20 response at 24 weeks was seen in 74.3% of people in the 50 mg golimumab plus methotrexate group and 45.7% of people in the placebo plus methotrexate group. More participants in the 50 mg golimumab plus methotrexate group had an ACR50 response at 24 weeks than participants in the placebo plus methotrexate group (40.0% and 11.4% respectively). An ACR70 response at 24 weeks was seen in 20.0% of participants in the 50 mg golimumab plus methotrexate group and 5.7% of those in the placebo plus methotrexate group. The ACR20 and 50 responses for the golimumab plus methotrexate group were statistically significantly different from the placebo plus methotrexate group. However, the ACR70 responses were not statistically significantly different between the treatment arms.
In the second trial (Kay et al. 2008) the proportion of participants who experienced at least one adverse event was slightly higher in the 50 mg golimumab plus methotrexate group than in the placebo plus methotrexate group (91.9% and 85.3% respectively).
Following consultation on the appraisal consultation document, the manufacturer provided further data from the trial by Kay et al. (2008) to support the dosage frequency used in the marketing authorisation. The manufacturer provided additional data for the three groups who received golimumab at unlicensed dosages not included in the submission (50 mg and 100 mg once every 2 weeks, and 100 mg once every 4 weeks). The manufacturer reported that no clear dosage–response relationship was observed, and that the lowest dosage regimen (that is, 50 mg once every 4 weeks) had an ACR response similar to that observed in the higher dosages.
## TNF inhibitor-experienced population
The manufacturer's submission included a single phase III randomised double-blind placebo-controlled trial (GO‑AFTER) for the TNF inhibitor-experienced population. The trial had three groups and the manufacturer's submission focused on two of the groups: the placebo group (n=155) and the group who received 50 mg golimumab (n=153) rather than the group who received the unlicensed dose of 100 mg golimumab. The trial participants had had active rheumatoid arthritis (defined as persistent disease activity with at least four swollen joints and four tender joints) for at least 3 months and had been treated with at least one dose of a TNF inhibitor (etanercept, adalimumab or infliximab). People in the trial were not required to take golimumab in combination with another DMARD. Approximately 66% received golimumab in combination with methotrexate.
The primary outcome was the proportion of participants with ACR20 response at 14 weeks. The duration of follow-up was 24 weeks. The secondary outcomes included ACR50, 70 and 90 at 14 weeks, ACR20, 50, 70 and 90 at 24 weeks and change from baseline in HAQ-DI score at 24 weeks. No data were collected for SF‑36, and no data were provided for radiographic progression.
A significantly higher proportion of the participants who received 50 mg golimumab had an ACR20 response at 14 weeks compared with placebo (35.3% and 18.1% respectively; p<0.001). An ACR20 response at 24 weeks was seen in 34.0% of participants in the 50 mg golimumab group compared with 16.8% of participants in the placebo group (p<0.001). An ACR50 response at 24 weeks was seen in more participants in the 50 mg golimumab group than in the placebo group (18.3% and 5.2% respectively; p<0.001). An ACR70 response at 24 weeks was seen in 11.8% of participants in the 50 mg golimumab group and 3.2% of those in the placebo group (p=0.004). Change in HAQ-DI from baseline was assessed at 24 weeks. For the 50 mg golimumab group there was a median improvement in HAQ-DI of 0.25. For the placebo group there was no change in the median HAQ-DI score.
No major differences in the number of reported adverse events were evident in the GO-AFTER study at 24 weeks. The number of serious adverse events at 24 weeks was slightly lower in the 50 mg golimumab group than in the placebo group.
To provide support for the radiographic data from the GO‑FORWARD trial, the manufacturer also provided data from the GO‑BEFORE trial. The GO‑BEFORE trial compared methotrexate plus placebo with golimumab plus methotrexate in participants who had rheumatoid arthritis not previously treated with methotrexate. Intention-to-treat analyses reported a statistically significant difference in mean change from baseline in radiographic progression at week 52 (1.37 in the methotrexate group and 0.74 in the 50 mg golimumab group ). Analyses of data from the participants who remained on their originally allocated treatment reported a change from baseline in radiographic progression at week 52 of 0.22 in the methotrexate group (n=9) and 0.06 in the 50 mg golimumab group (n=99). At week 104 the change from baseline in radiographic progression was 0.40 (n=10) and −0.10 (n=99) in each group respectively.
## Mixed treatment comparison and indirect comparison
No head-to-head trials analysing the efficacy of golimumab compared with other active treatment options were available. Therefore the manufacturer searched for trials of comparator interventions and completed mixed treatment and indirect comparison analyses to estimate the relative effect of golimumab versus the comparators. The manufacturer included comparators that had been recommended by NICE at the time of submission. For the DMARD-experienced population comparisons were made with placebo, adalimumab, certolizumab pegol, etanercept and infliximab. For the TNF inhibitor-experienced population comparisons were made with placebo and rituximab. Following consultation on the appraisal consultation document, the manufacturer submitted additional cost-effectiveness analyses for the comparison of golimumab, tocilizumab and abatacept. However, separate data on the relative clinical effectiveness of golimumab compared with tocilizumab and abatacept were not provided.
Twenty trials were included in the mixed treatment comparison for the DMARD-experienced population. The results from the random effects model showed that for each ACR response, golimumab was statistically significantly superior to placebo. In comparison with adalimumab, certolizumab pegol, etanercept or infliximab there were no statistically significant differences in ACR20, ACR50 or ACR70 response rates. However, the point estimates favoured the other TNF inhibitors, except in the comparison with infliximab. For ACR20 the median relative risks and 95% credibility intervals for golimumab were 0.98 (0.55 to 1.46) compared with adalimumab, 0.72 (0.41 to 1.06) compared with certolizumab pegol, 0.93 (0.51 to 1.43) compared with etanercept and 1.05 (0.57 to 1.65) compared with infliximab. For ACR50, the median relative risks and 95% credibility intervals for golimumab were 0.90 (0.40 to 1.76) compared with adalimumab, 0.63 (0.27 to 1.31) compared with certolizumab pegol, 0.98 (0.40 to 1.99) compared with etanercept and 0.99 (0.42 to 2.04) compared with infliximab. For ACR70, the median relative risks and 95% credibility intervals for golimumab were 0.75 (0.28 to 1.86) compared with adalimumab, 0.47 (0.16 to 1.35) compared with certolizumab pegol, 0.32 (0.09 to 1.15) compared with etanercept and 1.16 (0.40 to 3.00) compared with infliximab.
Sensitivity analyses were performed for ACR20 and ACR50 responses in which the TEMPO etanercept trial was excluded because of a greater response within its placebo arm compared with other studies. The exclusion of the TEMPO trial resulted in raised relative risks for ACR20 and ACR50, indicating increased efficacy for etanercept in comparison with golimumab. However, these results were statistically significant only in the fixed effects model for the ACR20 response. Exclusion of the TEMPO trial also altered the estimates of relative risk for golimumab in comparison with the other treatments. When golimumab was compared with certolizumab pegol, the differences were statistically significant in the fixed effects model and for ACR20 in the random effects model, with both favouring certolizumab pegol.
A mixed treatment comparison was carried out for selected safety outcomes. Golimumab was estimated to be associated with a greater number of serious adverse events than all comparators except certolizumab pegol. However, none of the differences was statistically significant, and all had wide credibility intervals. The estimated rate of serious infections for golimumab was similar to the rates for infliximab and etanercept, and lower than those for adalimumab and certolizumab pegol. These differences reached statistical significance for the comparison of golimumab with certolizumab pegol. However, all had wide credibility intervals. Golimumab was estimated to have fewer discontinuations because of adverse events. However, this reached statistical significance only in the comparison of golimumab with certolizumab pegol.
Two trials were used in the indirect comparison analyses of golimumab (GO‑AFTER) and rituximab (REFLEX) for the TNF inhibitor-experienced population. In these analyses (based on the methods developed by Bucher et al. ) golimumab and rituximab were indirectly compared, with placebo as the comparator. Although the estimates of ACR response favoured rituximab, there were no statistically significant differences between golimumab and rituximab. For ACR20 the relative risk was 0.71 (95% CI 0.42 to 1.20). For ACR50 and ACR70 the corresponding figures were 0.66 (95% CI 0.25 to 1.76) and 0.30 (95% CI 0.05 to 1.66).
The indirect comparison suggested that the relative risks of serious adverse events were similar for golimumab and rituximab, although these were associated with wide confidence intervals. The relative risk estimate for serious infections was slightly lower for golimumab compared with rituximab but this difference was not statistically significant. Golimumab was associated with statistically significantly lower rates of discontinuation due to adverse events.
## Review from the ERG
The ERG considered the clinical effectiveness review methods and results to be reasonably clearly presented, with adequate systematic searches conducted. The ERG stated that all the relevant RCTs for golimumab and the comparators appeared to have been included and the golimumab trials were of reasonable methodological quality. The ERG considered that the mixed treatment comparisons and indirect comparisons used appropriate trials.
The ERG commented that the populations in GO‑FORWARD and Kay et al. (2008) were generally representative of the UK population with rheumatoid arthritis, although in the GO‑FORWARD trial the proportion of people who received glucocorticoid therapy was higher than the UK average. Similarly, steroid use in the GO‑AFTER population may have been higher than the average in the UK population with rheumatoid arthritis, and in this study only 66% of the participants had also received methotrexate.
The ERG noted inconsistencies between the data presented for ACR20 and ACR50 responses in Kay et al. (2008). Different values were presented in the original study publication (week 16) and in the efficacy meta-analyses in the manufacturer's submission. The ERG was unclear how the original efficacy data from Kay et al. (2008) had been derived and handled in the meta-analyses.
The ERG commented on the complexities involved in comparing data across the interventions in the mixed treatment and indirect comparison analyses because response rates can be influenced by changes in patient populations over time. It noted that the certolizumab pegol trials had a higher ratio of ACR responses on active treatment compared with placebo, and these trials may not be comparable with the trials of other TNF inhibitors.
The ERG reviewed the additional data provided by the manufacturer. The ERG welcomed the SF‑36 data from the GO‑FORWARD trial and confirmed that SF‑36 data were not collected in the GO‑AFTER trial. The ERG reported that the radiographic progression data from the GO‑BEFORE trial appeared to suggest a reduction in progression of structural damage for participants with rheumatoid arthritis not previously treated with methotrexate. The ERG also stated that the summary of the 24‑week data from the GO‑FORWARD trial was appropriate. The ERG noted that interpretation of the longer-term data from this trial was limited by cross-over between treatments.
# Cost effectiveness
The manufacturer provided two sets of cost-effectiveness analyses, the first in the original submission and the second in response to a request from NICE as part of the preliminary recommendations, which was provided after consultation on the appraisal consultation document. Both sets of analyses were reviewed by the ERG. Following this review and consideration by the Appraisal Committee, the second set of analyses was not considered to form a sufficiently robust basis for decision making because it was not internally consistent. The manufacturer was asked to resubmit these data. The resubmitted data were also reviewed by the ERG. The original submission and the resubmitted data are included in this section.
## Original submission
The manufacturer submitted two decision-analytic Markov models, each with a lifetime horizon. Both models evaluated golimumab as part of a sequence of treatments: one evaluated golimumab in a DMARD-experienced population (comparing golimumab with TNF inhibitors and methotrexate in people whose disease had had an inadequate response to two DMARDs) and the other evaluated golimumab in a TNF inhibitor-experienced population (comparing golimumab with rituximab and methotrexate in people whose disease had had an inadequate response to two DMARDs and a TNF inhibitor). All treatments were given in combination with methotrexate. Methotrexate monotherapy was included as a comparator in each model because it represented the placebo arm in the indirect and mixed treatment comparisons. The manufacturer did not include technologies being appraised by NICE at the time of its submission (tocilizumab, abatacept and the use of etanercept, infliximab and adalimumab after the failure of a first TNF inhibitor) as comparators.
On starting treatment, people could have either an ACR20 response, ACR50 response or no response. The probability of response for golimumab and methotrexate monotherapy was derived from the GO‑FORWARD and GO‑AFTER trials. To derive efficacies for the other comparators the response for golimumab was adjusted using the relative effects estimated from the mixed treatment and indirect comparison analyses. For each ACR response criterion the corresponding change in HAQ‑DI was calculated based on data from the GO‑FORWARD and GO‑AFTER trials. The HAQ‑DI was in turn mapped to EQ‑5D with an equation used in NICE technology appraisal guidance 130 ('Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis'). People progressed to the next treatment if they did not have at least an ACR20 response at 6 months, or if they stopped treatment because of a lack of efficacy or an adverse event. In both models, people progressed to leflunomide, gold, azathioprine, ciclosporin and then palliative treatment.
At the start of the models people were aged 50 years in the DMARD-experienced population and 54 years in the TNF inhibitor-experienced population. HAQ scores for people entering the model were derived from the baseline characteristics of the GO‑FORWARD and GO‑AFTER trials: 1.41 and 1.58 respectively. While people were receiving a treatment, it was assumed that their disease severity increased over time. This was modelled with an annual worsening of HAQ score (that is, an HAQ progression rate). The HAQ progression rate was 0.045 for a person being treated with DMARDs, 0.00 for TNF inhibitors, 0.045 for rituximab and 0.09 for palliative treatment.
Costs relating to treatment, administration, monitoring and hospitalisation were included in the economic models using 2006 reference costs and 2008 unit costs. Following a clarification request, the manufacturer incorporated 2008 reference costs and 2009 unit costs. It was assumed that a course of rituximab was given once every 6 months. The cost of joint replacement was not included in the model. Costs and quality-adjusted life years (QALYs) were discounted at a rate of 3.5%.
The results from the economic model were presented incrementally with all treatments compared with each other, and for each treatment individually in comparison with methotrexate. The deterministic results for the DMARD-experienced population showed that the incremental cost-effectiveness ratios (ICERs) were £31,464 (£34,030 additional costs and 1.082 additional QALYs) and £31,444 (£37,702 additional costs and 1.199 additional QALYs) per QALY gained for infliximab and certolizumab pegol respectively in comparison with methotrexate, and £25,346 (£31,878 additional costs and 1.258 additional QALYs) per QALY gained for golimumab in comparison with methotrexate. The ICERs for adalimumab and etanercept in comparison with methotrexate were £25,353 (£31,006 additional costs and 1.223 additional QALYs) and £24,514 (£38,339 additional costs and 1.564 additional QALYs) per QALY gained respectively. The incremental analysis showed that infliximab and certolizumab pegol were both dominated by golimumab because golimumab was more effective and less costly. However, adalimumab and golimumab were both extendedly dominated by etanercept. Etanercept generated the most QALYs of any strategy, at a lower cost per QALY ratio (£24,514 per QALY gained in comparison with methotrexate).
The results for the deterministic base-case analysis of golimumab in a TNF inhibitor-experienced population show that rituximab was dominated by golimumab because golimumab was less costly and more effective (£31 fewer costs and 0.189 additional QALYs). Golimumab compared with methotrexate had an ICER of £28,286 (£16,502 additional costs and 0.583 additional QALYs) per QALY gained whereas rituximab compared with methotrexate had an ICER of £41,935 (£16,533 additional costs and 0.394 additional QALYs) per QALY gained.
## Comments from the ERG on the manufacturer's original submission
The ERG noted that the model results (total costs and QALYs, time in states, HAQ scores and incremental costs and QALYs) appeared plausible given the parameter inputs. It commented that the model was generally of a high quality. The ERG identified some programming errors in the model that it corrected. However, these errors did not change the conclusion in the manufacturer's submission that, compared with methotrexate, golimumab has an ICER that is comparable to other TNF inhibitors but that golimumab is never the most cost-effective TNF inhibitor treatment.
The ERG considered that it would have been appropriate to include ACR70 response data in the model so that all the available clinical evidence is used to evaluate golimumab. The manufacturer justified the exclusion of these data by stating that there was not a statistically significant difference between golimumab and the comparators and that incorporating this outcome would only add an element of uncertainty to the model inputs. The ERG noted that this reason was not justified because there was also no statistically significant difference in the ACR20 and ACR50 response data for golimumab and the comparators, but these data had been included in the model.
The ERG undertook a number of exploratory analyses to address some of its concerns. The original model used 2006 reference costs and 2008 unit costs. However, after clarification, the manufacturer incorporated 2008 reference costs and 2009 unit costs. The ERG used the updated reference and unit costs and found that they had little impact on the incremental costs for the different treatments in the DMARD-experienced population, and so the resulting ICERs did not change substantially.
The ERG identified an error in the model for infliximab in the DMARD-experienced population, which resulted in a cost being allocated when a person dies. There was also an error in the modelling of HAQ decrements for certolizumab pegol. Correcting the infliximab costs reduced the total cost of infliximab treatment, and it was no longer dominated by adalimumab. Correcting the HAQ decrements for certolizumab pegol meant that it was the optimal intervention instead of etanercept.
The economic model used the response rates from the GO‑FORWARD trial to estimate the probability of ACR response and the probability of stopping treatment because of an adverse event at 6 months in the golimumab and methotrexate groups. However, the model used the mixed treatment comparison to estimate the rates of these events for the comparators; this approach excludes the evidence from Kay et al. (2008). In the exploratory analysis the ERG used the mixed treatment comparison, incorporating the evidence from Kay et al. (2008) to estimate the probability of these outcomes in the placebo group, which is used to populate the methotrexate arm of the economic model. Using the mixed treatment comparison rather than the GO‑FORWARD study alone to inform the golimumab versus methotrexate comparison did not substantially alter the results.
The cumulative impact of the changes described in sections 3.42–3.44 reduced all the ICERs for all TNF inhibitors in comparison with methotrexate in the DMARD-experienced group. The ICERs for infliximab and certolizumab pegol in comparison with methotrexate were £24,137 and £20,800 per QALY gained. The ICER for golimumab compared with methotrexate was £24,794 per QALY gained. The ICERs for adalimumab and etanercept in comparison with methotrexate were £24,800 and £23,990 per QALY gained. The incremental analysis suggested that certolizumab pegol including its patient access scheme is the optimal treatment strategy, dominating etanercept and extendedly dominating golimumab, adalimumab and infliximab.
The ERG stated that for the TNF inhibitor-experienced population there was considerable uncertainty in the HAQ progression rate estimates and the re-administration frequency of rituximab. The ERG commented that the manufacturer assumed a HAQ progression rate equal to the rate for DMARDs rather than for TNF inhibitors, which may underestimate the benefit of rituximab. The ERG also commented that the model assumes that rituximab is re‑administered every 6 months but it considered that 9 months would be more reflective of current clinical practice. The ERG amended the model so that rituximab had a zero HAQ progression rate (equal to that of TNF inhibitors) rather than the 0.045 that was assumed in the base-case analysis. The ERG also amended the model so that each person received two infusions in the first 6 months and then one infusion every 9 months. The costs were updated as described for the DMARD-experienced population.
The cumulative impact of the changes described in 3.46 reduced the ICERs for golimumab and rituximab in comparison with methotrexate (£28,115 and £10,088 per QALY gained respectively). The incremental analysis showed that rituximab dominated golimumab.
Following comments received during consultation on the appraisal consultation document about the inclusion of the TEMPO study and the TNF inhibitor monotherapy studies in the base-case analysis, the ERG performed sensitivity analyses to assess the impact on the ICERs of separately excluding the monotherapy studies and the TEMPO study. In an incremental analysis, when the TEMPO study is excluded etanercept is no longer dominated by certolizumab pegol and it becomes the optimum strategy. When the TNF inhibitor monotherapy studies are excluded, the results do not differ substantially from the base case, with certolizumab pegol remaining the optimum strategy.
## Resubmitted additional analyses provided by the manufacturer following consultation on the appraisal consultation document
In response to a request from NICE, the manufacturer provided additional analyses of the cost effectiveness of golimumab. The analyses included:
incorporation of ACR70 response data and disease progression on palliative treatment reflected as an increase in HAQ score of 0.06 per year in the economic model
a sensitivity analysis in which SF‑36 data are included in the economic model using mapping to SF‑6D
cost-effectiveness results for the comparison of golimumab, abatacept and tocilizumab for the group of people whose disease has responded inadequately to a TNF inhibitor.
The manufacturer did not provide any analyses that reported the estimates of cost effectiveness of including the 100 mg dose of golimumab for people weighing over 100 kg whose rheumatoid arthritis does not respond to the 50 mg dose. The manufacturer submitted a patient access scheme that would provide the 100 mg dose at the same cost as the 50 mg dose in this population. This scheme has been approved by the Department of Health.
In the resubmitted analyses (described in 3.58 and 3.59) the manufacturer corrected the internal inconsistencies previously present in the analyses. The analyses also incorporated the changes made by the ERG in response to the original submission (that is, updated unit costs and corrections to the HAQ decrements for certolizumab pegol and costs for infliximab). The analyses also included ACR70 response data and a progression rate while on palliative treatment of 0.06 HAQ score units a year.
The results from the economic model for the DMARD-experienced population were presented for each treatment in comparison with methotrexate. Including ACR70 response data in the model produced ICERs that were £21,944 and £25,825 per QALY gained for certolizumab pegol and infliximab respectively in comparison with methotrexate, and £26,996 per QALY gained for golimumab in comparison with methotrexate. The ICERs for adalimumab and etanercept in comparison with methotrexate were £25,523 and £27,157 per QALY gained respectively.
A sensitivity analysis was provided that included the SF‑36 data from the GO‑FORWARD study converted to SF‑6D. The SF‑6D scores were calculated only for ACR20 and ACR50 responses. The results showed that the ICERs were £27,413 and £29,484 per QALY gained for certolizumab pegol and infliximab respectively in comparison with methotrexate and £31,046 per QALY gained for golimumab in comparison with methotrexate. The ICERs for etanercept and adalimumab in comparison with methotrexate were £30,936 and £30,893 per QALY gained respectively.
The results from the economic model for the TNF inhibitor-experienced population were presented for golimumab, rituximab abatacept and tocilizumab in comparison with methotrexate. The analyses incorporated a progression rate while on palliative treatment of 0.06 HAQ score units a year, and zero while on treatment with either golimumab, abatacept or tocilizumab. The progression rate for rituximab was 0.045 HAQ score units per year.
The analyses produced ICERs of £35,288, £32,036 and £35,382 per QALY gained for tocilizumab, golimumab and abatacept respectively in comparison with methotrexate, and £59,328 per QALY gained for rituximab in comparison with methotrexate. One-way sensitivity analyses assuming that people on rituximab experienced no disease progression while on treatment reduced the ICER for rituximab compared with methotrexate to £24,683 per QALY gained. An alternative one-way sensitivity analysis that assumed re-treatment with rituximab every 9 months reduced the ICER for rituximab to £28,047 per QALY gained in comparison with methotrexate.
## ERG comments on the manufacturer's resubmitted additional analyses
The ERG stated that the results from the manufacturer's resubmitted analyses were consistent with the electronic models provided. The ERG confirmed that the changes reported to have been implemented by the manufacturer had been completed appropriately and that errors previously identified had been corrected. The ERG noted that the results provided were deterministic and that no incremental analyses were included.
For the DMARD-experienced population, the ERG re-ran the manufacturer's model using a probabilistic analysis and presented the results incrementally. The incremental probabilistic analysis suggested that certolizumab pegol was the most cost-effective option, with an ICER in comparison with methotrexate of £22,693 per QALY gained. All other treatments were either dominated or extendedly dominated by certolizumab pegol. For each of the other treatments in comparison with methotrexate the probabilistic analysis produced ICERs for infliximab, golimumab, adalimumab and etanercept of £25,541, £27,946, £25,951, and £27,129 per QALY gained respectively.
The ERG reviewed the sensitivity analysis provided by the manufacturer that used the SF‑36 values converted to SF‑6D. The ERG noted that the manufacturer had not directly used the SF‑6D values for the placebo and methotrexate group; rather, it had estimated the ratio between the HAQ scores from the two groups in the clinical trial and then applied this ratio to the SF‑6D scores for the golimumab group to obtain a value for the methotrexate group. The HAQ adjustment resulted in lower SF‑6D scores associated with ACR20, ACR50 and ACR70 responses for the methotrexate group compared with the golimumab group. The ERG stated that it was unclear why the manufacturer had chosen this method.
The ERG re-ran the manufacturer's model using a probabilistic analysis and presented the results incrementally. The incremental probabilistic analysis suggested that certolizumab pegol was the most cost-effective option with an ICER in comparison with methotrexate of £27,182 per QALY gained. All other treatments were either dominated or extendedly dominated by certolizumab pegol. For each of the other treatments in comparison with methotrexate the probabilistic analysis produced ICERs for infliximab, golimumab, adalimumab and etanercept of £28,990, £31,420, £30,129, and £30,412 per QALY gained respectively.
The ERG checked the revised model for the TNF inhibitor-experienced population and stated that the changes had been implemented appropriately. The ERG cross-checked the cost-effectiveness estimates in the model with the study papers and relevant NICE technology appraisals and reported that the values used in the model corresponded. The ERG stated that a full validation of the model was not possible. However, the model maintained internal consistency and the clinical effectiveness results matched those in previous submissions.
The ERG re-ran the manufacturer's model using a probabilistic analysis. The ICER for golimumab compared with methotrexate was £32,979 per QALY gained. The ICERs for rituximab, abatacept and tocilizumab compared with methotrexate were £68,663, £34,155, and £34,644 per QALY gained respectively. The ERG produced a sensitivity analysis that assumed that the rate of underlying disease progression while on treatment with rituximab was zero (that is, the same assumption as the other biological treatments), and that rituximab was administered every 9 months rather than every 6 months. This reduced the ICER for rituximab in comparison with methotrexate from £68,663 to £12,196 per QALY gained.
Full details of all the evidence are in the manufacturer's submissions and the ERG reports, which are available from www.nice.org.uk/guidance/TA225# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of golimumab, having considered evidence on the nature of rheumatoid arthritis and the value placed on the benefits of golimumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee discussed the clinical management of rheumatoid arthritis. The clinical specialists explained that ideally DMARD therapy should be started as early as possible after diagnosis to reduce joint damage, and that for the majority of people therapy with conventional DMARDs is sufficient. However, they explained that for a small proportion of people conventional DMARDs do not adequately control disease, and for this group of people biological DMARDs such as TNF inhibitors are needed. The Committee heard from the patient experts and clinical specialists that it is not possible to predict which TNF inhibitor will produce the best effect for each person. Therefore people prefer to have a choice of treatments and hence another treatment option would be welcome. The clinical specialists explained that they discuss with patients the different options for treatment and the choice of treatment is a joint decision between the clinician and the patient. The Committee understood that the availability of a range of treatments was valued by clinicians and patients.
The Committee heard from the clinical specialists and the patient experts that golimumab is administered once per month and this may be an advantage for people who have difficulty injecting themselves because of the joint damage caused by the disease and for people who have a fear of injections. The patient experts stated that once-monthly administration may be more convenient if they want to travel, as trips could more easily be planned around once‑a‑month administration. A once-monthly treatment may also be beneficial for people who experience injection-site reactions. However, the Committee heard from the clinical specialists that the length of the half-life of golimumab may be a disadvantage if a person needs to stop treatment quickly, for example if they had an adverse reaction or had unplanned surgery, since it would take time for the treatment effects (on immunity, for example) to wear off. The Committee accepted that the once-monthly administration of golimumab may be beneficial for people with rheumatoid arthritis.
The Committee discussed the dosing frequency of golimumab in response to comments received during consultation. The Committee noted that evidence regarding the choice of dose had been provided by the manufacturer from a phase II study (Kay et al. 2008). The Committee considered that the data comparing four different doses and schedules of golimumab showed that the dosing regimen of once every 4 weeks had similar ACR response rates to the fortnightly dosing regimen, and that no clear dosage–response relationship was observed. The Committee accepted that the data showed that 50 mg golimumab once every 4 weeks is the minimum effective dosage.
# Clinical effectiveness
The Committee considered the evidence on the clinical effectiveness of golimumab in combination with methotrexate and noted that the manufacturer's submission considered golimumab at two positions in the treatment pathway – after treatment with conventional DMARDs only, and after treatment with both conventional DMARDs and a TNF inhibitor. The Committee heard from clinical specialists how golimumab would fit into the current treatment pathway. It heard that golimumab may be used either as a first TNF inhibitor therapy in people whose disease has not responded to conventional DMARD therapy, or as a second TNF inhibitor therapy in people who have had previous therapy with a TNF inhibitor. Following comments received during consultation regarding the marketing authorisation for golimumab, the manufacturer was asked to confirm whether the marketing authorisation for golimumab includes people who have had previous therapy with a TNF inhibitor. The manufacturer stated that golimumab was approved on the basis of the GO‑FORWARD and GO‑AFTER studies and that its use in people who have had previous therapy with a TNF inhibitor is consistent with the marketing authorisation and the evidence. The Committee concluded that the two positions in the treatment pathway as included in the manufacturer's submission were appropriate to be considered in this appraisal.
For people who have previously had only conventional DMARDs, the Committee considered the evidence from the two placebo-controlled trials of golimumab in combination with methotrexate (GO‑FORWARD and Kay et al. 2008). It noted that golimumab in combination with methotrexate had greater clinical effectiveness than placebo in combination with methotrexate. The Committee then discussed the mixed treatment comparison presented by the manufacturer in the absence of head‑to‑head trials comparing the efficacy of golimumab with that of the other available TNF inhibitors. The Committee noted that the mixed treatment comparison suggested that there were no statistically significant differences in ACR20, ACR50 and ACR70 response rates between golimumab and the other TNF inhibitors, and that the credibility intervals around the estimates were wide. The Committee heard from clinical specialists that they considered the different TNF inhibitors to have broadly similar efficacy. The Committee discussed the potential heterogeneity between the studies included in the comparison, recognising concerns about the comparability of the certolizumab pegol studies. It further noted comments received in consultation that it was inappropriate to include the TEMPO study and the TNF inhibitor monotherapy studies in the mixed treatment comparison. However, the Committee noted the sensitivity analyses performed by the ERG, which showed that the exclusion of these studies did not significantly alter the estimates of cost effectiveness. The Committee concluded that, based on the ACR response rates, golimumab had been demonstrated to be more effective than placebo and that there was no convincing evidence that golimumab was either more or less effective than the other TNF inhibitors.
The Committee considered the evidence on the clinical effectiveness of golimumab compared with placebo for the people who had had previous treatment with both conventional DMARDs and a TNF inhibitor. It noted that there was a single trial (GO‑AFTER) comparing golimumab with placebo and this trial showed that golimumab had greater clinical effectiveness than placebo. The Committee discussed the indirect comparison of golimumab and rituximab performed in the absence of head-to-head trials comparing the efficacy of golimumab with that of rituximab. It agreed that rituximab is an appropriate comparator for this population, although it was aware that since the manufacturer's submission NICE has published technology appraisal guidance recommending the use of tocilizumab, abatacept and a second TNF inhibitor in certain people who have had previous treatment with a TNF inhibitor. The Committee concluded that although the point estimates favoured rituximab, the indirect comparison did not demonstrate any statistically significant differences in clinical efficacy between golimumab and rituximab. The Committee noted that the additional analyses provided by the manufacturer included cost-effectiveness results for the comparison of golimumab, tocilizumab and abatacept in people who have had previous treatment with a TNF inhibitor. However, the Committee noted that separate data on the clinical effectiveness of golimumab compared with tocilizumab and abatacept were not provided.
The Committee discussed the long-term data for ACR response and proportion of people maintaining a HAQ improvement equal to or greater than 0.25 in the DMARD-experienced population in the GO‑FORWARD trial. The Committee noted limitations to the data, specifically that the trial had a placebo-controlled phase only up to 24 weeks, and included participants in the placebo arm who had crossed over to golimumab at week 14 because their disease was inadequately controlled. Despite these limitations the Committee agreed that the data suggested that the efficacy of golimumab was maintained over the long term. The Committee also discussed the long-term SF‑36 data submitted by the manufacturer and accepted that golimumab in combination with methotrexate had been shown to have a positive benefit on health-related quality of life compared with placebo. The Committee concluded that these data suggested that efficacy of golimumab was maintained.
The Committee considered clinical-effectiveness evidence for subgroups of people in the GO‑FORWARD trial who had either moderately or severely active rheumatoid arthritis as defined by their baseline DAS28 score. It noted that the analysis was in a small number of people, particularly the subgroup with moderately active rheumatoid arthritis. It further noted that the analysis was post hoc although it had been provided in line with the scope for the appraisal. For these reasons the Committee concluded that there was uncertainty surrounding the results. It noted that the majority of clinical evidence is in people with severely active rheumatoid arthritis.
The Committee discussed the 52- and 104‑week radiographic progression data (measured by the vdH‑S) from the GO‑FORWARD study submitted by the manufacturer following consultation on the appraisal consultation document. It noted that these data showed no statistically significant difference from baseline in vdH‑S score between golimumab 50 mg and placebo. The Committee heard from the manufacturer that both groups in the trial had shown minimal radiographic progression, which meant that golimumab could not improve on the results seen in the placebo group. The Committee noted a number of explanations provided for the minimal progression in both groups, including the short placebo-controlled period, the use of radiographic outcomes as secondary endpoints in relation to the size of the study and lower baseline disease activity levels in the golimumab trials compared with trials of other biological treatments. The Committee then discussed the 52‑week radiographic progression data from the GO‑BEFORE study provided as supporting evidence for the GO‑FORWARD data. It noted that these data had been used to support the licence extension for golimumab. The Committee was not persuaded that the data had demonstrated an absence of underlying radiographic progression while on treatment with golimumab, but it concluded that the data demonstrated that the combination of golimumab and methotrexate reduced the rate of radiographic progression.
The Committee discussed the adverse events seen in the golimumab RCTs and the results from the mixed treatment comparison and the indirect comparison of golimumab and the comparators in both populations. It noted that the data from the mixed treatment and indirect comparisons suggested few statistically significant differences in relative risk between the treatments but that these were associated with considerable uncertainty. It heard from the clinical specialists that there are no long-term adverse event data for golimumab but that they expected the adverse event profile of golimumab to be no different from that of other TNF inhibitors. The clinical specialists suggested that since golimumab is administered once a month, there might be fewer adverse events compared with other TNF inhibitors as a result of the reduced frequency of administration. The Committee concluded that there was uncertainty surrounding the adverse event profile of golimumab because of the limited long-term data, but that golimumab's adverse event profile had not been shown to be different from that of other TNF inhibitors.
# Cost effectiveness
The Committee considered the economic model that evaluated golimumab as part of a sequence of treatments in people who had had previous treatment with conventional DMARDs only and who had not had a previous TNF inhibitor. It noted that, on the whole, the model used similar assumptions to other models submitted in previous appraisals of TNF inhibitors in rheumatoid arthritis, but that there were some differences from the other models, for example the exclusion of ACR70 response data, alternative rates of disease progression while on treatment and alternative methods for deriving estimates of utility. The Committee noted that the ACR70 response data and rates of underlying disease progression, similar to those used in other NICE technology appraisals, had subsequently been appropriately included in a revised economic model.
The Committee considered the utility estimates incorporated in the original model, and noted that the utility was derived from the ACR response, which was converted to a change in HAQ score and then mapped to EQ‑5D. The Committee recognised that a similar approach to mapping had been used in previous NICE technology appraisals of biological treatments for rheumatoid arthritis. However, the Committee noted that this was different from the NICE reference case, which recommends inclusion of directly collected utility data. The Committee then discussed the sensitivity analysis submitted by the manufacturer following the consultation on the appraisal consultation document, using the SF‑36 data from the GO‑FORWARD study. It noted comments from the ERG about the method that the manufacturer used to generate the SF‑6D for the methotrexate group and that the ERG was unclear why this approach had been taken. The Committee considered that a more appropriate method for the analysis would have been to use the data from the placebo group directly. However, it concluded that the sensitivity analysis suggested that the methodology to derive the utility in the base-case analysis had not been shown to be unreasonable.
The Committee discussed the 100 mg dose, which is indicated for people who weigh more than 100 kg and whose rheumatoid arthritis has not responded after three or four doses of golimumab. It noted that evidence for the clinical and cost effectiveness of this dose was not included in the original submission. The Committee understood that even though the proportion of people who received this dose might be quite small, if the acquisition cost was included in the model the ICER for golimumab would be expected to be higher than that estimated in the base case presented by the manufacturer. The Committee noted that following consultation on the appraisal consultation document, the manufacturer did not submit any additional data regarding the 100 mg dose, but instead proposed a patient access scheme that would provide the 100 mg dose at the same cost as the 50 mg dose in people for whom the higher dose is suitable. The Committee recognised that the patient access scheme has been accepted by the Department of Health. The Committee considered that analyses should have been presented both with and without the proposed patient access scheme, but concluded that with the patient access scheme, the manufacturer's analysis including only the costs of the 50 mg dose could be used as a basis for decision making.
The Committee noted that the economic analysis from the manufacturer had assumed that there was no progression of disease while on treatment with a TNF inhibitor, but that there was progression while on treatment with conventional DMARDs and on palliative treatment. The Committee discussed the progression of disease while on treatment with TNF inhibitors for people who have had therapy with conventional DMARDs only. The Committee considered that an assumption of no progression while on treatment with a TNF inhibitor could be an overestimate of the benefits of treatment. However, it heard from clinical specialists that although no progression on treatment may appear optimistic, findings from long-term studies suggest that it is a reasonable assumption for people whose rheumatoid arthritis responds to treatment. The Committee recognised that similar assumptions had been made in other NICE technology appraisals of TNF inhibitor treatments for rheumatoid arthritis. The Committee was aware of the long-term radiographic progression data submitted by the manufacturer following consultation on the appraisal consultation document (see 4.9). It noted that these data showed that golimumab reduced the rate of radiographic progression, albeit in a different population. The Committee concluded that in line with NICE technology appraisals of other TNF inhibitors, it would be appropriate to consider the estimates of cost effectiveness that assumed no disease progression while on treatment with a TNF inhibitor. However, it considered that this assumption was uncertain and may overestimate the benefits of treatment.
The Committee then discussed the revised version of the economic model and sensitivity analyses submitted by the manufacturer that included ACR70 response data and a rate of disease progression while on palliative treatment of 0.06 HAQ score units per year. The Committee discussed the ERG's review of the revised model, noting that the ERG considered that the errors in the previous model had been corrected and changes implemented appropriately. The Committee noted that the ICERs for golimumab were at the upper end of the range of £25,000–£28,000 per QALY gained produced by other drugs in the class; however, the frequency of administration may generate additional health-related benefits. The Committee noted that the 100 mg dose of golimumab was not considered in the economic model, but that because of the patient access scheme (as described in 2.4), the cost of the 100 mg dose would be equal to that of the 50 mg dose. The Committee was persuaded that, on balance, with the patient access scheme golimumab could be considered a cost-effective option for the treatment of rheumatoid arthritis if used in the same way as other TNF inhibitors, as recommended in 'Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis' (NICE technology appraisal guidance 130) and 'Certolizumab pegol for the treatment of rheumatoid arthritis' (NICE technology appraisal guidance 186).
The Committee considered the economic model for the group of people who have had previous treatment with both conventional DMARDs and a TNF inhibitor. It noted that the base-case analysis showed that rituximab was dominated by golimumab because golimumab was less costly and more effective. It was aware that in this analysis it was assumed that rituximab is re-administered every 6 months. The Committee heard that the ERG considered re-administration of rituximab every 9 months to be more reflective of clinical practice. The Committee further heard from clinical specialists that for people responding to rituximab treatment the re-treatment intervals would be greater than 6 months. The Committee heard from the ERG about the costs for the first year of rituximab treatment that are included in the model. For the first 6 months of treatment, 1.5 courses of rituximab are included and 1 course of rituximab is included for the second 6 months. The Committee heard that it is unclear why a greater number of courses are required in the first 6 months than in subsequent 6-month periods. The Committee concluded that the rituximab costs had been overestimated in the original economic model, and that a re-treatment interval of 9 months is more appropriate.
The Committee discussed the progression of disease while on treatment for people who have had previous treatment with conventional DMARDs and a TNF inhibitor. It noted that the manufacturer had assumed that the TNF inhibitors all stop progression of disease while on treatment, but that for rituximab it was assumed that the disease continues to worsen while on treatment by an increase of 0.045 per year in HAQ score. It noted that this is the same as the rate used for conventional DMARDs. The Committee heard from the ERG and clinical specialists that this underestimates the benefits of rituximab, and that it would have been more appropriate to assume that, for people whose disease responds to treatment, rituximab reduces the progression of disease to the same extent as the TNF inhibitors. The Committee was not persuaded that it is appropriate to assume a differential rate of underlying progression of disease between rituximab and golimumab, and concluded that this assumption overestimates the cost effectiveness of golimumab compared with rituximab.
The Committee discussed the results of the manufacturer's revised version of the economic model and the ERG's exploratory analyses for the group of people who have had previous treatment with both conventional DMARDs and a TNF inhibitor, which compared golimumab with rituximab. It agreed that the ERG's amendments to increase the time between treatment intervals for rituximab and remove the assumption of a differential rate of underlying progression of disease were appropriate. The Committee noted that when these assumptions were changed rituximab was associated with lower costs and more QALYs than golimumab. The Committee therefore concluded that golimumab would not be a cost-effective use of NHS resources in people who have had previous treatment with conventional DMARDs and a TNF inhibitor and for whom rituximab is an appropriate treatment option.
The Committee recognised that in August 2010 NICE published technology appraisal guidance recommending the TNF inhibitors adalimumab, etanercept, infliximab and abatacept, as well as tocilizumab, for people with rheumatoid arthritis who are unable to have rituximab therapy because of contraindications or if rituximab is withdrawn because of an adverse event ('Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor' and 'Tocilizumab for the treatment of rheumatoid arthritis' ). The Committee agreed that it was appropriate to consider this group of people and the treatment options now available to them. The Committee discussed the revised analyses submitted by the manufacturer and noted that these did not include the other TNF inhibitors (that is, adalimumab, etanercept and infliximab), but did include abatacept and tocilizumab. It further noted the manufacturer's rationale that the other TNF inhibitors could not be included because there were no data from RCTs for these agents in this position in the treatment pathway. The Committee noted that the ICERs for golimumab in comparison with methotrexate were similar to those for abatacept and tocilizumab. The Committee understood that both abatacept and tocilizumab had been recommended for this patient group in NICE technology appraisal guidance (NICE technology appraisal guidance 195 and NICE technology appraisal guidance 198), with most plausible ICERs of between £20,000–30,000 per QALY gained, and that the TNF inhibitors: adalimumab, etanercept and infliximab had also been recommended in this way with ICERs in this range. On balance the Committee considered that the evidence before it indicated that golimumab would be no less cost effective than the other TNF inhibitors when used in this population. Therefore the Committee concluded that with the patient access scheme, golimumab is an appropriate use of NHS resources in people with rheumatoid arthritis who are unable to have rituximab therapy because of contraindications or if rituximab is withdrawn because of an adverse event, if used in the same way as other TNF inhibitors, as recommended in 'Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor' (NICE technology appraisal guidance 195).
# Summary of Appraisal Committee's key conclusions
TA225
Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease‑modifying anti-rheumatic drugs
Section
Key conclusions
Golimumab in combination with methotrexate is recommended as an option for the treatment of rheumatoid arthritis in adults whose rheumatoid arthritis has responded inadequately to conventional disease-modifying anti-rheumatic drugs (DMARDs) only, including methotrexate, if:
it is used as described for other tumour necrosis factor (TNF) inhibitor treatments in 'Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis' (NICE technology appraisal guidance 130), and
the manufacturer provides the 100 mg dose of golimumab at the same cost as the 50 mg dose, agreed as part of the patient access scheme.
January 2016: This recommendation has been updated by NICE technology appraisal guidance 375.
Golimumab in combination with methotrexate is recommended as an option for the treatment of rheumatoid arthritis in adults whose rheumatoid arthritis has responded inadequately to other DMARDs, including a TNF inhibitor, if:
it is used as described for other TNF inhibitor treatments in 'Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor' (NICE technology appraisal guidance 195), and
the manufacturer provides the 100 mg dose of golimumab at the same cost as the 50 mg dose, agreed as part of the patient access scheme.
The key drivers for these recommendations were:
in people whose rheumatoid arthritis has had an inadequate response to previous treatment with conventional DMARDs only, the evidence suggests that golimumab has efficacy and cost-effectiveness estimates that are similar to those of the other TNF inhibitors that have been recommended by NICE
in people whose rheumatoid arthritis has responded inadequately to other DMARDs, including a TNF inhibitor, and for whom rituximab is appropriate, rituximab is associated with lower costs and more QALYs than golimumab
in people whose rheumatoid arthritis has responded inadequately to other DMARDs, including a TNF inhibitor, and for whom rituximab is contraindicated or withdrawn because of an adverse event, the evidence indicated that golimumab would be no less cost effective than abatacept or tocilizumab or the other TNF inhibitors when used in this population.
Current practice
Clinical need of patients, including the availability of alternative treatments
The clinical specialists explained that ideally DMARD therapy should be started as early as possible after diagnosis to reduce joint damage and for the majority of people therapy with conventional DMARDs is sufficient. However, for a small proportion of people conventional DMARDs do not adequately control disease, and for this group of people biological DMARDs such as TNF inhibitors are needed.
It is not possible to predict which TNF inhibitor will produce the best effect for each person. Therefore people prefer a choice of treatments and another treatment option would be welcome.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
Golimumab is administered once per month and this may be an advantage for people who have difficulty injecting themselves because of the joint damage caused by the disease and for people who have a fear of injections. Once-monthly administration may be more convenient for people who travel and may be beneficial for people who experience injection-site reactions.
What is the position of the treatment in the pathway of care for the condition?
Both the marketing authorisation and clinician opinion indicate that golimumab may be used either as a first TNF inhibitor therapy in people whose disease has not responded to conventional DMARD therapy, or as second TNF inhibitor therapy in people who have had previous therapy with a TNF inhibitor.
Adverse effects
There is uncertainty about the adverse event profile of golimumab in the absence of long-term data. However, the clinical specialists expect the adverse event profile of golimumab to be no different from that of other TNF inhibitors.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The manufacturer's submission considered golimumab at two positions in the treatment pathway – after treatment with conventional DMARDs and not a TNF inhibitor, and after treatment with both conventional DMARDs and a TNF inhibitor.
For people who had previously had only conventional DMARDs, there were two clinical trials but there were no head-to-head trials between golimumab and other available TNF inhibitors. As a result, the manufacturer had conducted a mixed treatment comparison and an indirect comparison.
For the people who had had previous treatment with both conventional DMARDs and a TNF inhibitor, there was a single trial comparing golimumab with placebo. In the absence of head-to-head trials the manufacturer carried out an indirect comparison of golimumab and rituximab.
Relevance to general clinical practice in the NHS
The relevance of the evidence to the UK population in clinical practice was not identified as an issue.
Uncertainties generated by the evidence
For both populations, there were no statistically significant differences in ACR20, ACR50 and ACR70 response rates between golimumab and the active comparators in the mixed treatment and indirect comparisons. However, the credibility intervals around the point estimates were wide.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee considered clinical-effectiveness evidence for subgroups of people in the GO-FORWARD trial who either had moderately or severely active rheumatoid arthritis as defined by their baseline DAS28 score.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that for people who had previously had only conventional DMARDs, based on the ACR response rates, golimumab had been demonstrated to be more clinically effective than placebo and that there was no convincing evidence that golimumab was either more or less effective than the other TNF inhibitors.
For people who had previously had both conventional DMARDs and a TNF inhibitor, the Committee considered that golimumab had greater clinical effectiveness than placebo. It noted that the point estimates for the comparison of rituximab and golimumab favour rituximab but that there are no statistically significant differences in clinical efficacy between golimumab and rituximab.
Evidence for cost effectiveness
Availability and nature of evidence
The economic model evaluated golimumab as part of a sequence of treatments. One model evaluated golimumab in people who had had previous treatment with conventional DMARDs only, and the other in people who had had treatment with both conventional DMARDs and a TNF inhibitor.
Revised models were provided following a request for further data to be provided by the manufacturer.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted that the economic analysis from the manufacturer had assumed that there was no progression of disease while on treatment with a TNF inhibitor, but that there was progression while on treatment with conventional DMARDs and on palliative treatment. The Committee considered that an assumption of no progression while on treatment with a TNF inhibitor could be an overestimate of the benefits of treatment.
The Committee noted that the manufacturer had assumed that the TNF inhibitors all stop progression of disease while on treatment, but that for rituximab it was assumed that the disease continues to worsen while on treatment by an increase of 0.045 per year in HAQ score. It noted that this is the same as the rate used for conventional DMARDs. The Committee heard from the ERG and clinical specialists that this underestimates the benefits of rituximab.
The Committee noted that the economic model assumes that rituximab is re-administered every 6 months. The Committee heard that the ERG and the clinical specialists considered that re-administration of rituximab every 9 months to be more reflective of clinical practice. The Committee concluded that the rituximab costs had been overestimated in the original economic model, and that a re-treatment interval of 9 months is more appropriate.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee considered the utility estimates incorporated in the original model, and noted that the utility formula was derived from the ACR response, which was converted to a change in HAQ score and then mapped to EQ-5D.
The Committee discussed the sensitivity analysis submitted by the manufacturer following the consultation on the appraisal consultation document, using the SF-36 data from the GO-FORWARD study. It concluded that the sensitivity analysis suggested that the methodology to derive the utility in the base-case analysis had not been shown to be unreasonable.
The Committee noted the frequency of administration may generate additional health-related benefits.
Are there specific groups of people for whom the technology is particularly cost effective?
N/A
Most likely cost‑effectiveness estimate (given as an ICER)
The Committee considered the revised economic model for people who have previously received conventional DMARDs. It noted that the ICERs for golimumab were at the upper end of the range of £25,000−£28,000 per QALY gained produced by other drugs in the class; however, the frequency of administration would generate additional health-related benefits. The Committee was persuaded that, on balance, with the patient access scheme golimumab could be considered a cost-effective option for the treatment of rheumatoid arthritis if used in the same way as other TNF inhibitors, as recommended in NICE technology appraisal guidance 130 and NICE technology appraisal guidance 186.
For the group of people who have had both conventional DMARDs and a TNF inhibitor, and for whom rituximab is appropriate, the Committee considered that rituximab is associated with lower costs and more QALYs than golimumab. The Committee therefore concluded that golimumab would not be a cost-effective use of NHS resources in people who have had previous treatment with conventional DMARDs and a TNF inhibitor and for whom rituximab is an appropriate treatment option.
For the group of people who have had previous treatment with both conventional DMARDs and a TNF inhibitor and for whom rituximab is contraindicated or withdrawn because of an adverse event, the Committee understood that both abatacept and tocilizumab had been recommended for this patient group, with most plausible ICERs of between £20,000–30,000 per QALY gained, and that adalimumab, etanercept and infliximab had also been recommended in this way with ICERs in this range. On balance the Committee considered that the evidence before it indicated that golimumab would be no less cost effective than the other TNF inhibitors when used in this population. Therefore the Committee concluded that golimumab is an appropriate use of NHS resources in people with rheumatoid arthritis who are unable to have rituximab therapy because of contraindications or if rituximab is withdrawn because of an adverse event.
Additional factors taken into account
Patient access schemes
(Pharmaceutical Price Regulation Scheme )
The manufacturer has agreed a patient access scheme with the Department of Health, in which the 100 mg dose of golimumab will be available to the NHS at the same cost as the 50 mg dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.
End-of-life considerations
The supplementary advice was not relevant to this appraisal.
Equalities considerations and social value judgements
No equalities issues were raised in the appraisal.
# Related NICE guidance
Tocilizumab for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 198 (2010).
Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. NICE technology appraisal guidance 195 (2010).
Certolizumab pegol for the treatment of rheumatoid arthritis in adults. NICE technology appraisal guidance 186 (2010).
Rheumatoid arthritis: the management of rheumatoid arthritis in adults. NICE clinical guideline 79 (2009).
Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 130 (2007).# Review of guidance
The guidance on this technology in people who have had previous treatment with conventional DMARDs only will be reviewed with NICE technology appraisal guidance 130 and 186. The guidance on this technology in people who have had previous treatment with both conventional DMARDs and a TNF inhibitor will be reviewed with the review of NICE technology appraisal guidance 195 in June 2013. Andrew DillonChief ExecutiveJune 2011# Changes after publication
January 2016: Recommendation 1.1 has been updated by the recommendations in the NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed.# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your
responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
ISBN: 978-1-4731-1623-8
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{'Guidance': "This recommendation has been replaced by the recommendations in the NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed.\n\nGolimumab in combination with methotrexate is recommended as an option for the treatment of rheumatoid arthritis in adults whose rheumatoid arthritis has responded inadequately to other DMARDs, including a TNF inhibitor, if:\n\nit is used as described for other TNF inhibitor treatments in 'Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor' (NICE technology appraisal guidance 195), and\n\nthe manufacturer provides the 100 mg dose of golimumab at the same cost as the 50 mg dose, agreed as part of the patient access scheme.\n\nWhen using the disease activity score (DAS28), healthcare professionals should take into account any physical, sensory or learning disabilities, communication difficulties, or disease characteristics that could adversely affect patient assessment and make any adjustments they consider appropriate.", 'The technology ': "Golimumab (Simponi, Schering Plough) is a human monoclonal antibody that prevents the binding of TNF to its receptors, thereby neutralising its activity. In October 2009, golimumab, in combination with methotrexate, received a marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to disease-modifying anti-rheumatic drug (DMARD) therapy including methotrexate has been inadequate. The summary of product characteristics (SPC) notes that golimumab has also been shown to improve physical function in this population. In February 2011, the marketing authorisation was amended to indicate that golimumab has also been shown to reduce the rate of progression of joint damage as measured by X‑ray when given in combination with methotrexate.\n\nGolimumab is contraindicated in people with moderate to severe heart failure, hereditary problems of fructose intolerance, active tuberculosis and other severe infections. Before initiating therapy, physicians should evaluate people for prior evidence of hepatitis\xa0B virus infection, and both active and inactive (latent) tuberculosis infection. The SPC reports that the most common adverse reactions are upper respiratory tract infections, including nasopharyngitis, pharyngitis, laryngitis and rhinitis. For full details of adverse effects, contraindications, special warnings and precautions for use, see the SPC.\n\nGolimumab is injected subcutaneously via a pre-filled injection pen. The recommended dosage is 50\xa0mg given once a month, on the same date each month. The SPC states that in people who weigh more than 100\xa0kg whose rheumatoid arthritis does not show an adequate clinical response after three or four doses, the dosage may be increased to 100\xa0mg once a month. The cost of a syringe or pen pre-filled with 50\xa0mg of golimumab is £774.58 ('Monthly Index of Medical Specialities' [MIMS], December 2010). The annual drug cost of golimumab is £9295 (50\xa0mg dose). Costs may vary in different settings because of negotiated procurement discounts.\n\nThe manufacturer has agreed a patient access scheme with the Department of Health, in which the 100\xa0mg dose of golimumab will be available to the NHS at the same cost as the 50\xa0mg dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Details of the patient access scheme are provided separately from this document as part of the evidence submitted.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of golimumab and reviews of these submissions by the Evidence Review Group (ERG; appendix B).\n\n# Clinical effectiveness\n\nThe submission considered people who had never received a TNF\xa0inhibitor (the DMARD-experienced population) separately from people who had had previous therapy with a TNF inhibitor (the TNF\xa0inhibitor-experienced population).\n\n## DMARD-experienced population\n\nTwo trials with DMARD-experienced participants were included in the submission – a phase\xa0III randomised controlled trial (RCT) with four groups (GO‑FORWARD) and a phase II dose-ranging trial with five groups (Kay et al. 2008). The trials investigated the efficacy and the dose effect of golimumab. The manufacturer's submission focused on the groups who had received the licensed dosage of 50\xa0mg golimumab monthly.\n\nGO‑FORWARD was a multicentre randomised double-blind trial that compared 50\xa0mg golimumab every 4\xa0weeks plus methotrexate (15\xa0mg or more every week) (n=89) with placebo plus methotrexate (15\xa0mg or more every week) (n=133). The trial participants had had active rheumatoid arthritis (defined as persistent disease activity with at least four swollen joints and four tender joints) for at least 3\xa0months and had received methotrexate for at least 3\xa0months. The trial included a controlled phase to 24\xa0weeks and an open-label extension to 5\xa0years. Participants whose disease was inadequately controlled in the placebo arm could cross over to the golimumab arm at week\xa014. All other participants in the placebo arm crossed over to the golimumab arm at week\xa024. Participants whose disease was inadequately controlled on 50\xa0mg golimumab were able to cross over to the 100\xa0mg golimumab arm.\n\nThe primary outcome measures were the proportion of participants with an ACR20 response at 14\xa0weeks and an improvement from baseline in the Health Assessment Questionnaire – Disability Index (HAQ-DI) score at 24\xa0weeks. Secondary outcome measures included ACR20 response at 24\xa0weeks, ACR50 response at 14 and 24\xa0weeks, ACR70 response at 14 and 24\xa0weeks, Disease Activity Score (DAS)\xa028 at 14 and 24\xa0weeks and improvement from baseline HAQ‑DI score at 14\xa0weeks. Health-related quality of life was measured using the SF‑36 tool.\n\nA significantly greater proportion of participants who received 50\xa0mg golimumab plus methotrexate had an ACR20 response at 14\xa0weeks compared with participants who received placebo plus methotrexate (55.1% and 33.1% respectively; p=0.001). Improvement in HAQ-DI score at 24\xa0weeks was significantly greater in the 50\xa0mg golimumab plus methotrexate group compared with the placebo plus methotrexate group (median 0.375 and 0.125 respectively; p<0.001).\n\nFollowing consultation on the appraisal consultation document, the manufacturer provided long-term outcomes data from 52- and 104‑week follow-up on ACR responses and on the proportion of participants maintaining a HAQ improvement greater than or equal to 0.25. These data suggested that for the people who continued to receive golimumab the response to treatment was maintained.\n\nThe manufacturer also reported that for key secondary endpoints a significantly greater proportion of participants in the 50\xa0mg golimumab plus methotrexate group had a response compared with participants in the placebo plus methotrexate group. An ACR20 response at 24\xa0weeks was seen in 59.6% of the participants who received 50\xa0mg golimumab plus methotrexate compared with 27.8% of the participants who received placebo plus methotrexate (p<0.001). More participants in the 50\xa0mg golimumab plus methotrexate group had an ACR50 response at 24\xa0weeks than in the placebo plus methotrexate group (37.1% and 13.5% respectively; p<0.001). An ACR70 response at 24\xa0weeks was seen in 20.2% of the 50\xa0mg golimumab plus methotrexate group compared with 5.3% of the placebo plus methotrexate group (p<0.001).\n\nThe manufacturer submitted SF‑36 data from the GO‑FORWARD trial following consultation on the appraisal consultation document. At 24\xa0weeks there was a statistically significant improvement in the physical component summary score in people treated with golimumab compared with placebo (mean change 8.23 and 2.54 respectively, p<0.001). There were statistically significant changes in six of the eight domains, including all physical health domains, in people treated with golimumab compared with placebo. Social functioning and role–emotional domains did not show statistically significant improvements in people treated with golimumab compared with placebo. Data on golimumab from 104‑week follow-up suggested that changes in SF‑36 were maintained.\n\nFollowing consultation on the appraisal consultation document, 24‑week and 52‑week radiographic progression data from the GO‑FORWARD trial were submitted. This reported no difference in the mean change from baseline in the van der Heijde modified Sharp (vdH-S) score between the 50\xa0mg golimumab group and the placebo group (mean change 0.93 and 1.10 respectively, p=0.855). Median change was reported to be zero in both golimumab and placebo groups. Further 52‑week and 104‑week follow-up data were provided by the manufacturer. The key data were marked as academic in confidence and so cannot be reported here. The manufacturer noted a number of factors that could account for the minimal progression rates observed in both the placebo and golimumab groups in the GO‑FORWARD trial, including the use of radiographic outcomes as a secondary endpoint, the crossing over of all participants treated with placebo at week\xa024 and a lower baseline disease activity in the trial compared with trials of other biological therapies.\n\nThe manufacturer submitted a subgroup analysis that assessed people with moderate (DAS\xa028 score of between 3.2 and 5.1) and severe (DAS\xa028 score greater than 5.1) disease activity from the GO‑FORWARD study separately. The analysis reported relative risks for ACR20, ACR50 and ACR70 response at 24\xa0weeks. For people with moderately active rheumatoid arthritis treated with golimumab (n=18) and placebo (n=28), the relative risks of achieving an ACR20, ACR50 and ACR70 response with golimumab compared with placebo were 2.67 (95% confidence interval [CI] 1.30 to 5.48), 1.78 (95% CI 0.78 to 4.05) and 3.89 (95% CI 0.84 to 17.95) respectively. For people with severely active rheumatoid arthritis treated with golimumab (n=71) and placebo (n=104), the relative risks of achieving an ACR20, ACR50 and ACR70 response with golimumab compared with placebo were 2.00 (95% CI 1.39 to 2.87), 3.33 (95% CI 1.75 to 6.32) and 3.81 (95% CI 1.42 to 10.21) respectively.\n\nThe manufacturer reported similar rates of adverse events at 16\xa0weeks in the 50\xa0mg golimumab plus methotrexate and the placebo plus methotrexate groups (68.5% and 60.9% respectively). The incidence of serious adverse events at 16\xa0weeks was 5.6% in the 50\xa0mg golimumab plus methotrexate group and 2.3% in the placebo plus methotrexate group. Long-term safety data were provided by the manufacturer following consultation on the appraisal consultation document. These were 52- and 104‑week safety data in trial participants with psoriatic arthritis, rheumatoid arthritis and ankylosing spondylitis who had received treatment with golimumab across all of the original phase\xa0III studies. These data were marked as confidential and therefore cannot be reported.\n\nThe second trial (Kay et al. 2008) was a multicentre randomised double-blind study, two arms of which compared 50\xa0mg golimumab (every 4\xa0weeks) plus methotrexate (10\xa0mg or more every week) (n=35) with placebo plus methotrexate (10\xa0mg or more every week) (n=35). The trial participants had had active rheumatoid arthritis (defined as persistent disease activity with at least six swollen joints and six tender joints) for at least 3\xa0months and had been treated with methotrexate for at least 3\xa0months. The primary outcome was the proportion of people who had an ACR20 response at 16\xa0weeks. Secondary outcomes included ACR20, 50 and 70 responses over time until 52\xa0weeks, numeric index of the ACR response at 16\xa0weeks and DAS28 at 16\xa0weeks.\n\nPrimary outcome data were not presented separately for the 50\xa0mg golimumab group in the manufacturer's submission. However, they were available from a published paper, which showed that an ACR20 response at 16\xa0weeks was seen in 60.0% of people who received 50\xa0mg golimumab plus methotrexate and 37.1% of people who received placebo plus methotrexate.\n\nAn ACR20 response at 24\xa0weeks was seen in 74.3% of people in the 50\xa0mg golimumab plus methotrexate group and 45.7% of people in the placebo plus methotrexate group. More participants in the 50\xa0mg golimumab plus methotrexate group had an ACR50 response at 24\xa0weeks than participants in the placebo plus methotrexate group (40.0% and 11.4% respectively). An ACR70 response at 24\xa0weeks was seen in 20.0% of participants in the 50\xa0mg golimumab plus methotrexate group and 5.7% of those in the placebo plus methotrexate group. The ACR20 and 50 responses for the golimumab plus methotrexate group were statistically significantly different from the placebo plus methotrexate group. However, the ACR70 responses were not statistically significantly different between the treatment arms.\n\nIn the second trial (Kay et al. 2008) the proportion of participants who experienced at least one adverse event was slightly higher in the 50\xa0mg golimumab plus methotrexate group than in the placebo plus methotrexate group (91.9% and 85.3% respectively).\n\nFollowing consultation on the appraisal consultation document, the manufacturer provided further data from the trial by Kay et al. (2008) to support the dosage frequency used in the marketing authorisation. The manufacturer provided additional data for the three groups who received golimumab at unlicensed dosages not included in the submission (50\xa0mg and 100\xa0mg once every 2\xa0weeks, and 100\xa0mg once every 4\xa0weeks). The manufacturer reported that no clear dosage–response relationship was observed, and that the lowest dosage regimen (that is, 50\xa0mg once every 4\xa0weeks) had an ACR response similar to that observed in the higher dosages.\n\n## TNF inhibitor-experienced population\n\nThe manufacturer's submission included a single phase\xa0III randomised double-blind placebo-controlled trial (GO‑AFTER) for the TNF inhibitor-experienced population. The trial had three groups and the manufacturer's submission focused on two of the groups: the placebo group (n=155) and the group who received 50\xa0mg golimumab (n=153) rather than the group who received the unlicensed dose of 100\xa0mg golimumab. The trial participants had had active rheumatoid arthritis (defined as persistent disease activity with at least four swollen joints and four tender joints) for at least 3\xa0months and had been treated with at least one dose of a TNF inhibitor (etanercept, adalimumab or infliximab). People in the trial were not required to take golimumab in combination with another DMARD. Approximately 66% received golimumab in combination with methotrexate.\n\nThe primary outcome was the proportion of participants with ACR20 response at 14\xa0weeks. The duration of follow-up was 24\xa0weeks. The secondary outcomes included ACR50, 70 and 90 at 14\xa0weeks, ACR20, 50, 70 and 90 at 24\xa0weeks and change from baseline in HAQ-DI score at 24\xa0weeks. No data were collected for SF‑36, and no data were provided for radiographic progression.\n\nA significantly higher proportion of the participants who received 50\xa0mg golimumab had an ACR20 response at 14\xa0weeks compared with placebo (35.3% and 18.1% respectively; p<0.001). An ACR20 response at 24\xa0weeks was seen in 34.0% of participants in the 50\xa0mg golimumab group compared with 16.8% of participants in the placebo group (p<0.001). An ACR50 response at 24\xa0weeks was seen in more participants in the 50\xa0mg golimumab group than in the placebo group (18.3% and 5.2% respectively; p<0.001). An ACR70 response at 24\xa0weeks was seen in 11.8% of participants in the 50\xa0mg golimumab group and 3.2% of those in the placebo group (p=0.004). Change in HAQ-DI from baseline was assessed at 24\xa0weeks. For the 50\xa0mg golimumab group there was a median improvement in HAQ-DI of 0.25. For the placebo group there was no change in the median HAQ-DI score.\n\nNo major differences in the number of reported adverse events were evident in the GO-AFTER study at 24\xa0weeks. The number of serious adverse events at 24\xa0weeks was slightly lower in the 50\xa0mg golimumab group than in the placebo group.\n\nTo provide support for the radiographic data from the GO‑FORWARD trial, the manufacturer also provided data from the GO‑BEFORE trial. The GO‑BEFORE trial compared methotrexate plus placebo with golimumab plus methotrexate in participants who had rheumatoid arthritis not previously treated with methotrexate. Intention-to-treat analyses reported a statistically significant difference in mean change from baseline in radiographic progression at week\xa052 (1.37 in the methotrexate group [n=160] and 0.74 in the 50\xa0mg golimumab group [n=159] [p=0.015]). Analyses of data from the participants who remained on their originally allocated treatment reported a change from baseline in radiographic progression at week\xa052 of 0.22 in the methotrexate group (n=9) and 0.06 in the 50\xa0mg golimumab group (n=99). At week\xa0104 the change from baseline in radiographic progression was 0.40 (n=10) and −0.10 (n=99) in each group respectively.\n\n## Mixed treatment comparison and indirect comparison\n\nNo head-to-head trials analysing the efficacy of golimumab compared with other active treatment options were available. Therefore the manufacturer searched for trials of comparator interventions and completed mixed treatment and indirect comparison analyses to estimate the relative effect of golimumab versus the comparators. The manufacturer included comparators that had been recommended by NICE at the time of submission. For the DMARD-experienced population comparisons were made with placebo, adalimumab, certolizumab pegol, etanercept and infliximab. For the TNF inhibitor-experienced population comparisons were made with placebo and rituximab. Following consultation on the appraisal consultation document, the manufacturer submitted additional cost-effectiveness analyses for the comparison of golimumab, tocilizumab and abatacept. However, separate data on the relative clinical effectiveness of golimumab compared with tocilizumab and abatacept were not provided.\n\nTwenty trials were included in the mixed treatment comparison for the DMARD-experienced population. The results from the random effects model showed that for each ACR response, golimumab was statistically significantly superior to placebo. In comparison with adalimumab, certolizumab pegol, etanercept or infliximab there were no statistically significant differences in ACR20, ACR50 or ACR70 response rates. However, the point estimates favoured the other TNF inhibitors, except in the comparison with infliximab. For ACR20 the median relative risks and 95% credibility intervals for golimumab were 0.98 (0.55 to 1.46) compared with adalimumab, 0.72 (0.41 to 1.06) compared with certolizumab pegol, 0.93 (0.51 to 1.43) compared with etanercept and 1.05 (0.57 to 1.65) compared with infliximab. For ACR50, the median relative risks and 95% credibility intervals for golimumab were 0.90 (0.40 to 1.76) compared with adalimumab, 0.63 (0.27 to 1.31) compared with certolizumab pegol, 0.98 (0.40 to 1.99) compared with etanercept and 0.99 (0.42 to 2.04) compared with infliximab. For ACR70, the median relative risks and 95% credibility intervals for golimumab were 0.75 (0.28 to 1.86) compared with adalimumab, 0.47 (0.16 to 1.35) compared with certolizumab pegol, 0.32 (0.09 to 1.15) compared with etanercept and 1.16 (0.40 to 3.00) compared with infliximab.\n\nSensitivity analyses were performed for ACR20 and ACR50 responses in which the TEMPO etanercept trial was excluded because of a greater response within its placebo arm compared with other studies. The exclusion of the TEMPO trial resulted in raised relative risks for ACR20 and ACR50, indicating increased efficacy for etanercept in comparison with golimumab. However, these results were statistically significant only in the fixed effects model for the ACR20 response. Exclusion of the TEMPO trial also altered the estimates of relative risk for golimumab in comparison with the other treatments. When golimumab was compared with certolizumab pegol, the differences were statistically significant in the fixed effects model and for ACR20 in the random effects model, with both favouring certolizumab pegol.\n\nA mixed treatment comparison was carried out for selected safety outcomes. Golimumab was estimated to be associated with a greater number of serious adverse events than all comparators except certolizumab pegol. However, none of the differences was statistically significant, and all had wide credibility intervals. The estimated rate of serious infections for golimumab was similar to the rates for infliximab and etanercept, and lower than those for adalimumab and certolizumab pegol. These differences reached statistical significance for the comparison of golimumab with certolizumab pegol. However, all had wide credibility intervals. Golimumab was estimated to have fewer discontinuations because of adverse events. However, this reached statistical significance only in the comparison of golimumab with certolizumab pegol.\n\nTwo trials were used in the indirect comparison analyses of golimumab (GO‑AFTER) and rituximab (REFLEX) for the TNF inhibitor-experienced population. In these analyses (based on the methods developed by Bucher et al. ) golimumab and rituximab were indirectly compared, with placebo as the comparator. Although the estimates of ACR response favoured rituximab, there were no statistically significant differences between golimumab and rituximab. For ACR20 the relative risk was 0.71 (95% CI 0.42 to 1.20). For ACR50 and ACR70 the corresponding figures were 0.66 (95% CI 0.25 to 1.76) and 0.30 (95% CI 0.05 to 1.66).\n\nThe indirect comparison suggested that the relative risks of serious adverse events were similar for golimumab and rituximab, although these were associated with wide confidence intervals. The relative risk estimate for serious infections was slightly lower for golimumab compared with rituximab but this difference was not statistically significant. Golimumab was associated with statistically significantly lower rates of discontinuation due to adverse events.\n\n## Review from the ERG\n\nThe ERG considered the clinical effectiveness review methods and results to be reasonably clearly presented, with adequate systematic searches conducted. The ERG stated that all the relevant RCTs for golimumab and the comparators appeared to have been included and the golimumab trials were of reasonable methodological quality. The ERG considered that the mixed treatment comparisons and indirect comparisons used appropriate trials.\n\nThe ERG commented that the populations in GO‑FORWARD and Kay et al. (2008) were generally representative of the UK population with rheumatoid arthritis, although in the GO‑FORWARD trial the proportion of people who received glucocorticoid therapy was higher than the UK average. Similarly, steroid use in the GO‑AFTER population may have been higher than the average in the UK population with rheumatoid arthritis, and in this study only 66% of the participants had also received methotrexate.\n\nThe ERG noted inconsistencies between the data presented for ACR20 and ACR50 responses in Kay et al. (2008). Different values were presented in the original study publication (week\xa016) and in the efficacy meta-analyses in the manufacturer's submission. The ERG was unclear how the original efficacy data from Kay et al. (2008) had been derived and handled in the meta-analyses.\n\nThe ERG commented on the complexities involved in comparing data across the interventions in the mixed treatment and indirect comparison analyses because response rates can be influenced by changes in patient populations over time. It noted that the certolizumab pegol trials had a higher ratio of ACR responses on active treatment compared with placebo, and these trials may not be comparable with the trials of other TNF inhibitors.\n\nThe ERG reviewed the additional data provided by the manufacturer. The ERG welcomed the SF‑36 data from the GO‑FORWARD trial and confirmed that SF‑36 data were not collected in the GO‑AFTER trial. The ERG reported that the radiographic progression data from the GO‑BEFORE trial appeared to suggest a reduction in progression of structural damage for participants with rheumatoid arthritis not previously treated with methotrexate. The ERG also stated that the summary of the 24‑week data from the GO‑FORWARD trial was appropriate. The ERG noted that interpretation of the longer-term data from this trial was limited by cross-over between treatments.\n\n# Cost effectiveness\n\nThe manufacturer provided two sets of cost-effectiveness analyses, the first in the original submission and the second in response to a request from NICE as part of the preliminary recommendations, which was provided after consultation on the appraisal consultation document. Both sets of analyses were reviewed by the ERG. Following this review and consideration by the Appraisal Committee, the second set of analyses was not considered to form a sufficiently robust basis for decision making because it was not internally consistent. The manufacturer was asked to resubmit these data. The resubmitted data were also reviewed by the ERG. The original submission and the resubmitted data are included in this section.\n\n## Original submission\n\nThe manufacturer submitted two decision-analytic Markov models, each with a lifetime horizon. Both models evaluated golimumab as part of a sequence of treatments: one evaluated golimumab in a DMARD-experienced population (comparing golimumab with TNF inhibitors and methotrexate in people whose disease had had an inadequate response to two DMARDs) and the other evaluated golimumab in a TNF inhibitor-experienced population (comparing golimumab with rituximab and methotrexate in people whose disease had had an inadequate response to two DMARDs and a TNF inhibitor). All treatments were given in combination with methotrexate. Methotrexate monotherapy was included as a comparator in each model because it represented the placebo arm in the indirect and mixed treatment comparisons. The manufacturer did not include technologies being appraised by NICE at the time of its submission (tocilizumab, abatacept and the use of etanercept, infliximab and adalimumab after the failure of a first TNF inhibitor) as comparators.\n\nOn starting treatment, people could have either an ACR20 response, ACR50 response or no response. The probability of response for golimumab and methotrexate monotherapy was derived from the GO‑FORWARD and GO‑AFTER trials. To derive efficacies for the other comparators the response for golimumab was adjusted using the relative effects estimated from the mixed treatment and indirect comparison analyses. For each ACR response criterion the corresponding change in HAQ‑DI was calculated based on data from the GO‑FORWARD and GO‑AFTER trials. The HAQ‑DI was in turn mapped to EQ‑5D with an equation used in NICE technology appraisal guidance\xa0130 ('Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis'). People progressed to the next treatment if they did not have at least an ACR20 response at 6\xa0months, or if they stopped treatment because of a lack of efficacy or an adverse event. In both models, people progressed to leflunomide, gold, azathioprine, ciclosporin and then palliative treatment.\n\nAt the start of the models people were aged 50\xa0years in the DMARD-experienced population and 54\xa0years in the TNF inhibitor-experienced population. HAQ scores for people entering the model were derived from the baseline characteristics of the GO‑FORWARD and GO‑AFTER trials: 1.41 and 1.58 respectively. While people were receiving a treatment, it was assumed that their disease severity increased over time. This was modelled with an annual worsening of HAQ score (that is, an HAQ progression rate). The HAQ progression rate was 0.045 for a person being treated with DMARDs, 0.00 for TNF inhibitors, 0.045 for rituximab and 0.09 for palliative treatment.\n\nCosts relating to treatment, administration, monitoring and hospitalisation were included in the economic models using 2006 reference costs and 2008 unit costs. Following a clarification request, the manufacturer incorporated 2008 reference costs and 2009 unit costs. It was assumed that a course of rituximab was given once every 6\xa0months. The cost of joint replacement was not included in the model. Costs and quality-adjusted life years (QALYs) were discounted at a rate of 3.5%.\n\nThe results from the economic model were presented incrementally with all treatments compared with each other, and for each treatment individually in comparison with methotrexate. The deterministic results for the DMARD-experienced population showed that the incremental cost-effectiveness ratios (ICERs) were £31,464 (£34,030 additional costs and 1.082 additional QALYs) and £31,444 (£37,702 additional costs and 1.199 additional QALYs) per QALY gained for infliximab and certolizumab pegol respectively in comparison with methotrexate, and £25,346 (£31,878 additional costs and 1.258 additional QALYs) per QALY gained for golimumab in comparison with methotrexate. The ICERs for adalimumab and etanercept in comparison with methotrexate were £25,353 (£31,006 additional costs and 1.223 additional QALYs) and £24,514 (£38,339 additional costs and 1.564 additional QALYs) per QALY gained respectively. The incremental analysis showed that infliximab and certolizumab pegol were both dominated by golimumab because golimumab was more effective and less costly. However, adalimumab and golimumab were both extendedly dominated by etanercept. Etanercept generated the most QALYs of any strategy, at a lower cost per QALY ratio (£24,514 per QALY gained in comparison with methotrexate).\n\nThe results for the deterministic base-case analysis of golimumab in a TNF inhibitor-experienced population show that rituximab was dominated by golimumab because golimumab was less costly and more effective (£31 fewer costs and 0.189 additional QALYs). Golimumab compared with methotrexate had an ICER of £28,286 (£16,502 additional costs and 0.583 additional QALYs) per QALY gained whereas rituximab compared with methotrexate had an ICER of £41,935 (£16,533 additional costs and 0.394 additional QALYs) per QALY gained.\n\n## Comments from the ERG on the manufacturer's original submission\n\nThe ERG noted that the model results (total costs and QALYs, time in states, HAQ scores and incremental costs and QALYs) appeared plausible given the parameter inputs. It commented that the model was generally of a high quality. The ERG identified some programming errors in the model that it corrected. However, these errors did not change the conclusion in the manufacturer's submission that, compared with methotrexate, golimumab has an ICER that is comparable to other TNF inhibitors but that golimumab is never the most cost-effective TNF inhibitor treatment.\n\nThe ERG considered that it would have been appropriate to include ACR70 response data in the model so that all the available clinical evidence is used to evaluate golimumab. The manufacturer justified the exclusion of these data by stating that there was not a statistically significant difference between golimumab and the comparators and that incorporating this outcome would only add an element of uncertainty to the model inputs. The ERG noted that this reason was not justified because there was also no statistically significant difference in the ACR20 and ACR50 response data for golimumab and the comparators, but these data had been included in the model.\n\nThe ERG undertook a number of exploratory analyses to address some of its concerns. The original model used 2006 reference costs and 2008 unit costs. However, after clarification, the manufacturer incorporated 2008 reference costs and 2009 unit costs. The ERG used the updated reference and unit costs and found that they had little impact on the incremental costs for the different treatments in the DMARD-experienced population, and so the resulting ICERs did not change substantially.\n\nThe ERG identified an error in the model for infliximab in the DMARD-experienced population, which resulted in a cost being allocated when a person dies. There was also an error in the modelling of HAQ decrements for certolizumab pegol. Correcting the infliximab costs reduced the total cost of infliximab treatment, and it was no longer dominated by adalimumab. Correcting the HAQ decrements for certolizumab pegol meant that it was the optimal intervention instead of etanercept.\n\nThe economic model used the response rates from the GO‑FORWARD trial to estimate the probability of ACR response and the probability of stopping treatment because of an adverse event at 6\xa0months in the golimumab and methotrexate groups. However, the model used the mixed treatment comparison to estimate the rates of these events for the comparators; this approach excludes the evidence from Kay et al. (2008). In the exploratory analysis the ERG used the mixed treatment comparison, incorporating the evidence from Kay et al. (2008) to estimate the probability of these outcomes in the placebo group, which is used to populate the methotrexate arm of the economic model. Using the mixed treatment comparison rather than the GO‑FORWARD study alone to inform the golimumab versus methotrexate comparison did not substantially alter the results.\n\nThe cumulative impact of the changes described in sections\xa03.42–3.44 reduced all the ICERs for all TNF inhibitors in comparison with methotrexate in the DMARD-experienced group. The ICERs for infliximab and certolizumab pegol in comparison with methotrexate were £24,137 and £20,800 per QALY gained. The ICER for golimumab compared with methotrexate was £24,794 per QALY gained. The ICERs for adalimumab and etanercept in comparison with methotrexate were £24,800 and £23,990 per QALY gained. The incremental analysis suggested that certolizumab pegol including its patient access scheme is the optimal treatment strategy, dominating etanercept and extendedly dominating golimumab, adalimumab and infliximab.\n\nThe ERG stated that for the TNF inhibitor-experienced population there was considerable uncertainty in the HAQ progression rate estimates and the re-administration frequency of rituximab. The ERG commented that the manufacturer assumed a HAQ progression rate equal to the rate for DMARDs rather than for TNF inhibitors, which may underestimate the benefit of rituximab. The ERG also commented that the model assumes that rituximab is re‑administered every 6\xa0months but it considered that 9\xa0months would be more reflective of current clinical practice. The ERG amended the model so that rituximab had a zero HAQ progression rate (equal to that of TNF inhibitors) rather than the 0.045 that was assumed in the base-case analysis. The ERG also amended the model so that each person received two infusions in the first 6\xa0months and then one infusion every 9\xa0months. The costs were updated as described for the DMARD-experienced population.\n\nThe cumulative impact of the changes described in 3.46 reduced the ICERs for golimumab and rituximab in comparison with methotrexate (£28,115 and £10,088 per QALY gained respectively). The incremental analysis showed that rituximab dominated golimumab.\n\nFollowing comments received during consultation on the appraisal consultation document about the inclusion of the TEMPO study and the TNF inhibitor monotherapy studies in the base-case analysis, the ERG performed sensitivity analyses to assess the impact on the ICERs of separately excluding the monotherapy studies and the TEMPO study. In an incremental analysis, when the TEMPO study is excluded etanercept is no longer dominated by certolizumab pegol and it becomes the optimum strategy. When the TNF inhibitor monotherapy studies are excluded, the results do not differ substantially from the base case, with certolizumab pegol remaining the optimum strategy.\n\n## Resubmitted additional analyses provided by the manufacturer following consultation on the appraisal consultation document\n\nIn response to a request from NICE, the manufacturer provided additional analyses of the cost effectiveness of golimumab. The analyses included:\n\nincorporation of ACR70 response data and disease progression on palliative treatment reflected as an increase in HAQ score of 0.06 per year in the economic model\n\na sensitivity analysis in which SF‑36 data are included in the economic model using mapping to SF‑6D\n\ncost-effectiveness results for the comparison of golimumab, abatacept and tocilizumab for the group of people whose disease has responded inadequately to a TNF inhibitor.\n\nThe manufacturer did not provide any analyses that reported the estimates of cost effectiveness of including the 100\xa0mg dose of golimumab for people weighing over 100\xa0kg whose rheumatoid arthritis does not respond to the 50\xa0mg dose. The manufacturer submitted a patient access scheme that would provide the 100\xa0mg dose at the same cost as the 50\xa0mg dose in this population. This scheme has been approved by the Department of Health.\n\nIn the resubmitted analyses (described in 3.58 and 3.59) the manufacturer corrected the internal inconsistencies previously present in the analyses. The analyses also incorporated the changes made by the ERG in response to the original submission (that is, updated unit costs and corrections to the HAQ decrements for certolizumab pegol and costs for infliximab). The analyses also included ACR70 response data and a progression rate while on palliative treatment of 0.06 HAQ score units a year.\n\nThe results from the economic model for the DMARD-experienced population were presented for each treatment in comparison with methotrexate. Including ACR70 response data in the model produced ICERs that were £21,944 and £25,825 per QALY gained for certolizumab pegol and infliximab respectively in comparison with methotrexate, and £26,996 per QALY gained for golimumab in comparison with methotrexate. The ICERs for adalimumab and etanercept in comparison with methotrexate were £25,523 and £27,157 per QALY gained respectively.\n\nA sensitivity analysis was provided that included the SF‑36 data from the GO‑FORWARD study converted to SF‑6D. The SF‑6D scores were calculated only for ACR20 and ACR50 responses. The results showed that the ICERs were £27,413 and £29,484 per QALY gained for certolizumab pegol and infliximab respectively in comparison with methotrexate and £31,046 per QALY gained for golimumab in comparison with methotrexate. The ICERs for etanercept and adalimumab in comparison with methotrexate were £30,936 and £30,893 per QALY gained respectively.\n\nThe results from the economic model for the TNF inhibitor-experienced population were presented for golimumab, rituximab abatacept and tocilizumab in comparison with methotrexate. The analyses incorporated a progression rate while on palliative treatment of 0.06 HAQ score units a year, and zero while on treatment with either golimumab, abatacept or tocilizumab. The progression rate for rituximab was 0.045 HAQ score units per year.\n\nThe analyses produced ICERs of £35,288, £32,036 and £35,382 per QALY gained for tocilizumab, golimumab and abatacept respectively in comparison with methotrexate, and £59,328 per QALY gained for rituximab in comparison with methotrexate. One-way sensitivity analyses assuming that people on rituximab experienced no disease progression while on treatment reduced the ICER for rituximab compared with methotrexate to £24,683 per QALY gained. An alternative one-way sensitivity analysis that assumed re-treatment with rituximab every 9\xa0months reduced the ICER for rituximab to £28,047 per QALY gained in comparison with methotrexate.\n\n## ERG comments on the manufacturer's resubmitted additional analyses\n\nThe ERG stated that the results from the manufacturer's resubmitted analyses were consistent with the electronic models provided. The ERG confirmed that the changes reported to have been implemented by the manufacturer had been completed appropriately and that errors previously identified had been corrected. The ERG noted that the results provided were deterministic and that no incremental analyses were included.\n\nFor the DMARD-experienced population, the ERG re-ran the manufacturer's model using a probabilistic analysis and presented the results incrementally. The incremental probabilistic analysis suggested that certolizumab pegol was the most cost-effective option, with an ICER in comparison with methotrexate of £22,693 per QALY gained. All other treatments were either dominated or extendedly dominated by certolizumab pegol. For each of the other treatments in comparison with methotrexate the probabilistic analysis produced ICERs for infliximab, golimumab, adalimumab and etanercept of £25,541, £27,946, £25,951, and £27,129 per QALY gained respectively.\n\nThe ERG reviewed the sensitivity analysis provided by the manufacturer that used the SF‑36 values converted to SF‑6D. The ERG noted that the manufacturer had not directly used the SF‑6D values for the placebo and methotrexate group; rather, it had estimated the ratio between the HAQ scores from the two groups in the clinical trial and then applied this ratio to the SF‑6D scores for the golimumab group to obtain a value for the methotrexate group. The HAQ adjustment resulted in lower SF‑6D scores associated with ACR20, ACR50 and ACR70 responses for the methotrexate group compared with the golimumab group. The ERG stated that it was unclear why the manufacturer had chosen this method.\n\nThe ERG re-ran the manufacturer's model using a probabilistic analysis and presented the results incrementally. The incremental probabilistic analysis suggested that certolizumab pegol was the most cost-effective option with an ICER in comparison with methotrexate of £27,182 per QALY gained. All other treatments were either dominated or extendedly dominated by certolizumab pegol. For each of the other treatments in comparison with methotrexate the probabilistic analysis produced ICERs for infliximab, golimumab, adalimumab and etanercept of £28,990, £31,420, £30,129, and £30,412 per QALY gained respectively.\n\nThe ERG checked the revised model for the TNF inhibitor-experienced population and stated that the changes had been implemented appropriately. The ERG cross-checked the cost-effectiveness estimates in the model with the study papers and relevant NICE technology appraisals and reported that the values used in the model corresponded. The ERG stated that a full validation of the model was not possible. However, the model maintained internal consistency and the clinical effectiveness results matched those in previous submissions.\n\nThe ERG re-ran the manufacturer's model using a probabilistic analysis. The ICER for golimumab compared with methotrexate was £32,979 per QALY gained. The ICERs for rituximab, abatacept and tocilizumab compared with methotrexate were £68,663, £34,155, and £34,644 per QALY gained respectively. The ERG produced a sensitivity analysis that assumed that the rate of underlying disease progression while on treatment with rituximab was zero (that is, the same assumption as the other biological treatments), and that rituximab was administered every 9\xa0months rather than every 6\xa0months. This reduced the ICER for rituximab in comparison with methotrexate from £68,663 to £12,196 per QALY gained.\n\nFull details of all the evidence are in the manufacturer's submissions and the ERG reports, which are available from www.nice.org.uk/guidance/TA225", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of golimumab, having considered evidence on the nature of rheumatoid arthritis and the value placed on the benefits of golimumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the clinical management of rheumatoid arthritis. The clinical specialists explained that ideally DMARD therapy should be started as early as possible after diagnosis to reduce joint damage, and that for the majority of people therapy with conventional DMARDs is sufficient. However, they explained that for a small proportion of people conventional DMARDs do not adequately control disease, and for this group of people biological DMARDs such as TNF inhibitors are needed. The Committee heard from the patient experts and clinical specialists that it is not possible to predict which TNF inhibitor will produce the best effect for each person. Therefore people prefer to have a choice of treatments and hence another treatment option would be welcome. The clinical specialists explained that they discuss with patients the different options for treatment and the choice of treatment is a joint decision between the clinician and the patient. The Committee understood that the availability of a range of treatments was valued by clinicians and patients.\n\nThe Committee heard from the clinical specialists and the patient experts that golimumab is administered once per month and this may be an advantage for people who have difficulty injecting themselves because of the joint damage caused by the disease and for people who have a fear of injections. The patient experts stated that once-monthly administration may be more convenient if they want to travel, as trips could more easily be planned around once‑a‑month administration. A once-monthly treatment may also be beneficial for people who experience injection-site reactions. However, the Committee heard from the clinical specialists that the length of the half-life of golimumab may be a disadvantage if a person needs to stop treatment quickly, for example if they had an adverse reaction or had unplanned surgery, since it would take time for the treatment effects (on immunity, for example) to wear off. The Committee accepted that the once-monthly administration of golimumab may be beneficial for people with rheumatoid arthritis.\n\nThe Committee discussed the dosing frequency of golimumab in response to comments received during consultation. The Committee noted that evidence regarding the choice of dose had been provided by the manufacturer from a phase\xa0II study (Kay et al. 2008). The Committee considered that the data comparing four different doses and schedules of golimumab showed that the dosing regimen of once every 4\xa0weeks had similar ACR response rates to the fortnightly dosing regimen, and that no clear dosage–response relationship was observed. The Committee accepted that the data showed that 50\xa0mg golimumab once every 4\xa0weeks is the minimum effective dosage.\n\n# Clinical effectiveness\n\nThe Committee considered the evidence on the clinical effectiveness of golimumab in combination with methotrexate and noted that the manufacturer's submission considered golimumab at two positions in the treatment pathway – after treatment with conventional DMARDs only, and after treatment with both conventional DMARDs and a TNF inhibitor. The Committee heard from clinical specialists how golimumab would fit into the current treatment pathway. It heard that golimumab may be used either as a first TNF inhibitor therapy in people whose disease has not responded to conventional DMARD therapy, or as a second TNF inhibitor therapy in people who have had previous therapy with a TNF inhibitor. Following comments received during consultation regarding the marketing authorisation for golimumab, the manufacturer was asked to confirm whether the marketing authorisation for golimumab includes people who have had previous therapy with a TNF inhibitor. The manufacturer stated that golimumab was approved on the basis of the GO‑FORWARD and GO‑AFTER studies and that its use in people who have had previous therapy with a TNF inhibitor is consistent with the marketing authorisation and the evidence. The Committee concluded that the two positions in the treatment pathway as included in the manufacturer's submission were appropriate to be considered in this appraisal.\n\nFor people who have previously had only conventional DMARDs, the Committee considered the evidence from the two placebo-controlled trials of golimumab in combination with methotrexate (GO‑FORWARD and Kay et al. 2008). It noted that golimumab in combination with methotrexate had greater clinical effectiveness than placebo in combination with methotrexate. The Committee then discussed the mixed treatment comparison presented by the manufacturer in the absence of head‑to‑head trials comparing the efficacy of golimumab with that of the other available TNF inhibitors. The Committee noted that the mixed treatment comparison suggested that there were no statistically significant differences in ACR20, ACR50 and ACR70 response rates between golimumab and the other TNF inhibitors, and that the credibility intervals around the estimates were wide. The Committee heard from clinical specialists that they considered the different TNF inhibitors to have broadly similar efficacy. The Committee discussed the potential heterogeneity between the studies included in the comparison, recognising concerns about the comparability of the certolizumab pegol studies. It further noted comments received in consultation that it was inappropriate to include the TEMPO study and the TNF inhibitor monotherapy studies in the mixed treatment comparison. However, the Committee noted the sensitivity analyses performed by the ERG, which showed that the exclusion of these studies did not significantly alter the estimates of cost effectiveness. The Committee concluded that, based on the ACR response rates, golimumab had been demonstrated to be more effective than placebo and that there was no convincing evidence that golimumab was either more or less effective than the other TNF inhibitors.\n\nThe Committee considered the evidence on the clinical effectiveness of golimumab compared with placebo for the people who had had previous treatment with both conventional DMARDs and a TNF inhibitor. It noted that there was a single trial (GO‑AFTER) comparing golimumab with placebo and this trial showed that golimumab had greater clinical effectiveness than placebo. The Committee discussed the indirect comparison of golimumab and rituximab performed in the absence of head-to-head trials comparing the efficacy of golimumab with that of rituximab. It agreed that rituximab is an appropriate comparator for this population, although it was aware that since the manufacturer's submission NICE has published technology appraisal guidance recommending the use of tocilizumab, abatacept and a second TNF inhibitor in certain people who have had previous treatment with a TNF inhibitor. The Committee concluded that although the point estimates favoured rituximab, the indirect comparison did not demonstrate any statistically significant differences in clinical efficacy between golimumab and rituximab. The Committee noted that the additional analyses provided by the manufacturer included cost-effectiveness results for the comparison of golimumab, tocilizumab and abatacept in people who have had previous treatment with a TNF inhibitor. However, the Committee noted that separate data on the clinical effectiveness of golimumab compared with tocilizumab and abatacept were not provided.\n\nThe Committee discussed the long-term data for ACR response and proportion of people maintaining a HAQ improvement equal to or greater than 0.25 in the DMARD-experienced population in the GO‑FORWARD trial. The Committee noted limitations to the data, specifically that the trial had a placebo-controlled phase only up to 24\xa0weeks, and included participants in the placebo arm who had crossed over to golimumab at week\xa014 because their disease was inadequately controlled. Despite these limitations the Committee agreed that the data suggested that the efficacy of golimumab was maintained over the long term. The Committee also discussed the long-term SF‑36 data submitted by the manufacturer and accepted that golimumab in combination with methotrexate had been shown to have a positive benefit on health-related quality of life compared with placebo. The Committee concluded that these data suggested that efficacy of golimumab was maintained.\n\nThe Committee considered clinical-effectiveness evidence for subgroups of people in the GO‑FORWARD trial who had either moderately or severely active rheumatoid arthritis as defined by their baseline DAS28 score. It noted that the analysis was in a small number of people, particularly the subgroup with moderately active rheumatoid arthritis. It further noted that the analysis was post hoc although it had been provided in line with the scope for the appraisal. For these reasons the Committee concluded that there was uncertainty surrounding the results. It noted that the majority of clinical evidence is in people with severely active rheumatoid arthritis.\n\nThe Committee discussed the 52- and 104‑week radiographic progression data (measured by the vdH‑S) from the GO‑FORWARD study submitted by the manufacturer following consultation on the appraisal consultation document. It noted that these data showed no statistically significant difference from baseline in vdH‑S score between golimumab 50\xa0mg and placebo. The Committee heard from the manufacturer that both groups in the trial had shown minimal radiographic progression, which meant that golimumab could not improve on the results seen in the placebo group. The Committee noted a number of explanations provided for the minimal progression in both groups, including the short placebo-controlled period, the use of radiographic outcomes as secondary endpoints in relation to the size of the study and lower baseline disease activity levels in the golimumab trials compared with trials of other biological treatments. The Committee then discussed the 52‑week radiographic progression data from the GO‑BEFORE study provided as supporting evidence for the GO‑FORWARD data. It noted that these data had been used to support the licence extension for golimumab. The Committee was not persuaded that the data had demonstrated an absence of underlying radiographic progression while on treatment with golimumab, but it concluded that the data demonstrated that the combination of golimumab and methotrexate reduced the rate of radiographic progression.\n\nThe Committee discussed the adverse events seen in the golimumab RCTs and the results from the mixed treatment comparison and the indirect comparison of golimumab and the comparators in both populations. It noted that the data from the mixed treatment and indirect comparisons suggested few statistically significant differences in relative risk between the treatments but that these were associated with considerable uncertainty. It heard from the clinical specialists that there are no long-term adverse event data for golimumab but that they expected the adverse event profile of golimumab to be no different from that of other TNF inhibitors. The clinical specialists suggested that since golimumab is administered once a month, there might be fewer adverse events compared with other TNF inhibitors as a result of the reduced frequency of administration. The Committee concluded that there was uncertainty surrounding the adverse event profile of golimumab because of the limited long-term data, but that golimumab's adverse event profile had not been shown to be different from that of other TNF inhibitors.\n\n# Cost effectiveness\n\nThe Committee considered the economic model that evaluated golimumab as part of a sequence of treatments in people who had had previous treatment with conventional DMARDs only and who had not had a previous TNF inhibitor. It noted that, on the whole, the model used similar assumptions to other models submitted in previous appraisals of TNF inhibitors in rheumatoid arthritis, but that there were some differences from the other models, for example the exclusion of ACR70 response data, alternative rates of disease progression while on treatment and alternative methods for deriving estimates of utility. The Committee noted that the ACR70 response data and rates of underlying disease progression, similar to those used in other NICE technology appraisals, had subsequently been appropriately included in a revised economic model.\n\nThe Committee considered the utility estimates incorporated in the original model, and noted that the utility was derived from the ACR response, which was converted to a change in HAQ score and then mapped to EQ‑5D. The Committee recognised that a similar approach to mapping had been used in previous NICE technology appraisals of biological treatments for rheumatoid arthritis. However, the Committee noted that this was different from the NICE reference case, which recommends inclusion of directly collected utility data. The Committee then discussed the sensitivity analysis submitted by the manufacturer following the consultation on the appraisal consultation document, using the SF‑36 data from the GO‑FORWARD study. It noted comments from the ERG about the method that the manufacturer used to generate the SF‑6D for the methotrexate group and that the ERG was unclear why this approach had been taken. The Committee considered that a more appropriate method for the analysis would have been to use the data from the placebo group directly. However, it concluded that the sensitivity analysis suggested that the methodology to derive the utility in the base-case analysis had not been shown to be unreasonable.\n\nThe Committee discussed the 100\xa0mg dose, which is indicated for people who weigh more than 100\xa0kg and whose rheumatoid arthritis has not responded after three or four doses of golimumab. It noted that evidence for the clinical and cost effectiveness of this dose was not included in the original submission. The Committee understood that even though the proportion of people who received this dose might be quite small, if the acquisition cost was included in the model the ICER for golimumab would be expected to be higher than that estimated in the base case presented by the manufacturer. The Committee noted that following consultation on the appraisal consultation document, the manufacturer did not submit any additional data regarding the 100\xa0mg dose, but instead proposed a patient access scheme that would provide the 100\xa0mg dose at the same cost as the 50\xa0mg dose in people for whom the higher dose is suitable. The Committee recognised that the patient access scheme has been accepted by the Department of Health. The Committee considered that analyses should have been presented both with and without the proposed patient access scheme, but concluded that with the patient access scheme, the manufacturer's analysis including only the costs of the 50\xa0mg dose could be used as a basis for decision making.\n\nThe Committee noted that the economic analysis from the manufacturer had assumed that there was no progression of disease while on treatment with a TNF inhibitor, but that there was progression while on treatment with conventional DMARDs and on palliative treatment. The Committee discussed the progression of disease while on treatment with TNF inhibitors for people who have had therapy with conventional DMARDs only. The Committee considered that an assumption of no progression while on treatment with a TNF inhibitor could be an overestimate of the benefits of treatment. However, it heard from clinical specialists that although no progression on treatment may appear optimistic, findings from long-term studies suggest that it is a reasonable assumption for people whose rheumatoid arthritis responds to treatment. The Committee recognised that similar assumptions had been made in other NICE technology appraisals of TNF inhibitor treatments for rheumatoid arthritis. The Committee was aware of the long-term radiographic progression data submitted by the manufacturer following consultation on the appraisal consultation document (see 4.9). It noted that these data showed that golimumab reduced the rate of radiographic progression, albeit in a different population. The Committee concluded that in line with NICE technology appraisals of other TNF inhibitors, it would be appropriate to consider the estimates of cost effectiveness that assumed no disease progression while on treatment with a TNF inhibitor. However, it considered that this assumption was uncertain and may overestimate the benefits of treatment.\n\nThe Committee then discussed the revised version of the economic model and sensitivity analyses submitted by the manufacturer that included ACR70 response data and a rate of disease progression while on palliative treatment of 0.06 HAQ score units per year. The Committee discussed the ERG's review of the revised model, noting that the ERG considered that the errors in the previous model had been corrected and changes implemented appropriately. The Committee noted that the ICERs for golimumab were at the upper end of the range of £25,000–£28,000 per QALY gained produced by other drugs in the class; however, the frequency of administration may generate additional health-related benefits. The Committee noted that the 100\xa0mg dose of golimumab was not considered in the economic model, but that because of the patient access scheme (as described in 2.4), the cost of the 100\xa0mg dose would be equal to that of the 50\xa0mg dose. The Committee was persuaded that, on balance, with the patient access scheme golimumab could be considered a cost-effective option for the treatment of rheumatoid arthritis if used in the same way as other TNF inhibitors, as recommended in 'Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis' (NICE technology appraisal guidance 130) and 'Certolizumab pegol for the treatment of rheumatoid arthritis' (NICE technology appraisal guidance 186).\n\nThe Committee considered the economic model for the group of people who have had previous treatment with both conventional DMARDs and a TNF inhibitor. It noted that the base-case analysis showed that rituximab was dominated by golimumab because golimumab was less costly and more effective. It was aware that in this analysis it was assumed that rituximab is re-administered every 6\xa0months. The Committee heard that the ERG considered re-administration of rituximab every 9\xa0months to be more reflective of clinical practice. The Committee further heard from clinical specialists that for people responding to rituximab treatment the re-treatment intervals would be greater than 6\xa0months. The Committee heard from the ERG about the costs for the first year of rituximab treatment that are included in the model. For the first 6\xa0months of treatment, 1.5\xa0courses of rituximab are included and 1\xa0course of rituximab is included for the second 6\xa0months. The Committee heard that it is unclear why a greater number of courses are required in the first 6\xa0months than in subsequent 6-month periods. The Committee concluded that the rituximab costs had been overestimated in the original economic model, and that a re-treatment interval of 9\xa0months is more appropriate.\n\nThe Committee discussed the progression of disease while on treatment for people who have had previous treatment with conventional DMARDs and a TNF inhibitor. It noted that the manufacturer had assumed that the TNF inhibitors all stop progression of disease while on treatment, but that for rituximab it was assumed that the disease continues to worsen while on treatment by an increase of 0.045 per year in HAQ score. It noted that this is the same as the rate used for conventional DMARDs. The Committee heard from the ERG and clinical specialists that this underestimates the benefits of rituximab, and that it would have been more appropriate to assume that, for people whose disease responds to treatment, rituximab reduces the progression of disease to the same extent as the TNF inhibitors. The Committee was not persuaded that it is appropriate to assume a differential rate of underlying progression of disease between rituximab and golimumab, and concluded that this assumption overestimates the cost effectiveness of golimumab compared with rituximab.\n\nThe Committee discussed the results of the manufacturer's revised version of the economic model and the ERG's exploratory analyses for the group of people who have had previous treatment with both conventional DMARDs and a TNF inhibitor, which compared golimumab with rituximab. It agreed that the ERG's amendments to increase the time between treatment intervals for rituximab and remove the assumption of a differential rate of underlying progression of disease were appropriate. The Committee noted that when these assumptions were changed rituximab was associated with lower costs and more QALYs than golimumab. The Committee therefore concluded that golimumab would not be a cost-effective use of NHS resources in people who have had previous treatment with conventional DMARDs and a TNF inhibitor and for whom rituximab is an appropriate treatment option.\n\nThe Committee recognised that in August 2010 NICE published technology appraisal guidance recommending the TNF inhibitors adalimumab, etanercept, infliximab and abatacept, as well as tocilizumab, for people with rheumatoid arthritis who are unable to have rituximab therapy because of contraindications or if rituximab is withdrawn because of an adverse event ('Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor' [NICE technology appraisal guidance 195] and 'Tocilizumab for the treatment of rheumatoid arthritis' [NICE technology appraisal guidance 198]). The Committee agreed that it was appropriate to consider this group of people and the treatment options now available to them. The Committee discussed the revised analyses submitted by the manufacturer and noted that these did not include the other TNF inhibitors (that is, adalimumab, etanercept and infliximab), but did include abatacept and tocilizumab. It further noted the manufacturer's rationale that the other TNF inhibitors could not be included because there were no data from RCTs for these agents in this position in the treatment pathway. The Committee noted that the ICERs for golimumab in comparison with methotrexate were similar to those for abatacept and tocilizumab. The Committee understood that both abatacept and tocilizumab had been recommended for this patient group in NICE technology appraisal guidance (NICE technology appraisal guidance 195 and NICE technology appraisal guidance 198), with most plausible ICERs of between £20,000–30,000 per QALY gained, and that the TNF inhibitors: adalimumab, etanercept and infliximab had also been recommended in this way with ICERs in this range. On balance the Committee considered that the evidence before it indicated that golimumab would be no less cost effective than the other TNF inhibitors when used in this population. Therefore the Committee concluded that with the patient access scheme, golimumab is an appropriate use of NHS resources in people with rheumatoid arthritis who are unable to have rituximab therapy because of contraindications or if rituximab is withdrawn because of an adverse event, if used in the same way as other TNF inhibitors, as recommended in 'Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor' (NICE technology appraisal guidance 195).\n\n# Summary of Appraisal Committee's key conclusions\n\nTA225\n\n\n\nGolimumab for the treatment of rheumatoid arthritis after the failure of previous disease‑modifying anti-rheumatic drugs\n\n\n\nSection\n\nKey conclusions\n\nGolimumab in combination with methotrexate is recommended as an option for the treatment of rheumatoid arthritis in adults whose rheumatoid arthritis has responded inadequately to conventional disease-modifying anti-rheumatic drugs (DMARDs) only, including methotrexate, if:\n\nit is used as described for other tumour necrosis factor (TNF) inhibitor treatments in 'Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis' (NICE technology appraisal guidance 130), and\n\nthe manufacturer provides the 100\xa0mg dose of golimumab at the same cost as the 50\xa0mg dose, agreed as part of the patient access scheme.\n\nJanuary 2016: This recommendation has been updated by NICE technology appraisal guidance 375.\n\nGolimumab in combination with methotrexate is recommended as an option for the treatment of rheumatoid arthritis in adults whose rheumatoid arthritis has responded inadequately to other DMARDs, including a TNF inhibitor, if:\n\nit is used as described for other TNF inhibitor treatments in 'Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor' (NICE technology appraisal guidance 195), and\n\nthe manufacturer provides the 100\xa0mg dose of golimumab at the same cost as the 50\xa0mg dose, agreed as part of the patient access scheme.\n\nThe key drivers for these recommendations were:\n\nin people whose rheumatoid arthritis has had an inadequate response to previous treatment with conventional DMARDs only, the evidence suggests that golimumab has efficacy and cost-effectiveness estimates that are similar to those of the other TNF inhibitors that have been recommended by NICE\n\nin people whose rheumatoid arthritis has responded inadequately to other DMARDs, including a TNF inhibitor, and for whom rituximab is appropriate, rituximab is associated with lower costs and more QALYs than golimumab\n\nin people whose rheumatoid arthritis has responded inadequately to other DMARDs, including a TNF inhibitor, and for whom rituximab is contraindicated or withdrawn because of an adverse event, the evidence indicated that golimumab would be no less cost effective than abatacept or tocilizumab or the other TNF inhibitors when used in this population.\n\n, 1.2, 4.16, 4.19, 4.20\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\n\n\nThe clinical specialists explained that ideally DMARD therapy should be started as early as possible after diagnosis to reduce joint damage and for the majority of people therapy with conventional DMARDs is sufficient. However, for a small proportion of people conventional DMARDs do not adequately control disease, and for this group of people biological DMARDs such as TNF inhibitors are needed.\n\nIt is not possible to predict which TNF inhibitor will produce the best effect for each person. Therefore people prefer a choice of treatments and another treatment option would be welcome.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nGolimumab is administered once per month and this may be an advantage for people who have difficulty injecting themselves because of the joint damage caused by the disease and for people who have a fear of injections. Once-monthly administration may be more convenient for people who travel and may be beneficial for people who experience injection-site reactions.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nBoth the marketing authorisation and clinician opinion indicate that golimumab may be used either as a first TNF inhibitor therapy in people whose disease has not responded to conventional DMARD therapy, or as second TNF inhibitor therapy in people who have had previous therapy with a TNF inhibitor.\n\n\n\nAdverse effects\n\nThere is uncertainty about the adverse event profile of golimumab in the absence of long-term data. However, the clinical specialists expect the adverse event profile of golimumab to be no different from that of other TNF inhibitors.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\n\n\nThe manufacturer's submission considered golimumab at two positions in the treatment pathway – after treatment with conventional DMARDs and not a TNF inhibitor, and after treatment with both conventional DMARDs and a TNF inhibitor.\n\nFor people who had previously had only conventional DMARDs, there were two clinical trials but there were no head-to-head trials between golimumab and other available TNF inhibitors. As a result, the manufacturer had conducted a mixed treatment comparison and an indirect comparison.\n\nFor the people who had had previous treatment with both conventional DMARDs and a TNF inhibitor, there was a single trial comparing golimumab with placebo. In the absence of head-to-head trials the manufacturer carried out an indirect comparison of golimumab and rituximab.\n\n, 4.6, 4.7\n\nRelevance to general clinical practice in the NHS\n\nThe relevance of the evidence to the UK population in clinical practice was not identified as an issue.\n\n\n\nUncertainties generated by the evidence\n\nFor both populations, there were no statistically significant differences in ACR20, ACR50 and ACR70 response rates between golimumab and the active comparators in the mixed treatment and indirect comparisons. However, the credibility intervals around the point estimates were wide.\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee considered clinical-effectiveness evidence for subgroups of people in the GO-FORWARD trial who either had moderately or severely active rheumatoid arthritis as defined by their baseline DAS28 score.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\n\n\nThe Committee concluded that for people who had previously had only conventional DMARDs, based on the ACR response rates, golimumab had been demonstrated to be more clinically effective than placebo and that there was no convincing evidence that golimumab was either more or less effective than the other TNF inhibitors.\n\nFor people who had previously had both conventional DMARDs and a TNF inhibitor, the Committee considered that golimumab had greater clinical effectiveness than placebo. It noted that the point estimates for the comparison of rituximab and golimumab favour rituximab but that there are no statistically significant differences in clinical efficacy between golimumab and rituximab.\n\n, 4.7\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nThe economic model evaluated golimumab as part of a sequence of treatments. One model evaluated golimumab in people who had had previous treatment with conventional DMARDs only, and the other in people who had had treatment with both conventional DMARDs and a TNF inhibitor.\n\nRevised models were provided following a request for further data to be provided by the manufacturer.\n\n, 4.16, 4.17\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that the economic analysis from the manufacturer had assumed that there was no progression of disease while on treatment with a TNF inhibitor, but that there was progression while on treatment with conventional DMARDs and on palliative treatment. The Committee considered that an assumption of no progression while on treatment with a TNF inhibitor could be an overestimate of the benefits of treatment.\n\nThe Committee noted that the manufacturer had assumed that the TNF inhibitors all stop progression of disease while on treatment, but that for rituximab it was assumed that the disease continues to worsen while on treatment by an increase of 0.045 per year in HAQ score. It noted that this is the same as the rate used for conventional DMARDs. The Committee heard from the ERG and clinical specialists that this underestimates the benefits of rituximab.\n\nThe Committee noted that the economic model assumes that rituximab is re-administered every 6\xa0months. The Committee heard that the ERG and the clinical specialists considered that re-administration of rituximab every 9\xa0months to be more reflective of clinical practice. The Committee concluded that the rituximab costs had been overestimated in the original economic model, and that a re-treatment interval of 9\xa0months is more appropriate.\n\n, 4.18, 4.17\n\nIncorporation of health-related quality-of-life benefits and utility values\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee considered the utility estimates incorporated in the original model, and noted that the utility formula was derived from the ACR response, which was converted to a change in HAQ score and then mapped to EQ-5D.\n\nThe Committee discussed the sensitivity analysis submitted by the manufacturer following the consultation on the appraisal consultation document, using the SF-36 data from the GO-FORWARD study. It concluded that the sensitivity analysis suggested that the methodology to derive the utility in the base-case analysis had not been shown to be unreasonable.\n\nThe Committee noted the frequency of administration may generate additional health-related benefits.\n\n, 4.16\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nN/A\n\n\n\nMost likely cost‑effectiveness estimate (given as an ICER)\n\n\n\nThe Committee considered the revised economic model for people who have previously received conventional DMARDs. It noted that the ICERs for golimumab were at the upper end of the range of £25,000−£28,000 per QALY gained produced by other drugs in the class; however, the frequency of administration would generate additional health-related benefits. The Committee was persuaded that, on balance, with the patient access scheme golimumab could be considered a cost-effective option for the treatment of rheumatoid arthritis if used in the same way as other TNF inhibitors, as recommended in NICE technology appraisal guidance 130 and NICE technology appraisal guidance 186.\n\nFor the group of people who have had both conventional DMARDs and a TNF inhibitor, and for whom rituximab is appropriate, the Committee considered that rituximab is associated with lower costs and more QALYs than golimumab. The Committee therefore concluded that golimumab would not be a cost-effective use of NHS resources in people who have had previous treatment with conventional DMARDs and a TNF inhibitor and for whom rituximab is an appropriate treatment option.\n\nFor the group of people who have had previous treatment with both conventional DMARDs and a TNF inhibitor and for whom rituximab is contraindicated or withdrawn because of an adverse event, the Committee understood that both abatacept and tocilizumab had been recommended for this patient group, with most plausible ICERs of between £20,000–30,000 per QALY gained, and that adalimumab, etanercept and infliximab had also been recommended in this way with ICERs in this range. On balance the Committee considered that the evidence before it indicated that golimumab would be no less cost effective than the other TNF inhibitors when used in this population. Therefore the Committee concluded that golimumab is an appropriate use of NHS resources in people with rheumatoid arthritis who are unable to have rituximab therapy because of contraindications or if rituximab is withdrawn because of an adverse event.\n\n, 4.19, 4.20\n\nAdditional factors taken into account\n\nPatient access schemes\n\n(Pharmaceutical Price Regulation Scheme [PPRS])\n\nThe manufacturer has agreed a patient access scheme with the Department of Health, in which the 100\xa0mg dose of golimumab will be available to the NHS at the same cost as the 50\xa0mg dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\n\n\n\nEnd-of-life considerations\n\nThe supplementary advice was not relevant to this appraisal.\n\n\n\nEqualities considerations and social value judgements\n\n\n\nNo equalities issues were raised in the appraisal.\n\n", 'Related NICE guidance': 'Tocilizumab for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 198 (2010).\n\nAdalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. NICE technology appraisal guidance 195 (2010).\n\nCertolizumab pegol for the treatment of rheumatoid arthritis in adults. NICE technology appraisal guidance 186 (2010).\n\nRheumatoid arthritis: the management of rheumatoid arthritis in adults. NICE clinical guideline 79 (2009).\n\nAdalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 130 (2007).', 'Review of guidance': 'The guidance on this technology in people who have had previous treatment with conventional DMARDs only will be reviewed with NICE technology appraisal guidance 130 and 186. The guidance on this technology in people who have had previous treatment with both conventional DMARDs and a TNF inhibitor will be reviewed with the review of NICE technology appraisal guidance 195 in June 2013. Andrew DillonChief ExecutiveJune 2011', 'Changes after publication': 'January 2016: Recommendation 1.1 has been updated by the recommendations in the NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour\n responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nISBN: 978-1-4731-1623-8'}
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https://www.nice.org.uk/guidance/ta225
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Evidence-based recommendations on golimumab (Simponi) for treating rheumatoid arthritis in adults.
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Rituximab for the first-line maintenance treatment of follicular non-Hodgkin's lymphoma
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Rituximab for the first-line maintenance treatment of follicular non-Hodgkin's lymphoma
Evidence-based recommendations on rituximab (MabThera) for the maintenance treatment of follicular non-Hodgkin’s lymphoma in adults.
# Guidance
Rituximab maintenance therapy is recommended as an option for the treatment of people with follicular non‑Hodgkin's lymphoma that has responded to first-line induction therapy with rituximab in combination with chemotherapy.# The technology
Rituximab (MabThera, Roche Products) is a chimeric (mouse/human) genetically engineered monoclonal antibody. It targets the CD20 surface antigen of mature B-cell lymphocytes. Rituximab has a marketing authorisation for the 'treatment of follicular lymphoma patients responding to induction therapy'. Other licensed indications for rituximab in non-Hodgkin's lymphoma include 'the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy'; 'the treatment of patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy'; and 'the treatment of patients with CD20 positive diffuse large B cell non-Hodgkin's lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy'.
Allergic and skin reactions are the most common adverse effects of rituximab infusion. Reactions during infusion can include bronchospasm and hypotension, which can be severe or life-threatening. Severe reactions occur more commonly in people with a high tumour burden, and the incidence and severity of infusion reactions decrease with successive infusions. Rituximab treatment can also be associated with blood and bone-marrow toxicity, characterised by neutropenia and leucopenia, which can lead to infections. In addition, treatment with rituximab may cause flu-like symptoms, and has been associated with progressive multifocal leukoencephalopathy. For full details of side effects and contraindications, see the summary of product characteristics.
For people with previously untreated follicular lymphoma that has responded to first-line induction treatment, the recommended dose of rituximab as maintenance treatment is 375 mg/m² body surface area, administered by intravenous infusion once every 2 months. Treatment should start 2 months after the last dose of first-line induction therapy and continue until the disease progresses, or for a maximum period of 2 years. The cost of one 100-mg vial is £174.63, and one 500-mg vial is £873.15 (excluding VAT; 'British national formulary' edition 61). The manufacturer estimates that for a person with an average body surface area of 1.8 m², the average cost of rituximab maintenance treatment for 2 years is £14,669 (excluding VAT). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rituximab and a review of this submission by the Evidence Review Group (ERG; appendix B).
The manufacturer presented information addressing the decision problem; that is, whether rituximab maintenance treatment is a clinically effective and cost-effective use of NHS resources, compared with standard management without rituximab for people with follicular lymphoma that has responded to first-line induction chemotherapy combined with rituximab. The outcomes defining effectiveness included progression-free survival, overall survival, response rates, adverse effects of treatment and health‑related quality of life.
The manufacturer undertook a systematic literature review and identified only one trial, the Primary Rituximab and Maintenance (PRIMA) trial, that met its inclusion criteria. The manufacturer presented evidence analysed after a median follow-up of 25 months (at the close of the PRIMA trial), but also provided data from two post-study observational periods with median follow-up periods of 36 and 38 months. In the absence of long-term data from the PRIMA trial, the manufacturer used data from the European Organisation for Research and Treatment of Cancer (EORTC) 20981 study to model the expected longer term outcomes that may have been experienced by participants in the PRIMA trial, had the trial gone on longer. The patient population in the EORTC 20981 study (see section 3.4), however, was different from that of the PRIMA trial.
The PRIMA trial was a phase III, open-label, multicentre, randomised trial with two treatment phases. The trial included 1193 people with previously untreated advanced follicular lymphoma with an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 and a median age of 57 years. In the first phase (induction phase or first-line treatment), participants had one of three different regimens, all of which included rituximab: R-CVP (rituximab with cyclophosphamide, vincristine and prednisolone ), R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone ) or R-FCM (rituximab with fludarabine, cyclophosphamide and mitoxantrone ). People whose disease had either a partial or complete response to first-line treatment (n = 1019) entered the second phase of the trial, and were randomised to receive either rituximab maintenance treatment (n = 506) or no treatment (that is, observation; n = 513). People in the maintenance arm received 375 mg/m² rituximab intravenously: one dose every 8 weeks for 2 years, for a total of 12 doses or until disease progression, whichever occurred first. The trial was designed initially to estimate event-free survival as the primary outcome. However, during the course of the trial, the manufacturer amended the protocol in line with recommendations from regulatory authorities and changed the primary outcome to progression-free survival. Length of follow-up was increased from 5 to 7 years, and the study population was increased from 900 to 1200 participants. Secondary clinical outcomes included overall survival, event-free survival, time to next anti-lymphoma treatment, overall response rate at the end of the maintenance observation phase, the proportion of people with histological transformation at first progression, quality of life and safety. Quality-of-life data were collected in the trial using the Functional Assessment of Cancer Therapy – General (FACT-G) questionnaire and the EORTC Quality of Life Questionnaire – Core 30 (EORTC QLQ-C30). After a median follow-up of 25 months, a Data and Safety Monitoring Committee judged that the trial had met its primary objective at the pre-specified interim analysis and recommended closure of the trial. However, investigators continued to follow patients during an observational post-study period to collect longer term data.
The EORTC 20981 study was a phase III, open-label randomised trial that included people with relapsed or resistant follicular non-Hodgkin's lymphoma (n = 465) who had not previously been treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or R-CHOP. Instead, patients had been treated with at least 2 months of single-agent therapy (such as chlorambucil) and/or at least two consecutive cycles of combination chemotherapy (such as CVP ) or purine analogues. Therefore, these patients differed from those in the decision problem in that their disease had progressed after first-line therapy, and they had not been previously treated with R‑CHOP, R-CVP or R-FCM as in the PRIMA trial. Participants were randomised to treatment with R‑CHOP or CHOP alone after enrolment. People whose disease responded to second-line therapy (n = 334) were then randomised to either second-line maintenance treatment with 375 mg/m² rituximab (one dose every 3 months for 2 years or until relapse) or observation until relapse.
The results of the PRIMA trial showed that after 25 months' median follow-up, the risk of disease progression was halved in the rituximab maintenance arm compared with the observation arm (hazard ratio 0.50; 95% confidence interval 0.39 to 0.64; p < 0.0001) as assessed by the study investigators. This result was based on 18.4% (93 of 505) of people in the rituximab maintenance arm and 33.9% (174 of 513) of people in the observation arm having experienced an event (disease progression, relapse or death). The estimate of the hazard ratio associated with treatment was slightly higher when assessed by an independent review committee. After a median follow-up of 36 months, progression-free survival was statistically significantly improved in people randomised to the rituximab maintenance arm (PFS 74.9%; 95% CI 70.9 to 78.9) compared with those randomised to the observation arm (PFS 57.6%; 95% CI 53.2 to 62.0). The risk of disease progression was significantly reduced for people in the rituximab maintenance arm (HR 0.55; 95% CI 0.44 to 0.68; p < 0.0001). However, too few patients randomised to the rituximab maintenance arm had progressed during the study period to estimate the median time to progression. For patients randomised to observation, the median time to progression was estimated to be 48.3 months (95% CI 38.0 to not reached). After 36 and 38 months' median follow-up, a statistically significant difference in overall survival could not be established between the two arms because of the low number of deaths that had occurred.
During first-line induction therapy, most people in the PRIMA trial experienced an adverse event and 25% experienced a serious adverse event, consistent with the known safety profiles of these induction regimens. After the first-line maintenance phase of the trial, significantly more grade 3 or 4 adverse events occurred in people in the rituximab maintenance arm (24%) compared with people in the observation arm (17%; risk ratio 1.46; 95% CI 1.14 to 1.87; p = 0.0026).
In the EORTC 20981 study, second-line maintenance treatment with rituximab significantly improved progression-free survival compared with observation (median 3.7 years versus 1.3 years). Five-year overall survival was not significantly different between the arms (74% in the rituximab maintenance arm and 64% in the observation arm). Second-line maintenance treatment with rituximab was associated with statistically significant increases in grade 3 and 4 infections compared with observation.
The manufacturer also provided a summary of other studies, as supporting evidence, of the efficacy and safety of rituximab maintenance in people with previously untreated or relapsed or refractory follicular lymphoma. In the ECOG 1496 study, rituximab maintenance led to longer progression-free survival compared with observation (HR 0.4; p < 0.0001) in people who had previously received CVP as induction therapy. Interim data from another study (SAKK 35/98), which is still ongoing to compare a short course of rituximab maintenance (375 mg/m² every 2 months for a total of four doses) and prolonged rituximab maintenance (375 mg/m² every 2 months for a maximum of 5 years) with observation, demonstrated a longer event-free survival after prolonged rituximab maintenance compared with observation in people with either previously treated or previously untreated follicular lymphoma after induction with rituximab monotherapy. Preliminary safety results from this study also indicate that prolongation of maintenance therapy beyond 2 years does not lead to an obvious increase in toxicity.
The manufacturer produced a Markov economic model to estimate all costs and benefits over a lifetime resulting from the treatment of follicular lymphoma with rituximab compared with observation after first-line induction with different regimens of rituximab and chemotherapy (R-CHOP, R-CVP or R-FCM). Although listed as a comparator in the decision problem for this appraisal, ibritumomab tiuxetan was considered by the manufacturer to not be an appropriate comparator for inclusion in the economic model because of limited evidence available to support its benefits, and because data for local use suggested that it is seldom prescribed in the UK. The model had four distinct health states: progression-free survival while in the first-line maintenance phase (PF1), progression-free survival after receiving second-line induction treatment with rituximab in combination with chemotherapy (PF2), progressive disease (PD) and death. The manufacturer assumed that all people enter the economic model in the PF1 health state after successfully completing induction treatment (that is, the start of the model reflected the second phase of the PRIMA trial). The model had a cycle of 1 month and a time horizon of 25 years. A half cycle correction was applied to the model.
Data from the PRIMA trial (after 38 months' median follow-up) and the EORTC 20981 study were used by the manufacturer to estimate the transition probabilities between the health states in the economic model. To estimate median progression-free survival, which could not be estimated from the PRIMA trial directly, the manufacturer used the Gompertz function to extrapolate progression-free survival data beyond the end of the PRIMA trial. The manufacturer considered that this function provided a better fit than alternative functions. Based on the results from the PRIMA trial, the EORTC 20981 study and expert opinion, the manufacturer assumed that people in the PF1 health state retain a clinical benefit from rituximab maintenance treatment for 6 years; that is, 4 years beyond the end of treatment in the PRIMA trial. After this time, the risk of disease progression for people in the PF1 health state was assumed to be equal in both the rituximab maintenance and observation arms of the model (that is, both groups progress at the same rate after 6 years). Data from the EORTC 20981 study were used to derive the long-term outcomes, including death, for people according to the treatment they received after progressing from the PF1 health state.
In the PRIMA trial, participants did not routinely complete EQ-5D questionnaires. Instead, health-related quality-of-life data were collected in the PRIMA trial using the FACT-G and EORTC QLQ-C30 questionnaires developed to assess the quality of life of people with cancer. Overall, no differences in health-related quality-of-life data were observed between the rituximab maintenance and observation arms.
The manufacturer conducted a systematic literature review to identify studies addressing quality of life, but it considered that only one study (Pettengel et al. 2008) met the inclusion criteria. In this study, 215 adults with follicular lymphoma and an ECOG score of 0−2 completed EQ-5D questionnaires during outpatient appointments across eight sites in the UK. Patients were placed in one of five categories according to the stage of their disease: 'active disease – newly diagnosed', 'active disease – relapsed', 'partial response', 'complete response to therapy (or remission)' and 'disease free (no detectable disease)'. Mean utility values from this study were 0.88 (from 'disease free' category), 0.79 (from 'complete response to therapy' category) and 0.62 (from 'active disease – relapsed' category). These utility values were assigned to the PF1, PF2 and PD health states respectively in the manufacturer's economic model. The economic model did not include values for the disutility associated with grade 3 and 4 adverse events, or with receiving chemotherapy.
The manufacturer included costs associated with drug acquisition and administration, supportive care, management of adverse events and monitoring for each health state in the economic model. The primary sources of these costs were the BNF (edition 56 was used by the manufacturer, and edition 59 by the ERG; however, the costs were the same in both editions), the NHS Reference Cost Schedule 2008/09 and the Personal Social Services Research Unit 2009 (unit costs of health and social care). The manufacturer assumed that grade 3 and 4 adverse events incur equivalent costs, as estimated from the PRIMA and EORTC 20981 studies. Costs and benefits were discounted at 3.5% per year.
In the base-case analysis from the manufacturer's original submission, which assumed that the clinical benefit of rituximab is sustained over 6 years, the incremental cost‑effectiveness ratio (ICER) of rituximab maintenance treatment compared with observation was £15,978 per quality-adjusted life year (QALY) gained (incremental costs = £18,681; incremental QALYs = 1.169). Sensitivity analyses explored the impact of varying costs of adverse events (±50%), monthly supportive care (±50%), and administering rituximab (for example, nursing time; upper = £267, lower = £176). In sensitivity analyses, the manufacturer also tested the impact of varying the time horizon (20 years and 30 years), using other types of parametric functions to extrapolate progression-free survival data from the PRIMA trial, and assuming that people who progress from the PF1 health state die (probability of death was 100%, extreme scenario) rather than experience disease progression. From the analyses, the manufacturer concluded that the model was not sensitive to assumptions around the type of parametric extrapolation fitted to the PRIMA data, around costs of supportive care and administration, or around the time horizon. The model was sensitive to assumptions regarding the duration of treatment effect; when the manufacturer assumed that the effect of treatment stopped after 47 months (instead of after 72 months as in the base case), the ICER increased to £21,151 per QALY gained. When the manufacturer assumed that all people died after progressing from the PF1 health state (extreme scenario), the ICER decreased to £13,901 per QALY gained.
The manufacturer conducted probabilistic sensitivity analyses of all major parameters in the model except age, weight and height. The mean ICER from this analysis was £15,770 per QALY gained, and the manufacturer estimated that the probability of rituximab maintenance treatment being cost effective at £20,000 per QALY gained or less was 84.2%, and at £30,000 per QALY gained or less was 99.7%, compared with observation. The manufacturer concluded that these results demonstrated that the ICER was robust even under a wide range of variation in the model parameters.
The ERG considered that the PRIMA trial was well designed and, although it was an open-label trial, the results of progression-free survival could be considered robust because the trial used a blinded independent review committee. In the ERG's view, the rituximab chemotherapy regimens used in the induction phase of the PRIMA trial (that is, R-CHOP, R-CVP and R-FCM) were appropriate and in line with the rituximab chemotherapy regimens used in UK clinical practice. Overall, the ERG considered the results of the PRIMA trial to be generalisable to the UK setting, and that the manufacturer's decision not to include ibritumomab tiuxetan as a comparator in the economic analysis was justified.
The ERG was concerned that follow-up data were not available beyond 4 years and that the manufacturer could not estimate the median time to progression or to death by treatment group. The ERG cautioned that the data were immature (few events), which might have led the results to overestimate the clinical benefits of rituximab maintenance treatment. The ERG noted a meta-regression analysis (Bassler et al. 2010), which found large differences in the size of treatment effects between trials that were stopped early (regardless of the reason) and similar trials that ran for their originally specified time period. Using data from this study, the ERG adjusted the progression-free survival hazard ratio from the PRIMA trial to account for early reporting bias and noted that the hazard ratio increased by 30.7% from 0.55 (manufacturer's base case) to 0.719 (95% CI 0.575 to 0.889). The ERG suggested that sensitivity analyses that include the adjusted progression-free survival hazard ratio should be considered by the Committee.
The ERG noted that treatments administered after participants' disease had progressed may have affected the rate of overall survival in the PRIMA trial. The ERG stated that the post-progression treatments in the manufacturer's submission were in line with those used in UK clinical practice. However, from the data provided, the ERG was unsure whether the time at which these treatments were offered in the trial reflected the time that they would be offered in routine practice.
Although the ERG identified a number of problems with the structure and implementation of the manufacturer's model, the ERG did not expect these problems to have a major impact on the cost-effectiveness results. The ERG noted that the manufacturer did not model the disutilities associated with grade 3 and 4 adverse events. The ERG stated that this omission would favour the rituximab maintenance arm because people treated with rituxmab experience more adverse events than those not treated with rituximab (observation). The ERG was concerned that the manufacturer may have underestimated the costs of adverse events experienced in the PF2 health state because most of the people in the PRIMA trial had not progressed beyond the first-line maintenance or observation phase at the time of data analysis (up to 38 months).
The ERG noted the low proportion of patients censored (less than 3%) during the first 800 days of the PRIMA trial, and that this proportion increased greatly (70% for rituximab maintenance and 50% for observation) by 1600 days. Consequently, the ERG believed that the Kaplan–Meier estimate of progression-free survival becomes uncertain after 800 days. The ERG had concerns about the use of long-term modelling to inform the duration of treatment benefit estimated in the economic model. The ERG noted that the manufacturer used the Gompertz parametric function in their original analyses, which generated the highest overall estimate compared with other algorithms (such as an exponential function), to model progression-free survival.
The ERG was concerned about the manufacturer's use of data from the EORTC 20981 study to inform the economic model. The ERG noted that the participants in this study received different induction treatments to those in the PRIMA study (the EORTC 20981 study included people if their disease had relapsed after two previous non-anthracycline-containing chemotherapy regimens) and that only half of the patients in the EORTC 20981 study received induction treatment with a rituximab-containing regimen. Therefore, the ERG questioned whether the manufacturer could reliably use the outcomes from the EORTC 20981 study to predict future outcomes for participants in the PRIMA trial.
The ERG noted that, in the base case, the manufacturer assumed rituximab maintenance treatment had a clinical benefit for 6 years (that is, the hazard ratio from the PRIMA trial was applied for 6 years). In addition, the ERG noted that a large proportion of the gain in progression-free survival in the model arises beyond 4 years. Therefore, the ERG cautioned that if the gain in progression-free survival progressively declines, the ICER could substantially increase depending on the time period over which one assumes a difference between the treatment arms (that is, the time until the progression-free survival curves for each arm converge). The ERG also noted that the ICERs in the manufacturer's analyses were sensitive to the age at which a patient is assumed to start treatment and suggested that the manufacturer should have adjusted this variable in its sensitivity analyses.
The ERG noted that the manufacturer's model projects future benefits associated with the increased time that a person's disease remains progression free. The manufacturer's base-case modelling estimated that the mean time before a person's disease progresses is 8.64 years for the observation arm and 10.65 years for people who receive rituximab maintenance therapy; a gain of 2.01 years. The ERG noted that the manufacturer's analysis assumed that almost all of this gain in progression-free survival occurs in the PF1 health state. This implied that the majority (89.2%) of the gains in progression-free survival achieved directly by extending the first-line induction response translated into overall survival gains. The ERG cautioned that this should represent the 'best possible' scenario and would require strong supportive evidence from clinical trials before it could be accepted. The ERG explored how different conversion rates of progression-free survival gain to overall survival gain affect the estimated ICER, and predicted that at least 50% of progression-free survival gain would need to be converted into overall survival gain to achieve an ICER below £30,000 per QALY gained. The ERG further noted that if a function other than the Gompertz parametric function were used to extrapolate and convert progression-free survival into overall survival, then the conversion rate would need to be even higher for the ICER to remain below £30,000 per QALY gained.
The ERG noted that the manufacturer's model included utility values of 0.88 and 0.79 for the PF1 and PF2 health states respectively. The ERG considered that the same utility value should be used in both health states, because people in both states are in remission or have a full response. The ERG conducted a sensitivity analysis assuming that both health states have a utility value of 0.79, and noted that the QALY gain associated with maintenance treatment with rituximab dropped by more than 10% and the ICER increased by 11%.
In response to comments on the first and second appraisal consultation documents, the manufacturer provided revised cost-effectiveness analyses that modelled the effect on the ICER of different assumptions including progression-free survival translating into overall survival in a range from 50% to 100%; the clinical benefit from rituximab lasting for 28 months, 36 months or 48 months; and the mean age of a patient at induction being 62.5 years. Although the Committee requested analysis of potential utility gains associated with delaying the need for chemotherapy after relapse, the manufacturer was unable to incorporate these because of limitations in the structure of the model.
In response to the ERG's concern during the second Appraisal Committee meeting that the duration of clinical benefit (that is, the period during which rituximab is better than, rather than equal to, observation) may last only 28 months (based on the cumulative hazard plots from the PRIMA trial), the manufacturer provided an alternative method to model the rituximab treatment effect stopping at 28 months. This entailed using an exponential function (instead of the Gompertz function from the original submission) to extrapolate the hazard ratio observed in the rituximab arm for 28 months to the observation arm (HR 0.48; 95% CI 0.377 to 0.613). From 28 months onwards a HR of 1.00 was then applied to both arms in the model. The manufacturer considered that this alternative modelling approach was a more accurate method for this particular sensitivity analysis, but emphasised that it represented the worst-case clinical scenario and was not in line with available clinical evidence or expert opinion and therefore should be treated with caution.
The manufacturer noted that the cost of first-line rituximab induction therapy was included incorrectly in the original economic model and that once this had been amended, and the age at the start of treatment adjusted to 62.5 years, the revised base-case ICER (which assumed that rituximab maintenance treatment had a clinical benefit for 72 months) decreased to £15,404 per QALY gained (incremental costs = £16,918; incremental QALYs = 1.10). The manufacturer considered that the assumptions in its revised base-case analysis allowed for an undiscounted conversion rate of 89.2% from progression-free survival to overall survival. The manufacturer explained that the conversion rate is not a specific input in the model, and therefore, to analyse the effect of assuming different conversion rates, other parameters in the model had to be altered. When a conversion rate of 70%, 80% or 90% was assumed in the manufacturer's sensitivity analysis, the ICERs ranged from £17,349 to £18,615 per QALY gained when the duration of clinical benefit from rituximab maintenance was 28 months (using an exponential function); £25,038 to £27,397 per QALY gained when the duration of clinical benefit was 36 months and £21,507 to £23,355 per QALY gained when the duration of clinical benefit was 48 months (both using the Gompertz function). The manufacturer questioned the plausibility of these revised analyses because they were based on assumptions that the manufacturer considered worse than those observed in clinical practice and in the clinical trials.
The ERG provided an additional critique of the sensitivity analyses conducted by the manufacturer in response to the two appraisal consultation documents (sections 3.25 to 3.27). It noted that the manufacturer had not corrected the model for certain errors that the ERG had previously identified. After revising these errors, the ERG noted that the new base-case ICER increased slightly to £17,136 per QALY gained. The ERG considered that the structure of the manufacturer's model did not allow sufficient flexibility to enable the sensitivity analyses, which the Committee had requested from the manufacturer, to be robustly undertaken.
The ERG conducted its own exploratory sensitivity analyses of the clinical scenarios requested by the Committee; that is, assuming rituximab maintenance has a clinical benefit of 28 months, 36 months or 48 months and a conversion rate of progression-free survival to overall survival of 70%, 80% and 90%. The ERG considered that it was not possible to adjust the parameters in the manufacturer's model to assess the impact of different assumptions on the proportion of progression-free survival gain which may be expected to result in overall survival gain. Instead, the ERG adjusted the outcomes and costs generated by the model to reflect long-term outcome scenarios, and calculate the post-progression survival rate per patient. This estimate was subsequently discounted using a simple linear regression equation and used to revise the estimated overall discounted cost per patient in the model.
After adjusting the mean age of the population in the model at the start of treatment to 62.5 years, and using a hazard ratio for progression-free survival of 0.55 (in line with the manufacturer's base case), the ICERs in the ERG's analyses ranged from £24,595 to £27,558 per QALY gained, if the duration of clinical benefit was 48 months; £31,067 to £35,327 per QALY gained, if the duration of clinical benefit was 36 months; and £38,234 to £43,934 per QALY gained, if the duration of clinical benefit was assumed to be only 28 months. The ERG also presented sensitivity analyses using its revised hazard ratio of 0.719 (adjusted for early reporting bias) and noted that the ICERs ranged from £39,319 to £66,870 per QALY gained. The ERG also explored the effect on the ICER of adjusting the hazard ratios for progression-free survival for specific patient ages to reflect a reduction in clinical effect with the increase of age, however this did not change the ICER substantively.
Full details of all the evidence are in the manufacturer's submission and the ERG report; these and the responses to consultation on the first and second appraisal consultation documents (ACD) from consultees and commentators are available from www.nice.org.uk/guidance/TA226# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rituximab maintenance treatment for people with follicular non-Hodgkin's lymphoma that has responded to first-line induction therapy with rituximab in combination with chemotherapy, having considered evidence on the nature of follicular non-Hodgkin's lymphoma and the value placed on the benefits of rituximab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources and comments received during consultation on both appraisal consultation documents.
The Committee noted that the decision problem for this topic defines the population as 'adults with advanced follicular lymphoma that has responded to first-line chemotherapy', and that the population considered by the manufacturer was 'adults with advanced follicular lymphoma that has responded to first-line treatment with rituximab plus chemotherapy'. The manufacturer indicated that the population in its analysis was restricted to those who had high tumour burden (indicative of advanced disease) and who had received first-line treatment with rituximab plus chemotherapy because this reflected standard first-line treatment used in UK clinical practice. The Committee noted that the manufacturer assumed that rituximab maintenance would be given for a maximum period of 2 years or until disease progression, in line with the marketing authorisation. The Committee also noted that the manufacturer had not identified any clinical evidence to support the use of ibritumomab tiuxetan as a maintenance treatment for people who have received first-line treatment with rituximab in combination with chemotherapy, and that ibritumomab tiuxetan is infrequently used in the UK. For these reasons the manufacturer excluded ibritumomab tiuxetan from the list of the comparators originally specified in the decision problem. The Committee accepted the manufacturer's justifications for the changes to the decision problem.
The Committee was aware that rituximab in combination with chemotherapy is currently the standard of care in the UK for first‑line induction therapy of people with follicular non-Hodgkin's lymphoma. The Committee noted that 'Rituximab for the treatment of follicular lymphoma' (NICE technology appraisal guidance 110) recommends R-CVP for the first-line induction treatment of advanced follicular non-Hodgkin's lymphoma, but that other rituxmab-containing chemotherapeutic regimens (such as R-CHOP and R-FCM) are routinely used, but have not yet been appraised by NICE. The Committee noted that 'watchful waiting' (observation) is the current standard treatment for people with advanced follicular non-Hodgkin's lymphoma that has responded to first-line induction therapy. The Committee heard from the clinical specialists that current management aims to prolong remission, delay progression (and therefore delay the use of chemotherapy) and improve quality of life. The clinical specialists expressed the view that rituximab maintenance treatment after first-line induction therapy constituted optimal management for non-Hodgkin's lymphoma because it can offer people longer periods of remission and better quality of life. The Committee was also aware that rituximab is used in combination with chemotherapy for people whose disease has relapsed or did not respond to treatment, or as monotherapy for maintenance treatment after successful second‑line treatment of recurrent or refractory disease (in line with 'Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma ' ).
The Committee heard from patient experts that using rituximab maintenance treatment instead of watchful waiting may delay the need for eventual chemotherapy on relapse of the disease. The patient experts also expressed the view that chemotherapy is associated with more adverse events than rituximab, that it may cause symptoms worse than those caused by follicular non-Hodgkin's lymphoma itself, and that chemotherapy therefore has a substantial negative impact on an individual's quality of life. The patient experts stated that while on chemotherapy they experienced symptoms of weakness and fatigue and were not able to do simple routine tasks without the support of family and carers. However, they were aware that people who received rituximab maintenance treatment did not have adverse effects associated with chemotherapy and were able to continue with their normal daily routine.
# Clinical effectiveness
The Committee considered the data presented by the manufacturer on the clinical effectiveness of rituximab maintenance treatment after first-line induction with rituximab plus chemotherapy. The Committee noted that the manufacturer derived data on efficacy primarily from the PRIMA trial that compared rituximab maintenance with observation in people whose disease had responded to first-line induction therapy. The Committee noted that the most recent data from this trial were available from the post‑study observational follow‑up period, which had a median follow-up of 38 months, and indicated that progression-free survival was statistically significantly improved in people who had been randomised to rituximab maintenance treatment compared with people who had been randomised to observation. The Committee was aware that the manufacturer could not estimate time to progression for patients randomised to rituximab, because too few people had progressed during the trial, and the manufacturer therefore had to extrapolate this value using a statistical distribution. The Committee noted the concerns of the ERG that because progression-free survival had been estimated from the period after the end of the trial, patients may have received other therapies, which in turn could have affected the chance of disease progression. The Committee also noted that despite following patients beyond the end of the trial, the manufacturer could not estimate the overall survival associated with rituximab maintenance treatment because of the small number of deaths during this period. The Committee was aware that the trial stopped earlier than originally planned on advice from a Data and Safety Monitoring Committee (section 3.3), and heard from the ERG that there is evidence suggesting that studies that have stopped earlier than planned often overestimate the clinical benefit. However, the Committee was satisfied, after advice from the clinical specialists, that progression-free survival for people treated with rituximab maintenance therapy in the PRIMA trial reflected the clinicians' observations from clinical practice. The Committee concluded that the available evidence shows that first‑line maintenance treatment with rituximab significantly improves progression-free survival compared with observation (36 months' median PFS: 74.9% vs 57.6% respectively; HR 0.55; p < 0.0001), but that the size of the overall survival benefit could not be determined.
The Committee was aware that the PRIMA trial was the only trial that directly addressed the decision problem, and included the relevant population, intervention, comparison and outcomes. The Committee heard from the clinical specialists that the results from the PRIMA trial inform clinical practice in the UK. The Committee learned from the manufacturer that another trial (ECOG 1496) demonstrated that rituximab maintenance led to longer progression-free survival compared with observation, but that this trial had been conducted in people who had not previously had first-line induction treatment with rituximab-containing chemotherapy. The Committee understood that another trial (SAKK 35/98) had observed a longer event-free survival for people randomised to rituximab maintenance compared with those who had been randomised to no treatment (observation), but that the participants of this trial had either not been treated before rituximab maintenance or had only received an induction regimen with rituximab monotherapy, not rituximab combined with chemotherapy.
The Committee considered the adverse-event profile of rituximab. It noted that the incidence of grade 3 or 4 adverse events was significantly higher in the rituximab maintenance arm than in the observation arm of the PRIMA trial (section 3.6). However, the Committee heard from the clinical specialists and patient experts that rituximab maintenance treatment is generally well tolerated and that adverse events are easily managed. The patient experts also considered the adverse effects associated with rituximab maintenance therapy to be less severe than those experienced with chemotherapy on relapse of disease. The Committee concluded that, overall, most adverse events associated with rituximab treatment are not severe, and that using rituximab to extend remission may delay the need for chemotherapy and, in turn, delay the associated adverse events.
# Cost effectiveness
The Committee reviewed the original and revised economic analyses provided by the manufacturer and the exploratory sensitivity analyses performed by the ERG. It heard from the ERG that inconsistencies and errors were identified in the manufacturer's revised model, but that correcting them had only a small effect on the manufacturer's base-case results. The Committee noted that in the PRIMA trial the median age at randomisation was 57 years. However, it heard from the clinical specialists that the mean age at the start of first-line treatment in the UK is usually between 60 and 65 years. The Committee acknowledged that people in clinical trials tend to be younger and fitter than those in clinical practice, but it noted from sensitivity analyses conducted by the ERG that the ICER varied depending on the age assumed at the start of treatment. Therefore the Committee considered that the average age of people with advanced non-Hodgkin's lymphoma seen in UK clinical practice should be used in the analysis to provide a more accurate estimate. The Committee considered the revised base-case ICER from the manufacturer of £15,400 per QALY gained, which assumed that the mean age at induction was 62.5 years. The Committee heard from the ERG that the method that the manufacturer had used to adjust for age in its economic model did not reflect the prognostic importance of incident age. The Committee considered exploratory sensitivity analyses from the ERG in which the hazard ratios for progression-free survival were adjusted for specific patient ages to reflect a reduction in clinical effect with the increase of age. The Committee noted that age was not the only variable that had an impact on prognosis and, therefore considered that the ERG's adjustment of the hazard ratios for different age groups was not needed. The Committee was satisfied that the manufacturer's base-case analysis had appropriately adjusted for age and reflected the average patient population seen in UK clinical practice.
The Committee noted that the manufacturer had assumed in the base case that the clinical benefit of rituximab maintenance would last for 6 years (2 years of treatment and 4 years of sustained benefit once treatment was stopped). The Committee heard from the ERG that the manufacturer's extrapolation of the clinical benefit of rituximab beyond the period observed in the PRIMA trial assumed a proportional increase in survival with time, which may not reflect the true effect. The Committee also noted the ERG's concerns that patient-level data from the PRIMA trial indicated that the duration of effect from rituximab maintenance treatment appears to be 28 months, after which time patients treated with rituximab maintenance therapy experience a rate of progression no better or worse than that of patients not treated with rituximab maintenance therapy. The Committee heard from the clinical specialists that data from the PRIMA trial demonstrated that rituximab maintenance treatment is clinically effective to 36 months at least and without evidence that the effect diminishes over time; therefore, assuming a duration of benefit of only 28 months, as suggested by the ERG, may underestimate the actual effect of treatment. The Committee also heard from the clinical specialists that the period over which rituximab is likely to have an additional benefit over observation is probably 3 to 4 years (that is, 1 to 2 years beyond treatment). However, it further heard from the clinical specialists that it was not possible to predict a definite time period, and a duration of effect of up to 6 years, as seen in the EORTC 20981 study for second-line rituximab maintenance treatment, could be plausible. The Committee considered sensitivity analyses conducted by the manufacturer that assumed a duration of treatment effect of 28 months, 36 months and 48 months and noted that the ICERs ranged from £17,300 to £27,400 per QALY gained. The Committee noted that these estimates were lower than those calculated by the ERG for the same scenarios (range: £24,600 to £43,900 per QALY gained) but acknowledged that the manufacturer and the ERG had used different modelling approaches to calculate their results (section 3.29). The Committee considered that the duration of clinical benefit of rituximab maintenance was a key driver of cost effectiveness, but was satisfied that the manufacturer's sensitivity analyses presented the most plausible range of estimates for the treatment effect in line with clinical opinion and the available data.
The Committee noted that the manufacturer's revised base-case analysis assumed that most (89.2%) of the progression-free survival benefit translated to an overall survival gain in its model. The Committee heard from the clinical specialists that it was not possible to verify the specific conversion rate from progression-free survival to overall survival from the literature or clinical experience, but that they would expect a conversion rate of at least 70%. The Committee also heard from the clinical specialists that patients with non-Hodgkin's follicular lymphoma live longer than in the past, and it is reasonable to assume that this is at least partly due to the introduction of treatment with rituximab. The Committee considered that the manufacturer should have sought data from patient registries or observational data to validate the conversion rate assumed for the base-case estimate, and to confirm the degree to which rituximab maintenance treatment might prolong life. However, it was satisfied that the manufacturer's sensivity analyses, which assumed conversion rates of 70%, 80% and 90%, provided a plausible range of conversion rate estimates. The Committee heard from the manufacturer that the conversion rate was not an actual input in the model and could only be adjusted by artificially modifying other parameters. As such, the manufacturer was concerned that its revised analyses, which were requested by the Committee, were driven by implausible assumptions. The Committee noted the manufacturer's concerns but was satisfied that the sensitivity analyses addressed the uncertainty that the Committee initially had about the translation from progression-free survival to overall survival gain in the original analysis.
The Committee considered the concerns of the ERG that the early closure of the PRIMA trial may have overestimated the benefit from rituximab, and therefore the hazard ratio for progression-free survival (0.55) derived from the PRIMA trial should be increased to adjust for this bias. The Committee noted the revised sensitivity analyses from the ERG, which took account of the adjusted hazard ratio, but considered that adjusting for early reporting bias is not routinely included in technology appraisals and is not a current requirement in the NICE methods guide. The Committee therefore concluded that the manufacturer had used an appropriate hazard ratio and that the ERG's revised analyses using the higher hazard ratio would not be considered.
The Committee discussed the utility values used in the manufacturer's model. The Committee appreciated that no differences in health-related quality of life were observed between the arms of the PRIMA trial. The Committee considered sensitivity analyses from the ERG that showed that changes to the gains in utility in different health states in the model had a marginal effect on the base-case ICER, and the Committee was therefore persuaded that the ICERs presented by the manufacturer were largely driven by gains in overall survival.
The Committee noted that the ICERs for rituximab maintenance compared with observation in the manufacturer's submission and sensitivity analyses were less than £30,000 per QALY gained for most scenarios. The Committee also noted that the ERG's exploratory sensitivity analyses, which assumed a duration of clinical benefit from rituximab maintenance treatment of 36 to 48 months (in line with clinical opinion), resulted in ICERs ranging from £24,600 to £35,000 per QALY gained, depending on the conversion rate of progression-free survival to overall survival gain assumed. The Committee was aware that the model did not include the utility associated with delaying chemotherapy, and that if it were included, it would decrease the ICER (that is, improve the cost effectiveness) to an estimate which would be considered as a cost-effective use of NHS resources. Therefore, the Committee considered that rituximab maintenance therapy should be recommended as an option for the treatment of people with follicular non-Hodgkin's lymphoma that has responded to first-line induction treatment with rituximab in combination with chemotherapy.
# Summary of Appraisal Committee's key conclusions
TA226 (STA)
Appraisal title: Rituximab for the first-line maintenance treatment of follicular non-Hodgkin's lymphoma
Section
Key conclusion
Rituximab maintenance therapy is recommended as an option for the treatment of people with follicular non-Hodgkin's lymphoma that has responded to first-line induction therapy with rituximab in combination with chemotherapy.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee heard from the clinical specialists that current management aims to prolong remission, delay progression (and therefore delay the use of chemotherapy), and improve quality of life. 'Watchful waiting' (observation) is the current standard treatment for people with advanced follicular non-Hodgkin's lymphoma that has responded to first-line induction therapy.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The clinical specialists expressed the view that rituximab maintenance treatment constituted optimal management because it could offer people longer periods of remission and better quality of life if used after first-line induction therapy.
Patient experts expressed the view that using rituximab maintenance treatment instead of watchful waiting may delay the need for eventual chemotherapy on relapse of the disease.
What is the position of the treatment in the pathway of care for the condition?
Rituximab has a UK marketing authorisation for the 'treatment of follicular lymphoma patients responding to induction therapy'.
Adverse effects
The incidence of grade 3 or 4 adverse events was significantly higher in the rituximab maintenance arm than in the observation arm of the PRIMA trial (24% vs 17%, p = 0.0026).
The Committee heard from the clinical specialists and patient experts that rituximab maintenance treatment is generally well tolerated and that adverse events are easily managed. The patient experts also highlighted that they consider the side effects associated with rituximab maintenance therapy to be less severe than those experienced with chemotherapy, which may be given if the disease relapses.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The manufacturer derived efficacy data primarily from the PRIMA trial that compared rituximab maintenance with observation in people whose disease had responded to first-line induction therapy. The Committee noted that the most recent data from this trial were available from the post-study observational follow-up period, which had a median follow-up of 38 months. The Committee heard from the clinical specialists that the results from the PRIMA trial inform clinical practice in the UK.
The Committee was aware that the trial stopped earlier than originally planned on advice from a Data and Safety Monitoring Committee, but heard from the ERG that evidence suggests that studies which stop earlier than planned often overestimate the clinical benefit. However, the Committee was satisfied, after advice from the clinical specialists, that progression-free survival for people treated with rituximab maintenance therapy in the PRIMA trial reflected the clinicians' observations from clinical practice.
Relevance to general clinical practice in the NHS
The Committee noted that in the PRIMA trial the median age at randomisation was 57 years. However, it heard from the clinical specialists that the mean age at the start of first-line treatment in the UK is usually between 60 and 65 years. Although the Committee acknowledged that people in clinical trials tend to be younger and fitter than those in clinical practice, it noted from sensitivity analyses conducted by the ERG that the manufacturer's base-case ICER varied depending on the age assumed at the start of treatment and therefore may have added uncertainty.
The Committee considered the revised base case from the manufacturer, which assumed that the mean age at induction was 62.5 years. It was satisfied that this analysis had appropriately adjusted for age and reflected the average patient population seen in UK clinical practice.
Uncertainties generated by the evidence
The Committee noted that because of the small number of deaths during the trial period, overall survival associated with rituximab maintenance treatment could not be estimated.
The Committee noted that the manufacturer assumed in the base case that the clinical benefit of rituximab maintenance would last for 6 years (2 years of treatment and 4 years of sustained benefit once treatment was stopped). The Committee noted the ERG's concerns that patient-level data for rituximab maintenance treatment from the PRIMA trial indicated that the duration of treatment effect appears to be 28 months. The Committee heard from the clinical specialists that data from the PRIMA trial indicated that rituximab maintenance treatment is clinically effective to at least 36 months and there is no evidence that the effect diminishes over time; therefore assuming a duration of benefit of only 28 months, as suggested by the ERG, may underestimate the actual effect of treatment. The Committee heard from the clinical specialists that rituximab is likely to provide a benefit for 3 to 4 years (that is, 1 to 2 years beyond treatment); however, it was not possible to predict a definite time period.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
Not applicable.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that the available evidence shows that first-line maintenance treatment with rituximab improves progression-free survival compared with observation (36 months' median PFS: 74.9% vs 57.6% respectively; HR 0.55; p < 0.0001), but that the size of the overall survival benefit could not be determined.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee heard from the ERG that inconsistencies and errors were identified in the manufacturer's model, but that correcting them only had a small effect on the manufacturer's base-case results.
The Committee heard from the manufacturer that its revised analyses, which were requested by the Committee, were driven by implausible assumptions. The Committee noted the manufacturer's concerns but was satisfied that the sensitivity analyses addressed the uncertainty that the Committee initially had when it considered the original analysis.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted that the manufacturer had assumed that the clinical benefit of rituximab maintenance would last for 6 years (2 years of treatment and 4 years of sustained benefit once treatment was stopped). The Committee heard from the ERG that the manufacturer's extrapolation of the clinical benefit of rituximab beyond the observed period in the PRIMA trial assumed a proportional increase in survival with time, which may not reflect the true effect.
The Committee considered sensitivity analyses conducted by the manufacturer that assumed a duration of treatment effect of 28 months, 36 months and 48 months and noted that the ICERs ranged from £17,300 to £27,400 per QALY gained. The Committee noted that these estimates were lower than those calculated by the ERG for the same scenarios but acknowledged that the manufacturer and the ERG had used different modelling approaches (section 3.29). The Committee was satisfied that the manufacturer's sensitivity analyses presented the most plausible range of estimates for the treatment effect in line with clinical opinion and the available data.
The Committee noted that the manufacturer's revised base-case analysis assumed that most (89.2%) of the progression-free survival benefit translated to an overall survival gain in its model. The Committee heard from the clinical specialists that it was not possible to verify the specific conversion rate from progression-free survival to overall survival from the literature or clinical experience, but that they would expect a conversion rate of at least 70%. The Committee was satisfied that the manufacturer's sensitivity analyses, which assumed conversion rates of 70%, 80% and 90%, provided a plausible range of conversion rate estimates.
The Committee considered the concerns of the ERG that the early closure of the PRIMA trial may have overestimated the benefit from rituximab, and therefore the hazard ratio for progression-free survival (0.55) derived from the PRIMA trial should be increased to adjust for this bias. The Committee noted the revised sensitivity analyses from the ERG, which took account of the adjusted hazard ratio, but considered that adjusting for early reporting bias is not routinely included in technology appraisals and is not a current requirement in the NICE methods guide.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The manufacturer's model included utility values of 0.88 and 0.79 for the PF1 and PF2 health states respectively. The Committee considered sensitivity analyses from the ERG that showed that changes to the gains in utility in different health states in the manufacturer's model had a marginal effect on the base-case ICER, and the Committee was therefore persuaded that the ICERs presented by the manufacturer were largely driven by gains in overall survival.
The Committee was aware that the model did not include the utility associated with delaying chemotherapy, and that if it were included, it would likely decrease the ICER (that is, improve the cost effectiveness). Although the Committee requested analysis of potential utility gains associated with delaying the need for chemotherapy after relapse, the manufacturer was unable to incorporate these because of limitations in the structure of the model.
Are there specific groups of people for whom the technology is particularly cost effective?
Not applicable.
What are the key drivers of cost effectiveness?
The key drivers of cost effectiveness were assumptions about the duration of clinical benefit of rituximab maintenance, the conversion rate of progression-free survival to overall survival and the underestimation in the economic model of the utility associated with delaying chemotherapy treatment.
The Committee was satisfied that the manufacturer's sensitivity analyses presented the most plausible range of estimates for the duration of treatment effect and the translation from progression-free survival to overall survival gain.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee noted that the ICERs for rituximab maintenance compared with observation in the manufacturer's submission and sensitivity analyses were less than £30,000 per QALY gained for most scenarios. The Committee also noted that the ERG's exploratory sensitivity analyses, which assumed a duration of clinical benefit from rituximab maintenance treatment of 36 to 48 months (in line with clinical opinion), had ICERs ranging from £24,600 to £35,000 per QALY gained, depending on the conversion rate of progression-free survival to overall survival gain assumed. The Committee was aware that the model did not include the utility associated with delaying chemotherapy, and that if it were included, it would decrease the ICER (that is, improve the cost effectiveness) to an estimate which would be considered as a cost-effective use of NHS resources. Therefore the Committee considered that rituximab maintenance therapy should be recommended as an option for treatment for people with non-Hodgkin's lymphoma that has responded to first-line induction therapy with rituximab in combination with chemotherapy.
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
No equalities issues were raised during the scoping exercise or during the course of the appraisal.
–# Related NICE guidance
Published
Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma (review of technology appraisal guidance 37). NICE technology appraisal guidance 137 (2008). Available from www.nice.org.uk/guidance/TA137
Rituximab for the treatment of follicular lymphoma. NICE technology appraisal guidance 110 (2006). Available from www.nice.org.uk/guidance/TA110
Improving outcomes in haematological cancers – the manual. NICE cancer service guidance haemato-oncology (2003). Available from www.nice.org.uk/guidance/CSGHO
Under development
NICE is developing the following guidance (details available from www.nice.org.uk):
Rituximab for the treatment of follicular lymphoma (review of technology appraisal guidance 110). NICE technology appraisal. Publication expected December 2011.# Review of guidance
The guidance on this technology will be considered for review in May 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew Dillon
Chief Executive
June 2011# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your
responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': "Rituximab maintenance therapy is recommended as an option for the treatment of people with follicular non‑Hodgkin's lymphoma that has responded to first-line induction therapy with rituximab in combination with chemotherapy.", 'The technology ': "Rituximab (MabThera, Roche Products) is a chimeric (mouse/human) genetically engineered monoclonal antibody. It targets the CD20 surface antigen of mature B-cell lymphocytes. Rituximab has a marketing authorisation for the 'treatment of follicular lymphoma patients responding to induction therapy'. Other licensed indications for rituximab in non-Hodgkin's lymphoma include 'the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy'; 'the treatment of patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy'; and 'the treatment of patients with CD20 positive diffuse large B cell non-Hodgkin's lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy'.\n\nAllergic and skin reactions are the most common adverse effects of rituximab infusion. Reactions during infusion can include bronchospasm and hypotension, which can be severe or life-threatening. Severe reactions occur more commonly in people with a high tumour burden, and the incidence and severity of infusion reactions decrease with successive infusions. Rituximab treatment can also be associated with blood and bone-marrow toxicity, characterised by neutropenia and leucopenia, which can lead to infections. In addition, treatment with rituximab may cause flu-like symptoms, and has been associated with progressive multifocal leukoencephalopathy. For full details of side effects and contraindications, see the summary of product characteristics.\n\nFor people with previously untreated follicular lymphoma that has responded to first-line induction treatment, the recommended dose of rituximab as maintenance treatment is 375\xa0mg/m² body surface area, administered by intravenous infusion once every 2\xa0months. Treatment should start 2\xa0months after the last dose of first-line induction therapy and continue until the disease progresses, or for a maximum period of 2\xa0years. The cost of one 100-mg vial is £174.63, and one 500-mg vial is £873.15 (excluding VAT; 'British national formulary' [BNF] edition 61). The manufacturer estimates that for a person with an average body surface area of 1.8\xa0m², the average cost of rituximab maintenance treatment for 2\xa0years is £14,669 (excluding VAT). Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rituximab and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer presented information addressing the decision problem; that is, whether rituximab maintenance treatment is a clinically effective and cost-effective use of NHS resources, compared with standard management without rituximab for people with follicular lymphoma that has responded to first-line induction chemotherapy combined with rituximab. The outcomes defining effectiveness included progression-free survival, overall survival, response rates, adverse effects of treatment and health‑related quality of life.\n\nThe manufacturer undertook a systematic literature review and identified only one trial, the Primary Rituximab and Maintenance (PRIMA) trial, that met its inclusion criteria. The manufacturer presented evidence analysed after a median follow-up of 25\xa0months (at the close of the PRIMA trial), but also provided data from two post-study observational periods with median follow-up periods of 36 and 38\xa0months. In the absence of long-term data from the PRIMA trial, the manufacturer used data from the European Organisation for Research and Treatment of Cancer (EORTC) 20981 study to model the expected longer term outcomes that may have been experienced by participants in the PRIMA trial, had the trial gone on longer. The patient population in the EORTC 20981 study (see section 3.4), however, was different from that of the PRIMA trial.\n\nThe PRIMA trial was a phase III, open-label, multicentre, randomised trial with two treatment phases. The trial included 1193\xa0people with previously untreated advanced follicular lymphoma with an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 and a median age of 57\xa0years. In the first phase (induction phase or first-line treatment), participants had one of three different regimens, all of which included rituximab: R-CVP (rituximab with cyclophosphamide, vincristine and prednisolone [n\xa0=\xa0268]), R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone [n\xa0=\xa0881]) or R-FCM (rituximab with fludarabine, cyclophosphamide and mitoxantrone [n\xa0=\xa044]). People whose disease had either a partial or complete response to first-line treatment (n\xa0=\xa01019) entered the second phase of the trial, and were randomised to receive either rituximab maintenance treatment (n\xa0=\xa0506) or no treatment (that is, observation; n\xa0=\xa0513). People in the maintenance arm received 375\xa0mg/m² rituximab intravenously: one dose every 8\xa0weeks for 2\xa0years, for a total of 12\xa0doses or until disease progression, whichever occurred first. The trial was designed initially to estimate event-free survival as the primary outcome. However, during the course of the trial, the manufacturer amended the protocol in line with recommendations from regulatory authorities and changed the primary outcome to progression-free survival. Length of follow-up was increased from 5\xa0to 7\xa0years, and the study population was increased from 900 to 1200 participants. Secondary clinical outcomes included overall survival, event-free survival, time to next anti-lymphoma treatment, overall response rate at the end of the maintenance observation phase, the proportion of people with histological transformation at first progression, quality of life and safety. Quality-of-life data were collected in the trial using the Functional Assessment of Cancer Therapy – General (FACT-G) questionnaire and the EORTC Quality of Life Questionnaire – Core 30 (EORTC QLQ-C30). After a median follow-up of 25\xa0months, a Data and Safety Monitoring Committee judged that the trial had met its primary objective at the pre-specified interim analysis and recommended closure of the trial. However, investigators continued to follow patients during an observational post-study period to collect longer term data.\n\nThe EORTC 20981 study was a phase III, open-label randomised trial that included people with relapsed or resistant follicular non-Hodgkin's lymphoma (n\xa0=\xa0465) who had not previously been treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or R-CHOP. Instead, patients had been treated with at least 2\xa0months of single-agent therapy (such as chlorambucil) and/or at least two consecutive cycles of combination chemotherapy (such as CVP [cyclophosphamide, vincristine and prednisolone]) or purine analogues. Therefore, these patients differed from those in the decision problem in that their disease had progressed after first-line therapy, and they had not been previously treated with R‑CHOP, R-CVP or R-FCM as in the PRIMA trial. Participants were randomised to treatment with R‑CHOP or CHOP alone after enrolment. People whose disease responded to second-line therapy (n\xa0=\xa0334) were then randomised to either second-line maintenance treatment with 375\xa0mg/m² rituximab (one dose every 3\xa0months for 2\xa0years or until relapse) or observation until relapse.\n\nThe results of the PRIMA trial showed that after 25\xa0months' median follow-up, the risk of disease progression was halved in the rituximab maintenance arm compared with the observation arm (hazard ratio [HR] 0.50; 95% confidence interval [CI] 0.39 to 0.64; p\xa0<\xa00.0001) as assessed by the study investigators. This result was based on 18.4% (93 of 505) of people in the rituximab maintenance arm and 33.9% (174 of 513) of people in the observation arm having experienced an event (disease progression, relapse or death). The estimate of the hazard ratio associated with treatment was slightly higher when assessed by an independent review committee. After a median follow-up of 36 months, progression-free survival was statistically significantly improved in people randomised to the rituximab maintenance arm (PFS 74.9%; 95% CI\xa070.9 to 78.9) compared with those randomised to the observation arm (PFS 57.6%; 95% CI 53.2 to 62.0). The risk of disease progression was significantly reduced for people in the rituximab maintenance arm (HR 0.55; 95% CI 0.44 to 0.68; p\xa0<\xa00.0001). However, too few patients randomised to the rituximab maintenance arm had progressed during the study period to estimate the median time to progression. For patients randomised to observation, the median time to progression was estimated to be 48.3\xa0months (95% CI 38.0 to not reached). After 36 and 38\xa0months' median follow-up, a statistically significant difference in overall survival could not be established between the two arms because of the low number of deaths that had occurred.\n\nDuring first-line induction therapy, most people in the PRIMA trial experienced an adverse event and 25% experienced a serious adverse event, consistent with the known safety profiles of these induction regimens. After the first-line maintenance phase of the trial, significantly more grade\xa03 or 4 adverse events occurred in people in the rituximab maintenance arm (24%) compared with people in the observation arm (17%; risk ratio 1.46; 95% CI 1.14 to 1.87; p\xa0=\xa00.0026).\n\nIn the EORTC 20981 study, second-line maintenance treatment with rituximab significantly improved progression-free survival compared with observation (median 3.7\xa0years versus 1.3\xa0years). Five-year overall survival was not significantly different between the arms (74% in the rituximab maintenance arm and 64% in the observation arm). Second-line maintenance treatment with rituximab was associated with statistically significant increases in grade\xa03 and 4 infections compared with observation.\n\nThe manufacturer also provided a summary of other studies, as supporting evidence, of the efficacy and safety of rituximab maintenance in people with previously untreated or relapsed or refractory follicular lymphoma. In the ECOG\xa01496 study, rituximab maintenance led to longer progression-free survival compared with observation (HR 0.4; p\xa0<\xa00.0001) in people who had previously received CVP as induction therapy. Interim data from another study (SAKK 35/98), which is still ongoing to compare a short course of rituximab maintenance (375 mg/m² every 2\xa0months for a total of four doses) and prolonged rituximab maintenance (375\xa0mg/m² every 2 months for a maximum of 5 years) with observation, demonstrated a longer event-free survival after prolonged rituximab maintenance compared with observation in people with either previously treated or previously untreated follicular lymphoma after induction with rituximab monotherapy. Preliminary safety results from this study also indicate that prolongation of maintenance therapy beyond 2 years does not lead to an obvious increase in toxicity.\n\nThe manufacturer produced a Markov economic model to estimate all costs and benefits over a lifetime resulting from the treatment of follicular lymphoma with rituximab compared with observation after first-line induction with different regimens of rituximab and chemotherapy (R-CHOP, R-CVP or R-FCM). Although listed as a comparator in the decision problem for this appraisal, ibritumomab tiuxetan was considered by the manufacturer to not be an appropriate comparator for inclusion in the economic model because of limited evidence available to support its benefits, and because data for local use suggested that it is seldom prescribed in the UK. The model had four distinct health states: progression-free survival while in the first-line maintenance phase (PF1), progression-free survival after receiving second-line induction treatment with rituximab in combination with chemotherapy (PF2), progressive disease (PD) and death. The manufacturer assumed that all people enter the economic model in the PF1 health state after successfully completing induction treatment (that is, the start of the model reflected the second phase of the PRIMA trial). The model had a cycle of 1\xa0month and a time horizon of 25\xa0years. A half cycle correction was applied to the model.\n\nData from the PRIMA trial (after 38\xa0months' median follow-up) and the EORTC 20981 study were used by the manufacturer to estimate the transition probabilities between the health states in the economic model. To estimate median progression-free survival, which could not be estimated from the PRIMA trial directly, the manufacturer used the Gompertz function to extrapolate progression-free survival data beyond the end of the PRIMA trial. The manufacturer considered that this function provided a better fit than alternative functions. Based on the results from the PRIMA trial, the EORTC 20981 study and expert opinion, the manufacturer assumed that people in the PF1 health state retain a clinical benefit from rituximab maintenance treatment for 6\xa0years; that is, 4\xa0years beyond the end of treatment in the PRIMA trial. After this time, the risk of disease progression for people in the PF1 health state was assumed to be equal in both the rituximab maintenance and observation arms of the model (that is, both groups progress at the same rate after 6\xa0years). Data from the EORTC 20981 study were used to derive the long-term outcomes, including death, for people according to the treatment they received after progressing from the PF1 health state.\n\nIn the PRIMA trial, participants did not routinely complete EQ-5D questionnaires. Instead, health-related quality-of-life data were collected in the PRIMA trial using the FACT-G and EORTC QLQ-C30 questionnaires developed to assess the quality of life of people with cancer. Overall, no differences in health-related quality-of-life data were observed between the rituximab maintenance and observation arms.\n\nThe manufacturer conducted a systematic literature review to identify studies addressing quality of life, but it considered that only one study (Pettengel et al. 2008) met the inclusion criteria. In this study, 215 adults with follicular lymphoma and an ECOG score of 0−2 completed EQ-5D questionnaires during outpatient appointments across eight sites in the UK. Patients were placed in one of five categories according to the stage of their disease: 'active disease – newly diagnosed', 'active disease – relapsed', 'partial response', 'complete response to therapy (or remission)' and 'disease free (no detectable disease)'. Mean utility values from this study were 0.88 (from 'disease free' category), 0.79 (from 'complete response to therapy' category) and 0.62 (from 'active disease – relapsed' category). These utility values were assigned to the PF1, PF2 and PD health states respectively in the manufacturer's economic model. The economic model did not include values for the disutility associated with grade\xa03 and 4 adverse events, or with receiving chemotherapy.\n\nThe manufacturer included costs associated with drug acquisition and administration, supportive care, management of adverse events and monitoring for each health state in the economic model. The primary sources of these costs were the BNF (edition 56 was used by the manufacturer, and edition 59 by the ERG; however, the costs were the same in both editions), the NHS Reference Cost Schedule 2008/09 and the Personal Social Services Research Unit 2009 (unit costs of health and social care). The manufacturer assumed that grade\xa03 and 4 adverse events incur equivalent costs, as estimated from the PRIMA and EORTC\xa020981 studies. Costs and benefits were discounted at 3.5% per year.\n\nIn the base-case analysis from the manufacturer's original submission, which assumed that the clinical benefit of rituximab is sustained over 6\xa0years, the incremental cost‑effectiveness ratio (ICER) of rituximab maintenance treatment compared with observation was £15,978 per quality-adjusted life year (QALY) gained (incremental costs\xa0=\xa0£18,681; incremental QALYs\xa0=\xa01.169). Sensitivity analyses explored the impact of varying costs of adverse events (±50%), monthly supportive care (±50%), and administering rituximab (for example, nursing time; upper\xa0=\xa0£267, lower\xa0=\xa0£176). In sensitivity analyses, the manufacturer also tested the impact of varying the time horizon (20\xa0years and 30\xa0years), using other types of parametric functions to extrapolate progression-free survival data from the PRIMA trial, and assuming that people who progress from the PF1 health state die (probability of death was 100%, extreme scenario) rather than experience disease progression. From the analyses, the manufacturer concluded that the model was not sensitive to assumptions around the type of parametric extrapolation fitted to the PRIMA data, around costs of supportive care and administration, or around the time horizon. The model was sensitive to assumptions regarding the duration of treatment effect; when the manufacturer assumed that the effect of treatment stopped after 47\xa0months (instead of after 72\xa0months as in the base case), the ICER increased to £21,151 per QALY gained. When the manufacturer assumed that all people died after progressing from the PF1 health state (extreme scenario), the ICER decreased to £13,901 per QALY gained.\n\nThe manufacturer conducted probabilistic sensitivity analyses of all major parameters in the model except age, weight and height. The mean ICER from this analysis was £15,770 per QALY gained, and the manufacturer estimated that the probability of rituximab maintenance treatment being cost effective at £20,000 per QALY gained or less was 84.2%, and at £30,000 per QALY gained or less was 99.7%, compared with observation. The manufacturer concluded that these results demonstrated that the ICER was robust even under a wide range of variation in the model parameters.\n\nThe ERG considered that the PRIMA trial was well designed and, although it was an open-label trial, the results of progression-free survival could be considered robust because the trial used a blinded independent review committee. In the ERG's view, the rituximab chemotherapy regimens used in the induction phase of the PRIMA trial (that is, R-CHOP, R-CVP and R-FCM) were appropriate and in line with the rituximab chemotherapy regimens used in UK clinical practice. Overall, the ERG considered the results of the PRIMA trial to be generalisable to the UK setting, and that the manufacturer's decision not to include ibritumomab tiuxetan as a comparator in the economic analysis was justified.\n\nThe ERG was concerned that follow-up data were not available beyond 4\xa0years and that the manufacturer could not estimate the median time to progression or to death by treatment group. The ERG cautioned that the data were immature (few events), which might have led the results to overestimate the clinical benefits of rituximab maintenance treatment. The ERG noted a meta-regression analysis (Bassler et al. 2010), which found large differences in the size of treatment effects between trials that were stopped early (regardless of the reason) and similar trials that ran for their originally specified time period. Using data from this study, the ERG adjusted the progression-free survival hazard ratio from the PRIMA trial to account for early reporting bias and noted that the hazard ratio increased by 30.7% from 0.55 (manufacturer's base case) to 0.719 (95% CI 0.575 to 0.889). The ERG suggested that sensitivity analyses that include the adjusted progression-free survival hazard ratio should be considered by the Committee.\n\nThe ERG noted that treatments administered after participants' disease had progressed may have affected the rate of overall survival in the PRIMA trial. The ERG stated that the post-progression treatments in the manufacturer's submission were in line with those used in UK clinical practice. However, from the data provided, the ERG was unsure whether the time at which these treatments were offered in the trial reflected the time that they would be offered in routine practice.\n\nAlthough the ERG identified a number of problems with the structure and implementation of the manufacturer's model, the ERG did not expect these problems to have a major impact on the cost-effectiveness results. The ERG noted that the manufacturer did not model the disutilities associated with grade\xa03 and 4 adverse events. The ERG stated that this omission would favour the rituximab maintenance arm because people treated with rituxmab experience more adverse events than those not treated with rituximab (observation). The ERG was concerned that the manufacturer may have underestimated the costs of adverse events experienced in the PF2 health state because most of the people in the PRIMA trial had not progressed beyond the first-line maintenance or observation phase at the time of data analysis (up to 38\xa0months).\n\nThe ERG noted the low proportion of patients censored (less than 3%) during the first 800\xa0days of the PRIMA trial, and that this proportion increased greatly (70% for rituximab maintenance and 50% for observation) by 1600\xa0days. Consequently, the ERG believed that the Kaplan–Meier estimate of progression-free survival becomes uncertain after 800\xa0days. The ERG had concerns about the use of long-term modelling to inform the duration of treatment benefit estimated in the economic model. The ERG noted that the manufacturer used the Gompertz parametric function in their original analyses, which generated the highest overall estimate compared with other algorithms (such as an exponential function), to model progression-free survival.\n\nThe ERG was concerned about the manufacturer's use of data from the EORTC 20981 study to inform the economic model. The ERG noted that the participants in this study received different induction treatments to those in the PRIMA study (the EORTC 20981 study included people if their disease had relapsed after two previous non-anthracycline-containing chemotherapy regimens) and that only half of the patients in the EORTC 20981 study received induction treatment with a rituximab-containing regimen. Therefore, the ERG questioned whether the manufacturer could reliably use the outcomes from the EORTC 20981 study to predict future outcomes for participants in the PRIMA trial.\n\nThe ERG noted that, in the base case, the manufacturer assumed rituximab maintenance treatment had a clinical benefit for 6\xa0years (that is, the hazard ratio from the PRIMA trial was applied for 6\xa0years). In addition, the ERG noted that a large proportion of the gain in progression-free survival in the model arises beyond 4\xa0years. Therefore, the ERG cautioned that if the gain in progression-free survival progressively declines, the ICER could substantially increase depending on the time period over which one assumes a difference between the treatment arms (that is, the time until the progression-free survival curves for each arm converge). The ERG also noted that the ICERs in the manufacturer's analyses were sensitive to the age at which a patient is assumed to start treatment and suggested that the manufacturer should have adjusted this variable in its sensitivity analyses.\n\nThe ERG noted that the manufacturer's model projects future benefits associated with the increased time that a person's disease remains progression free. The manufacturer's base-case modelling estimated that the mean time before a person's disease progresses is 8.64\xa0years for the observation arm and 10.65\xa0years for people who receive rituximab maintenance therapy; a gain of 2.01\xa0years. The ERG noted that the manufacturer's analysis assumed that almost all of this gain in progression-free survival occurs in the PF1 health state. This implied that the majority (89.2%) of the gains in progression-free survival achieved directly by extending the first-line induction response translated into overall survival gains. The ERG cautioned that this should represent the 'best possible' scenario and would require strong supportive evidence from clinical trials before it could be accepted. The ERG explored how different conversion rates of progression-free survival gain to overall survival gain affect the estimated ICER, and predicted that at least 50% of progression-free survival gain would need to be converted into overall survival gain to achieve an ICER below £30,000 per QALY gained. The ERG further noted that if a function other than the Gompertz parametric function were used to extrapolate and convert progression-free survival into overall survival, then the conversion rate would need to be even higher for the ICER to remain below £30,000 per QALY gained.\n\nThe ERG noted that the manufacturer's model included utility values of 0.88 and 0.79 for the PF1 and PF2 health states respectively. The ERG considered that the same utility value should be used in both health states, because people in both states are in remission or have a full response. The ERG conducted a sensitivity analysis assuming that both health states have a utility value of 0.79, and noted that the QALY gain associated with maintenance treatment with rituximab dropped by more than 10% and the ICER increased by 11%.\n\nIn response to comments on the first and second appraisal consultation documents, the manufacturer provided revised cost-effectiveness analyses that modelled the effect on the ICER of different assumptions including progression-free survival translating into overall survival in a range from 50% to 100%; the clinical benefit from rituximab lasting for 28\xa0months, 36\xa0months or 48\xa0months; and the mean age of a patient at induction being 62.5\xa0years. Although the Committee requested analysis of potential utility gains associated with delaying the need for chemotherapy after relapse, the manufacturer was unable to incorporate these because of limitations in the structure of the model.\n\nIn response to the ERG's concern during the second Appraisal Committee meeting that the duration of clinical benefit (that is, the period during which rituximab is better than, rather than equal to, observation) may last only 28\xa0months (based on the cumulative hazard plots from the PRIMA trial), the manufacturer provided an alternative method to model the rituximab treatment effect stopping at 28\xa0months. This entailed using an exponential function (instead of the Gompertz function from the original submission) to extrapolate the hazard ratio observed in the rituximab arm for 28\xa0months to the observation arm (HR 0.48; 95% CI 0.377 to 0.613). From 28 months onwards a HR of 1.00 was then applied to both arms in the model. The manufacturer considered that this alternative modelling approach was a more accurate method for this particular sensitivity analysis, but emphasised that it represented the worst-case clinical scenario and was not in line with available clinical evidence or expert opinion and therefore should be treated with caution.\n\nThe manufacturer noted that the cost of first-line rituximab induction therapy was included incorrectly in the original economic model and that once this had been amended, and the age at the start of treatment adjusted to 62.5\xa0years, the revised base-case ICER (which assumed that rituximab maintenance treatment had a clinical benefit for 72\xa0months) decreased to £15,404 per QALY gained (incremental costs\xa0=\xa0£16,918; incremental QALYs\xa0=\xa01.10). The manufacturer considered that the assumptions in its revised base-case analysis allowed for an undiscounted conversion rate of 89.2% from progression-free survival to overall survival. The manufacturer explained that the conversion rate is not a specific input in the model, and therefore, to analyse the effect of assuming different conversion rates, other parameters in the model had to be altered. When a conversion rate of 70%, 80% or 90% was assumed in the manufacturer's sensitivity analysis, the ICERs ranged from £17,349 to £18,615 per QALY gained when the duration of clinical benefit from rituximab maintenance was 28\xa0months (using an exponential function); £25,038 to £27,397 per QALY gained when the duration of clinical benefit was 36\xa0months and £21,507 to £23,355 per QALY gained when the duration of clinical benefit was 48\xa0months (both using the Gompertz function). The manufacturer questioned the plausibility of these revised analyses because they were based on assumptions that the manufacturer considered worse than those observed in clinical practice and in the clinical trials.\n\nThe ERG provided an additional critique of the sensitivity analyses conducted by the manufacturer in response to the two appraisal consultation documents (sections 3.25 to 3.27). It noted that the manufacturer had not corrected the model for certain errors that the ERG had previously identified. After revising these errors, the ERG noted that the new base-case ICER increased slightly to £17,136 per QALY gained. The ERG considered that the structure of the manufacturer's model did not allow sufficient flexibility to enable the sensitivity analyses, which the Committee had requested from the manufacturer, to be robustly undertaken.\n\nThe ERG conducted its own exploratory sensitivity analyses of the clinical scenarios requested by the Committee; that is, assuming rituximab maintenance has a clinical benefit of 28\xa0months, 36\xa0months or 48\xa0months and a conversion rate of progression-free survival to overall survival of 70%, 80% and 90%. The ERG considered that it was not possible to adjust the parameters in the manufacturer's model to assess the impact of different assumptions on the proportion of progression-free survival gain which may be expected to result in overall survival gain. Instead, the ERG adjusted the outcomes and costs generated by the model to reflect long-term outcome scenarios, and calculate the post-progression survival rate per patient. This estimate was subsequently discounted using a simple linear regression equation and used to revise the estimated overall discounted cost per patient in the model.\n\nAfter adjusting the mean age of the population in the model at the start of treatment to 62.5\xa0years, and using a hazard ratio for progression-free survival of 0.55 (in line with the manufacturer's base case), the ICERs in the ERG's analyses ranged from £24,595 to £27,558 per QALY gained, if the duration of clinical benefit was 48\xa0months; £31,067 to £35,327 per QALY gained, if the duration of clinical benefit was 36\xa0months; and £38,234 to £43,934 per QALY gained, if the duration of clinical benefit was assumed to be only 28\xa0months. The ERG also presented sensitivity analyses using its revised hazard ratio of 0.719 (adjusted for early reporting bias) and noted that the ICERs ranged from £39,319 to £66,870 per QALY gained. The ERG also explored the effect on the ICER of adjusting the hazard ratios for progression-free survival for specific patient ages to reflect a reduction in clinical effect with the increase of age, however this did not change the ICER substantively.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report; these and the responses to consultation on the first and second appraisal consultation documents (ACD) from consultees and commentators are available from www.nice.org.uk/guidance/TA226", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rituximab maintenance treatment for people with follicular non-Hodgkin's lymphoma that has responded to first-line induction therapy with rituximab in combination with chemotherapy, having considered evidence on the nature of follicular non-Hodgkin's lymphoma and the value placed on the benefits of rituximab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources and comments received during consultation on both appraisal consultation documents.\n\nThe Committee noted that the decision problem for this topic defines the population as 'adults with advanced follicular lymphoma that has responded to first-line chemotherapy', and that the population considered by the manufacturer was 'adults with advanced follicular lymphoma that has responded to first-line treatment with rituximab plus chemotherapy'. The manufacturer indicated that the population in its analysis was restricted to those who had high tumour burden (indicative of advanced disease) and who had received first-line treatment with rituximab plus chemotherapy because this reflected standard first-line treatment used in UK clinical practice. The Committee noted that the manufacturer assumed that rituximab maintenance would be given for a maximum period of 2\xa0years or until disease progression, in line with the marketing authorisation. The Committee also noted that the manufacturer had not identified any clinical evidence to support the use of ibritumomab tiuxetan as a maintenance treatment for people who have received first-line treatment with rituximab in combination with chemotherapy, and that ibritumomab tiuxetan is infrequently used in the UK. For these reasons the manufacturer excluded ibritumomab tiuxetan from the list of the comparators originally specified in the decision problem. The Committee accepted the manufacturer's justifications for the changes to the decision problem.\n\nThe Committee was aware that rituximab in combination with chemotherapy is currently the standard of care in the UK for first‑line induction therapy of people with follicular non-Hodgkin's lymphoma. The Committee noted that 'Rituximab for the treatment of follicular lymphoma' (NICE technology appraisal guidance 110) recommends R-CVP for the first-line induction treatment of advanced follicular non-Hodgkin's lymphoma, but that other rituxmab-containing chemotherapeutic regimens (such as R-CHOP and R-FCM) are routinely used, but have not yet been appraised by NICE. The Committee noted that 'watchful waiting' (observation) is the current standard treatment for people with advanced follicular non-Hodgkin's lymphoma that has responded to first-line induction therapy. The Committee heard from the clinical specialists that current management aims to prolong remission, delay progression (and therefore delay the use of chemotherapy) and improve quality of life. The clinical specialists expressed the view that rituximab maintenance treatment after first-line induction therapy constituted optimal management for non-Hodgkin's lymphoma because it can offer people longer periods of remission and better quality of life. The Committee was also aware that rituximab is used in combination with chemotherapy for people whose disease has relapsed or did not respond to treatment, or as monotherapy for maintenance treatment after successful second‑line treatment of recurrent or refractory disease (in line with 'Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma [review of technology appraisal guidance 37]' [NICE technology appraisal guidance 137]).\n\nThe Committee heard from patient experts that using rituximab maintenance treatment instead of watchful waiting may delay the need for eventual chemotherapy on relapse of the disease. The patient experts also expressed the view that chemotherapy is associated with more adverse events than rituximab, that it may cause symptoms worse than those caused by follicular non-Hodgkin's lymphoma itself, and that chemotherapy therefore has a substantial negative impact on an individual's quality of life. The patient experts stated that while on chemotherapy they experienced symptoms of weakness and fatigue and were not able to do simple routine tasks without the support of family and carers. However, they were aware that people who received rituximab maintenance treatment did not have adverse effects associated with chemotherapy and were able to continue with their normal daily routine.\n\n# Clinical effectiveness\n\nThe Committee considered the data presented by the manufacturer on the clinical effectiveness of rituximab maintenance treatment after first-line induction with rituximab plus chemotherapy. The Committee noted that the manufacturer derived data on efficacy primarily from the PRIMA trial that compared rituximab maintenance with observation in people whose disease had responded to first-line induction therapy. The Committee noted that the most recent data from this trial were available from the post‑study observational follow‑up period, which had a median follow-up of 38\xa0months, and indicated that progression-free survival was statistically significantly improved in people who had been randomised to rituximab maintenance treatment compared with people who had been randomised to observation. The Committee was aware that the manufacturer could not estimate time to progression for patients randomised to rituximab, because too few people had progressed during the trial, and the manufacturer therefore had to extrapolate this value using a statistical distribution. The Committee noted the concerns of the ERG that because progression-free survival had been estimated from the period after the end of the trial, patients may have received other therapies, which in turn could have affected the chance of disease progression. The Committee also noted that despite following patients beyond the end of the trial, the manufacturer could not estimate the overall survival associated with rituximab maintenance treatment because of the small number of deaths during this period. The Committee was aware that the trial stopped earlier than originally planned on advice from a Data and Safety Monitoring Committee (section 3.3), and heard from the ERG that there is evidence suggesting that studies that have stopped earlier than planned often overestimate the clinical benefit. However, the Committee was satisfied, after advice from the clinical specialists, that progression-free survival for people treated with rituximab maintenance therapy in the PRIMA trial reflected the clinicians' observations from clinical practice. The Committee concluded that the available evidence shows that first‑line maintenance treatment with rituximab significantly improves progression-free survival compared with observation (36\xa0months' median PFS: 74.9% vs 57.6% respectively; HR 0.55; p\xa0<\xa00.0001), but that the size of the overall survival benefit could not be determined.\n\nThe Committee was aware that the PRIMA trial was the only trial that directly addressed the decision problem, and included the relevant population, intervention, comparison and outcomes. The Committee heard from the clinical specialists that the results from the PRIMA trial inform clinical practice in the UK. The Committee learned from the manufacturer that another trial (ECOG\xa01496) demonstrated that rituximab maintenance led to longer progression-free survival compared with observation, but that this trial had been conducted in people who had not previously had first-line induction treatment with rituximab-containing chemotherapy. The Committee understood that another trial (SAKK 35/98) had observed a longer event-free survival for people randomised to rituximab maintenance compared with those who had been randomised to no treatment (observation), but that the participants of this trial had either not been treated before rituximab maintenance or had only received an induction regimen with rituximab monotherapy, not rituximab combined with chemotherapy.\n\nThe Committee considered the adverse-event profile of rituximab. It noted that the incidence of grade 3 or 4 adverse events was significantly higher in the rituximab maintenance arm than in the observation arm of the PRIMA trial (section 3.6). However, the Committee heard from the clinical specialists and patient experts that rituximab maintenance treatment is generally well tolerated and that adverse events are easily managed. The patient experts also considered the adverse effects associated with rituximab maintenance therapy to be less severe than those experienced with chemotherapy on relapse of disease. The Committee concluded that, overall, most adverse events associated with rituximab treatment are not severe, and that using rituximab to extend remission may delay the need for chemotherapy and, in turn, delay the associated adverse events.\n\n# Cost effectiveness\n\nThe Committee reviewed the original and revised economic analyses provided by the manufacturer and the exploratory sensitivity analyses performed by the ERG. It heard from the ERG that inconsistencies and errors were identified in the manufacturer's revised model, but that correcting them had only a small effect on the manufacturer's base-case results. The Committee noted that in the PRIMA trial the median age at randomisation was 57\xa0years. However, it heard from the clinical specialists that the mean age at the start of first-line treatment in the UK is usually between 60 and 65\xa0years. The Committee acknowledged that people in clinical trials tend to be younger and fitter than those in clinical practice, but it noted from sensitivity analyses conducted by the ERG that the ICER varied depending on the age assumed at the start of treatment. Therefore the Committee considered that the average age of people with advanced non-Hodgkin's lymphoma seen in UK clinical practice should be used in the analysis to provide a more accurate estimate. The Committee considered the revised base-case ICER from the manufacturer of £15,400 per QALY gained, which assumed that the mean age at induction was 62.5\xa0years. The Committee heard from the ERG that the method that the manufacturer had used to adjust for age in its economic model did not reflect the prognostic importance of incident age. The Committee considered exploratory sensitivity analyses from the ERG in which the hazard ratios for progression-free survival were adjusted for specific patient ages to reflect a reduction in clinical effect with the increase of age. The Committee noted that age was not the only variable that had an impact on prognosis and, therefore considered that the ERG's adjustment of the hazard ratios for different age groups was not needed. The Committee was satisfied that the manufacturer's base-case analysis had appropriately adjusted for age and reflected the average patient population seen in UK clinical practice.\n\nThe Committee noted that the manufacturer had assumed in the base case that the clinical benefit of rituximab maintenance would last for 6\xa0years (2\xa0years of treatment and 4\xa0years of sustained benefit once treatment was stopped). The Committee heard from the ERG that the manufacturer's extrapolation of the clinical benefit of rituximab beyond the period observed in the PRIMA trial assumed a proportional increase in survival with time, which may not reflect the true effect. The Committee also noted the ERG's concerns that patient-level data from the PRIMA trial indicated that the duration of effect from rituximab maintenance treatment appears to be 28\xa0months, after which time patients treated with rituximab maintenance therapy experience a rate of progression no better or worse than that of patients not treated with rituximab maintenance therapy. The Committee heard from the clinical specialists that data from the PRIMA trial demonstrated that rituximab maintenance treatment is clinically effective to 36\xa0months at least and without evidence that the effect diminishes over time; therefore, assuming a duration of benefit of only 28\xa0months, as suggested by the ERG, may underestimate the actual effect of treatment. The Committee also heard from the clinical specialists that the period over which rituximab is likely to have an additional benefit over observation is probably 3 to 4\xa0years (that is, 1 to 2\xa0years beyond treatment). However, it further heard from the clinical specialists that it was not possible to predict a definite time period, and a duration of effect of up to 6\xa0years, as seen in the EORTC 20981 study for second-line rituximab maintenance treatment, could be plausible. The Committee considered sensitivity analyses conducted by the manufacturer that assumed a duration of treatment effect of 28\xa0months, 36\xa0months and 48\xa0months and noted that the ICERs ranged from £17,300 to £27,400 per QALY gained. The Committee noted that these estimates were lower than those calculated by the ERG for the same scenarios (range: £24,600 to £43,900 per QALY gained) but acknowledged that the manufacturer and the ERG had used different modelling approaches to calculate their results (section 3.29). The Committee considered that the duration of clinical benefit of rituximab maintenance was a key driver of cost effectiveness, but was satisfied that the manufacturer's sensitivity analyses presented the most plausible range of estimates for the treatment effect in line with clinical opinion and the available data.\n\nThe Committee noted that the manufacturer's revised base-case analysis assumed that most (89.2%) of the progression-free survival benefit translated to an overall survival gain in its model. The Committee heard from the clinical specialists that it was not possible to verify the specific conversion rate from progression-free survival to overall survival from the literature or clinical experience, but that they would expect a conversion rate of at least 70%. The Committee also heard from the clinical specialists that patients with non-Hodgkin's follicular lymphoma live longer than in the past, and it is reasonable to assume that this is at least partly due to the introduction of treatment with rituximab. The Committee considered that the manufacturer should have sought data from patient registries or observational data to validate the conversion rate assumed for the base-case estimate, and to confirm the degree to which rituximab maintenance treatment might prolong life. However, it was satisfied that the manufacturer's sensivity analyses, which assumed conversion rates of 70%, 80% and 90%, provided a plausible range of conversion rate estimates. The Committee heard from the manufacturer that the conversion rate was not an actual input in the model and could only be adjusted by artificially modifying other parameters. As such, the manufacturer was concerned that its revised analyses, which were requested by the Committee, were driven by implausible assumptions. The Committee noted the manufacturer's concerns but was satisfied that the sensitivity analyses addressed the uncertainty that the Committee initially had about the translation from progression-free survival to overall survival gain in the original analysis.\n\nThe Committee considered the concerns of the ERG that the early closure of the PRIMA trial may have overestimated the benefit from rituximab, and therefore the hazard ratio for progression-free survival (0.55) derived from the PRIMA trial should be increased to adjust for this bias. The Committee noted the revised sensitivity analyses from the ERG, which took account of the adjusted hazard ratio, but considered that adjusting for early reporting bias is not routinely included in technology appraisals and is not a current requirement in the NICE methods guide. The Committee therefore concluded that the manufacturer had used an appropriate hazard ratio and that the ERG's revised analyses using the higher hazard ratio would not be considered.\n\nThe Committee discussed the utility values used in the manufacturer's model. The Committee appreciated that no differences in health-related quality of life were observed between the arms of the PRIMA trial. The Committee considered sensitivity analyses from the ERG that showed that changes to the gains in utility in different health states in the model had a marginal effect on the base-case ICER, and the Committee was therefore persuaded that the ICERs presented by the manufacturer were largely driven by gains in overall survival.\n\nThe Committee noted that the ICERs for rituximab maintenance compared with observation in the manufacturer's submission and sensitivity analyses were less than £30,000 per QALY gained for most scenarios. The Committee also noted that the ERG's exploratory sensitivity analyses, which assumed a duration of clinical benefit from rituximab maintenance treatment of 36 to 48\xa0months (in line with clinical opinion), resulted in ICERs ranging from £24,600 to £35,000 per QALY gained, depending on the conversion rate of progression-free survival to overall survival gain assumed. The Committee was aware that the model did not include the utility associated with delaying chemotherapy, and that if it were included, it would decrease the ICER (that is, improve the cost effectiveness) to an estimate which would be considered as a cost-effective use of NHS resources. Therefore, the Committee considered that rituximab maintenance therapy should be recommended as an option for the treatment of people with follicular non-Hodgkin's lymphoma that has responded to first-line induction treatment with rituximab in combination with chemotherapy.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA226 (STA)\n\nAppraisal title: Rituximab for the first-line maintenance treatment of follicular non-Hodgkin's lymphoma\n\nSection\n\nKey conclusion\n\nRituximab maintenance therapy is recommended as an option for the treatment of people with follicular non-Hodgkin's lymphoma that has responded to first-line induction therapy with rituximab in combination with chemotherapy.\n\n, 4.13\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard from the clinical specialists that current management aims to prolong remission, delay progression (and therefore delay the use of chemotherapy), and improve quality of life. 'Watchful waiting' (observation) is the current standard treatment for people with advanced follicular non-Hodgkin's lymphoma that has responded to first-line induction therapy.\n\n\n\n\n\n\n\n\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe clinical specialists expressed the view that rituximab maintenance treatment constituted optimal management because it could offer people longer periods of remission and better quality of life if used after first-line induction therapy.\n\nPatient experts expressed the view that using rituximab maintenance treatment instead of watchful waiting may delay the need for eventual chemotherapy on relapse of the disease.\n\n\n\n\n\n\n\n\n\n\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nRituximab has a UK marketing authorisation for the 'treatment of follicular lymphoma patients responding to induction therapy'.\n\n\n\nAdverse effects\n\nThe incidence of grade 3 or 4 adverse events was significantly higher in the rituximab maintenance arm than in the observation arm of the PRIMA trial (24% vs 17%, p\xa0=\xa00.0026).\n\nThe Committee heard from the clinical specialists and patient experts that rituximab maintenance treatment is generally well tolerated and that adverse events are easily managed. The patient experts also highlighted that they consider the side effects associated with rituximab maintenance therapy to be less severe than those experienced with chemotherapy, which may be given if the disease relapses.\n\n, 4.7\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe manufacturer derived efficacy data primarily from the PRIMA trial that compared rituximab maintenance with observation in people whose disease had responded to first-line induction therapy. The Committee noted that the most recent data from this trial were available from the post-study observational follow-up period, which had a median follow-up of 38\xa0months. The Committee heard from the clinical specialists that the results from the PRIMA trial inform clinical practice in the UK.\n\nThe Committee was aware that the trial stopped earlier than originally planned on advice from a Data and Safety Monitoring Committee, but heard from the ERG that evidence suggests that studies which stop earlier than planned often overestimate the clinical benefit. However, the Committee was satisfied, after advice from the clinical specialists, that progression-free survival for people treated with rituximab maintenance therapy in the PRIMA trial reflected the clinicians' observations from clinical practice.\n\n, 4.6\n\nRelevance to general clinical practice in the NHS\n\nThe Committee noted that in the PRIMA trial the median age at randomisation was 57\xa0years. However, it heard from the clinical specialists that the mean age at the start of first-line treatment in the UK is usually between 60 and 65\xa0years. Although the Committee acknowledged that people in clinical trials tend to be younger and fitter than those in clinical practice, it noted from sensitivity analyses conducted by the ERG that the manufacturer's base-case ICER varied depending on the age assumed at the start of treatment and therefore may have added uncertainty.\n\nThe Committee considered the revised base case from the manufacturer, which assumed that the mean age at induction was 62.5\xa0years. It was satisfied that this analysis had appropriately adjusted for age and reflected the average patient population seen in UK clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee noted that because of the small number of deaths during the trial period, overall survival associated with rituximab maintenance treatment could not be estimated.\n\nThe Committee noted that the manufacturer assumed in the base case that the clinical benefit of rituximab maintenance would last for 6\xa0years (2\xa0years of treatment and 4\xa0years of sustained benefit once treatment was stopped). The Committee noted the ERG's concerns that patient-level data for rituximab maintenance treatment from the PRIMA trial indicated that the duration of treatment effect appears to be 28\xa0months. The Committee heard from the clinical specialists that data from the PRIMA trial indicated that rituximab maintenance treatment is clinically effective to at least 36\xa0months and there is no evidence that the effect diminishes over time; therefore assuming a duration of benefit of only 28\xa0months, as suggested by the ERG, may underestimate the actual effect of treatment. The Committee heard from the clinical specialists that rituximab is likely to provide a benefit for 3 to 4 years (that is, 1 to 2 years beyond treatment); however, it was not possible to predict a definite time period.\n\n\n\n\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNot applicable.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that the available evidence shows that first-line maintenance treatment with rituximab improves progression-free survival compared with observation (36\xa0months' median PFS: 74.9% vs 57.6% respectively; HR 0.55; p\xa0<\xa00.0001), but that the size of the overall survival benefit could not be determined.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee heard from the ERG that inconsistencies and errors were identified in the manufacturer's model, but that correcting them only had a small effect on the manufacturer's base-case results.\n\nThe Committee heard from the manufacturer that its revised analyses, which were requested by the Committee, were driven by implausible assumptions. The Committee noted the manufacturer's concerns but was satisfied that the sensitivity analyses addressed the uncertainty that the Committee initially had when it considered the original analysis.\n\n\n\n\n\n\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that the manufacturer had assumed that the clinical benefit of rituximab maintenance would last for 6\xa0years (2\xa0years of treatment and 4\xa0years of sustained benefit once treatment was stopped). The Committee heard from the ERG that the manufacturer's extrapolation of the clinical benefit of rituximab beyond the observed period in the PRIMA trial assumed a proportional increase in survival with time, which may not reflect the true effect.\n\nThe Committee considered sensitivity analyses conducted by the manufacturer that assumed a duration of treatment effect of 28\xa0months, 36\xa0months and 48\xa0months and noted that the ICERs ranged from £17,300 to £27,400 per QALY gained. The Committee noted that these estimates were lower than those calculated by the ERG for the same scenarios but acknowledged that the manufacturer and the ERG had used different modelling approaches (section 3.29). The Committee was satisfied that the manufacturer's sensitivity analyses presented the most plausible range of estimates for the treatment effect in line with clinical opinion and the available data.\n\nThe Committee noted that the manufacturer's revised base-case analysis assumed that most (89.2%) of the progression-free survival benefit translated to an overall survival gain in its model. The Committee heard from the clinical specialists that it was not possible to verify the specific conversion rate from progression-free survival to overall survival from the literature or clinical experience, but that they would expect a conversion rate of at least 70%. The Committee was satisfied that the manufacturer's sensitivity analyses, which assumed conversion rates of 70%, 80% and 90%, provided a plausible range of conversion rate estimates.\n\nThe Committee considered the concerns of the ERG that the early closure of the PRIMA trial may have overestimated the benefit from rituximab, and therefore the hazard ratio for progression-free survival (0.55) derived from the PRIMA trial should be increased to adjust for this bias. The Committee noted the revised sensitivity analyses from the ERG, which took account of the adjusted hazard ratio, but considered that adjusting for early reporting bias is not routinely included in technology appraisals and is not a current requirement in the NICE methods guide.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe manufacturer's model included utility values of 0.88 and 0.79 for the PF1 and PF2 health states respectively. The Committee considered sensitivity analyses from the ERG that showed that changes to the gains in utility in different health states in the manufacturer's model had a marginal effect on the base-case ICER, and the Committee was therefore persuaded that the ICERs presented by the manufacturer were largely driven by gains in overall survival.\n\nThe Committee was aware that the model did not include the utility associated with delaying chemotherapy, and that if it were included, it would likely decrease the ICER (that is, improve the cost effectiveness). Although the Committee requested analysis of potential utility gains associated with delaying the need for chemotherapy after relapse, the manufacturer was unable to incorporate these because of limitations in the structure of the model.\n\n\n\n, 3.24, 4.12\n\n\n\n\n\n\n\n\n\n, 4.13\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe key drivers of cost effectiveness were assumptions about the duration of clinical benefit of rituximab maintenance, the conversion rate of progression-free survival to overall survival and the underestimation in the economic model of the utility associated with delaying chemotherapy treatment.\n\nThe Committee was satisfied that the manufacturer's sensitivity analyses presented the most plausible range of estimates for the duration of treatment effect and the translation from progression-free survival to overall survival gain.\n\n, 4.10\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee noted that the ICERs for rituximab maintenance compared with observation in the manufacturer's submission and sensitivity analyses were less than £30,000 per QALY gained for most scenarios. The Committee also noted that the ERG's exploratory sensitivity analyses, which assumed a duration of clinical benefit from rituximab maintenance treatment of 36 to 48\xa0months (in line with clinical opinion), had ICERs ranging from £24,600 to £35,000 per QALY gained, depending on the conversion rate of progression-free survival to overall survival gain assumed. The Committee was aware that the model did not include the utility associated with delaying chemotherapy, and that if it were included, it would decrease the ICER (that is, improve the cost effectiveness) to an estimate which would be considered as a cost-effective use of NHS resources. Therefore the Committee considered that rituximab maintenance therapy should be recommended as an option for treatment for people with non-Hodgkin's lymphoma that has responded to first-line induction therapy with rituximab in combination with chemotherapy.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n–\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nNo equalities issues were raised during the scoping exercise or during the course of the appraisal.\n\n–", 'Related NICE guidance': "Published\n\nRituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma (review of technology appraisal guidance 37). NICE technology appraisal guidance 137 (2008). Available from www.nice.org.uk/guidance/TA137\n\nRituximab for the treatment of follicular lymphoma. NICE technology appraisal guidance 110 (2006). Available from www.nice.org.uk/guidance/TA110\n\nImproving outcomes in haematological cancers – the manual. NICE cancer service guidance haemato-oncology (2003). Available from www.nice.org.uk/guidance/CSGHO\n\nUnder development\n\nNICE is developing the following guidance (details available from www.nice.org.uk):\n\nRituximab for the treatment of follicular lymphoma (review of technology appraisal guidance 110). NICE technology appraisal. Publication expected December 2011.", 'Review of guidance': 'The guidance on this technology will be considered for review in May 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew Dillon\n\nChief Executive\n\nJune 2011', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour\n responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta226
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Evidence-based recommendations on rituximab (MabThera) for the maintenance treatment of follicular non-Hodgkin’s lymphoma in adults.
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182496c3c613dc54f634b9d304490a80407c368b
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nice
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Endoscopic radical inguinal lymphadenectomy
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Endoscopic radical inguinal lymphadenectomy
# Guidance
Current evidence on the safety and efficacy of endoscopic radical inguinal lymphadenectomy is inadequate in quantity. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake endoscopic radical inguinal lymphadenectomy should take the following actions.
Inform the clinical governance leads in their Trusts.
Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended (available from www.nice.org.uk/IPG398publicinfo).
Audit and review clinical outcomes of all patients having endoscopic radical inguinal lymphadenectomy (see section 3.1).
This procedure should be carried out only in centres which specialise in the treatment of cancers requiring radical inguinal lymphadenectomy as part of their management, and by surgeons with training and experience in this type of endoscopic surgery.
Publications on the use of this procedure should clearly describe case selection, and should report rates of local recurrence and survival, as well as adverse events. NICE may review this procedure on publication of further evidence.# The procedure
# Indications and current treatments
Patients with penile, vulval or anal cancer, or melanoma of the leg, may require radical inguinal lymphadenectomy as part of the management of their condition.
The standard method for radical inguinal lymphadenectomy is an open operation through an incision in the groin.
# Outline of the procedure
The endoscopic approach has theoretical advantages of reduced postoperative pain, morbidity and recovery time compared with the open procedure.
Endoscopic radical inguinal lymphadenectomy is carried out with the patient under general anaesthesia. Ultrasound guidance may be used. Three or four small incisions are made in the area of the femoral triangle for insertion of ports, and the working space is insufflated with CO2. The lymph nodes are dissected endoscopically. Resected nodes are placed in an impermeable sac and removed through one of the port sites. Resection of the saphenous vein may also be required. A suction drain is normally inserted at the end of the procedure..
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/879/overview
# Efficacy
A non-randomised study of 15 patients (30 limbs) treated by endoscopic (20 limbs) or open (10 limbs) radical inguinal lymphadenectomy reported that the mean number of lymph nodes removed was 10.75 and 9.7 respectively (p = 0.3).
A case series of 5 patients reported recurrence in 2 patients. One patient had recurrence with multiple visceral metastases after the procedure. The other patient had recurrence in a lymph node outside of the inguinal area, which was subsequently resected (follow-up not stated).
In the non-randomised study of 15 patients treated by endoscopic or open radical inguinal lymphadenectomy, mean length of hospital stay in patients who had the endoscopic procedure in 1 lower limb and the open procedure in the other (n = 10) was 6.4 days compared with 24 hours for patients who had bilateral endoscopic procedures (n = 5) (p < 0.001). Mean times to return to usual activities were 21 days and 14 days respectively (p = 0.032).
The non-randomised study of 15 patients reported that wound drains remained in place for a shorter time after the endoscopic procedure compared with the open procedure (4.9 days vs 6.4 days, p = 0.008).
The Specialist Advisers listed key efficacy outcomes as conversion to open procedure, length of hospital stay and time to full recovery, adequate clearance of lymph nodes and recurrence of cancer.
# Safety
The non-randomised study of 15 patients treated by endoscopic or open radical inguinal lymphadenectomy reported lymphatic complications in both groups (10% vs 20% , p = 0.58) during 32-month follow-up. In the endoscopic group, lymphorrhoea was reported in 1 patient and unilateral limited lymphocele (requiring 3 evacuation punctures) in 1 patient. In the open group, chronic lymphoedema was reported in 1 patient and lymphocele (which spontaneously resolved within 2 months) in 1 patient. A case series of 8 patients reported 3 patients with lymphoceles.
Skin-related complications were reported in 5% (1/20) and 50% (5/10) of limbs in the non-randomised study of 15 patients (30 treated limbs) treated by either endoscopic or open radical inguinal lymphadenectomy respectively (p = 0.009). A case series of 5 patients reported cellulitis in 2 patients; 1 of these patients had a severe infection at the site of prior sentinel node biopsy (follow-up not stated).
Flap necrosis was reported in 6% (1/16) and 44% (7/16) of limbs in a non-randomised controlled study of 16 patients (32 limbs) treated by endoscopic inguinal lymphadenectomy or open groin node dissection respectively.
The Specialist Advisers considered theoretical adverse events to include damage to femoral vessel or femoral nerve, port-site metastasis, gas embolus, lymph leak, lymphocele and seroma.
# Other comments
The Committee noted that endoscopic radical inguinal lymphadenectomy has the potential to achieve lower morbidity rates than those associated with the open procedure. They also noted that endoscopic radical inguinal lymphadenectomy is an uncommon procedure and considered that acquisition of comparative data may therefore be difficult.# Further information
This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion), available from www.nice.org.uk/guidance/IPG398
For related NICE guidance see www.nice.org.uk
Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG398/publicinfo
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{'Guidance': "Current evidence on the safety and efficacy of endoscopic radical inguinal lymphadenectomy is inadequate in quantity. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake endoscopic radical inguinal lymphadenectomy should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended (available from www.nice.org.uk/IPG398publicinfo).\n\nAudit and review clinical outcomes of all patients having endoscopic radical inguinal lymphadenectomy (see section 3.1).\n\nThis procedure should be carried out only in centres which specialise in the treatment of cancers requiring radical inguinal lymphadenectomy as part of their management, and by surgeons with training and experience in this type of endoscopic surgery.\n\nPublications on the use of this procedure should clearly describe case selection, and should report rates of local recurrence and survival, as well as adverse events. NICE may review this procedure on publication of further evidence.", 'The procedure': '# Indications and current treatments\n\nPatients with penile, vulval or anal cancer, or melanoma of the leg, may require radical inguinal lymphadenectomy as part of the management of their condition.\n\nThe standard method for radical inguinal lymphadenectomy is an open operation through an incision in the groin.\n\n# Outline of the procedure\n\nThe endoscopic approach has theoretical advantages of reduced postoperative pain, morbidity and recovery time compared with the open procedure.\n\nEndoscopic radical inguinal lymphadenectomy is carried out with the patient under general anaesthesia. Ultrasound guidance may be used. Three or four small incisions are made in the area of the femoral triangle for insertion of ports, and the working space is insufflated with CO2. The lymph nodes are dissected endoscopically. Resected nodes are placed in an impermeable sac and removed through one of the port sites. Resection of the saphenous vein may also be required. A suction drain is normally inserted at the end of the procedure..\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/879/overview\n\n# Efficacy\n\nA non-randomised study of 15 patients (30 limbs) treated by endoscopic (20 limbs) or open (10 limbs) radical inguinal lymphadenectomy reported that the mean number of lymph nodes removed was 10.75 and 9.7 respectively (p = 0.3).\n\nA case series of 5 patients reported recurrence in 2 patients. One patient had recurrence with multiple visceral metastases after the procedure. The other patient had recurrence in a lymph node outside of the inguinal area, which was subsequently resected (follow-up not stated).\n\nIn the non-randomised study of 15 patients treated by endoscopic or open radical inguinal lymphadenectomy, mean length of hospital stay in patients who had the endoscopic procedure in 1 lower limb and the open procedure in the other (n = 10) was 6.4 days compared with 24 hours for patients who had bilateral endoscopic procedures (n = 5) (p < 0.001). Mean times to return to usual activities were 21 days and 14 days respectively (p = 0.032).\n\nThe non-randomised study of 15 patients reported that wound drains remained in place for a shorter time after the endoscopic procedure compared with the open procedure (4.9 days vs 6.4 days, p = 0.008).\n\nThe Specialist Advisers listed key efficacy outcomes as conversion to open procedure, length of hospital stay and time to full recovery, adequate clearance of lymph nodes and recurrence of cancer.\n\n# Safety\n\nThe non-randomised study of 15 patients treated by endoscopic or open radical inguinal lymphadenectomy reported lymphatic complications in both groups (10% [2/20] vs 20% [2/10], p = 0.58) during 32-month follow-up. In the endoscopic group, lymphorrhoea was reported in 1 patient and unilateral limited lymphocele (requiring 3 evacuation punctures) in 1 patient. In the open group, chronic lymphoedema was reported in 1 patient and lymphocele (which spontaneously resolved within 2 months) in 1 patient. A case series of 8 patients reported 3 patients with lymphoceles.\n\nSkin-related complications were reported in 5% (1/20) and 50% (5/10) of limbs in the non-randomised study of 15 patients (30 treated limbs) treated by either endoscopic or open radical inguinal lymphadenectomy respectively (p = 0.009). A case series of 5 patients reported cellulitis in 2 patients; 1 of these patients had a severe infection at the site of prior sentinel node biopsy (follow-up not stated).\n\nFlap necrosis was reported in 6% (1/16) and 44% (7/16) of limbs in a non-randomised controlled study of 16 patients (32 limbs) treated by endoscopic inguinal lymphadenectomy or open groin node dissection respectively.\n\nThe Specialist Advisers considered theoretical adverse events to include damage to femoral vessel or femoral nerve, port-site metastasis, gas embolus, lymph leak, lymphocele and seroma.\n\n# Other comments\n\nThe Committee noted that endoscopic radical inguinal lymphadenectomy has the potential to achieve lower morbidity rates than those associated with the open procedure. They also noted that endoscopic radical inguinal lymphadenectomy is an uncommon procedure and considered that acquisition of comparative data may therefore be difficult.', 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion), available from www.nice.org.uk/guidance/IPG398\n\nFor related NICE guidance see www.nice.org.uk\n\nInformation for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG398/publicinfo"}
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https://www.nice.org.uk/guidance/ipg398
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b95de9393b70163d0d6aca3a3364ecc5299333bf
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nice
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Thoracoscopic exclusion of the left atrial appendage (with or without surgical ablation) for non-valvular atrial fibrillation for the prevention of thromboembolism
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Thoracoscopic exclusion of the left atrial appendage (with or without surgical ablation) for non-valvular atrial fibrillation for the prevention of thromboembolism
# Guidance
Current evidence on the safety and efficacy of thoracoscopic exclusion of the left atrial appendage (LAA) for non-valvular atrial fibrillation (AF) for the prevention of thromboembolism as an adjunctive procedure to surgical ablative techniques is inadequate in quantity and quality. Therefore this procedure should only be used as an adjunct to surgical ablation with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake thoracoscopic exclusion of the LAA for non-valvular AF for the prevention of thromboembolism as an adjunct to surgical ablation should take the following actions.
Inform the clinical governance leads in their Trusts.
Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended (available from www.nice.org.uk/guidance/IPG400/publicinfo).
Audit and review clinical outcomes of all patients having thoracoscopic exclusion of the LAA for non-valvular AF for the prevention of thromboembolism as an adjunctive procedure to ablative techniques (see section 3.1).
Current evidence on the safety and efficacy of thoracoscopic exclusion of the LAA for non-valvular AF for the prevention of thromboembolism when used in isolation is inadequate. Therefore this procedure should only be used in the context of research. Research studies should clearly define patient selection. They should report the cardiac rhythm achieved after surgery and also adverse events, particularly stroke and death, in both the short and longer term.
Patient selection should be carried out by a multidisciplinary team including a cardiac surgeon and other clinicians experienced in the management of patients with AF who are at risk of stroke. Patients should be considered for alternative treatments to reduce the risk of thromboembolism associated with AF, and should be informed about these alternatives.
This procedure should be carried out only by cardiac surgeons with experience in thoracoscopic surgery and specific training in the procedure.# The procedure
# Indications and current treatments
Atrial fibrillation is the irregular and rapid beating of the atria. Patients with AF may be asymptomatic or may have symptoms such as fatigue, palpitations and chest pain. They also have an increased risk of thromboembolic stroke. In non-valvular AF, thrombi largely develop in the LAA.
Patients with AF who are considered to be at high risk of thromboembolic stroke are usually treated with anticoagulation therapy. If a patient is unable to tolerate anticoagulation, then surgical obliteration of the LAA through a percutaneous or open approach may be offered.
# Outline of the procedure
Thoracoscopic exclusion of the LAA for non-valvular AF for the prevention of thromboembolism is usually carried out with the patient under general anaesthesia, and often alongside other procedures such as radiofrequency or microwave ablation to treat AF. Under thoracoscopic guidance the pericardium is opened and the atrial appendage excluded, usually using staples. A chest drain may be used to allow lung re-expansion. Postoperative transoesophageal echocardiography may be used to confirm exclusion of the LAA.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/857/overview
# Efficacy
A case series of 100 patients treated by thoracoscopic LAA exclusion (n = 85) and epicardial radiofrequency ablation reported cerebrovascular accidents in 2% (2/88) of patients followed up and transient ischaemic attack (TIA) in 2% (2/88) of patients over a mean follow-up of 23 months.
A case series of 15 patients treated by the procedure alone reported an overall stroke rate of 4% per patient-year (95% confidence interval 1.0 to 16) (mean follow-up 42 months). Of these, 1 patient had a fatal stroke 55 months after the procedure.
The Specialist Advisers listed key efficacy outcomes as total exclusion of the LAA with endothelialisation and a demonstrable absence of residual appendage on echocardiography, and prevention of sequelae of thrombus such as stroke or TIA.
# Safety
Death was reported in 3% (3/100) of patients in the case series of 100 patients (not otherwise described).
Thoracotomy for postoperative bleeding from the LAA was reported in 1 patient in the case series of 15 patients. Intraoperative conversion to mini-thoracotomy to control bleeding was required in 3% (3/100) of patients in the case series of 100 patients.
Conversion to median sternotomy because of severe pleural adhesions was required in 1 patient in a case series of 30 patients; 7% (2/30) of patients required drainage of pneumothorax after removal of chest drains.
Prolonged postoperative air leak and chronic pleuritic pain were each reported in 1 patient in the case series of 15 patients.
Acute subendocardial infarction (recovery within 12 days) was reported in 1 patient in a case series of 81 patients.
The Specialist Advisers listed anecdotal adverse events as incomplete exclusion with residual appendage, and neuralgia from the thoracoscopic port sites.
# Other comments
The Committee considered the prevention of stroke to be the most important efficacy outcome of this procedure. However, its evaluation is complicated by the concomitant use of procedures to ablate AF and the variable use of anticoagulants.
The Committee was advised that new devices are available for this procedure that avoid the use of staples.# Further information
This guidance requires that clinicians undertaking the procedure as an adjunct to ablative techniques make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion), available from www.nice.org.uk/guidance/IPG400
For related NICE guidance see www.nice.org.uk
Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG400/publicinfo
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{'Guidance': "Current evidence on the safety and efficacy of thoracoscopic exclusion of the left atrial appendage (LAA) for non-valvular atrial fibrillation (AF) for the prevention of thromboembolism as an adjunctive procedure to surgical ablative techniques is inadequate in quantity and quality. Therefore this procedure should only be used as an adjunct to surgical ablation with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake thoracoscopic exclusion of the LAA for non-valvular AF for the prevention of thromboembolism as an adjunct to surgical ablation should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended (available from www.nice.org.uk/guidance/IPG400/publicinfo).\n\nAudit and review clinical outcomes of all patients having thoracoscopic exclusion of the LAA for non-valvular AF for the prevention of thromboembolism as an adjunctive procedure to ablative techniques (see section 3.1).\n\nCurrent evidence on the safety and efficacy of thoracoscopic exclusion of the LAA for non-valvular AF for the prevention of thromboembolism when used in isolation is inadequate. Therefore\xa0this procedure should only be used in the context of research. Research studies should clearly define patient selection. They should report the cardiac rhythm achieved after surgery and also adverse events, particularly stroke and death, in both the short and longer term.\n\nPatient selection should be carried out by a multidisciplinary team including a cardiac surgeon and other clinicians experienced in the management of patients with AF who are at risk of stroke. Patients should be considered for alternative treatments to reduce the risk of thromboembolism associated with AF, and should be informed about these alternatives.\n\nThis procedure should be carried out only by cardiac surgeons with experience in thoracoscopic surgery and specific training in the procedure.", 'The procedure': '# Indications and current treatments\n\nAtrial fibrillation is the irregular and rapid beating of the atria. Patients with AF may be asymptomatic or may have symptoms such as fatigue, palpitations and chest pain. They also have an increased risk of thromboembolic stroke. In non-valvular AF, thrombi largely develop in the LAA.\n\nPatients with AF who are considered to be at high risk of thromboembolic stroke are usually treated with anticoagulation therapy. If a patient is unable to tolerate anticoagulation, then surgical obliteration of the LAA through a percutaneous or open approach may be offered.\n\n# Outline of the procedure\n\nThoracoscopic exclusion of the LAA for non-valvular AF for the prevention of thromboembolism is usually carried out with the patient under general anaesthesia, and often alongside other procedures such as radiofrequency or microwave ablation to treat AF. Under thoracoscopic guidance the pericardium is opened and the atrial appendage excluded, usually using staples. A chest drain may be used to allow lung re-expansion. Postoperative transoesophageal echocardiography may be used to confirm exclusion of the LAA.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/857/overview\n\n# Efficacy\n\nA case series of 100 patients treated by thoracoscopic LAA exclusion (n\xa0=\xa085) and epicardial radiofrequency ablation reported cerebrovascular accidents in 2% (2/88) of patients followed up and transient ischaemic attack (TIA) in 2% (2/88) of patients over a mean follow-up of 23 months.\n\nA case series of 15 patients treated by the procedure alone reported an overall stroke rate of 4% per patient-year (95% confidence interval 1.0 to 16) (mean follow-up 42 months). Of these, 1 patient had a fatal stroke 55 months after the procedure.\n\nThe Specialist Advisers listed key efficacy outcomes as total exclusion of the LAA with endothelialisation and a demonstrable absence of residual appendage on echocardiography, and prevention of sequelae of thrombus such as stroke or TIA.\n\n# Safety\n\nDeath was reported in 3% (3/100) of patients in the case series of 100 patients (not otherwise described).\n\nThoracotomy for postoperative bleeding from the LAA was reported in 1\xa0patient in the case series of 15 patients. Intraoperative conversion to mini-thoracotomy to control bleeding was required in 3% (3/100) of patients in the case series of 100 patients.\n\nConversion to median sternotomy because of severe pleural adhesions was required in 1 patient in a case series of 30 patients; 7% (2/30) of patients required drainage of pneumothorax after removal of chest drains.\n\nProlonged postoperative air leak and chronic pleuritic pain were each reported in 1 patient in the case series of 15 patients.\n\nAcute subendocardial infarction (recovery within 12 days) was reported in 1\xa0patient in a case series of 81 patients.\n\nThe Specialist Advisers listed anecdotal adverse events as incomplete exclusion with residual appendage, and neuralgia from the thoracoscopic port sites.\n\n# Other comments\n\nThe Committee considered the prevention of stroke to be the most important efficacy outcome of this procedure. However, its evaluation is complicated by the concomitant use of procedures to ablate AF and the variable use of anticoagulants.\n\nThe Committee was advised that new devices are available for this procedure that avoid the use of staples.', 'Further information': "This guidance requires that clinicians undertaking the procedure as an adjunct to ablative techniques make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion), available from www.nice.org.uk/guidance/IPG400\n\nFor related NICE guidance see www.nice.org.uk\n\nInformation for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG400/publicinfo"}
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https://www.nice.org.uk/guidance/ipg400
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56b801ddcfee86fd72e775b0c1f68bb2b5bdfcfe
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nice
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Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
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Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
Evidence-based recommendations on cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for treating intermittent claudication in adults with peripheral arterial disease.
# Guidance
Naftidrofuryl oxalate is recommended as an option for the treatment of intermittent claudication in people with peripheral arterial disease for whom vasodilator therapy is considered appropriate after taking into account other treatment options. Treatment with naftidrofuryl oxalate should be started with the least costly licensed preparation.
Cilostazol, pentoxifylline and inositol nicotinate are not recommended for the treatment of intermittent claudication in people with peripheral arterial disease.
People currently receiving cilostazol, pentoxifylline and inositol nicotinate should have the option to continue treatment until they and their clinicians consider it appropriate to stop.# Clinical need and practice
Peripheral arterial disease, also known as peripheral vascular disease, is a condition in which arteries that carry blood to the legs or arms are narrowed or blocked. The main cause of peripheral arterial disease is atherosclerosis. The major risk factors for peripheral arterial disease are smoking, diabetes mellitus and pre-existing cardiovascular disease. Other factors include increasing age, male sex, ethnicity, hypertension, hypercholesterolaemia, renal insufficiency and a sedentary lifestyle
The Fontaine scheme classifies four stages of peripheral arterial disease. Peripheral arterial disease can be asymptomatic (Fontaine stage I) or symptomatic (Fontaine stages II–IV). The most common symptom of peripheral arterial disease is intermittent claudication (Fontaine stage II), which is characterised by pain in the legs or buttocks that occurs with exercise and is relieved with rest. Two further stages exist: pain in the extremities at rest (ischaemic rest pain, Fontaine stage III) and necrosis and gangrene (Fontaine stage IV).
The pain associated with intermittent claudication occurs because of a lack of oxygen in the leg muscles owing to the impaired blood supply. Rest normalises blood flow and relieves the pain. Intermittent claudication is most commonly associated with disease in the femoropopliteal segment of the arterial circulation. Peripheral arterial disease can also be present at the aorto–iliac level causing pain in the thigh, hip or buttock. Peripheral arterial disease can also cause foot pain. Around 20% of people aged 55–75 years have evidence of peripheral arterial disease in the legs and a quarter of these have symptoms.
Intermittent claudication worsens people's quality of life because it restricts their mobility. People with peripheral arterial disease, and specifically with intermittent claudication, are at increased risk of myocardial infarction and stroke. Additionally, people with intermittent claudication are at higher risk from cardiovascular mortality than people with asymptomatic peripheral arterial disease.
The diagnosis of intermittent claudication includes a clinical history that assesses the presence and character of the pain. A clinician may also measure a patient's ankle-brachial pressure index, that is, the ratio of the blood pressure in the lower leg to the blood pressure in the arm at rest. A value of 0.9 indicates disease, and high values (that is, greater than 1.3) may reflect arterial stiffening associated with disease.
Evaluating the presence and progression of disease takes into account symptoms and signs (for example, the development of ischaemic ulcers). As an objective measure, walking on a treadmill, either at a fixed speed and slope, or a fixed speed and increasing slope, determines how far a patient can walk before developing claudication pain and how far a patient can walk with pain before having to stop.
A number of interventions are used to manage intermittent claudication. Stopping smoking and increasing exercise can help reduce symptoms of claudication. People are more likely to benefit from supervised exercise programmes than from unsupervised exercise. Vasoactive drugs including cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate have marketing authorisations for the symptomatic relief of intermittent claudication and are considered in this appraisal. Angioplasty (that is, mechanical widening of the blood vessel) or other revascularisation (for example, arterial bypass) may be undertaken for people whose symptoms continue despite treatment. To reduce the risk of a heart attack or stroke, interventions include helping patients stop smoking, lowering cholesterol, controlling blood pressure, offering aspirin, and, in people with diabetes, controlling glycaemia.# The technologies
Cilostazol (Pletal, Otsuka Pharmaceuticals) is an oral phosphodiesterase III inhibitor. Cilostazol is a direct arterial vasodilator and it also inhibits platelet aggregation. Cilostazol has a UK marketing authorisation for the 'improvement of the maximal and pain-free walking distances in patients with intermittent claudication, who do not have rest pain and who do not have evidence of peripheral tissue necrosis'. Cilostazol is contraindicated in people with severe renal impairment (creatinine clearance of 25 ml/min or lower), moderate or severe hepatic impairment, congestive heart failure and pregnancy. Cilostazol is also contraindicated in people with any known predisposition to bleeding or with any history of ventricular tachycardia, ventricular fibrillation or multifocal ventricular ectopic beats. For full details of side effects and contraindications see the summaries of product characteristics.
Cilostazol is available as a 50 or 100 mg tablet at a cost of £35.31 for a 56-tablet pack (price for either dose, excluding VAT; 'British national formulary' edition 60). The recommended dose is 100 mg twice daily. Therefore, assuming 100 mg tablets are used, the average monthly cost is £38.26. Costs may vary in different settings because of negotiated procurement discounts.
Naftidrofuryl oxalate (Praxilene, Merk Serono) is an oral peripheral vasodilator that selectively blocks vascular and platelet 5-hydroxytryptamine 2 (5-HT2) receptors. Naftidrofuryl oxalate has a UK marketing authorisation for 'peripheral vascular disorders – intermittent claudication, night cramps, rest pain, incipient gangrene, trophic ulcers, Raynaud's syndrome, diabetic arteriopathy and acrocyanosis'. Naftidrofuryl oxalate is contraindicated in people with a history of hyperoxaluria or recurrent calcium-containing stones. For full details of side effects and contraindications see the summary of product characteristics.
Naftidrofuryl oxalate is available as a branded preparation of 100 mg capsules at a cost of £8.10 for an 84-capsule pack (excluding VAT; BNF edition 60). Generic preparations are also available at a cost of £5.30 (excluding VAT; BNF edition 60), and since January 2011 at a cost of £4.52 (excluding VAT; BNF edition 61) for a 100 mg 84-capsule pack. The recommended dose is one or two 100 mg capsules three times daily. Therefore, for the branded preparation the average monthly cost is £8.80 assuming three 100 mg capsules daily or £17.89 assuming six 100 mg capsules daily. For the generic preparation (that is at a cost of £5.30, excluding VAT; BNF edition 60) the average monthly cost is £4.90 for three 100 mg capsules daily or £9.79 assuming six 100 mg capsules daily. Costs may vary in different settings because of negotiated procurement discounts.
Pentoxifylline (Trental 400, Sanofi-Aventis) is an oral peripheral vasodilator derived from methylxanthine. Pentoxifylline has a UK marketing authorisation for the 'treatment of peripheral vascular disease, including intermittent claudication and rest pain'. Pentoxifylline is contraindicated in people with cerebral haemorrhage, extensive retinal haemorrhage, acute myocardial infarction and severe cardiac arrhythmias. For full details of side effects and contraindications see the summary of product characteristics.
Pentoxifylline is available as a 400 mg tablet at a cost of £19.68 for a 90-tablet pack (excluding VAT; BNF edition 60). The recommended dose is one tablet three times daily. Therefore, the average monthly cost is £19.90. However, the summary of product characteristics states that two tablets daily may prove sufficient in some patients, particularly for maintenance therapy. Costs may vary in different settings because of negotiated procurement discounts.
Inositol nicotinate (Hexopal, Genus Pharmaceuticals) is an oral peripheral vasodilator that slows the release of nicotinic acid. Inositol nicotinate has a UK marketing authorisation for 'the symptomatic relief of severe intermittent claudication and Raynaud's phenomenon'. Inositol nicotinate is contraindicated in people who have suffered a recent myocardial infarction or are in the acute phase of a stroke. For full details of side effects and contraindications see the summaries of product characteristics.
Inositol nicotinate is available as a 500 mg tablet at a cost of £30.76 for a 100-tablet pack. It is also available as a 750 mg tablet at a cost of £51.03 for a 112-tablet pack (excluding VAT; BNF edition 60). The recommended dose is 3 g daily (that is, two 500 mg tablets three times a day), increased to 4 g daily if necessary. The average monthly cost, assuming two 500 mg tablets three times a day, is £56.14. Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
# Clinical effectiveness
The Assessment Group conducted a systematic review of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate within their licensed indications for the treatment of intermittent claudication in people with peripheral arterial disease whose symptoms continue despite conventional management. The Assessment Group identified 26 randomised controlled trials, including placebo-controlled trials, for all four of the vasoactive drugs. The only head-to-head comparison was between cilostazol and pentoxifylline. The Assessment Group stated that the quality of the trials was generally good: treatment groups within trials were comparable, blinding was maintained and trials presented intention-to-treat analyses.
## Cilostazol: maximum walking distance
The Assessment Group identified 11 randomised controlled trials of cilostazol 200 mg compared with placebo. In addition, three randomised controlled trials of cilostazol 200 mg compared with pentoxifylline 1200 mg and one randomised controlled trial of cilostazol 200 mg (with or without supervised exercise) compared with usual care (with or without supervised exercise) were identified. The duration of treatment of the randomised controlled trials ranged from 12 weeks to 24 weeks; 6 had a treatment duration of 24 weeks, 1 of 16 weeks and 3 of 12 weeks. The outcomes included in the trials were maximum walking distance (before having to stop because of pain), pain-free walking distance (before developing claudication pain), ankle brachial pressure index, cardiovascular events, mortality, adverse events and health-related quality of life. The mean baseline age of the participants across the trials ranged from 63 to 67 years. The number of participants in the trials ranged from 81 to 1435. Of the 11 randomised controlled trials, two recruited patients from the UK (n = 38 and 106).
Of the 11 trials of cilostazol 200 mg compared with placebo, ten reported the outcome of maximum walking distance. Of these, seven showed that cilostazol improved maximum walking distance to a statistically significant degree compared with placebo. Studies reported the mean improvement in maximum walking distance either in percentages or as an absolute value. Two of the studies reported percentages; one of these reported 161.7% mean improvement for the group randomised to cilostazol and 79% mean improvement for the group randomised to placebo. The other reported a 30.5% improvement for the group randomised to cilostazol and a 9.3% worsening for the group randomised to placebo. The other studies reported mean improvement in metres. The individual results for the groups randomised to cilostazol compared with placebo respectively were: 76.2 metres versus 21.1 metres, 107 metres versus 65 metres, 129.1 metres versus 26.8 metres, 96.4 metres versus 31.4 metres and 72.7 metres versus 25.8 metres. Three trials that compared cilostazol with pentoxifylline reported the outcome of maximum walking distance. Only one of these trials found a statistically significant improvement in maximum walking distance for cilostazol compared with pentoxifylline (mean maximum walking distance improved by 107 metres with cilostazol compared with 64 metres with pentoxifylline ). The other two studies showed no significant difference between cilostazol and pentoxifylline. One trial compared people randomised to cilostazol (with or without supervised exercise) with usual care (with or without supervised exercise). The results of this trial showed that all treatment groups improved regardless of randomisation, but that greater improvement occurred when cilostazol was added to supervised exercise (mean ratio – change in maximum walking distance: cilostazol plus exercise 2.58, cilostazol without exercise 1.69, usual care plus exercise 1.45, usual care without exercise 1.09, p = 0.005).
## Cilostazol: pain-free walking distance
For cilostazol 200 mg compared with placebo, 10 trials reported the outcome of pain-free walking distance. Of these, five trials showed that cilostazol improved pain-free walking distance to a statistically significant degree compared with placebo. In two of the trials, the mean (absolute) difference in metres was reported. The results for distances in people randomised to cilostazol compared with placebo respectively were 94 metres versus 57 metres, and 68 metres versus 23 metres. One trial showed a 31.7% improvement in people randomised to cilostazol compared with a 2.5% worsening with placebo. One trial reported only a p value (p < 0.05) and another one showed a net improvement of 22% between groups, with the comparison favouring cilostazol.
Three trials of cilostazol compared with pentoxifylline reported the outcome of pain-free walking distance, of which one found a statistically significant improvement for the group randomised to cilostazol compared with pentoxifylline (mean pain-free walking distance improved by 94 metres for those patients in the cilostazol group compared with 74 metres for those in the pentoxifylline group ). The results of the one trial comparing cilostazol (with or without supervised exercise) with usual care (with or without supervised exercise) showed an improvement in pain-free walking distance for all four randomisation groups (that is, cilostazol with supervised exercise, cilostazol without supervised exercise, usual care with supervised exercise and usual care without supervised exercise). However, there was no statistically significant effect of cilostazol when added to supervised exercise or usual care (mean ratio – change in maximum walking distance: cilostazol plus supervised exercise 3.84, cilostazol without supervise exercise 3.34, usual care plus supervised exercise 2.22, usual care without supervised exercise 1.23).
## Naftidrofuryl oxalate: maximum walking distance and pain-free walking distance
The Assessment Group identified four randomised controlled trials of naftidrofuryl oxalate 600 mg compared with placebo and one randomised controlled trial of naftidrofuryl oxalate 300 mg compared with placebo. The duration of treatment of the trials ranged from 12 weeks to 24 weeks; three were 24 weeks long and two were 12 weeks long. The outcomes included in these studies were maximum walking distance, pain-free walking distance, ankle brachial pressure index, cardiovascular events, mortality, adverse events and health-related quality of life. The mean baseline age of the participants receiving naftidrofuryl oxalate in three of the trials ranged from 58 to 67 years. Baseline age of participants in the remaining trials was not reported in the assessment report. The number of participants in the trials ranged from 50 to 754. Only one randomised controlled trial recruited UK patients (n = 50).
Two trials of naftidrofuryl oxalate 600 mg compared with placebo included the outcome of maximum walking distance. One of the trials showed a statistically significant improvement in maximum walking distance for naftidrofuryl oxalate compared with placebo (p < 0.001). In this trial, the maximum walking distance of patients randomised to naftidrofuryl oxalate was improved by 158.7 metres compared with 28.1 metres for placebo. For the outcome of pain-free walking distance, five trials that compared naftidrofuryl oxalate with placebo reported this outcome. Four of the trials showed a statistically significant improvement in pain-free walking distance with naftidrofuryl oxalate compared with placebo (mean differences in metres were 204.0, 158.2, 201.4 and 93.0 for those in the naftidrofuryl oxalate groups compared with 51.0, 29.9, 98.0 and 36.0 for those in the placebo group respectively).
## Pentoxifylline: maximum walking distance and pain-free walking distance
The Assessment Group identified nine randomised controlled trials of pentoxifylline 1200 mg compared with placebo. The treatment durations ranged from 8 weeks to 52 weeks (one had a treatment duration of 52 weeks, six of 24 weeks, and two of 8 weeks). The outcomes included in these trials were maximum walking distance, pain-free walking distance, ankle brachial pressure index, cardiovascular events (and cardiovascular events leading to withdrawal), mortality, adverse events and health-related quality of life. The mean baseline age of the participants receiving pentoxifylline ranged from 59 to 68 years. The number of participants in the trials ranged from 24 to 524. None of the nine randomised controlled trials recruited patients from the UK.
Of the nine trials of pentoxifylline 1200 mg, eight reported the outcome of maximum walking distance. Two of the eight trials showed a statistically significant improvement in maximum walking distance for the group randomised to pentoxifylline compared with placebo. One of these trials reported a 13.9% improvement for people in the pentoxifylline group compared with 3.3% improvement for those in the placebo group. The other trial reported a mean difference improvement of 136 metres for people in the pentoxifylline group compared with 6 metres for those in the placebo group.
Seven trials that compared pentoxifylline 1200 mg with placebo reported the outcome of pain-free walking distance. Two trials showed a statistically significant improvement in pain-free walking distance in people randomised to pentoxifylline compared with placebo. One of these reported a mean difference in improvement of 74 metres with pentoxifylline compared with 57 metres with placebo (p = 0.07). The other trial reported a 47% improvement (geometric mean) for the group randomised to pentoxifylline compared with 26% for the group randomised to placebo (2-sided p = 0.042).
## Inositol nicotinate: maximum walking distance
The Assessment Group identified three randomised controlled trials of inositol nicotinate 4 g compared with placebo. The duration of treatment in each of the trials was 12 weeks. The outcomes included were pain-free walking paces, maximum walking distance, ankle brachial pressure index, time to claudication, cardiovascular events, mortality and adverse events. The mean baseline age of the participants receiving inositol nicotinate ranged from 61 to 68 years. The number of participants in the trials ranged from 80 to 123. One trial reported the outcome of maximum walking distance. The results of this trial showed no statistically significant differences between the groups given inositol nicotinate and placebo. None of the three trials reported pain-free walking distance.
## Assessment Group meta-analyses
The Assessment Group conducted a meta-analysis of the data for maximum walking distance for cilostazol relative to placebo, reanalysing results from a previous Cochrane review. A random effects meta-analysis of the change in walking distance from baseline showed that treatment with cilostazol compared with placebo resulted in an increase of 52.27 metres in absolute walking distance (95% credible interval 24.93 to 86.57).
The Assessment Group also undertook a network meta-analysis of the data for maximum walking distance for the overall comparison of treatment options. The objective of the meta-analysis was to estimate the effect of treatment for each drug in comparison with placebo, and, if possible, compared with each other. This consisted of an analysis of the change from baseline to end of study in log mean maximum walking distance (log metre) from ten out of the 26 trials (seven two-arm, and three three-arm 24 week trials leading to 16 comparisons) that the Assessment Group had indentified for cilostazol, naftidrofuryl oxalate and pentoxifylline. Reasons for excluding studies included that studies were shorter than 24 weeks in duration, were not written in English, lacked endpoints (for example, maximum walking distance or pain-free walking distance), did not report results in a way that allowed comparison of results across trials, used inappropriately low drug dosages, were secondary analyses, used an unlicensed route of administration (that is, intravenous pentoxifylline), included people with disease classified as high Fontaine stages (for example gangrene), or included people who were receiving concurrent revascularisation. The Assessment Group stated that inositol nicotinate was not included in the meta-analysis because the studies lacked 24-week data or data reported in the trials were not suitable for inclusion (there was no information on percentage change from baseline and no information on maximum walking distance or pain-free walking distance). The Assessment Group transformed the data on maximum walking distance to the logarithm scale to produce a scale on which the treatment effects could be assumed to be linear.
The random effects meta-analysis of the change from baseline to end of study in log mean maximum walking distance showed that the greatest increase compared with placebo was for naftidrofuryl (60.3%), followed by cilostazol (24.6%) and pentoxifylline (10.6%). The 95% credible intervals for naftidrofuryl oxalate and cilostazol suggested that there was an increase in the percentage change from baseline walking distance when compared with placebo, although there was some uncertainty about the true effect. Variation between studies was moderate, suggesting that the treatment effect varied depending on the characteristics of the study.
The Assessment Group also undertook a network meta-analysis of the data for pain-free walking distance for the overall comparison of treatment options. This included the same trials as the meta-analysis of maximum walking distance. The random-effects meta-analysis of the change from baseline in log pain-free walking distance showed that treatment with naftidrofuryl oxalate compared with placebo had the greatest effect (64.2%) followed by cilostazol (13.4%) and pentoxifylline (9.2%). The 95% credible interval suggested that treatment with naftidrofuryl oxalate and cilostazol compared with placebo resulted in increases in the percentage change from baseline pain-free walking distance, although there was some uncertainty about the true effect. The variation between studies was moderate, and probably reflected differences in the design of the studies.
## Adverse events
The reporting of adverse event data varied across the trials. A number of trials reported only the adverse events that led patients to stop taking the drug. Other studies reported no clear clinical criteria for adverse events. Only two trials that reported adverse events had a follow-up of more than 24 weeks. These factors meant the Assessment Group could not undertake a meta-analysis of adverse events.
Of the 26 trials included in the Assessment Group's systematic review, 18 reported on deaths (nine comparing cilostazol with placebo, two comparing cilostazol with pentoxifylline, one comparing naftidrofuryl oxalate with placebo, five comparing pentoxifylline with placebo and one comparing inositol with placebo). Follow-up was relatively short and no significant differences in mortality rates were reported between any treatment groups.
Cardiovascular events were reported in 18 of the 26 trials identified by the Assessment Group (eight comparing cilostazol with placebo, which were included in a published analysis of adverse events; one comparing naftidrofuryl oxalate with placebo; six comparing pentoxifylline with placebo; and three comparing inositol nicotinate with placebo). No significant differences in cardiovascular events were observed between any treatment groups.
With respect to other adverse events, eight of the trials comparing cilostazol with placebo were included in a published analysis of adverse events. The results showed a higher frequency of headaches, diarrhoea, peripheral oedema and palpitations in the cilostazol groups than in the placebo groups. In three trials that compared cilostazol with pentoxifylline, similar rates of serious adverse events and adverse events were reported in both treatment groups.
In the studies that compared pentoxifylline with placebo, similar rates of adverse and serious adverse events were reported in both groups. Non-serious adverse events were mostly headaches or gastrointestinal complaints.
In the studies that compared 600 mg or 300 mg of naftidrofuryl oxalate with placebo the rates of adverse events and serious adverse events were similar between treatment groups.
Four trials that compared inositol nicotinate with placebo reported only adverse events that led to withdrawal from trials, and these were similar between treatment groups and mostly related to difficulty in swallowing or gastrointestinal problems.
# Cost effectiveness
None of the five manufacturers submitted cost-effectiveness evidence or an economic model.
The Assessment Group developed a de novo Markov economic model to estimate the cost effectiveness of the vasoactive drugs cilostazol, naftidrofuryl oxalate and pentoxifylline compared with each other and with no vasoactive drugs. The Assessment Group stated that it excluded inositol nicotinate from the main analysis because it had not been possible to include it in the meta-analyses of maximum walking distance and pain-free walking distance. Instead, the cost effectiveness of inositol nicotinate was assessed in a threshold analysis to determine how effective (in terms of quality-adjusted life years ) inositol nicotinate would have to be to consider it a cost-effective use of NHS resources.
The model had three distinct health states: treatment with one of the four drugs under evaluation, no treatment (in which patients received none of the four drugs or had received the drug but had discontinued it) and death. The Assessment Group did not include a state reflecting progression of disease in the economic model, because the drugs under evaluation relieve symptoms and are not assumed to affect disease progression or the incidence of cardiovascular events. The model assumed that treatment with vasoactive drugs improved quality of life. It also assumed that a person could stop drug treatment because of adverse events, deaths or for other reasons of non-adherence. The model assumed no further benefit once drug treatment was stopped. The model had a cycle of 1 week and a lifetime horizon.
The population included in the economic model comprised people with peripheral arterial disease, whose intermittent claudication had been stable for at least 3 months and whose symptoms continued despite conventional management including exercise and stopping smoking. The Assessment Group chose 66 years as the average age of patients with intermittent claudication based on one of the trials comparing cilostazol with placebo, which had the longest follow-up period and the largest sample size of all randomised controlled trials included in the Assessment Group's systematic review. The economic model did not distinguish between people followed in primary and secondary care. An exploratory subgroup analysis was presented for people who have more severe intermittent claudication who might have angioplasty after stopping one of the vasoactive drugs.
Only two randomised controlled trials (both for cilostazol) included in the Assessment Group's systematic review provided quality of life data from SF-36. The Assessment Group converted these to utility values using a published algorithm. The Assessment Group requested patient-level or summary SF-36 data from the authors of both trials in which the SF-36 questionnaire was used. The Assessment Group aimed to use the data to determine a relationship between the change in mean walking distance and the change in SF-36 to the change in utility scores, which it could then use to estimate the utility gain for each of the four vasoactive drugs. The authors of one trial comparing cilostazol with no vasoactive treatment provided a complete set of patient-level data (n = 106) for mean walking distance and SF-36 scores.
The Assessment Group estimated utility values using a published algorithm for converting SF-36 data at week 0 and 24. The patient-level data were used to test for a correlation between the change in maximum walking distance and the change in utility values from week 0 to week 24. The Assessment Group then used a linear regression model to estimate the absolute changes in utility values from the absolute change in the maximum walking distance on the logarithm scale during the period of the randomised controlled trial. The Assessment Group applied a regression model to all four treatments and to no vasoactive treatment to estimate the absolute changes in utility values given a certain change in mean walking distance from week 0 to week 24. The Assessment Group also estimated a mean baseline (that is, at week 0) utility value of 0.4838 using the patient-level data.
The Assessment Group applied age-adjusted utility values for the general population (that is, for people unlikely to have intermittent claudication) from a published algorithm. The Assessment Group then adjusted these utility values for the general population downwards to account for the lower average utility associated with intermittent claudication. The Assessment Group estimated that at 24 weeks the mean utility of a person who had not been treated with a vasoactive drug was 0.4873, compared with values of 0.4973 for cilostazol, 0.5088 for naftidrofuryl oxalate and 0.4919 for pentoxifylline.
The Assessment Group assumed that mortality rates did not differ whether a patient received treatment or not, or by which treatment a patient received, because vasoactive treatment provides only symptomatic relief and is unlikely to affect the progression of peripheral vascular, or other cardiovascular, disease. The Assessment Group obtained the death rates in the general population from the life tables for England and Wales (Office for National Statistics, 2008). The mortality of the general population was multiplied by a factor reflecting the increased mortality for patients with intermittent claudication (relative risk 1.6) based on a study of the risk of mortality and cardiovascular disease associated with a low ankle-brachial pressure index.
The Assessment Group based the costs of the drugs on the drug tariff of October 2010. If there was more than one licensed dose, the Assessment Group used the cost associated with the doses used in the trials included in its systematic review. In the base case, the model used the cost of generic naftidrofuryl oxalate. In sensitivity analyses, the Assessment Group explored the impact on the incremental cost-effectiveness ratio (ICER) of using the price of the branded preparation (see 4.2.11). The Assessment Group assumed that no difference existed in the costs of diagnosis and frequency of follow-up visits for people treated with vasoactive drugs compared with people not treated with vasoactive drugs.
The base-case results suggested that cilostazol compared with no vasoactive drug provided 0.019 additional QALYs at an additional cost of £964, resulting in an ICER OF £50,737 per QALY gained. Naftidrofuryl oxalate compared with no vasoactive drug provided 0.049 additional QALYs at an additional cost of £298, resulting in an ICER of £6070 per QALY gained. Pentoxifylline was estimated to have the smallest QALY gains (0.009) compared with no vasoactive drug at an additional cost of £493, resulting in an ICER of £54,777 per QALY gained. Overall, the results showed that both pentoxifylline and cilostazol are dominated by naftidrofuryl oxalate, which resulted in the largest total QALY gain and was associated with the lowest additional costs.
The Assessment Group undertook one-way sensitivity analyses using the following assumptions: that the utility value does not drop if the drug is stopped after 24 weeks; alternative baseline utility values; an alternative cost for naftidrofuryl oxalate (the price of the branded preparation); shorter time horizon; alternative starting age (55 years) and alternative rates of discontinuation. The results of the sensitivity analyses indicated that the ICERs of naftidrofuryl oxalate were relatively insensitive to different baseline utility values, alternative starting ages, and alternative long-term discontinuation rates. However, the ICER of naftidrofuryl oxalate decreased to £1538 per QALY gained when the effectiveness associated with the vasoactive drugs was assumed to continue over a patient's lifetime when they stop the drug after 24 weeks. The Assessment Group also explored the impact on the ICER of using the price of the branded preparation of naftidrofuryl oxalate in a sensitivity analysis, which increased the ICER to £11,060 per QALY gained. In all of the sensitivity analyses performed by the Assessment Group, both cilostazol and pentoxifylline were dominated or extendedly dominated by naftidrofuryl oxalate.
The Assessment Group provided threshold analyses that estimated the number of QALYs each drug would have to generate to result in ICERs below £20,000 and £30,000 per QALY gained. These analyses showed that naftidrofuryl oxalate needed the smallest QALY gains compared with no vasoactive treatment of 0.015 and 0.010. Pentoxifylline needed QALY gains of 0.025 and 0.016, cilostazol needed QALY gains of 0.048 and 0.032, and inositol nicotinate needed QALY gains of 0.085 and 0.056 respectively.
In response to consultation on the appraisal consultation document, the manufacturer of cilostazol expressed concerns that the network meta-analyses undertaken by the Assessment Group may have overestimated the clinical benefit of naftidrofuryl oxalate, and highlighted the exclusion of one of three excluded trials of naftidrofuryl oxalate from the network-meta analyses. The 24 week trial highlighted by the manufacturer was published in 1986 and compared naftidrofuryl oxalate 600 mg (n = 64) with placebo (n = 54). The Assessment Group had explained in its assessment report that this trial did not directly report maximum walking distance and had therefore been excluded. However, after consultation the Assessment Group identified data on maximum walking distance from the trial reported in a Cochrane review of naftidrofuryl oxalate for intermittent claudication, noting that it was not possible to validate the data from the original trial. The Assessment Group then undertook a sensitivity analysis to explore the impact on the ICER of including this trial in the meta-analysis. The results indicated that including the trial in the network meta-analysis reduced the estimated effectiveness of naftidrofuryl oxalate. However, naftidrofuryl oxalate continued to have a significant effect and its effectiveness relative to the other vasoactive drugs did not change. Including this data in the economic model increased the ICER for naftidrofuryl oxalate from £6070 (base case) to £8321 per QALY gained.
# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate having considered evidence on the nature of intermittent claudication in people with peripheral arterial disease and the value placed on the benefits of these drugs by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee discussed the current clinical management for intermittent claudication in people with peripheral arterial disease. It heard that it is common practice for a specialist vascular clinic to diagnose intermittent claudication before starting drug treatment aimed at relieving symptoms. It also heard that diagnosis and treatment with vasoactive drugs can take place in primary care. The Committee heard from the clinical specialists that vasoactive therapy was an important part of treatment for intermittent claudication, but represents one part of a wider programme of management. This approach involves pharmacological treatment (for example, therapy with antiplatelet drugs and statins to prevent myocardial infarction and stroke) and non-pharmacological treatment including changes in lifestyle (for example, stopping smoking), exercise programmes, and revascularisation (for example, angioplasty). The clinical specialists highlighted the importance of lifestyle changes and exercise programmes, in particular supervised programmes, in the clinical management of the condition, but also that few patients in the NHS had access to supervised programmes in England and Wales. The Committee accepted that that treatment with vasoactive drugs does not replace or precede the importance of stopping smoking and increasing exercise.
The Committee heard from the clinical specialists that vasoactive drugs relieve symptoms but do not delay progression of peripheral arterial disease or lower the incidence of myocardial infarction, stroke or lower extremity amputation. It also heard that most clinicians offer vasodilator therapy only to those patients for whom angioplasty is considered inappropriate or has failed. In addition, the clinical specialists explained that prescribing of vasoactive therapies varies across clinical practice, but that cilostazol and naftidrofuryl oxalate were more commonly prescribed than pentoxifylline and inositol nicotinate. The Committee heard from consultees and commentators that clinicians may offer vasodilator therapy before assessing whether angioplasty would be appropriate, while a patient is awaiting revascularisation, to patients who do not have easy access to a supervised exercise programme or for whom a trial of supervised exercise of 8–16 weeks did not improve the symptoms of claudication. The Committee was aware that a NICE clinical guideline on 'Lower limb peripheral arterial disease: diagnosis and management' is being developed to help define clinical practice, and that this appraisal would contribute to the guideline. For the purposes of this guidance, and reflecting the scope for this appraisal, the Committee concluded that it would only be appropriate to consider the use of vasodilators after taking into account other treatment options, for example exercise and treatment to reduce the risk of cardiovascular events. The Committee was aware that the clinical and cost effectiveness of the vasoactive drugs may vary depending on their place in the treatment pathway. However, the Committee concluded that its remit was to appraise cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate in a situation in which vasodilator therapy is deemed the most appropriate treatment option among the other treatment options available, such as exercise therapy or angioplasty (that is, when the vasodilator drugs would be compared with each other and with best supportive care). The Committee also concluded that drug treatment should not replace referral for consideration of specialist treatment.
The Committee considered groups of patients in which the clinical pathway might differ, and heard from the clinical specialists that patients with diabetes might have atherosclerotic disease that is less likely to respond to angioplasty. The Committee heard that patients with diabetes were more likely to have intermittent claudication than people without diabetes, but that a person with diabetes was more likely than a person without diabetes to have peripheral arterial disease without symptoms of pain. Given the evidence, the Committee accepted that there was no group of patients in which the clinical pathway might differ, and concluded that no specific recommendation for any subgroup of patients would be made.
The Committee discussed the clinical need of people with intermittent claudication. It was aware that severe pain on physical exertion has a large impact on the quality of life, resulting largely from restricted mobility. This may lead to loss of independence, limited social life and decreased participation in recreation and work activities. The Committee concluded that intermittent claudication negatively affects quality of life.
## Clinical effectiveness
The Committee considered the evidence for the clinical effectiveness of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate presented by the Assessment Group. The Committee noted that the trials reported a number of endpoints measuring efficacy including maximum walking distance, pain-free walking distance and ankle brachial pressure index. The Committee heard from the clinical specialists that neither the ankle brachial pressure index nor pain-free walking distance were clinically relevant outcome measures. The ankle brachial pressure index is used in clinical practice only as a diagnostic tool for peripheral arterial disease, and a patient is unlikely to be offered treadmill testing in the course of routine clinical practice. In addition, pain-free walking distance can be difficult to assess without using the fixed-speed treadmill because patients usually adjust the speed of their walking to avoid pain and to maximise walking distance. The Committee agreed that it was appropriate to focus on the Assessment Group's analyses of maximum walking distance.
The Committee considered the differences in clinical effectiveness between cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate from the maximum walking distances reported in the randomised controlled trials. It noted that the majority of the trials compared one of the four drugs with placebo and that the only head-to-head comparison was that of cilostazol compared with pentoxifylline. The Committee was aware that the size of the treatment effect reported in the trials for each of the drugs varied. The Committee noted that the publication dates of the included trials span 20 years (from 1989 to 2009) and heard from the Assessment Group that the variation in the size of the treatment effect across these trials was a result of the changes in standard clinical practice over time. The Committee heard from the clinical specialists that a clinically significant improvement in maximum walking distance approximated 50 metres, or, in relative terms, a 100% increase. The Committee also noted that in the trials, patients randomised to either treatment or placebo tended to improve. However, the Committee recognised that the evidence showed that cilostazol and naftidrofuryl oxalate clinically significantly improved maximum walking distance compared with placebo.
The Committee discussed the Assessment Group's network meta-analysis that estimated the change in log maximum walking distance from baseline to the end of the trial. It was aware that the Assessment Group had excluded trials of inositol nicotinate because the trials had follow-up periods of only 12 weeks and it considered the data reported in these trials to be unsuitable for inclusion in the meta-analysis because there was no information reported on proportional change from baseline. The Committee noted from the meta-analysis that treatment with naftidrofuryl oxalate had the greatest effect of the three drugs relative to placebo (that is, a 60% increase from baseline walking distance), followed by cilostazol (25%) and pentoxifylline (11%). Given these results, the Committee considered whether it would be appropriate to infer a difference in the clinical effectiveness of the drugs. The Committee noted the credible intervals around the estimates of effectiveness, which indicated some uncertainty about the true effects. The Committee discussed the duration of follow-up and the heterogeneity between trials. For example, the Committee heard that, in general, the trials did not differentiate between patients who had or had not had previous exercise therapy. The Committee also discussed that only one trial of naftidrofuryl oxalate was included in the meta-analysis. The Committee considered that the above-listed issues contributed to uncertainty in the results of the meta-analysis.
The Committee discussed the duration of follow-up of the trials included in the network meta-analysis. The Committee noted that the trials had a follow-up of 24 weeks, which it understood to be relatively short term compared with clinical practice, in which patients could take vasoactive drugs indefinitely. The Committee heard that trials in which an effect was seen at 24 weeks generally had also showed an effect at 12 weeks. The Committee heard from the clinical specialists that in current clinical practice clinicians stop vasoactive therapy if there is not an adequate response to treatment after 12 weeks. The Committee also heard from the Assessment Group that the trials of inositol nicotinate excluded from the meta-analysis were excluded for reasons other than their duration (for example, they did not include data on maximum walking distance or were reported in a way that did not allow comparison of results across studies). The Committee heard that there is no agreement about the magnitude of improvement in walking distance needed to define an adequate response to vasoactive therapy. The Committee considered whether the impact of the vasoactive drugs on walking distance was likely to be sustained in the long term. However, the clinical specialists did not expect that if effective treatment was stopped for a reason other than inadequate response that a patient would continue to experience relief of symptoms. The Committee accepted that the duration of follow-up of the trials did not lead to uncertainty around the size of effect.
The Committee then considered the differences between the trials included in the network meta-analysis. The Committee considered whether this could lead to bias in the analyses of the comparative clinical effectiveness of cilostazol, naftidrofuryl oxalate and pentoxifylline. The Committee heard from the Assessment Group that the eligibility criteria and baseline characteristics of patients recruited were similar across the trials. The Committee noted the concerns raised by the manufacturer of cilostazol about the inclusion of trials that used different treadmill protocols, but acknowledged that any differences that might exist between trials had been quantified by the use of a random effects network meta-analysis. The Committee accepted that the heterogeneity in the trials could lead to bias in the estimated effectiveness of these drugs, but was persuaded that the relative benefits in terms of improvement in maximum walking distance was plausible given the empirical data.
The Committee discussed the number of trials of naftidrofuryl oxalate included in the meta-analysis. It noted that only one out of the five trials of naftidrofuryl oxalate compared with placebo identified by the Assessment Group was included in the meta-analysis and in particular that the Assessment Group had excluded the largest trial, which included over 700 participants. The Committee recognised that these trials were excluded because they did not include data on maximum walking distance or that data on maximum walking distance was not comparable across studies. The Committee noted the concerns of some consultees and commentators about the degree of transparency of trial selection. The Assessment Group highlighted that a network meta-analysis is not restricted by the number of the studies for each treatment under evaluation, or by the number of the patients randomised to each treatment arm. The Assessment Group stated that the selection of trials followed a pre-planned protocol that allowed trials to be excluded. Trials were excluded if: duration was less than 24 weeks; data on maximum walking distance were not reported or were reported in a way that did not allow comparison of results across trials; the trial did not evaluate the licensed doses of the drug; or the trial was published in a language other than English (see section 4.1.13). The Committee understood that it was common practice among Assessment Groups to exclude publications in languages other than English because of resource constraints, but agreed that whenever possible non-English language publications should be included to reduce the risk of bias. The Assessment Group informed the Committee that a review of existing trial data was undertaken by the authors of the Cochrane review of naftidrofuryl oxalate for intermittent claudication which suggested that there was no evidence of publication bias. The Committee heard from the Assessment Group that relevant trials that were not published in English may have been missed, but that methodological studies have indicated that language restrictions do not often influence the results of systematic reviews of conventional medicines. The Committee accepted the Assessment Group's rationale for excluding studies from the meta-analysis and agreed that the Assessment Group's process was transparent.
The Committee noted that the Assessment Group had undertaken an additional sensitivity analysis that included data from a trial that it had excluded from its network meta-analysis but that had been highlighted for possible inclusion by the manufacturer (see section 4.2.13). It noted that including this trial resulted in a reduction in the estimated effectiveness of naftidrofuryl oxalate but that naftidrofuryl oxalate continued to have a significant effect and the effectiveness relative to the other vasoactive drugs did not change. The Committee concluded that the Assessment Group may have originally over-estimated the clinical effectiveness of naftidrofuryl oxalate as a result of excluding trials but was persuaded by the evidence presented that naftidrofuryl oxalate continued to have the largest effect compared with cilostazol and pentoxifylline.
The Committee noted that the point estimates for maximum walking distance for cilostazol, naftidrofuryl oxalate and pentoxifylline compared with placebo obtained from the meta-analysis were similar to those obtained from the direct estimates from the randomised clinical trials, but were associated with narrower credible intervals, indicating a greater degree of certainty about the effectiveness point estimates. The Committee concluded that based on the Assessment Group's network meta-analysis, cilostazol, naftidrofuryl oxalate and pentoxifylline improved maximum walking distance compared with placebo. In addition the Committee concluded that naftidrofuryl oxalate had been demonstrated to be more effective than cilostazol and pentoxifylline. Because the meta-analysis did not include any information on the clinical effectiveness of inositol nicotinate, the Committee concluded that it was unable to assess the efficacy of inositol nicotinate compared with cilostazol, naftidrofuryl oxalate and pentoxifylline.
The Committee discussed the adverse events seen in the trials of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate. It noted that the data from the trials suggested that non-serious adverse events (such as headaches and gastrointestinal complaints) and serious adverse events (such as cardiovascular events and death) did not differ between the groups given vasoactive drugs and those given placebo. The Committee acknowledged that the trials were not designed to address mortality, and, in any event, were too short or too small to detect a difference if one existed. The Committee also noted that the clinical specialists did not have concerns about the long-term safety of the vasoactive drugs. The Committee concluded that, based on the currently available information, there were no major concerns about the adverse effects of the vasodilator drugs being appraised.
## Cost effectiveness
The Committee examined the economic modelling developed for the appraisal and agreed that the Assessment Group's economic evaluation was of good quality. Because the drugs did not affect the risk of fatal cardiovascular disease, the Committee recognised that the QALYs in the model were driven by the utility gain from increased mobility rather than from any survival benefit. The Committee noted that the utility values used in the model were derived from a regression model using the change in maximum walking distance and SF-36 data, based on patient-level data from a trial of cilostazol compared with placebo. The Committee noted the concerns raised by the manufacturer of cilostazol that there was uncertainty about the association between maximum walking distance and utility because the trial from which the Assessment Group derived the estimates was small (n = 109), and the Assessment Group assumed that the association was the same for all of the vasoactive drugs. The Committee acknowledged this uncertainty but noted that the order of the utility values was consistent with the order of effectiveness of the vasoactive drugs as shown in the meta-analysis. The Committee was aware that commentators had called for future research to better quantify the association between clinical endpoints relevant to peripheral arterial disease and quality of life. The Committee also recognised the limited published evidence for quality of life associated with these drugs. It agreed that the approach used by the Assessment Group to obtain utility values for the economic model was acceptable, while proposing that further research be undertaken (see section 6.1).
The Committee then considered whether there were any other health-related benefits that had not been adequately captured in the Assessment Group's economic model. It heard from the manufacturer of cilostazol that because of cilostazol's pharmacological profile, the drug improves cardiovascular risk factors (for example, by its anti-platelet actions). The Committee was aware that the CASTLE trial ('Cilostazol: a study in long-term effects'), a randomised, double-blinded, placebo-controlled safety study of cilostazol compared with placebo, was designed to detect a difference in mortality, but found none. The manufacturer informed the Committee that cilostazol was used to prevent strokes, but that this benefit had not been demonstrated in the population identified in this appraisal, that is, people with intermittent claudication. Furthermore, the Committee noted that the manufacturer had not submitted any evidence related to these potential benefits in its original submission or during consultation. The Committee was aware that the marketing authorisation for cilostazol in the UK did not go beyond the treatment of intermittent claudication. The Committee concluded that there was no evidence available on benefits other than improvement in maximum walking distance related to health-related quality of life.
The Committee considered the ICERs derived from the Assessment Group's economic model of £50,700, £6070, £11,060 and £54,800 per QALY gained for cilostazol, generic naftidrofuryl oxalate, branded naftidrofuryl oxalate and pentoxifylline, respectively, when each was compared with placebo. The Committee was aware that naftidrofuryl oxalate was associated with the largest QALY gain and the lowest cost, thereby dominating cilostazol and pentoxifylline. The Committee recognised that there was uncertainty associated with the ICERs for naftidrofuryl oxalate because the data for naftidrofuryl oxalate included in the model were originally derived from only one trial. The Committee was aware of the additional sensitivity analysis undertaken by the Assessment Group (see 4.2.13), which indicated that the inclusion of the additional data for naftidrofuryl oxalate within the meta-analysis had a limited impact on the cost-effectiveness results. The Committee agreed that because of the low ICER for naftidrofuryl oxalate, the Committee could accept the uncertainty associated with the ICER. It therefore concluded that it could recommend naftidrofuryl oxalate as a cost-effective use of NHS resources when vasodilator therapy is considered appropriate after taking into account other treatment options, and that treatment with naftidrofuryl oxalate should be started with the least costly licensed preparation. The Committee also agreed that drug treatment should not replace referral for consideration of specialist treatment. The Committee agreed that it could not consider cilostazol and pentoxifylline to be appropriate treatment options, because naftidrofuryl oxalate dominates cilostazol and pentoxifylline. It noted that some consultees and commentators had agreed with the Committee's preliminary decision about this. The Committee noted that the ICERs for cilostazol and pentoxifylline compared with placebo exceeded those normally considered to be an acceptable use of NHS resources. It concluded that cilostazol and pentoxifylline could not be recommended as a cost-effective use of NHS resources for people with contraindications to naftidrofuryl oxalate.
The Committee considered the Assessment Group's threshold analysis of the cost effectiveness of inositol nicotinate. The Committee noted that the estimated QALY gains needed for the ICER of inositol nicotinate compared with placebo to fall below £20,000 or £30,000 per QALY gained were 0.085 or 0.056 respectively. The Committee was aware that these were much higher than the QALY gains actually calculated for naftidrofuryl oxalate (0.015 and 0.010 respectively). The Committee inferred that for inositol nicotinate to be considered cost effective, it would need to demonstrate a considerably greater impact on quality of life from improving maximum walking distance than those demonstrated for the other vasoactive drugs. The Committee did not consider this plausible, because the only trial in the Assessment Group's systematic review that reported that inositol nicotinate did not improve maximum walking distance any more than placebo. The Committee therefore concluded that it could not recommend inositol nicotinate as a cost-effective use of NHS resources.
The Committee considered whether its preliminary recommendations were associated with any issues related to equality legislation and the requirement for fairness. The Committee noted that no issues had been highlighted during the scoping exercise or during the course of the appraisal. The Committee was aware that the prevalence of peripheral arterial disease differs between ethnic groups, but concluded that the recommendations do not affect access to the technology for any specific groups.
# Summary of Appraisal Committee's key conclusions
TA223
Appraisal title: 'Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease'
Section
Key conclusion
Naftidrofuryl oxalate is recommended as an option for the treatment of intermittent claudication in people with peripheral arterial disease for whom vasodilator therapy is considered appropriate after taking into account other treatment options. Treatment with naftidrofuryl oxalate should be started with the least costly licensed preparation.
Cilostazol, pentoxifylline and inositol nicotinate are not recommended for the treatment of intermittent claudication in people with peripheral arterial disease.
Reasons for the recommendations:
The Committee concluded that naftidrofuryl oxalate is more effective than cilostazol and pentoxifylline. Because the meta-analysis did not include any trials of inositol nicotinate, the Committee was unable to assess the relative efficacy of inositol nicotinate.
The Committee concluded that there was uncertainty about the ICERs for naftidrofuryl oxalate but that this uncertainty could be accepted in light of the low ICERs of £6070 and £11,060 per QALY gained for the generic and branded preparation of naftidrofuryl oxalate respectively.
Naftidrofuryl oxalate dominated cilostazol and pentoxifylline, and even when compared with placebo the ICERs for cilostazol and pentoxifylline were £50,740 and £54,800 per QALY gained respectively.
From the threshold analysis, the Committee inferred that for inositol nicotinate to be considered cost effective it would need to demonstrate a considerably greater impact on quality of life from improving maximum walking distance than those demonstrated for the other vasoactive drugs. The Committee did not consider this assumption plausible, because the only trial in the Assessment Group's systematic review that reported maximum walking distance for inositol nicotinate did not show an improvement in maximum walking distance any greater than for placebo.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee was aware that severe pain on physical exertion has a large impact on the quality of life, resulting largely from restricted mobility. This may lead to loss of independence, limited social life and decreased participation in recreation and work activities. The Committee concluded that intermittent claudication negatively affects quality of life.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate are vasodilator drugs and have marketing authorisations for the symptomatic relief of intermittent claudication.
No specific claims of innovation were made.
What is the position of the treatment in the pathway of care for the condition?
The Committee heard from the clinical specialists that vasoactive therapy was an important part of treatment for intermittent claudication, but represents one part of a wider programme of management. This approach involves pharmacological (for example, therapy with antiplatelet drugs and statins to prevent myocardial infarction and stroke) and non-pharmacological treatment including changes in lifestyle (for example, stopping smoking), exercise programmes, and revascularisation (for example, angioplasty). The Committee accepted that treatment with vasoactive drugs does not replace or precede the importance of stopping smoking and increasing exercise.
The Committee heard from consultees and commentators that clinicians may offer vasodilator therapy before assessing whether angioplasty would be appropriate, while a patient is waiting revascularisation, to patients who do not have easy access to a supervised exercise programme or for whom a trial of supervised exercise of 8–16 weeks did not improve the symptoms of claudication. The Committee was aware that a NICE clinical guideline on 'Lower limb peripheral arterial disease: diagnosis and management' is being developed to help define clinical practice, and that this appraisal would contribute to the guideline.
Adverse effects
The Committee noted that the data from the trials suggested that non-serious adverse events (such as headaches and gastrointestinal complaints) and serious adverse events (such as cardiovascular events and death) did not differ between the groups given vasoactive drugs and those given placebo. The Committee concluded that, based on the currently available information, there were no major concerns about the adverse effects of the vasodilator drugs being appraised.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The trials reported a number of endpoints measuring efficacy including maximum walking distance, pain-free walking distance and ankle brachial pressure index. The Committee agreed that it was appropriate to focus on the Assessment Group's analyses of maximum walking distance.
The majority of the trials compared the four drugs with placebo and that one trial compared cilostazol with pentoxifylline.
The Assessment Group undertook a network meta-analysis that estimated the change from baseline in log maximum walking distance. The network meta-analysis excluded trials of inositol nicotinate.
Relevance to general clinical practice in the NHS
No specific issues were raised.
Uncertainties generated by the evidence
The Committee noted the credible intervals (from the network meta-analysis of maximum walking distance) around the estimates of effectiveness, which indicated some uncertainty about the true effects. The Committee discussed the duration of follow-up and the heterogeneity between trials. The Committee considered that the above-listed issues contributed to uncertainty in the results of the meta-analysis.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee considered groups of patients in which the clinical pathway might differ, and heard from the clinical specialists that patients with diabetes might have atherosclerotic disease that is less likely to respond to angioplasty. The Committee accepted that there was no group of patients in which the clinical pathway might differ and concluded that no specific recommendation for any subgroup would be made.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee recognised that the evidence for cilostazol and naftidrofuryl oxalate showed that there was a clinically significant improvement in maximum walking distance compared with the placebo groups.
The Committee noted from the meta-analysis that treatment with naftidrofuryl oxalate had the greatest effect relative to placebo (that is, a 60% increase from baseline walking distance), followed by cilostazol (25%) and pentoxifylline (11%). The Committee noted the credible intervals around the estimates of effectiveness, which indicated that there was some uncertainty about the true effects. The Committee considered the duration of follow-up and the heterogeneity between trials and the inclusion of only a single trial of naftidrofuryl oxalate, because these contributed to the uncertainty in the results of the meta-analysis. The Committee concluded that the Assessment Group may have over-estimated the clinical effectiveness of naftidrofuryl oxalate as a result of excluding trials but was persuaded by the evidence presented that naftidrofuryl oxalate had the largest effect compared with cilostazol and pentoxifylline.
Because the meta-analysis did not include any information on the clinical effectiveness of inositol nicotinate, the Committee concluded that it was unable to assess the efficacy of inositol nicotinate compared with cilostazol, naftidrofuryl oxalate and pentoxifylline.
Evidence for cost effectiveness
Availability and nature of evidence
None of the manufacturers submitted economic evaluations or economic models.
The Committee agreed that the Assessment Group's economic evaluation was of good quality.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted that the utility values used in the model were derived from a regression model using the change in maximum walking distance and SF-36 data, based on patient-level data from a trial of cilostazol compared with placebo. The Committee noted the concerns raised by the manufacturer of cilostazol that there was uncertainty about the association between maximum walking distance and utility because the trial from which the estimate was derived was small and the Assessment Group had assumed that the association was the same for all vasoactive drugs. However, the Committee noted that the order of the utility values was consistent with the order of effectiveness of the vasoactive drugs as shown in the meta-analysis. The Committee recognised the limited published evidence for quality of life associated with these drugs, and agreed that the approach used by the Assessment Group to obtain utility values for the economic model was acceptable, while proposing that further research be undertaken.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
Because the drugs did not affect the risk of fatal cardiovascular disease, the Committee recognised that the QALYs in the model were driven by the utility gain from increased mobility rather than from any survival benefit.
The Committee considered whether there were any other health-related benefits that had not been adequately captured in the Assessment Group's economic model. It heard from the manufacturer of cilostazol that because of cilostazol's pharmacological profile, the drug improves cardiovascular risk factors. The manufacturer informed the Committee that cilostazol was used to prevent strokes, but that this benefit had not been demonstrated in the population defined in this appraisal. Furthermore, the Committee noted that the manufacturer had not submitted any evidence related to these potential benefits. The Committee was aware that the marketing authorisation for cilostazol in the UK did not go beyond the treatment of intermittent claudication. The Committee concluded that there was no evidence available on benefits other than improvement in maximum walking distance related to health-related quality of life.
Are there specific groups of people for whom the technology is particularly cost effective?
Not applicable.
What are the key drivers of cost effectiveness?
No key drivers were identified apart from the differences between treatment costs and utility values related to the differences in maximum walking distance.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee recognised that there was uncertainty associated with the ICERs for naftidrofuryl oxalate compared with placebo (£11,060 for the branded version, £6070 for the generic version) because the data for naftidrofuryl oxalate included in the model were originally derived from only one trial. The Committee was aware of the additional sensitivity analyses undertaken by the Assessment Group, which indicated that the inclusion of the additional data for naftidrofuryl oxalate within the meta-analysis had a limited impact on the cost-effectiveness results (£8321 per QALY gained). The Committee agreed that because of the low ICERs for naftidrofuryl oxalate, it could accept the uncertainty associated with the ICERs.
The Committee noted that naftidrofuryl oxalate was associated with the largest QALY gain and lowest cost, thereby dominating cilostazol and pentoxifylline. The Committee also noted that the ICERs for cilostazol and pentoxifylline were £50,700 and £54,800 per QALY gained respectively when each was compared with placebo.
The Committee inferred that for inositol nicotinate to be considered cost effective, it would need to demonstrate considerably greater impacts on quality of life from improving maximum walking distance than those demonstrated for the other vasoactive drugs. The Committee did not consider this assumption plausible, because the only trial in the Assessment Group's systematic review that reported maximum walking distance for inositol nicotinate did not show an improvement in maximum walking distance any greater than for placebo.
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
The Committee noted that no issues had been highlighted during the scoping exercise or during the course of the appraisal. The Committee was aware that the prevalence of peripheral arterial disease differs between ethnic groups, but concluded that the recommendations do not affect access to the technology for any specific groups.
One clinical specialist and a representative of the Guideline Development Group developing the NICE clinical guideline 'Lower limb peripheral arterial disease: diagnosis and management' attended the Appraisal Committee meeting. For the purposes of this document they are both referred to as clinical specialists.# Recommendations for further research
A trial comparing the long-term effectiveness (beyond 24 weeks) of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate and placebo would be beneficial. It should collect utility data as well as walking distance outcomes.# Related NICE guidance
# Published
Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of NICE technology appraisal guidance 90). NICE technology appraisal guidance 210 (2010).
# Under development
NICE is developing the following guidance (details available from the NICE website):
Lower limb peripheral arterial disease. NICE clinical guideline. Publication expected October 2012.# Review of guidance
The guidance on this technology will be considered for review in May 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveMay 2011# Changes after publication
February 2014: implementation section updated to clarify that naftidrofuryl oxalate is recommended as an option for treating people with intermittent claudication who have peripheral arterial disease. Additional minor maintenance update also carried out.
March 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE multiple technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance ': 'Naftidrofuryl oxalate is recommended as an option for the treatment of intermittent claudication in people with peripheral arterial disease for whom vasodilator therapy is considered appropriate after taking into account other treatment options. Treatment with naftidrofuryl oxalate should be started with the least costly licensed preparation.\n\nCilostazol, pentoxifylline and inositol nicotinate are not recommended for the treatment of intermittent claudication in people with peripheral arterial disease.\n\nPeople currently receiving cilostazol, pentoxifylline and inositol nicotinate should have the option to continue treatment until they and their clinicians consider it appropriate to stop.', 'Clinical need and practice': "Peripheral arterial disease, also known as peripheral vascular disease, is a condition in which arteries that carry blood to the legs or arms are narrowed or blocked. The main cause of peripheral arterial disease is atherosclerosis. The major risk factors for peripheral arterial disease are smoking, diabetes mellitus and pre-existing cardiovascular disease. Other factors include increasing age, male sex, ethnicity, hypertension, hypercholesterolaemia, renal insufficiency and a sedentary lifestyle\n\nThe Fontaine scheme classifies four stages of peripheral arterial disease. Peripheral arterial disease can be asymptomatic (Fontaine stage I) or symptomatic (Fontaine stages II–IV). The most common symptom of peripheral arterial disease is intermittent claudication (Fontaine\xa0stage II), which is characterised by pain in the legs or buttocks that occurs with exercise and is relieved with rest. Two further stages exist: pain in the extremities at rest (ischaemic rest pain, Fontaine stage III) and necrosis and gangrene (Fontaine stage IV).\n\nThe pain associated with intermittent claudication occurs because of a lack of oxygen in the leg muscles owing to the impaired blood supply. Rest normalises blood flow and relieves the pain. Intermittent claudication is most commonly associated with disease in the femoropopliteal segment of the arterial circulation. Peripheral arterial disease can also be present at the aorto–iliac level causing pain in the thigh, hip or buttock. Peripheral arterial disease can also cause foot pain. Around 20% of people aged 55–75 years have evidence of peripheral arterial disease in the legs and a quarter of these have symptoms.\n\nIntermittent claudication worsens people's quality of life because it restricts their mobility. People with peripheral arterial disease, and specifically with intermittent claudication, are at increased risk of myocardial infarction and stroke. Additionally, people with intermittent claudication are at higher risk from cardiovascular mortality than people with asymptomatic peripheral arterial disease.\n\nThe diagnosis of intermittent claudication includes a clinical history that assesses the presence and character of the pain. A clinician may also measure a patient's ankle-brachial pressure index, that is, the ratio of the blood pressure in the lower leg to the blood pressure in the arm at rest. A value of 0.9 indicates disease, and high values (that is, greater than 1.3) may reflect arterial stiffening associated with disease.\n\nEvaluating the presence and progression of disease takes into account symptoms and signs (for example, the development of ischaemic ulcers). As an objective measure, walking on a treadmill, either at a fixed speed and slope, or a fixed speed and increasing slope, determines how far a patient can walk before developing claudication pain and how far a patient can walk with pain before having to stop.\n\nA number of interventions are used to manage intermittent claudication. Stopping smoking and increasing exercise can help reduce symptoms of claudication. People are more likely to benefit from supervised exercise programmes than from unsupervised exercise. Vasoactive drugs including cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate have marketing authorisations for the symptomatic relief of intermittent claudication and are considered in this appraisal. Angioplasty (that is, mechanical widening of the blood vessel) or other revascularisation (for example, arterial bypass) may be undertaken for people whose symptoms continue despite treatment. To reduce the risk of a heart attack or stroke, interventions include helping patients stop smoking, lowering cholesterol, controlling blood pressure, offering aspirin, and, in people with diabetes, controlling glycaemia.", 'The technologies': "Cilostazol (Pletal, Otsuka Pharmaceuticals) is an oral phosphodiesterase\xa0III inhibitor. Cilostazol is a direct arterial vasodilator and it also inhibits platelet aggregation. Cilostazol has a UK marketing authorisation for the 'improvement of the maximal and pain-free walking distances in patients with intermittent claudication, who do not have rest pain and who do not have evidence of peripheral tissue necrosis'. Cilostazol is contraindicated in people with severe renal impairment (creatinine clearance of 25\xa0ml/min or lower), moderate or severe hepatic impairment, congestive heart failure and pregnancy. Cilostazol is also contraindicated in people with any known predisposition to bleeding or with any history of ventricular tachycardia, ventricular fibrillation or multifocal ventricular ectopic beats. For full details of side effects and contraindications see the summaries of product characteristics.\n\nCilostazol is available as a 50 or 100 mg tablet at a cost of £35.31 for a 56-tablet pack (price for either dose, excluding VAT; 'British national formulary' [BNF] edition 60). The recommended dose is 100\xa0mg twice daily. Therefore, assuming 100 mg tablets are used, the average monthly cost is £38.26. Costs may vary in different settings because of negotiated procurement discounts.\n\nNaftidrofuryl oxalate (Praxilene, Merk Serono) is an oral peripheral vasodilator that selectively blocks vascular and platelet 5-hydroxytryptamine 2 (5-HT2) receptors. Naftidrofuryl oxalate has a UK marketing authorisation for 'peripheral vascular disorders – intermittent claudication, night cramps, rest pain, incipient gangrene, trophic ulcers, Raynaud's syndrome, diabetic arteriopathy and acrocyanosis'. Naftidrofuryl oxalate is contraindicated in people with a history of hyperoxaluria or recurrent calcium-containing stones. For full details of side effects and contraindications see the summary of product characteristics.\n\nNaftidrofuryl oxalate is available as a branded preparation of 100\xa0mg capsules at a cost of £8.10 for an 84-capsule pack (excluding VAT; BNF edition 60). Generic preparations are also available at a cost of £5.30 (excluding VAT; BNF edition 60), and since January 2011 at a cost of £4.52 (excluding VAT; BNF edition\xa061) for a 100\xa0mg 84-capsule pack. The recommended dose is one or two 100 mg capsules three times daily. Therefore, for the branded preparation the average monthly cost is £8.80 assuming three 100\xa0mg capsules daily or £17.89 assuming six 100\xa0mg capsules daily. For the generic preparation (that is at a cost of £5.30, excluding VAT; BNF edition 60) the average monthly cost is £4.90 for three 100 mg capsules daily or £9.79 assuming six 100\xa0mg capsules daily. Costs may vary in different settings because of negotiated procurement discounts.\n\nPentoxifylline (Trental 400, Sanofi-Aventis) is an oral peripheral vasodilator derived from methylxanthine. Pentoxifylline has a UK marketing authorisation for the 'treatment of peripheral vascular disease, including intermittent claudication and rest pain'. Pentoxifylline is contraindicated in people with cerebral haemorrhage, extensive retinal haemorrhage, acute myocardial infarction and severe cardiac arrhythmias. For full details of side effects and contraindications see the summary of product characteristics.\n\nPentoxifylline is available as a 400 mg tablet at a cost of £19.68 for a 90-tablet pack (excluding VAT; BNF edition 60). The recommended dose is one tablet three times daily. Therefore, the average monthly cost is £19.90. However, the summary of product characteristics states that two tablets daily may prove sufficient in some patients, particularly for maintenance therapy. Costs may vary in different settings because of negotiated procurement discounts.\n\nInositol nicotinate (Hexopal, Genus Pharmaceuticals) is an oral peripheral vasodilator that slows the release of nicotinic acid. Inositol nicotinate has a UK marketing authorisation for 'the symptomatic relief of severe intermittent claudication and Raynaud's phenomenon'. Inositol nicotinate is contraindicated in people who have suffered a recent myocardial infarction or are in the acute phase of a stroke. For full details of side effects and contraindications see the summaries of product characteristics.\n\nInositol nicotinate is available as a 500 mg tablet at a cost of £30.76 for a 100-tablet pack. It is also available as a 750 mg tablet at a cost of £51.03 for a 112-tablet pack (excluding VAT; BNF edition 60). The recommended dose is 3 g daily (that is, two 500\xa0mg tablets three times a day), increased to 4 g daily if necessary. The average monthly cost, assuming two 500 mg tablets three times a day, is £56.14. Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nThe Assessment Group conducted a systematic review of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate within their licensed indications for the treatment of intermittent claudication in people with peripheral arterial disease whose symptoms continue despite conventional management. The Assessment Group identified 26 randomised controlled trials, including placebo-controlled trials, for all four of the vasoactive drugs. The only head-to-head comparison was between cilostazol and pentoxifylline. The Assessment Group stated that the quality of the trials was generally good: treatment groups within trials were comparable, blinding was maintained and trials presented intention-to-treat analyses.\n\n## Cilostazol: maximum walking distance\n\nThe Assessment Group identified 11 randomised controlled trials of cilostazol 200 mg compared with placebo. In addition, three randomised controlled trials of cilostazol 200 mg compared with pentoxifylline 1200 mg and one randomised controlled trial of cilostazol 200 mg (with or without supervised exercise) compared with usual care (with or without supervised exercise) were identified. The duration of treatment of the randomised controlled trials ranged from 12 weeks to 24 weeks; 6 had a treatment duration of 24 weeks, 1 of 16 weeks and 3 of 12 weeks. The outcomes included in the trials were maximum walking distance (before having to stop because of pain), pain-free walking distance (before developing claudication pain), ankle brachial pressure index, cardiovascular events, mortality, adverse events and health-related quality of life. The mean baseline age of the participants across the trials ranged from 63 to 67 years. The number of participants in the trials ranged from 81 to 1435. Of the 11\xa0randomised controlled trials, two recruited patients from the UK (n\xa0=\xa038 and\xa0106).\n\nOf the 11 trials of cilostazol 200 mg compared with placebo, ten reported the outcome of maximum walking distance. Of these, seven showed that cilostazol improved maximum walking distance to a statistically significant degree compared with placebo. Studies reported the mean improvement in maximum walking distance either in percentages or as an absolute value. Two of the studies reported percentages; one of these reported 161.7% mean improvement for the group randomised to cilostazol and 79% mean improvement for the group randomised to placebo. The other reported a 30.5% improvement for the group randomised to cilostazol and a 9.3% worsening for the group randomised to placebo. The other studies reported mean improvement in metres. The individual results for the groups randomised to cilostazol compared with placebo respectively were: 76.2\xa0metres versus 21.1\xa0metres, 107 metres versus 65 metres, 129.1 metres versus 26.8 metres, 96.4\xa0metres versus 31.4\xa0metres and 72.7\xa0metres versus 25.8\xa0metres. Three trials that compared cilostazol with pentoxifylline reported the outcome of maximum walking distance. Only one of these trials found a statistically significant improvement in maximum walking distance for cilostazol compared with pentoxifylline (mean maximum walking distance improved by 107\xa0metres with cilostazol compared with 64 metres with pentoxifylline [p = 0.0002]). The other two studies showed no significant difference between cilostazol and pentoxifylline. One trial compared people randomised to cilostazol (with or without supervised exercise) with usual care (with or without supervised exercise). The results of this trial showed that all treatment groups improved regardless of randomisation, but that greater improvement occurred when cilostazol was added to supervised exercise (mean ratio – change in maximum walking distance:\xa0cilostazol plus exercise 2.58, cilostazol without exercise 1.69, usual care plus exercise 1.45, usual care without exercise 1.09, p\xa0=\xa00.005).\n\n## Cilostazol: pain-free walking distance\n\nFor cilostazol 200 mg compared with placebo, 10 trials reported the outcome of pain-free walking distance. Of these, five trials showed that cilostazol improved pain-free walking distance to a statistically significant degree compared with placebo. In two of the trials, the mean (absolute) difference in metres was reported. The results for distances in people randomised to cilostazol compared with placebo respectively were 94 metres versus 57\xa0metres, and 68\xa0metres versus 23 metres. One trial showed a 31.7% improvement in people randomised to cilostazol compared with a 2.5% worsening with placebo. One trial reported only a p\xa0value (p\xa0<\xa00.05) and another one showed a net improvement of 22% between groups, with the comparison favouring cilostazol.\n\nThree trials of cilostazol compared with pentoxifylline reported the outcome of pain-free walking distance, of which one found a statistically significant improvement for the group randomised to cilostazol compared with pentoxifylline (mean pain-free walking distance improved by 94\xa0metres for those patients in the cilostazol group compared with 74 metres for those in the pentoxifylline group [p = 0.02]). The results of the one trial comparing cilostazol (with or without supervised exercise) with usual care (with or without supervised exercise) showed an improvement in pain-free walking distance for all four randomisation groups (that is, cilostazol with supervised exercise, cilostazol without supervised exercise, usual care with supervised exercise and usual care without supervised exercise). However, there was no statistically significant effect of cilostazol when added to supervised exercise or usual care (mean ratio – change in maximum walking distance: cilostazol plus supervised exercise 3.84, cilostazol without supervise exercise 3.34, usual care plus supervised exercise 2.22, usual care without supervised exercise 1.23).\n\n## Naftidrofuryl oxalate: maximum walking distance and pain-free walking distance\n\nThe Assessment Group identified four randomised controlled trials of naftidrofuryl oxalate 600 mg compared with placebo and one randomised controlled trial of naftidrofuryl oxalate 300 mg compared with placebo. The duration of treatment of the trials ranged from 12 weeks to 24\xa0weeks; three were 24\xa0weeks long and two were 12 weeks long. The outcomes included in these studies were maximum walking distance, pain-free walking distance, ankle brachial pressure index, cardiovascular events, mortality, adverse events and health-related quality of life. The mean baseline age of the participants receiving naftidrofuryl oxalate in three of the trials ranged from 58 to 67 years. Baseline age of participants in the remaining trials was not reported in the assessment report. The number of participants in the trials ranged from 50 to 754. Only one randomised controlled trial recruited UK patients (n = 50).\n\nTwo trials of naftidrofuryl oxalate 600 mg compared with placebo included the outcome of maximum walking distance. One of the trials showed a statistically significant improvement in maximum walking distance for naftidrofuryl oxalate compared with placebo (p\xa0< 0.001). In this trial, the maximum walking distance of patients randomised to naftidrofuryl oxalate was improved by 158.7 metres compared with 28.1 metres for placebo. For the outcome of pain-free walking distance, five trials that compared naftidrofuryl oxalate with placebo reported this outcome. Four of the trials showed a statistically significant improvement in pain-free walking distance with naftidrofuryl oxalate compared with placebo (mean differences in metres were 204.0, 158.2, 201.4 and 93.0 for those in the naftidrofuryl oxalate groups compared with 51.0, 29.9, 98.0 and 36.0 for those in the placebo group respectively).\n\n## Pentoxifylline: maximum walking distance and pain-free walking distance\n\nThe Assessment Group identified nine randomised controlled trials of pentoxifylline 1200 mg compared with placebo. The treatment durations ranged from 8 weeks to 52 weeks (one had a treatment duration of 52 weeks, six of 24 weeks, and two of 8 weeks). The outcomes included in these trials were maximum walking distance, pain-free walking distance, ankle brachial pressure index, cardiovascular events (and cardiovascular events leading to withdrawal), mortality, adverse events and health-related quality of life. The mean baseline age of the participants receiving pentoxifylline ranged from 59 to 68 years. The number of participants in the trials ranged from 24 to 524. None of the nine randomised controlled trials recruited patients from the UK.\n\nOf the nine trials of pentoxifylline 1200 mg, eight reported the outcome of maximum walking distance. Two of the eight trials showed a statistically significant improvement in maximum walking distance for the group randomised to pentoxifylline compared with placebo. One of these trials reported a 13.9% improvement for people in the pentoxifylline group compared with 3.3% improvement for those in the placebo group. The other trial reported a mean difference improvement of 136 metres for people in the pentoxifylline group compared with 6 metres for those in the placebo group.\n\nSeven trials that compared pentoxifylline 1200 mg with placebo reported the outcome of pain-free walking distance. Two trials showed a statistically significant improvement in pain-free walking distance in people randomised to pentoxifylline compared with placebo. One of these reported a mean difference in improvement of 74 metres with pentoxifylline compared with 57 metres with placebo (p = 0.07). The other trial reported a 47% improvement (geometric mean) for the group randomised to pentoxifylline compared with 26% for the group randomised to placebo (2-sided p = 0.042).\n\n## Inositol nicotinate: maximum walking distance\n\nThe Assessment Group identified three randomised controlled trials of inositol nicotinate 4 g compared with placebo. The duration of treatment in each of the trials was 12 weeks. The outcomes included were pain-free walking paces, maximum walking distance, ankle brachial pressure index, time to claudication, cardiovascular events, mortality and adverse events. The mean baseline age of the participants receiving inositol nicotinate ranged from 61 to 68\xa0years. The number of participants in the trials ranged from 80 to 123. One trial reported the outcome of maximum walking distance. The results of this trial showed no statistically significant differences between the groups given inositol nicotinate and placebo. None of the three trials reported pain-free walking distance.\n\n## Assessment Group meta-analyses\n\nThe Assessment Group conducted a meta-analysis of the data for maximum walking distance for cilostazol relative to placebo, reanalysing results from a previous Cochrane review. A random effects meta-analysis of the change in walking distance from baseline showed that treatment with cilostazol compared with placebo resulted in an increase of 52.27 metres in absolute walking distance (95% credible interval [interval estimate based on Bayesian techniques] 24.93 to 86.57).\n\nThe Assessment Group also undertook a network meta-analysis of the data for maximum walking distance for the overall comparison of treatment options. The objective of the meta-analysis was to estimate the effect of treatment for each drug in comparison with placebo, and, if possible, compared with each other. This consisted of an analysis of the change from baseline to end of study in log mean maximum walking distance (log metre) from ten out of the 26\xa0trials (seven two-arm, and three three-arm 24 week trials leading to 16 comparisons) that the Assessment Group had indentified for cilostazol, naftidrofuryl oxalate and pentoxifylline. Reasons for excluding studies included that studies were shorter than 24 weeks in duration, were not written in English, lacked endpoints (for example, maximum walking distance or pain-free walking distance), did not report results in a way that allowed comparison of results across trials, used inappropriately low drug dosages, were secondary analyses, used an unlicensed route of administration (that is, intravenous pentoxifylline), included people with disease classified as high Fontaine stages (for example gangrene), or included people who were receiving concurrent revascularisation. The Assessment Group stated that inositol nicotinate was not included in the meta-analysis because the studies lacked 24-week data or data reported in the trials were not suitable for inclusion (there was no information on percentage change from baseline and no information on maximum walking distance or pain-free walking distance). The Assessment Group transformed the data on maximum walking distance to the logarithm scale to produce a scale on which the treatment effects could be assumed to be linear.\n\nThe random effects meta-analysis of the change from baseline to end of study in log mean maximum walking distance showed that the greatest increase compared with placebo was for naftidrofuryl (60.3%), followed by cilostazol (24.6%) and pentoxifylline (10.6%). The 95% credible intervals for naftidrofuryl oxalate and cilostazol suggested that there was an increase in the percentage change from baseline walking distance when compared with placebo, although there was some uncertainty about the true effect. Variation between studies was moderate, suggesting that the treatment effect varied depending on the characteristics of the study.\n\nThe Assessment Group also undertook a network meta-analysis of the data for pain-free walking distance for the overall comparison of treatment options. This included the same trials as the meta-analysis of maximum walking distance. The random-effects meta-analysis of the change from baseline in log pain-free walking distance showed that treatment with naftidrofuryl oxalate compared with placebo had the greatest effect (64.2%) followed by cilostazol (13.4%) and pentoxifylline (9.2%). The 95% credible interval suggested that treatment with naftidrofuryl oxalate and cilostazol compared with placebo resulted in increases in the percentage change from baseline pain-free walking distance, although there was some uncertainty about the true effect. The variation between studies was moderate, and probably reflected differences in the design of the studies.\n\n## Adverse events\n\nThe reporting of adverse event data varied across the trials. A number of trials reported only the adverse events that led patients to stop taking the drug. Other studies reported no clear clinical criteria for adverse events. Only two trials that reported adverse events had a follow-up of more than 24 weeks. These factors meant the Assessment Group could not undertake a meta-analysis of adverse events.\n\nOf the 26 trials included in the Assessment Group's systematic review, 18 reported on deaths (nine comparing cilostazol with placebo, two comparing cilostazol with pentoxifylline, one comparing naftidrofuryl oxalate with placebo, five comparing pentoxifylline with placebo and one comparing inositol with placebo). Follow-up was relatively short and no significant differences in mortality rates were reported between any treatment groups.\n\nCardiovascular events were reported in 18 of the 26\xa0trials identified by the Assessment Group (eight comparing cilostazol with placebo, which were included in a published analysis of adverse events; one comparing naftidrofuryl oxalate with placebo; six comparing pentoxifylline with placebo; and three comparing inositol nicotinate with placebo). No significant differences in cardiovascular events were observed between any treatment groups.\n\nWith respect to other adverse events, eight of the trials comparing cilostazol with placebo were included in a published analysis of adverse events. The results showed a higher frequency of headaches, diarrhoea, peripheral oedema and palpitations in the cilostazol groups than in the placebo groups. In three trials that compared cilostazol with pentoxifylline, similar rates of serious adverse events and adverse events were reported in both treatment groups.\n\nIn the studies that compared pentoxifylline with placebo, similar rates of adverse and serious adverse events were reported in both groups. Non-serious adverse events were mostly headaches or gastrointestinal complaints.\n\nIn the studies that compared 600 mg or 300 mg of naftidrofuryl oxalate with placebo the rates of adverse events and serious adverse events were similar between treatment groups.\n\nFour trials that compared inositol nicotinate with placebo reported only adverse events that led to withdrawal from trials, and these were similar between treatment groups and mostly related to difficulty in swallowing or gastrointestinal problems.\n\n# Cost effectiveness\n\nNone of the five manufacturers submitted cost-effectiveness evidence or an economic model.\n\nThe Assessment Group developed a de novo Markov economic model to estimate the cost effectiveness of the vasoactive drugs cilostazol, naftidrofuryl oxalate and pentoxifylline compared with each other and with no vasoactive drugs. The Assessment Group stated that it excluded inositol nicotinate from the main analysis because it had not been possible to include it in the meta-analyses of maximum walking distance and pain-free walking distance. Instead, the cost effectiveness of inositol nicotinate was assessed in a threshold analysis to determine how effective (in terms of quality-adjusted life years [QALYs]) inositol nicotinate would have to be to consider it a cost-effective use of NHS resources.\n\nThe model had three distinct health states: treatment with one of the four drugs under evaluation, no treatment (in which patients received none of the four drugs or had received the drug but had discontinued it) and death. The Assessment Group did not include a state reflecting progression of disease in the economic model, because the drugs under evaluation relieve symptoms and are not assumed to affect disease progression or the incidence of cardiovascular events. The model assumed that treatment with vasoactive drugs improved quality of life. It also assumed that a person could stop drug treatment because of adverse events, deaths or for other reasons of non-adherence. The model assumed no further benefit once drug treatment was stopped. The model had a cycle of 1 week and a lifetime horizon.\n\nThe population included in the economic model comprised people with peripheral arterial disease, whose intermittent claudication had been stable for at least 3 months and whose symptoms continued despite conventional management including exercise and stopping smoking. The Assessment Group chose 66\xa0years as the average age of patients with intermittent claudication based on one of the trials comparing cilostazol with placebo, which had the longest follow-up period and the largest sample size of all randomised controlled trials included in the Assessment Group's systematic review. The economic model did not distinguish between people followed in primary and secondary care. An exploratory subgroup analysis was presented for people who have more severe intermittent claudication who might have angioplasty after stopping one of the vasoactive drugs.\n\nOnly two randomised controlled trials (both for cilostazol) included in the Assessment Group's systematic review provided quality of life data from SF-36. The Assessment Group converted these to utility values using a published algorithm. The Assessment Group requested patient-level or summary SF-36 data from the authors of both trials in which the SF-36 questionnaire was used. The Assessment Group aimed to use the data to determine a relationship between the change in mean walking distance and the change in SF-36 to the change in utility scores, which it could then use to estimate the utility gain for each of the four vasoactive drugs. The authors of one trial comparing cilostazol with no vasoactive treatment provided a complete set of patient-level data (n = 106) for mean walking distance and SF-36 scores.\n\nThe Assessment Group estimated utility values using a published algorithm for converting SF-36 data at week 0 and 24. The patient-level data were used to test for a correlation between the change in maximum walking distance and the change in utility values from week 0 to week 24. The Assessment Group then used a linear regression model to estimate the absolute changes in utility values from the absolute change in the maximum walking distance on the logarithm scale during the period of the randomised controlled trial. The Assessment Group applied a regression model to all four treatments and to no vasoactive treatment to estimate the absolute changes in utility values given a certain change in mean walking distance from week 0 to week 24. The Assessment Group also estimated a mean baseline (that is, at week 0) utility value of 0.4838 using the patient-level data.\n\nThe Assessment Group applied age-adjusted utility values for the general population (that is, for people unlikely to have intermittent claudication) from a published algorithm. The Assessment Group then adjusted these utility values for the general population downwards to account for the lower average utility associated with intermittent claudication. The Assessment Group estimated that at 24 weeks the mean utility of a person who had not been treated with a vasoactive drug was 0.4873, compared with values of 0.4973 for cilostazol, 0.5088 for naftidrofuryl oxalate and 0.4919 for pentoxifylline.\n\nThe Assessment Group assumed that mortality rates did not differ whether a patient received treatment or not, or by which treatment a patient received, because vasoactive treatment provides only symptomatic relief and is unlikely to affect the progression of peripheral vascular, or other cardiovascular, disease. The Assessment Group obtained the death rates in the general population from the life tables for England and Wales (Office for National Statistics, 2008). The mortality of the general population was multiplied by a factor reflecting the increased mortality for patients with intermittent claudication (relative risk 1.6) based on a study of the risk of mortality and cardiovascular disease associated with a low ankle-brachial pressure index.\n\nThe Assessment Group based the costs of the drugs on the drug tariff of October\xa02010. If there was more than one licensed dose, the Assessment Group used the cost associated with the doses used in the trials included in its systematic review. In the base case, the model used the cost of generic naftidrofuryl oxalate. In sensitivity analyses, the Assessment Group explored the impact on the incremental cost-effectiveness ratio (ICER) of using the price of the branded preparation (see 4.2.11). The Assessment Group assumed that no difference existed in the costs of diagnosis and frequency of follow-up visits for people treated with vasoactive drugs compared with people not treated with vasoactive drugs.\n\nThe base-case results suggested that cilostazol compared with no vasoactive drug provided 0.019 additional QALYs at an additional cost of £964, resulting in an ICER OF £50,737 per QALY gained. Naftidrofuryl oxalate compared with no vasoactive drug provided 0.049 additional QALYs at an additional cost of £298, resulting in an ICER of £6070 per QALY gained. Pentoxifylline was estimated to have the smallest QALY gains (0.009) compared with no vasoactive drug at an additional cost of £493, resulting in an ICER of £54,777 per QALY gained. Overall, the results showed that both pentoxifylline and cilostazol are dominated by naftidrofuryl oxalate, which resulted in the largest total QALY gain and was associated with the lowest additional costs.\n\nThe Assessment Group undertook one-way sensitivity analyses using the following assumptions: that the utility value does not drop if the drug is stopped after 24 weeks; alternative baseline utility values; an alternative cost for naftidrofuryl oxalate (the price of the branded preparation); shorter time horizon; alternative starting age (55\xa0years) and alternative rates of discontinuation. The results of the sensitivity analyses indicated that the ICERs of naftidrofuryl oxalate were relatively insensitive to different baseline utility values, alternative starting ages, and alternative long-term discontinuation rates. However, the ICER of naftidrofuryl oxalate decreased to £1538 per QALY gained when the effectiveness associated with the vasoactive drugs was assumed to continue over a patient's lifetime when they stop the drug after 24 weeks. The Assessment Group also explored the impact on the ICER of using the price of the branded preparation of naftidrofuryl oxalate in a sensitivity analysis, which increased the ICER to £11,060 per QALY gained. In all of the sensitivity analyses performed by the Assessment Group, both cilostazol and pentoxifylline were dominated or extendedly dominated by naftidrofuryl oxalate.\n\nThe Assessment Group provided threshold analyses that estimated the number of QALYs each drug would have to generate to result in ICERs below £20,000 and £30,000 per QALY gained. These analyses showed that naftidrofuryl oxalate needed the smallest QALY gains compared with no vasoactive treatment of 0.015 and 0.010. Pentoxifylline needed QALY gains of 0.025 and 0.016, cilostazol needed QALY gains of 0.048 and 0.032, and inositol nicotinate needed QALY gains of 0.085 and 0.056 respectively.\n\nIn response to consultation on the appraisal consultation document, the manufacturer of cilostazol expressed concerns that the network meta-analyses undertaken by the Assessment Group may have overestimated the clinical benefit of naftidrofuryl oxalate, and highlighted the exclusion of one of three excluded trials of naftidrofuryl oxalate from the network-meta analyses. The 24\xa0week trial highlighted by the manufacturer was published in 1986 and compared naftidrofuryl oxalate 600\xa0mg (n\xa0=\xa064) with placebo (n\xa0=\xa054). The Assessment Group had explained in its assessment report that this trial did not directly report maximum walking distance and had therefore been excluded. However, after consultation the Assessment Group identified data on maximum walking distance from the trial reported in a Cochrane review of naftidrofuryl oxalate for intermittent claudication, noting that it was not possible to validate the data from the original trial. The Assessment Group then undertook a sensitivity analysis to explore the impact on the ICER of including this trial in the meta-analysis. The results indicated that including the trial in the network meta-analysis reduced the estimated effectiveness of naftidrofuryl oxalate. However, naftidrofuryl oxalate continued to have a significant effect and its effectiveness relative to the other vasoactive drugs did not change. Including this data in the economic model increased the ICER for naftidrofuryl oxalate from £6070 (base case) to £8321 per QALY gained.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate having considered evidence on the nature of intermittent claudication in people with peripheral arterial disease and the value placed on the benefits of these drugs by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the current clinical management for intermittent claudication in people with peripheral arterial disease. It heard that it is common practice for a specialist vascular clinic to diagnose intermittent claudication before starting drug treatment aimed at relieving symptoms. It also heard that diagnosis and treatment with vasoactive drugs can take place in primary care. The Committee heard from the clinical specialists that vasoactive therapy was an important part of treatment for intermittent claudication, but represents one part of a wider programme of management. This approach involves pharmacological treatment (for example, therapy with antiplatelet drugs and statins to prevent myocardial infarction and stroke) and non-pharmacological treatment including changes in lifestyle (for example, stopping smoking), exercise programmes, and revascularisation (for example, angioplasty). The clinical specialists highlighted the importance of lifestyle changes and exercise programmes, in particular supervised programmes, in the clinical management of the condition, but also that few patients in the NHS had access to supervised programmes in England and Wales. The Committee accepted that that treatment with vasoactive drugs does not replace or precede the importance of stopping smoking and increasing exercise.\n\nThe Committee heard from the clinical specialists that vasoactive drugs relieve symptoms but do not delay progression of peripheral arterial disease or lower the incidence of myocardial infarction, stroke or lower extremity amputation. It also heard that most clinicians offer vasodilator therapy only to those patients for whom angioplasty is considered inappropriate or has failed. In addition, the clinical specialists explained that prescribing of vasoactive therapies varies across clinical practice, but that cilostazol and naftidrofuryl oxalate were more commonly prescribed than pentoxifylline and inositol nicotinate. The Committee heard from consultees and commentators that clinicians may offer vasodilator therapy before assessing whether angioplasty would be appropriate, while a patient is awaiting revascularisation, to patients who do not have easy access to a supervised exercise programme or for whom a trial of supervised exercise of 8–16 weeks did not improve the symptoms of claudication. The Committee was aware that a NICE clinical guideline on 'Lower limb peripheral arterial disease: diagnosis and management' is being developed to help define clinical practice, and that this appraisal would contribute to the guideline. For the purposes of this guidance, and reflecting the scope for this appraisal, the Committee concluded that it would only be appropriate to consider the use of vasodilators after taking into account other treatment options, for example exercise and treatment to reduce the risk of cardiovascular events. The Committee was aware that the clinical and cost effectiveness of the vasoactive drugs may vary depending on their place in the treatment pathway. However, the Committee concluded that its remit was to appraise cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate in a situation in which vasodilator therapy is deemed the most appropriate treatment option among the other treatment options available, such as exercise therapy or angioplasty (that is, when the vasodilator drugs would be compared with each other and with best supportive care). The Committee also concluded that drug treatment should not replace referral for consideration of specialist treatment.\n\nThe Committee considered groups of patients in which the clinical pathway might differ, and heard from the clinical specialists that patients with diabetes might have atherosclerotic disease that is less likely to respond to angioplasty. The Committee heard that patients with diabetes were more likely to have intermittent claudication than people without diabetes, but that a person with diabetes was more likely than a person without diabetes to have peripheral arterial disease without symptoms of pain. Given the evidence, the Committee accepted that there was no group of patients in which the clinical pathway might differ, and concluded that no specific recommendation for any subgroup of patients would be made.\n\nThe Committee discussed the clinical need of people with intermittent claudication. It was aware that severe pain on physical exertion has a large impact on the quality of life, resulting largely from restricted mobility. This may lead to loss of independence, limited social life and decreased participation in recreation and work activities. The Committee concluded that intermittent claudication negatively affects quality of life.\n\n## Clinical effectiveness\n\nThe Committee considered the evidence for the clinical effectiveness of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate presented by the Assessment Group. The Committee noted that the trials reported a number of endpoints measuring efficacy including maximum walking distance, pain-free walking distance and ankle brachial pressure index. The Committee heard from the clinical specialists that neither the ankle brachial pressure index nor pain-free walking distance were clinically relevant outcome measures. The ankle brachial pressure index is used in clinical practice only as a diagnostic tool for peripheral arterial disease, and a patient is unlikely to be offered treadmill testing in the course of routine clinical practice. In addition, pain-free walking distance can be difficult to assess without using the fixed-speed treadmill because patients usually adjust the speed of their walking to avoid pain and to maximise walking distance. The Committee agreed that it was appropriate to focus on the Assessment Group's analyses of maximum walking distance.\n\nThe Committee considered the differences in clinical effectiveness between cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate from the maximum walking distances reported in the randomised controlled trials. It noted that the majority of the trials compared one of the four drugs with placebo and that the only head-to-head comparison was that of cilostazol compared with pentoxifylline. The Committee was aware that the size of the treatment effect reported in the trials for each of the drugs varied. The Committee noted that the publication dates of the included trials span 20 years (from 1989 to 2009) and heard from the Assessment Group that the variation in the size of the treatment effect across these trials was a result of the changes in standard clinical practice over time. The Committee heard from the clinical specialists that a clinically significant improvement in maximum walking distance approximated 50\xa0metres, or, in relative terms, a 100% increase. The Committee also noted that in the trials, patients randomised to either treatment or placebo tended to improve. However, the Committee recognised that the evidence showed that cilostazol and naftidrofuryl oxalate clinically significantly improved maximum walking distance compared with placebo.\n\nThe Committee discussed the Assessment Group's network meta-analysis that estimated the change in log maximum walking distance from baseline to the end of the trial. It was aware that the Assessment Group had excluded trials of inositol nicotinate because the trials had follow-up periods of only 12 weeks and it considered the data reported in these trials to be unsuitable for inclusion in the meta-analysis because there was no information reported on proportional change from baseline. The Committee noted from the meta-analysis that treatment with naftidrofuryl oxalate had the greatest effect of the three drugs relative to placebo (that is, a 60% increase from baseline walking distance), followed by cilostazol (25%) and pentoxifylline (11%). Given these results, the Committee considered whether it would be appropriate to infer a difference in the clinical effectiveness of the drugs. The Committee noted the credible intervals around the estimates of effectiveness, which indicated some uncertainty about the true effects. The Committee discussed the duration of follow-up and the heterogeneity between trials. For example, the Committee heard that, in general, the trials did not differentiate between patients who had or had not had previous exercise therapy. The Committee also discussed that only one trial of naftidrofuryl oxalate was included in the meta-analysis. The Committee considered that the above-listed issues contributed to uncertainty in the results of the meta-analysis.\n\nThe Committee discussed the duration of follow-up of the trials included in the network meta-analysis. The Committee noted that the trials had a follow-up of 24\xa0weeks, which it understood to be relatively short term compared with clinical practice, in which patients could take vasoactive drugs indefinitely. The Committee heard that trials in which an effect was seen at 24 weeks generally had also showed an effect at 12 weeks. The Committee heard from the clinical specialists that in current clinical practice clinicians stop vasoactive therapy if there is not an adequate response to treatment after 12\xa0weeks. The Committee also heard from the Assessment Group that the trials of inositol nicotinate excluded from the meta-analysis were excluded for reasons other than their duration (for example, they did not include data on maximum walking distance or were reported in a way that did not allow comparison of results across studies). The Committee heard that there is no agreement about the magnitude of improvement in walking distance needed to define an adequate response to vasoactive therapy. The Committee considered whether the impact of the vasoactive drugs on walking distance was likely to be sustained in the long term. However, the clinical specialists did not expect that if effective treatment was stopped for a reason other than inadequate response that a patient would continue to experience relief of symptoms. The Committee accepted that the duration of follow-up of the trials did not lead to uncertainty around the size of effect.\n\nThe Committee then considered the differences between the trials included in the network meta-analysis. The Committee considered whether this could lead to bias in the analyses of the comparative clinical effectiveness of cilostazol, naftidrofuryl oxalate and pentoxifylline. The Committee heard from the Assessment Group that the eligibility criteria and baseline characteristics of patients recruited were similar across the trials. The Committee noted the concerns raised by the manufacturer of cilostazol about the inclusion of trials that used different treadmill protocols, but acknowledged that any differences that might exist between trials had been quantified by the use of a random effects network meta-analysis. The Committee accepted that the heterogeneity in the trials could lead to bias in the estimated effectiveness of these drugs, but was persuaded that the relative benefits in terms of improvement in maximum walking distance was plausible given the empirical data.\n\nThe Committee discussed the number of trials of naftidrofuryl oxalate included in the meta-analysis. It noted that only one out of the five trials of naftidrofuryl oxalate compared with placebo identified by the Assessment Group was included in the meta-analysis and in particular that the Assessment Group had excluded the largest trial, which included over 700 participants. The Committee recognised that these trials were excluded because they did not include data on maximum walking distance or that data on maximum walking distance was not comparable across studies. The Committee noted the concerns of some consultees and commentators about the degree of transparency of trial selection. The Assessment Group highlighted that a network meta-analysis is not restricted by the number of the studies for each treatment under evaluation, or by the number of the patients randomised to each treatment arm. The Assessment Group stated that the selection of trials followed a pre-planned protocol that allowed trials to be excluded. Trials were excluded if: duration was less than 24 weeks; data on maximum walking distance were not reported or were reported in a way that did not allow comparison of results across trials; the trial did not evaluate the licensed doses of the drug; or the trial was published in a language other than English (see section 4.1.13). The Committee understood that it was common practice among Assessment Groups to exclude publications in languages other than English because of resource constraints, but agreed that whenever possible non-English language publications should be included to reduce the risk of bias. The Assessment Group informed the Committee that a review of existing trial data was undertaken by the authors of the Cochrane review of naftidrofuryl oxalate for intermittent claudication which suggested that there was no evidence of publication bias. The Committee heard from the Assessment Group that relevant trials that were not published in English may have been missed, but that methodological studies have indicated that language restrictions do not often influence the results of systematic reviews of conventional medicines. The Committee accepted the Assessment Group's rationale for excluding studies from the meta-analysis and agreed that the Assessment Group's process was transparent.\n\nThe Committee noted that the Assessment Group had undertaken an additional sensitivity analysis that included data from a trial that it had excluded from its network meta-analysis but that had been highlighted for possible inclusion by the manufacturer (see section 4.2.13). It noted that including this trial resulted in a reduction in the estimated effectiveness of naftidrofuryl oxalate but that naftidrofuryl oxalate continued to have a significant effect and the effectiveness relative to the other vasoactive drugs did not change. The Committee concluded that the Assessment Group may have originally over-estimated the clinical effectiveness of naftidrofuryl oxalate as a result of excluding trials but was persuaded by the evidence presented that naftidrofuryl oxalate continued to have the largest effect compared with cilostazol and pentoxifylline.\n\nThe Committee noted that the point estimates for maximum walking distance for cilostazol, naftidrofuryl oxalate and pentoxifylline compared with placebo obtained from the meta-analysis were similar to those obtained from the direct estimates from the randomised clinical trials, but were associated with narrower credible intervals, indicating a greater degree of certainty about the effectiveness point estimates. The Committee concluded that based on the Assessment Group's network meta-analysis, cilostazol, naftidrofuryl oxalate and pentoxifylline improved maximum walking distance compared with placebo. In addition the Committee concluded that naftidrofuryl oxalate had been demonstrated to be more effective than cilostazol and pentoxifylline. Because the meta-analysis did not include any information on the clinical effectiveness of inositol nicotinate, the Committee concluded that it was unable to assess the efficacy of inositol nicotinate compared with cilostazol, naftidrofuryl oxalate and pentoxifylline.\n\nThe Committee discussed the adverse events seen in the trials of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate. It noted that the data from the trials suggested that non-serious adverse events (such as headaches and gastrointestinal complaints) and serious adverse events (such as cardiovascular events and death) did not differ between the groups given vasoactive drugs and those given placebo. The Committee acknowledged that the trials were not designed to address mortality, and, in any event, were too short or too small to detect a difference if one existed. The Committee also noted that the clinical specialists did not have concerns about the long-term safety of the vasoactive drugs. The Committee concluded that, based on the currently available information, there were no major concerns about the adverse effects of the vasodilator drugs being appraised.\n\n## Cost effectiveness\n\nThe Committee examined the economic modelling developed for the appraisal and agreed that the Assessment Group's economic evaluation was of good quality. Because the drugs did not affect the risk of fatal cardiovascular disease, the Committee recognised that the QALYs in the model were driven by the utility gain from increased mobility rather than from any survival benefit. The Committee noted that the utility values used in the model were derived from a regression model using the change in maximum walking distance and SF-36 data, based on patient-level data from a trial of cilostazol compared with placebo. The Committee noted the concerns raised by the manufacturer of cilostazol that there was uncertainty about the association between maximum walking distance and utility because the trial from which the Assessment Group derived the estimates was small (n\xa0=\xa0109), and the Assessment Group assumed that the association was the same for all of the vasoactive drugs. The Committee acknowledged this uncertainty but noted that the order of the utility values was consistent with the order of effectiveness of the vasoactive drugs as shown in the meta-analysis. The Committee was aware that commentators had called for future research to better quantify the association between clinical endpoints relevant to peripheral arterial disease and quality of life. The Committee also recognised the limited published evidence for quality of life associated with these drugs. It agreed that the approach used by the Assessment Group to obtain utility values for the economic model was acceptable, while proposing that further research be undertaken (see section 6.1).\n\nThe Committee then considered whether there were any other health-related benefits that had not been adequately captured in the Assessment Group's economic model. It heard from the manufacturer of cilostazol that because of cilostazol's pharmacological profile, the drug improves cardiovascular risk factors (for example, by its anti-platelet actions). The Committee was aware that the CASTLE trial ('Cilostazol: a study in long-term effects'), a randomised, double-blinded, placebo-controlled safety study of cilostazol compared with placebo, was designed to detect a difference in mortality, but found none. The manufacturer informed the Committee that cilostazol was used to prevent strokes, but that this benefit had not been demonstrated in the population identified in this appraisal, that is, people with intermittent claudication. Furthermore, the Committee noted that the manufacturer had not submitted any evidence related to these potential benefits in its original submission or during consultation. The Committee was aware that the marketing authorisation for cilostazol in the UK did not go beyond the treatment of intermittent claudication. The Committee concluded that there was no evidence available on benefits other than improvement in maximum walking distance related to health-related quality of life.\n\nThe Committee considered the ICERs derived from the Assessment Group's economic model of £50,700, £6070, £11,060 and £54,800 per QALY gained for cilostazol, generic naftidrofuryl oxalate, branded naftidrofuryl oxalate and pentoxifylline, respectively, when each was compared with placebo. The Committee was aware that naftidrofuryl oxalate was associated with the largest QALY gain and the lowest cost, thereby dominating cilostazol and pentoxifylline. The Committee recognised that there was uncertainty associated with the ICERs for naftidrofuryl oxalate because the data for naftidrofuryl oxalate included in the model were originally derived from only one trial. The Committee was aware of the additional sensitivity analysis undertaken by the Assessment Group (see 4.2.13), which indicated that the inclusion of the additional data for naftidrofuryl oxalate within the meta-analysis had a limited impact on the cost-effectiveness results. The Committee agreed that because of the low ICER for naftidrofuryl oxalate, the Committee could accept the uncertainty associated with the ICER. It therefore concluded that it could recommend naftidrofuryl oxalate as a cost-effective use of NHS resources when vasodilator therapy is considered appropriate after taking into account other treatment options, and that treatment with naftidrofuryl oxalate should be started with the least costly licensed preparation. The Committee also agreed that drug treatment should not replace referral for consideration of specialist treatment. The Committee agreed that it could not consider cilostazol and pentoxifylline to be appropriate treatment options, because naftidrofuryl oxalate dominates cilostazol and pentoxifylline. It noted that some consultees and commentators had agreed with the Committee's preliminary decision about this. The Committee noted that the ICERs for cilostazol and pentoxifylline compared with placebo exceeded those normally considered to be an acceptable use of NHS resources. It concluded that cilostazol and pentoxifylline could not be recommended as a cost-effective use of NHS resources for people with contraindications to naftidrofuryl oxalate.\n\nThe Committee considered the Assessment Group's threshold analysis of the cost effectiveness of inositol nicotinate. The Committee noted that the estimated QALY gains needed for the ICER of inositol nicotinate compared with placebo to fall below £20,000 or £30,000 per QALY gained were 0.085 or 0.056 respectively. The Committee was aware that these were much higher than the QALY gains actually calculated for naftidrofuryl oxalate (0.015 and 0.010 respectively). The Committee inferred that for inositol nicotinate to be considered cost effective, it would need to demonstrate a considerably greater impact on quality of life from improving maximum walking distance than those demonstrated for the other vasoactive drugs. The Committee did not consider this plausible, because the only trial in the Assessment Group's systematic review that reported that inositol nicotinate did not improve maximum walking distance any more than placebo. The Committee therefore concluded that it could not recommend inositol nicotinate as a cost-effective use of NHS resources.\n\nThe Committee considered whether its preliminary recommendations were associated with any issues related to equality legislation and the requirement for fairness. The Committee noted that no issues had been highlighted during the scoping exercise or during the course of the appraisal. The Committee was aware that the prevalence of peripheral arterial disease differs between ethnic groups, but concluded that the recommendations do not affect access to the technology for any specific groups.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA223\n\nAppraisal title: 'Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease'\n\nSection\n\nKey conclusion\n\nNaftidrofuryl oxalate is recommended as an option for the treatment of intermittent claudication in people with peripheral arterial disease for whom vasodilator therapy is considered appropriate after taking into account other treatment options. Treatment with naftidrofuryl oxalate should be started with the least costly licensed preparation.\n\nCilostazol, pentoxifylline and inositol nicotinate are not recommended for the treatment of intermittent claudication in people with peripheral arterial disease.\n\nReasons for the recommendations:\n\n\n\n\n\nThe Committee concluded that naftidrofuryl oxalate is more effective than cilostazol and pentoxifylline. Because the meta-analysis did not include any trials of inositol nicotinate, the Committee was unable to assess the relative efficacy of inositol nicotinate.\n\n\n\n\n\nThe Committee concluded that there was uncertainty about the ICERs for naftidrofuryl oxalate but that this uncertainty could be accepted in light of the low ICERs of £6070 and £11,060 per QALY gained for the generic and branded preparation of naftidrofuryl oxalate respectively.\n\n\n\n\n\nNaftidrofuryl oxalate dominated cilostazol and pentoxifylline, and even when compared with placebo the ICERs for cilostazol and pentoxifylline were £50,740 and £54,800 per QALY gained respectively.\n\n\n\n\n\nFrom the threshold analysis, the Committee inferred that for inositol nicotinate to be considered cost effective it would need to demonstrate a considerably greater impact on quality of life from improving maximum walking distance than those demonstrated for the other vasoactive drugs. The Committee did not consider this assumption plausible, because the only trial in the Assessment Group's systematic review that reported maximum walking distance for inositol nicotinate did not show an improvement in maximum walking distance any greater than for placebo.\n\n\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee was aware that severe pain on physical exertion has a large impact on the quality of life, resulting largely from restricted mobility. This may lead to loss of independence, limited social life and decreased participation in recreation and work activities. The Committee concluded that intermittent claudication negatively affects quality of life.\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nCilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate are vasodilator drugs and have marketing authorisations for the symptomatic relief of intermittent claudication.\n\nNo specific claims of innovation were made.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee heard from the clinical specialists that vasoactive therapy was an important part of treatment for intermittent claudication, but represents one part of a wider programme of management. This approach involves pharmacological (for example, therapy with antiplatelet drugs and statins to prevent myocardial infarction and stroke) and non-pharmacological treatment including changes in lifestyle (for example, stopping smoking), exercise programmes, and revascularisation (for example, angioplasty). The Committee accepted that treatment with vasoactive drugs does not replace or precede the importance of stopping smoking and increasing exercise.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee heard from consultees and commentators that clinicians may offer vasodilator therapy before assessing whether angioplasty would be appropriate, while a patient is waiting revascularisation, to patients who do not have easy access to a supervised exercise programme or for whom a trial of supervised exercise of 8–16 weeks did not improve the symptoms of claudication. The Committee was aware that a NICE clinical guideline on 'Lower limb peripheral arterial disease: diagnosis and management' is being developed to help define clinical practice, and that this appraisal would contribute to the guideline.\n\n\n\n\n\nAdverse effects\n\nThe Committee noted that the data from the trials suggested that non-serious adverse events (such as headaches and gastrointestinal complaints) and serious adverse events (such as cardiovascular events and death) did not differ between the groups given vasoactive drugs and those given placebo. The Committee concluded that, based on the currently available information, there were no major concerns about the adverse effects of the vasodilator drugs being appraised.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe trials reported a number of endpoints measuring efficacy including maximum walking distance, pain-free walking distance and ankle brachial pressure index. The Committee agreed that it was appropriate to focus on the Assessment Group's analyses of maximum walking distance.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe majority of the trials compared the four drugs with placebo and that one trial compared cilostazol with pentoxifylline.\n\n\n\n\n\n\n\nThe Assessment Group undertook a network meta-analysis that estimated the change from baseline in log maximum walking distance. The network meta-analysis excluded trials of inositol nicotinate.\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\nNo specific issues were raised.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee noted the credible intervals (from the network meta-analysis of maximum walking distance) around the estimates of effectiveness, which indicated some uncertainty about the true effects. The Committee discussed the duration of follow-up and the heterogeneity between trials. The Committee considered that the above-listed issues contributed to uncertainty in the results of the meta-analysis.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe Committee considered groups of patients in which the clinical pathway might differ, and heard from the clinical specialists that patients with diabetes might have atherosclerotic disease that is less likely to respond to angioplasty. The Committee accepted that there was no group of patients in which the clinical pathway might differ and concluded that no specific recommendation for any subgroup would be made.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee recognised that the evidence for cilostazol and naftidrofuryl oxalate showed that there was a clinically significant improvement in maximum walking distance compared with the placebo groups.\n\n\n\n\n\n\n\nThe Committee noted from the meta-analysis that treatment with naftidrofuryl oxalate had the greatest effect relative to placebo (that is, a 60% increase from baseline walking distance), followed by cilostazol (25%) and pentoxifylline (11%). The Committee noted the credible intervals around the estimates of effectiveness, which indicated that there was some uncertainty about the true effects. The Committee considered the duration of follow-up and the heterogeneity between trials and the inclusion of only a single trial of naftidrofuryl oxalate, because these contributed to the uncertainty in the results of the meta-analysis. The Committee concluded that the Assessment Group may have over-estimated the clinical effectiveness of naftidrofuryl oxalate as a result of excluding trials but was persuaded by the evidence presented that naftidrofuryl oxalate had the largest effect compared with cilostazol and pentoxifylline.\n\n\n\n-4.3.12\n\n\n\nBecause the meta-analysis did not include any information on the clinical effectiveness of inositol nicotinate, the Committee concluded that it was unable to assess the efficacy of inositol nicotinate compared with cilostazol, naftidrofuryl oxalate and pentoxifylline.\n\n\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nNone of the manufacturers submitted economic evaluations or economic models.\n\n\n\n\n\n\n\nThe Committee agreed that the Assessment Group's economic evaluation was of good quality.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that the utility values used in the model were derived from a regression model using the change in maximum walking distance and SF-36 data, based on patient-level data from a trial of cilostazol compared with placebo. The Committee noted the concerns raised by the manufacturer of cilostazol that there was uncertainty about the association between maximum walking distance and utility because the trial from which the estimate was derived was small and the Assessment Group had assumed that the association was the same for all vasoactive drugs. However, the Committee noted that the order of the utility values was consistent with the order of effectiveness of the vasoactive drugs as shown in the meta-analysis. The Committee recognised the limited published evidence for quality of life associated with these drugs, and agreed that the approach used by the Assessment Group to obtain utility values for the economic model was acceptable, while proposing that further research be undertaken.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nBecause the drugs did not affect the risk of fatal cardiovascular disease, the Committee recognised that the QALYs in the model were driven by the utility gain from increased mobility rather than from any survival benefit.\n\n\n\n\n\nThe Committee considered whether there were any other health-related benefits that had not been adequately captured in the Assessment Group's economic model. It heard from the manufacturer of cilostazol that because of cilostazol's pharmacological profile, the drug improves cardiovascular risk factors. The manufacturer informed the Committee that cilostazol was used to prevent strokes, but that this benefit had not been demonstrated in the population defined in this appraisal. Furthermore, the Committee noted that the manufacturer had not submitted any evidence related to these potential benefits. The Committee was aware that the marketing authorisation for cilostazol in the UK did not go beyond the treatment of intermittent claudication. The Committee concluded that there was no evidence available on benefits other than improvement in maximum walking distance related to health-related quality of life.\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nNo key drivers were identified apart from the differences between treatment costs and utility values related to the differences in maximum walking distance.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee recognised that there was uncertainty associated with the ICERs for naftidrofuryl oxalate compared with placebo (£11,060 for the branded version, £6070 for the generic version) because the data for naftidrofuryl oxalate included in the model were originally derived from only one trial. The Committee was aware of the additional sensitivity analyses undertaken by the Assessment Group, which indicated that the inclusion of the additional data for naftidrofuryl oxalate within the meta-analysis had a limited impact on the cost-effectiveness results (£8321 per QALY gained). The Committee agreed that because of the low ICERs for naftidrofuryl oxalate, it could accept the uncertainty associated with the ICERs.\n\nThe Committee noted that naftidrofuryl oxalate was associated with the largest QALY gain and lowest cost, thereby dominating cilostazol and pentoxifylline. The Committee also noted that the ICERs for cilostazol and pentoxifylline were £50,700 and £54,800 per QALY gained respectively when each was compared with placebo.\n\n, 4.3.17\n\n\n\nThe Committee inferred that for inositol nicotinate to be considered cost effective, it would need to demonstrate considerably greater impacts on quality of life from improving maximum walking distance than those demonstrated for the other vasoactive drugs. The Committee did not consider this assumption plausible, because the only trial in the Assessment Group's systematic review that reported maximum walking distance for inositol nicotinate did not show an improvement in maximum walking distance any greater than for placebo.\n\n\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n\n\nEnd-of-life considerations\n\nNot applicable.\n\n\n\nEqualities considerations and social value judgements\n\nThe Committee noted that no issues had been highlighted during the scoping exercise or during the course of the appraisal. The Committee was aware that the prevalence of peripheral arterial disease differs between ethnic groups, but concluded that the recommendations do not affect access to the technology for any specific groups.\n\n\n\n One clinical specialist and a representative of the Guideline Development Group developing the NICE clinical guideline 'Lower limb peripheral arterial disease: diagnosis and management' attended the Appraisal Committee meeting. For the purposes of this document they are both referred to as clinical specialists.", 'Recommendations for further research ': 'A trial comparing the long-term effectiveness (beyond 24 weeks) of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate and placebo would be beneficial. It should collect utility data as well as walking distance outcomes.', 'Related NICE guidance': '# Published\n\nClopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of NICE technology appraisal guidance 90). NICE technology appraisal guidance 210 (2010).\n\n# Under development\n\nNICE is developing the following guidance (details available from the NICE website):\n\nLower limb peripheral arterial disease. NICE clinical guideline. Publication expected October 2012.', 'Review of guidance': 'The guidance on this technology will be considered for review in May 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveMay 2011', 'Changes after publication': 'February 2014: implementation section updated to clarify that naftidrofuryl oxalate is recommended as an option for treating people with intermittent claudication who have peripheral arterial disease. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta223
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Evidence-based recommendations on cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for treating intermittent claudication in adults with peripheral arterial disease.
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10ea6c0bf5f284009930e04177e06408eac4cf97
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nice
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Common mental health problems: identification and pathways to care
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Common mental health problems: identification and pathways to care
This guideline covers care for people aged 18 and over with common mental health problems, with a focus on primary care. It aims to improve access to services for adults and how mental health problems are identified and assessed, and makes recommendations on local care pathways.
# Introduction
Common mental health disorders, such as depression, generalised anxiety disorder, panic disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD) and social anxiety disorder (see NICE's guideline on social anxiety disorder), may affect up to 15% of the population at any one time. Depression and anxiety disorders can have a lifelong course of relapse and remission. There is considerable variation in the severity of common mental health disorders, but all can be associated with significant long-term disability. For example, depression is estimated to be the second greatest contributor to disability-adjusted life years throughout the developed world. It is also associated with high levels of morbidity and mortality, and is the most common disorder contributing to suicide.
The prevalence of individual common mental health disorders varies considerably. The 1-week prevalence rates from the Office of National Statistics 2007 national survey of adult psychiatric morbidity were 4.4% for generalised anxiety disorder, 3.0% for PTSD, 2.3% for depression, 1.4% for phobias, 1.1% for OCD, and 1.1% for panic disorder. Estimates of the proportion of people who are likely to experience specific disorders during their lifetime are from 4% to 10% for major depression, 2.5% to 5% for dysthymia, 5.7% for generalised anxiety disorder, 1.4% for panic disorder, 12.5% for specific phobias, 12.1% for social anxiety disorder, 1.6% for OCD and 6.8% for PTSD. More than half of people aged 16 to 64 years who meet the diagnostic criteria for at least 1 common mental health disorder experience comorbid anxiety and depressive disorders.
The vast majority (up to 90%) of depressive and anxiety disorders that are diagnosed are treated in primary care. However, many individuals do not seek treatment, and both anxiety and depression often go undiagnosed. Although under-recognition is generally more common in mild rather than severe cases, mild disorders are still a source of concern. Recognition of anxiety disorders by GPs is particularly poor, and only a small minority of people who experience anxiety disorders ever receive treatment. In part this may stem from GPs' difficulties in recognising the disorder, but it may also be caused by patients' worries about stigma, and avoidance on the part of individual patients.
The most common method of treatment for common mental health disorders in primary care is psychotropic medication. This is due to the limited availability of psychological interventions, despite the fact that these treatments are generally preferred by patients.
Since 2004, NICE has produced a series of guidelines on the care and treatment of common mental health disorders. Some of these guidelines focus on identification and recognition (for example, the guideline on depression), whereas others give little advice on identification (for example, the guideline on generalised anxiety disorder and panic disorder). In addition to the variable advice on identification and recognition, NICE guidelines have also varied in the amount of advice they have provided on assessment and appropriate referral for the treatment of these disorders.
The intention of this guideline, which is focused on primary care, is to improve access to services (including primary care services themselves), improve identification and recognition, and provide advice on the principles that need to be adopted to develop appropriate referral and local care pathways. It brings together advice from existing guidelines and combines it with new recommendations concerning access, assessment and local care pathways for common mental health disorders.
A number of the recommendations in this guideline were adapted from recommendations in other NICE guidelines for common mental health disorders. In doing so the Guideline Development Group were mindful that they had not reviewed the evidence for these recommendations and therefore when transferring them into this guideline were careful to preserve the meaning and intent of the original recommendation. Where recommendations were adapted, changes to wording or structure were made in order to fit the recommendation into this guideline; these adaptations preserved the meaning and intent of the recommendation but shifted the context in which the recommendation was made. In all cases the origin of any adapted recommendation is indicated in a note to the recommendation.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
This guideline was developed to provide an integrated approach to the identification and assessment of common mental health disorders, particularly in primary care. It draws together the recommendations from existing NICE guidance and addresses any gaps in the identification and assessment of these conditions. The guideline also provides advice for primary care and other staff on referral. Finally, it sets out guidance for the development of effective local care pathways for people with common mental health disorders.
The guideline is organised according to the principles of stepped care (see section 1.2).
# Improving access to services
Primary and secondary care clinicians, managers and commissioners should collaborate to develop local care pathways (see also section 1.5) that promote access to services for people with common mental health disorders by:
supporting the integrated delivery of services across primary and secondary care
having clear and explicit criteria for entry to the service
focusing on entry and not exclusion criteria
having multiple means (including self-referral) to access the service
providing multiple points of access that facilitate links with the wider healthcare system and community in which the service is located.
Provide information about the services and interventions that constitute the local care pathway, including the:
range and nature of the interventions provided
settings in which services are delivered
processes by which a person moves through the pathway
means by which progress and outcomes are assessed
delivery of care in related health and social care services.
When providing information about local care pathways to people with common mental health disorders and their families and carers, all healthcare professionals should:
take into account the person's knowledge and understanding of mental health disorders and their treatment
ensure that such information is appropriate to the communities using the pathway.
Provide all information about services in a range of languages and formats (visual, verbal and aural) and ensure that it is available from a range of settings throughout the whole community to which the service is responsible.
Primary and secondary care clinicians, managers and commissioners should collaborate to develop local care pathways (see also section 1.5) that promote access to services for people with common mental health disorders from a range of socially excluded groups including:
black and minority ethnic groups
-lder people
those in prison or in contact with the criminal justice system
ex-service personnel.
Support access to services and increase the uptake of interventions by:
ensuring systems are in place to provide for the overall coordination and continuity of care of people with common mental health disorders
designating a healthcare professional to oversee the whole period of care (usually a GP in primary care settings).
Support access to services and increase the uptake of interventions by providing services for people with common mental health disorders in a variety of settings. Use an assessment of local needs as a basis for the structure and distribution of services, which should typically include delivery of:
assessment and interventions outside normal working hours
interventions in the person's home or other residential settings
specialist assessment and interventions in non-traditional community-based settings (for example, community centres and social centres) and where appropriate, in conjunction with staff from those settings
both generalist and specialist assessment and intervention services in primary care settings.
Primary and secondary care clinicians, managers and commissioners should consider a range of support services to facilitate access and uptake of services. These may include providing:
crèche facilities
assistance with travel
advocacy services.
Consider modifications to the method and mode of delivery of assessment and treatment interventions and outcome monitoring (based on an assessment of local needs), which may typically include using:
technology (for example, text messages, email, telephone and computers) for people who may find it difficult to, or choose not to, attend a specific service
bilingual therapists or independent translators.
Be respectful of, and sensitive to, diverse cultural, ethnic and religious backgrounds when working with people with common mental health disorders, and be aware of the possible variations in the presentation of these conditions. Ensure competence in:
culturally sensitive assessment
using different explanatory models of common mental health disorders
addressing cultural and ethnic differences when developing and implementing treatment plans
working with families from diverse ethnic and cultural backgrounds.
Do not significantly vary the content and structure of assessments or interventions to address specific cultural or ethnic factors (beyond language and the cultural competence of staff), except as part of a formal evaluation of such modifications to an established intervention, as there is little evidence to support significant variations to the content and structure of assessments or interventions.
# Stepped care
A stepped-care model is used to organise the provision of services and to help people with common mental health disorders, their families, carers and healthcare professionals to choose the most effective interventions. The model presents an integrated overview of the key assessment and treatment interventions from this guideline. Recommendations focused solely on specialist mental health services are not included (these can be found in related guidance). Recommendation 1.5.1.3 in the section on developing local care pathways sets out the components of a stepped-care model of service delivery, which should be included in the design of local care pathways for people with common mental health disorders.
Focus of the intervention
Nature of the intervention
Step 3: Persistent subthreshold depressive symptoms or mild to moderate depression that has not responded to a low-intensity intervention; initial presentation of moderate or severe depression; GAD with marked functional impairment or that has not responded to a low-intensity intervention; moderate to severe panic disorder; OCD with moderate or severe functional impairment; PTSD.
Depression: CBT, IPT, behavioural activation, behavioural couples therapy, counselling, short-term psychodynamic psychotherapy, antidepressants, combined interventions, collaborative care (for people with depression and a chronic physical health problem), self-help groups. Discuss with the person the uncertainty of the effectiveness of counselling and psychodynamic psychotherapy in treating depression.
GAD: CBT, applied relaxation, drug treatment, combined interventions, self-help groups.
Panic disorder: CBT, antidepressants, self-help groups.
OCD: CBT (including ERP), antidepressants, combined interventions and case management, self-help groups.
PTSD: Trauma-focused CBT, EMDR, drug treatment.
All disorders: Support groups, befriending, rehabilitation programmes, educational and employment support services; referral for further assessment and interventions.
Step 2: Persistent subthreshold depressive symptoms or mild to moderate depression; GAD; mild to moderate panic disorder; mild to moderate OCD; PTSD (including people with mild to moderate PTSD).
Depression: Individual facilitated self-help (including potentially for women during pregnancy or the postnatal period), computerised CBT, structured physical activity, group-based peer support (self-help) programmes (for people with depression and a chronic physical health problem), antidepressants, self-help groups.
GAD
and panic disorder: Individual non-facilitated and facilitated self-help, psychoeducational groups, self-help groups.
OCD: Individual or group CBT (including ERP), self-help groups.
PTSD: Trauma-focused CBT or EMDR.
All disorders: Support groups, educational and employment support services; referral for further assessment and interventions.
Step 1: All disorders – known and suspected presentations of common mental health disorders.
All disorders: Identification, assessment, psychoeducation, active monitoring; referral for further assessment and interventions.
Abbreviations: CBT, cognitive behavioural therapy; EMDR, eye movement desensitisation and reprocessing; ERP, exposure and response prevention; GAD, generalised anxiety disorder; IPT, interpersonal therapy; OCD, obsessive-compulsive disorder; PTSD, post-traumatic stress disorder.
# Step 1: Identification and assessment
## Identification
Be alert to possible depression (particularly in people with a past history of depression, possible somatic symptoms of depression or a chronic physical health problem with associated functional impairment) and consider asking people who may have depression 2 questions, specifically:
During the last month, have you often been bothered by feeling down, depressed or hopeless?
During the last month, have you often been bothered by having little interest or pleasure in doing things? If a person answers 'yes' to either of the above questions, consider depression and follow the recommendations for assessment (see section 1.3.2).
Be alert to possible anxiety disorders (particularly in people with a past history of an anxiety disorder, possible somatic symptoms of an anxiety disorder or in those who have experienced a recent traumatic event). Consider asking the person about their feelings of anxiety and their ability to stop or control worry, using the 2-item Generalized Anxiety Disorder scale (GAD-2; see the full guideline).
If the person scores 3 or more on the GAD-2 scale, consider an anxiety disorder and follow the recommendations for assessment (see section 1.3.2).
If the person scores less than 3 on the GAD-2 scale, but you are still concerned they may have an anxiety disorder, ask the following: 'Do you find yourself avoiding places or activities and does this cause you problems?'. If the person answers 'yes' to this question, consider an anxiety disorder and follow the recommendations for assessment (see section 1.3.2).
For people with significant language or communication difficulties, for example people with sensory impairments or a learning disability, consider using the Distress Thermometer and/or asking a family member or carer about the person's symptoms to identify a possible common mental health disorder. If a significant level of distress is identified, offer further assessment or seek the advice of a specialist.The Distress Thermometer is a single-item question screen that will identify distress coming from any source. The person places a mark on the scale answering: 'How distressed have you been during the past week on a scale of 0 to 10?' Scores of 4 or more indicate a significant level of distress that should be investigated further. (See Roth AJ et al. for more information.)
## Assessment
If the identification questions (see section 1.3.1) indicate a possible common mental health disorder, but the practitioner is not competent to perform a mental health assessment, refer the person to an appropriate healthcare professional. If this professional is not the person's GP, inform the GP of the referral.
If the identification questions (see section 1.3.1) indicate a possible common mental health disorder, a practitioner who is competent to perform a mental health assessment should review the person's mental state and associated functional, interpersonal and social difficulties.
When assessing a person with a suspected common mental health disorder, consider using:
a diagnostic or problem identification tool or algorithm, for example, the Improving Access to Psychological Therapies (IAPT) screening prompts tool (see appendix C of the Improving Access to Psychological Therapies Manual: appendices and helpful resources).
a validated measure relevant to the disorder or problem being assessed, for example, the 9-item Patient Health Questionnaire (PHQ-9), the Hospital Anxiety and Depression Scale (HADS) or the 7-item Generalized Anxiety Disorder scale (GAD-7) to inform the assessment and support the evaluation of any intervention.
All staff carrying out the assessment of suspected common mental health disorders should be competent to perform an assessment of the presenting problem in line with the service setting in which they work, and be able to:
determine the nature, duration and severity of the presenting disorder
take into account not only symptom severity but also the associated functional impairment
identify appropriate treatment and referral options in line with relevant NICE guidance.
All staff carrying out the assessment of common mental health disorders should be competent in:
relevant verbal and non-verbal communication skills, including the ability to elicit problems, the perception of the problems and their impact, tailoring information, supporting participation in decision-making and discussing treatment options
the use of formal assessment measures and routine outcome measures in a variety of settings and environments.
In addition to assessing symptoms and associated functional impairment, consider how the following factors may have affected the development, course and severity of a person's presenting problem:
a history of any mental health disorder
a history of a chronic physical health problem
any past experience of, and response to, treatments
the quality of interpersonal relationships
living conditions and social isolation
a family history of mental illness
a history of domestic violence or sexual abuse
employment and immigration status.If appropriate, the impact of the presenting problem on the care of children and young people should also be assessed, and if necessary local safeguarding procedures followed.
When assessing a person with a suspected common mental health disorder, be aware of any learning disabilities or acquired cognitive impairments, and if necessary consider consulting with a relevant specialist when developing treatment plans and strategies.
If the presentation and history of a common mental health disorder suggest that it may be mild and self-limiting (that is, symptoms are improving) and the disorder is of recent onset, consider providing psychoeducation and active monitoring before offering or referring for further assessment or treatment. These approaches may improve less severe presentations and avoid the need for further interventions.
Always ask people with a common mental health disorder directly about suicidal ideation and intent. If there is a risk of self-harm or suicide:
assess whether the person has adequate social support and is aware of sources of help
arrange help appropriate to the level of risk (see the section on risk assessment and monitoring)
advise the person to seek further help if the situation deteriorates.
During pregnancy or the postnatal period, women requiring psychological interventions should be seen for treatment normally within 1 month of initial assessment, and no longer than 3 months afterwards. This is because of the lower threshold for access to psychological interventions during pregnancy and the postnatal period arising from the changing risk–benefit ratio for psychotropic medication at this time.
When considering drug treatments for common mental health disorders in women who are pregnant, breastfeeding or planning a pregnancy, consult NICE's guideline on antenatal and postnatal mental health for advice on prescribing.
## Risk assessment and monitoring
If a person with a common mental health disorder presents a high risk of suicide or potential harm to others, a risk of significant self-neglect, or severe functional impairment, assess and manage the immediate problem first and then refer to specialist services. Where appropriate inform families and carers.
If a person with a common mental health disorder presents considerable and immediate risk to themselves or others, refer them urgently to the emergency services or specialist mental health services.
If a person with a common mental health disorder, in particular depression, is assessed to be at risk of suicide:
take into account toxicity in overdose, if a drug is prescribed, and potential interaction with other prescribed medication; if necessary, limit the amount of drugs available
consider increasing the level of support, such as more frequent direct or telephone contacts
consider referral to specialist mental health services.
# Steps 2 and 3: Treatment and referral for treatment
The recommendations for treatment and referral are also presented in table form organised by disorder in the full guideline.
## Identifying the correct treatment options
When discussing treatment options with a person with a common mental health disorder, consider:
their past experience of the disorder
their experience of, and response to, previous treatment
the trajectory of symptoms
the diagnosis or problem specification, severity and duration of the problem
the extent of any associated functional impairment arising from the disorder itself or any chronic physical health problem
the presence of any social or personal factors that may have a role in the development or maintenance of the disorder
the presence of any comorbid disorders.
When discussing treatment options with a person with a common mental health disorder, provide information about:
the nature, content and duration of any proposed intervention
the acceptability and tolerability of any proposed intervention
possible interactions with any current interventions
the implications for the continuing provision of any current interventions.
When making a referral for the treatment of a common mental health disorder, take account of patient preference when choosing from a range of evidence-based treatments.
When offering treatment for a common mental health disorder or making a referral, follow the stepped-care approach, usually offering or referring for the least intrusive, most effective intervention first (see figure 1 on stepped-care model: a combined summary for common mental health disorders).
When a person presents with symptoms of anxiety and depression, assess the nature and extent of the symptoms, and if the person has:
depression that is accompanied by symptoms of anxiety, the first priority should usually be to treat the depressive disorder, in line with the NICE guideline on depression
an anxiety disorder and comorbid depression or depressive symptoms, consult the NICE guidelines for the relevant anxiety disorder and consider treating the anxiety disorder first
both anxiety and depressive symptoms, with no formal diagnosis, that are associated with functional impairment, discuss with the person the symptoms to treat first and the choice of intervention.
When a person presents with a common mental health disorder and harmful drinking or alcohol dependence, refer them for treatment of the alcohol misuse first as this may lead to significant improvement in depressive or anxiety symptoms.
When a person presents with a common mental health disorder and a mild learning disability or mild cognitive impairment:
where possible provide or refer for the same interventions as for other people with the same common mental health disorder
if providing interventions, adjust the method of delivery or duration of the assessment or intervention to take account of the disability or impairment.
When a person presents with a common mental health disorder and has a moderate to severe learning disability or a moderate to severe cognitive impairment, consult a specialist concerning appropriate referral and treatment options.
Do not routinely vary the treatment strategies and referral practice for common mental health disorders described in this guideline either by personal characteristics (for example, sex or ethnicity) or by depression subtype (for example, atypical depression or seasonal depression) as there is no convincing evidence to support such action.
If a person with a common mental health disorder needs social, educational or vocational support, consider:
informing them about self-help groups (but not for people with PTSD), support groups and other local and national resources
befriending or a rehabilitation programme for people with long-standing moderate or severe disorders
educational and employment support services.
## Step 2: Treatment and referral advice for subthreshold symptoms and mild to moderate common mental health disorders
For people with persistent subthreshold depressive symptoms or mild to moderate depression:
-ffer or refer for 1 or more of the following low-intensity interventions:
individual facilitated self-help based on the principles of cognitive behavioural therapy (CBT), except for women during pregnancy or the postnatal period (see below)
computerised CBT
a structured group physical activity programme
a group-based peer support (self-help) programme (for those who also have a chronic physical health problem)
for women during pregnancy or the postnatal period, consider:
individual facilitated self-help based on the principles of CBT.
For pregnant women who have subthreshold symptoms of depression and/or anxiety that significantly interfere with personal and social functioning, consider providing or referring for:
individual brief psychological treatment (4 to 6 sessions), such as interpersonal therapy (IPT) or CBT for women who have had a previous episode of depression or anxiety
social support during pregnancy and the postnatal period for women who have not had a previous episode of depression or anxiety; such support may consist of regular informal individual or group-based support.
Do not offer antidepressants routinely for people with persistent subthreshold depressive symptoms or mild depression, but consider them for, or refer for an assessment, people with:
initial presentation of subthreshold depressive symptoms that have been present for a long period (typically at least 2 years) or
subthreshold depressive symptoms or mild depression that persist after other interventions or
a past history of moderate or severe depression or
mild depression that complicates the care of a physical health problem.For guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
For people with generalised anxiety disorder that has not improved after psychoeducation and active monitoring, offer or refer for one of the following low-intensity interventions:
individual non-facilitated self-help
individual facilitated self-help
psychoeducational groups.
For people with mild to moderate panic disorder, offer or refer for 1 of the following low-intensity interventions:
individual non-facilitated self-help
individual facilitated self-help.
For people with mild to moderate OCD:
-ffer or refer for individual CBT including exposure and response prevention (ERP) of limited duration (typically up to 10 hours), which could be provided using self-help materials or by telephone or
refer for group CBT (including ERP) (note, group formats may deliver more than 10 hours of therapy).
For people with PTSD, including those with mild to moderate PTSD, refer for a formal psychological intervention (trauma-focused CBT or eye movement desensitisation and reprocessing ).
## Step 3: Treatment and referral advice for persistent subthreshold depressive symptoms or mild to moderate common mental health disorders with inadequate response to initial interventions, or moderate to severe common mental health disorders
For guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
If there has been an inadequate response following the delivery of a first-line treatment for persistent subthreshold depressive symptoms or mild to moderate common mental health disorders, a range of psychological, pharmacological or combined interventions may be considered. This section also recommends interventions or provides referral advice for first presentation of moderate to severe common mental health disorders.
For people with persistent subthreshold depressive symptoms or mild to moderate depression that has not responded to a low-intensity intervention, offer or refer for:
antidepressant medication or
a psychological intervention (CBT, IPT, behavioural activation or behavioural couples therapy).
For people with an initial presentation of moderate or severe depression, offer or refer for a psychological intervention (CBT or IPT) in combination with an antidepressant. (Adapted from NICE's guideline on depression.)
For people with moderate to severe depression and a chronic physical health problem consider referral to collaborative care if there has been no, or only a limited, response to psychological or drug treatment alone or combined in the current or in a past episode. (Adapted from NICE's guideline on depression.)
For people with depression who decline an antidepressant, CBT, IPT, behavioural activation and behavioural couples therapy, consider providing or referring for:
counselling for people with persistent subthreshold depressive symptoms or mild to moderate depression
short-term psychodynamic psychotherapy for people with mild to moderate depression. Discuss with the person the uncertainty of the effectiveness of counselling and psychodynamic psychotherapy in treating depression.
For people with generalised anxiety disorder who have marked functional impairment or have not responded to a low-intensity intervention, offer or refer for 1 of the following:
CBT or
applied relaxation or
if the person prefers, drug treatment.
For people with moderate to severe panic disorder (with or without agoraphobia), consider referral for:
CBT or
an antidepressant if the disorder is long-standing or the person has not benefitted from or has declined psychological interventions.
For people with OCD and moderate or severe functional impairment, and in particular where there is significant comorbidity with other common mental health disorders, offer or refer for:
CBT (including ERP) or antidepressant medication for moderate impairment
CBT (including ERP) combined with antidepressant medication and case management for severe impairment.Offer home-based treatment where the person is unable or reluctant to attend a clinic or has specific problems (for example, hoarding).
For people with long-standing OCD or with symptoms that are severely disabling and restrict their life, consider referral to a specialist mental health service.
For people with OCD who have not benefitted from 2 courses of CBT (including ERP) combined with antidepressant medication, refer to a service with specialist expertise in OCD.
For people with PTSD, offer or refer for a psychological intervention (trauma-focused CBT or EMDR). Do not delay the intervention or referral, particularly for people with severe and escalating symptoms in the first month after the traumatic event.
For people with PTSD, offer or refer for drug treatment only if a person declines an offer of a psychological intervention or expresses a preference for drug treatment.
## Treatment and referral advice to help prevent relapse
For people with a common mental health disorder who are at significant risk of relapse or have a history of recurrent problems, discuss with the person the treatments that might reduce the risk of recurrence. The choice of treatment or referral for treatment should be informed by the response to previous treatment, including residual symptoms, the consequences of relapse, any discontinuation symptoms when stopping medication, and the person's preference.
For people with a previous history of depression who are currently well and who are considered at risk of relapse despite taking antidepressant medication, or those who are unable to continue or choose not to continue antidepressant medication, offer or refer for 1 of the following:
individual CBT
mindfulness-based cognitive therapy (for those who have had 3 or more episodes).
For people who have had previous treatment for depression but continue to have residual depressive symptoms, offer or refer for 1 of the following:
individual CBT
mindfulness-based cognitive therapy (for those who have had 3 or more episodes).
# Developing local care pathways
Local care pathways should be developed to promote implementation of key principles of good care. Pathways should be:
negotiable, workable and understandable for people with common mental health disorders, their families and carers, and professionals
accessible and acceptable to all people in need of the services served by the pathway
responsive to the needs of people with common mental health disorders and their families and carers
integrated so that there are no barriers to movement between different levels of the pathway
-utcomes focused (including measures of quality, service-user experience and harm).
Responsibility for the development, management and evaluation of local care pathways should lie with a designated leadership team, which should include primary and secondary care clinicians, managers and commissioners. The leadership team should have particular responsibility for:
developing clear policy and protocols for the operation of the pathway
providing training and support on the operation of the pathway
auditing and reviewing the performance of the pathway.
Primary and secondary care clinicians, managers and commissioners should work together to design local care pathways that promote a stepped-care model of service delivery that:
provides the least intrusive, most effective intervention first
has clear and explicit criteria for the thresholds determining access to and movement between the different levels of the pathway
does not use single criteria such as symptom severity to determine movement between steps
monitors progress and outcomes to ensure the most effective interventions are delivered and the person moves to a higher step if needed.
Primary and secondary care clinicians, managers and commissioners should work together to design local care pathways that promote a range of evidence-based interventions at each step in the pathway and support people with common mental health disorders in their choice of interventions.
All staff should ensure effective engagement with families and carers, where appropriate, to:
inform and improve the care of the person with a common mental health disorder
meet the identified needs of the families and carers.
Primary and secondary care clinicians, managers and commissioners should work together to design local care pathways that promote the active engagement of all populations served by the pathway. Pathways should:
-ffer prompt assessments and interventions that are appropriately adapted to the cultural, gender, age and communication needs of people with common mental health disorders
keep to a minimum the number of assessments needed to access interventions.
Primary and secondary care clinicians, managers and commissioners should work together to design local care pathways that respond promptly and effectively to the changing needs of all populations served by the pathways. Pathways should have in place:
clear and agreed goals for the services offered to a person with a common mental health disorder
robust and effective means for measuring and evaluating the outcomes associated with the agreed goals
clear and agreed mechanisms for responding promptly to identified changes to the person's needs.
Primary and secondary care clinicians, managers and commissioners should work together to design local care pathways that provide an integrated programme of care across both primary and secondary care services. Pathways should:
minimise the need for transition between different services or providers
allow services to be built around the pathway and not the pathway around the services
establish clear links (including access and entry points) to other care pathways (including those for physical healthcare needs)
have designated staff who are responsible for the coordination of people's engagement with the pathway.
Primary and secondary care clinicians, managers and commissioners should work together to ensure effective communication about the functioning of the local care pathway. There should be protocols for:
sharing and communicating information with people with common mental health disorders, and where appropriate families and carers, about their care
sharing and communicating information about the care of service users with other professionals (including GPs)
communicating information between the services provided within the pathway
communicating information to services outside the pathway.
Primary and secondary care clinicians, managers and commissioners should work together to design local care pathways that have robust systems for outcome measurement in place, which should be used to inform all involved in a pathway about its effectiveness. This should include providing:
individual routine outcome measurement systems
effective electronic systems for the routine reporting and aggregation of outcome measures
effective systems for the audit and review of the overall clinical and cost effectiveness of the pathway.# Research recommendations
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.
# Comprehensive assessment versus a brief assessment
For people with a suspected common mental health disorder, what is the clinical and cost effectiveness of using a comprehensive assessment (conducted by mental health professional) versus a brief assessment (conducted by a paraprofessional)?
## Why this is important
Uncertainty remains about the accuracy and consequent identification of appropriate treatment by paraprofessionals in primary care. An assessment by a mental health professional is likely to result in more accurate identification of problems and appropriate treatment, but is likely to entail greater cost and potentially significant longer wait times for interventions, both of which can have deleterious effects on care.
This question should be answered using a randomised controlled design that reports short- and medium-term outcomes (including cost-effectiveness outcomes) of at least 12 months' duration.
# 'Walking across' from one assessment instrument to another
What methodology should be used to allow 'walking across' from one assessment instrument for common mental health disorders to another?
## Why is this important
A number of different ratings scales for depression and anxiety disorders are in current use, both in research studies and clinical practice. This makes obtaining comparative estimates of clinical outcomes at the individual level difficult when moving between research and clinical settings, and also between clinical settings. A method that allows for prompt and easy 'walking across' between assessment instruments would have a potentially significant clinical benefit in routine care.
This question should be answered by developing a new method and subsequent data analysis of existing datasets to facilitate comparison between commonly used measures.
# GAD-2 for people with suspected anxiety disorders
In people with suspected anxiety disorders, what is the clinical utility of using the GAD-2 compared with routine case identification to accurately identify different anxiety disorders? Should an avoidance question be added to improve case identification?
## Why is this important
There is good evidence of poor detection and under-recognition in primary care of anxiety disorders. Case identification questions for anxiety disorders are not well developed. There is reasonable evidence that the GAD-2 may have clinical utility as a case identification tool for anxiety disorders, in particular generalised anxiety disorder, but there is greater uncertainly about its utility for other anxiety disorders, especially those with an element of phobic avoidance. Understanding whether the GAD-2 plus or minus an additional phobia question would improve case identification for different anxiety disorders would be an important contribution to their identification.
These questions should be answered by a well-designed cohort study in which the GAD-2 is compared with a diagnostic gold-standard for a range of anxiety disorders. The cost effectiveness of this approach should also be assessed.
# Routine outcome measurement
In people with a common mental health disorder, what is the clinical utility of routine outcome measurement and is it cost effective compared with standard care?
## Why is this important
Routine outcome measurement is increasingly a part of the delivery of psychological interventions, particularly in the IAPT programme. There is evidence from this programme and from other studies that routine outcome measurement may bring real benefits. However, there is much less evidence for pharmacological interventions on the cost effectiveness of routine outcome measurement. If routine outcome measurement were shown to be cost effective across the range of common mental health disorders it could be associated with improved treatment outcomes, because of its impact on healthcare professionals' behaviour and the prompter availability of appropriate treatment interventions in light of feedback from the measurement.
This should be tested in a randomised controlled trial in which different frequencies of routine outcome measurement are compared, for example at the beginning and end of treatment, at regular intervals and at every appointment.
# Use of a simple algorithm compared with a standard clinical assessment
For people with a common mental health disorder, is the use of a simple algorithm (based on factors associated with treatment response), when compared with a standard clinical assessment, more clinically and cost effective?
## Why is this important
There are well-established systems for the assessment of mental states, in primary and secondary care services, for common mental health disorders. One key function of such assessment is to identify both appropriate treatments and to obtain an indication of likely response to such treatments, thereby informing patient choice and leading to clinically and cost-effective interventions. Although the reliability of diagnostic systems is much improved, data on appropriate treatment response indicators remain poor, with factors such as chronicity and severity emerging as some of the most reliable indicators. Other factors may also be identified, which, if they could be developed into a simple algorithms, could inform treatment choice decisions at many levels in the healthcare system. Treatment choice can include complex assessment and discussion of options but the validity of such assessments appears to be low. Would the use of a number of simple indicators (for example, chronicity, severity and comorbidity) provide a better indication of likely treatment response? Using existing individual patient data, could a simple algorithm be developed for testing in a prospective study?
This should be tested in a 2-stage programme of research: first, a review of existing trial datasets to identify potential predictors and then to develop an algorithm; second, a randomised controlled trial in which the algorithm is tested against expert clinical prediction.
# Priority of treatment for people with anxiety and depression
For people with both anxiety and depression, which disorder should be treated first to improve their outcomes?
## Why is this important
Comorbidity between depression and anxiety disorders is common. At present there is little empirical evidence to guide healthcare professionals or patients in choosing which disorder should be treated first. Given that for many disorders the treatment strategies, particularly for psychological approaches, can be very different, guidance for healthcare professionals and patients on the appropriate sequencing of psychological interventions would be likely to significantly improve outcomes.
This should be tested in a randomised trial in which patients who have a dual diagnosis of an anxiety disorder and depression, and where there is uncertainty about the appropriate sequencing of treatment, should be randomised to different sequencing of treatment. The clinical and cost effectiveness of the interventions should be tested at the end of treatment and at 12 months' follow-up.# Glossary
This provides definitions of a number of terms, based on definitions from related NICE guidelines. The list aims to cover the most commonly used terms and is not intended to be exhaustive.
Active monitoring: an active process of assessment, monitoring symptoms and functioning, advice and support for people with mild common mental health disorders that may spontaneously remit. It involves discussing the presenting problems and any concerns that the person may have about them, providing information about the nature and course of the disorder, arranging a further assessment, normally within 2 weeks, and making contact if the person does not attend follow-up appointments. Also known as 'watchful waiting'.
Applied relaxation: a psychological intervention that focuses on applying muscular relaxation in situations and occasions where the person is or might be anxious. The intervention usually consists of 12 to 15 weekly sessions (fewer if the person recovers sooner, more if clinically required), each lasting 1 hour.
Alcohol dependence: characterised by craving, tolerance, a preoccupation with alcohol and continued drinking in spite of harmful consequences.
Befriending: meeting and talking with someone with a mental health problem usually once a week; this would be provided as an adjunct to any psychological or pharmacological intervention. The befriender may accompany the befriendee on trips to broaden their range of activities and offer practical support with ongoing difficulties.
Behavioural activation: a psychological intervention for depression that aims to identify the effects of behaviour on current symptoms, mood and problem areas. It seeks to reduce symptoms and problematic behaviours through behavioural tasks related to reducing avoidance, activity scheduling, and enhancing positively reinforced behaviours. The intervention usually consists of 16 to 20 sessions over 3 to 4 months.
Behavioural couples therapy: a psychological intervention that aims to help people understand the effects of their interactions on each other as factors in the development and maintenance of symptoms and problems, and to change the nature of the interactions so that the person's mental health problems improve. The intervention should be based on behavioural principles and usually consists of 15 to 20 sessions over 5 to 6 months.
Cognitive behavioural therapy (CBT): a psychological intervention where the person works collaboratively with the therapist to identify the effects of thoughts, beliefs and interpretations on current symptoms, feelings states and problems areas. They learn the skills to identity, monitor and then counteract problematic thoughts, beliefs and interpretations related to the target symptoms or problems, and appropriate coping skills. Duration of treatment varies depending on the disorder and its severity but for people with depression it should be in the range of 16 to 20 sessions over 3 to 4 months; for people with GAD it should usually consist of 12 to 15 weekly sessions (fewer if the person recovers sooner, more if clinically required), each lasting 1 hour.
Collaborative care: in the context of this guideline, a coordinated approach to mental and physical healthcare involving the following elements: case management which is supervised and has support from a senior mental health professional; close collaboration between primary and secondary physical health services and specialist mental health services; a range of interventions consistent with those recommended in this guideline, including patient education, psychological and pharmacological interventions, and medication management; and long-term coordination of care and follow-up.
Computerised cognitive behavioural therapy: a form of cognitive behavioural therapy that is provided via a stand-alone computer-based or web-based programme. It should include an explanation of the CBT model, encourage tasks between sessions, and use thought-challenging and active monitoring of behaviour, thought patterns and outcomes. It should be supported by a trained practitioner who typically provides limited facilitation of the programme and reviews progress and outcome. The intervention typically takes place over 9 to 12 weeks, including follow-up.
Counselling: a short-term supportive approach that aims to help people explore their feelings and problems, and make dynamic changes in their lives and relationships. The intervention usually consists of 6 to 10 sessions over 8 to 12 weeks.
Eye movement desensitisation and reprocessing (EMDR): a psychological intervention for PTSD. During EMDR, the person is asked to concentrate on an image connected to the traumatic event and the related negative emotions, sensations and thoughts, while paying attention to something else, usually the therapist's fingers moving from side to side in front of the person's eyes. After each set of eye movements (about 20 seconds), the person is encouraged to discuss the images and emotions they felt during the eye movements. The process is repeated with a focus on any difficult, persisting memories. Once the person feels less distressed about the image, they are asked to concentrate on it while having a positive thought relating to it. The treatment should normally be 8 to 12 sessions when the PTSD results from a single event. When the trauma is discussed in the treatment session, longer sessions than usual are generally necessary (for example 90 minutes). Treatment should be regular and continuous (usually at least once a week).
Exposure and response prevention (ERP): a psychological intervention used for people with OCD that aims to help people to overcome their need to engage in obsessional and compulsive behaviours. With the support of a practitioner, the person is exposed to whatever makes them anxious, distressed or fearful. Rather than avoiding the situation, or repeating a compulsion, the person is trained in other ways of coping with anxiety, distress or fear. The process is repeated until the person no longer feels this way.
Facilitated self-help: in the context of this guideline, facilitated self-help (also known as guided self-help or bibliotherapy) is defined as a self-administered intervention, which makes use of a range of books or other self-help manuals, and electronic materials based on the principles of CBT and of an appropriate reading age. A trained practitioner typically facilitates the use of this material by introducing it, and reviewing progress and outcomes. The intervention consists of up to 6 to 8 sessions (face-to-face and via telephone) normally taking place over 9 to 12 weeks, including follow-up.
Group-based peer support (self-help) programme: in the context of this guideline, a support (self-help) programme delivered to groups of patients with depression and a shared chronic physical health problem. The focus is on sharing experiences and feelings associated with having a chronic physical health problem. The programme is supported by practitioners who facilitate attendance at the meetings, have knowledge of the patients' chronic physical health problem and its relationship to depression, and review the outcomes of the intervention with the individual patients. The intervention consists typically of 1 session per week over a period of 8 to 12 weeks.
Harmful drinking: a pattern of alcohol consumption causing health problems directly related to alcohol. This could include psychological problems such as depression, alcohol-related accidents or physical illness such as acute pancreatitis.
Interpersonal therapy (IPT): a psychological intervention that focuses on interpersonal issues. The person works with the therapist to identify the effects of problematic areas related to interpersonal conflicts, role transitions, grief and loss, and social skills, and their effects on current symptoms, feelings states and problems. They seek to reduce symptoms by learning to cope with or resolve such problems or conflicts. The intervention usually consists of 16 to 20 sessions over 3 to 4 months.
Low-intensity interventions: brief psychological interventions with reduced contact with a trained practitioner, where the focus is on a shared definition of the presenting problem, and the practitioner facilitates and supports the use of a range of self-help materials. The role adopted by the practitioner is one of coach or facilitator. Examples include facilitated and non-facilitated self-help, computerised CBT, physical activity programmes, group-based peer support (self-help) programmes, and psychoeducational groups.
Mindfulness-based cognitive therapy: a group-based skills training programme using techniques drawn from meditation and cognitive therapy designed specifically to prevent depressive relapse or recurrence of depression. Its aim is to enable people to learn to become more aware of bodily sensations, and thoughts and feelings associated with depressive relapse. The intervention usually consists of 8 weekly 2-hour sessions and 4 follow-up sessions in the 12 months after the end of treatment.
Non-facilitated self-help: in the context of this guideline, non-facilitated self-help (also known as pure self-help or bibliotherapy) is defined as a self-administered intervention, which makes use of written or electronic materials based on the principles of CBT and of an appropriate reading age. The intervention usually involves minimal contact with a practitioner (for example an occasional short telephone call of no more than 5 minutes) and includes instructions for the person to work systematically through the materials over a period of at least 6 weeks.
Paraprofessional: a staff member who is trained to deliver a range of specific healthcare interventions, but does not have NHS professional training, such as a psychological wellbeing practitioner.
Physical activity programme: in the context of this guideline, physical activity programmes are defined as structured and group-based (with support from a competent practitioner) and consist typically of 3 sessions per week of moderate duration (24 minutes to 1 hour) over 10 to 14 weeks (average 12 weeks).
Psychoeducation: the provision of information and advice about a disorder and its treatment. It usually involves an explanatory model of the symptoms and advice on how to cope with or overcome the difficulties a person may experience. It is usually of brief duration, instigated by a healthcare professional, and supported by the use of written materials.
Psychoeducational groups: a psychosocial group-based intervention based on the principles of CBT that has an interactive design and encourages observational learning. It may include presentations and self-help manuals. It is conducted by trained practitioners, with a ratio of 1 therapist to about 12 participants and usually consists of 6 weekly 2-hour sessions.
Somatic symptoms: physical symptoms of common mental health disorders, which form part of the cluster of symptoms that are necessary for achieving a diagnosis. They may include palpitations or muscular tension in an anxiety disorder or lethargy and sleep disturbance in depression. In some cases, they may be the main symptom with which a person first presents; they do not constitute a separate diagnosis and should be distinguished from somatoform disorders and medically unexplained symptoms.
Short-term psychodynamic psychotherapy: a psychological intervention where the therapist and person explore and gain insight into conflicts and how these are represented in current situations and relationships including the therapeutic relationship. Therapy is non-directive and recipients are not taught specific skills (for example, thought monitoring, re-evaluating, and problem solving.) The intervention usually consists of 16 to 20 sessions over 4 to 6 months.
Severity: see the section on assessing severity of common mental health disorders: definitions.
Trauma-focused CBT: a type of CBT specifically developed for people with PTSD that focuses on memories of trauma and negative thoughts and behaviours associated with such memories. The structure and content of the intervention are based on CBT principles with an explicit focus on the traumatic event that led to the disorder. The intervention normally consists of 8 to 12 sessions when the PTSD results from a single event. When the trauma is discussed in the treatment session, longer sessions than usual are generally necessary (for example 90 minutes). Treatment should be regular and continuous (usually at least once a week).
# Assessing severity of common mental health disorders: definitions
Assessing the severity of common mental health disorders is determined by 3 factors: symptom severity, duration of symptoms and associated functional impairment (for example, impairment of vocational, educational, social or other functioning).
Mild generally refers to relatively few core symptoms (although sufficient to achieve a diagnosis), a limited duration and little impact on day-to-day functioning.
Moderate refers to the presence of all core symptoms of the disorder plus several other related symptoms, duration beyond that required by minimum diagnostic criteria, and a clear impact on functioning.
Severe refers to the presence of most or all symptoms of the disorder, often of long duration and with very marked impact on functioning (for example, an inability to participate in work-related activities and withdrawal from interpersonal activities).
Persistent subthreshold refers to symptoms and associated functional impairment that do not meet full diagnostic criteria but have a substantial impact on a person's life, and which are present for a significant period of time (usually no less than 6 months and up to several years).
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{'Introduction': "Common mental health disorders, such as depression, generalised anxiety disorder, panic disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD) and social anxiety disorder (see NICE's guideline on social anxiety disorder), may affect up to 15% of the population at any one time. Depression and anxiety disorders can have a lifelong course of relapse and remission. There is considerable variation in the severity of common mental health disorders, but all can be associated with significant long-term disability. For example, depression is estimated to be the second greatest contributor to disability-adjusted life years throughout the developed world. It is also associated with high levels of morbidity and mortality, and is the most common disorder contributing to suicide.\n\nThe prevalence of individual common mental health disorders varies considerably. The 1-week prevalence rates from the Office of National Statistics 2007 national survey of adult psychiatric morbidity were 4.4% for generalised anxiety disorder, 3.0% for PTSD, 2.3% for depression, 1.4% for phobias, 1.1% for OCD, and 1.1% for panic disorder. Estimates of the proportion of people who are likely to experience specific disorders during their lifetime are from 4% to 10% for major depression, 2.5% to 5% for dysthymia, 5.7% for generalised anxiety disorder, 1.4% for panic disorder, 12.5% for specific phobias, 12.1% for social anxiety disorder, 1.6% for OCD and 6.8% for PTSD. More than half of people aged 16 to 64 years who meet the diagnostic criteria for at least 1 common mental health disorder experience comorbid anxiety and depressive disorders.\n\nThe vast majority (up to 90%) of depressive and anxiety disorders that are diagnosed are treated in primary care. However, many individuals do not seek treatment, and both anxiety and depression often go undiagnosed. Although under-recognition is generally more common in mild rather than severe cases, mild disorders are still a source of concern. Recognition of anxiety disorders by GPs is particularly poor, and only a small minority of people who experience anxiety disorders ever receive treatment. In part this may stem from GPs' difficulties in recognising the disorder, but it may also be caused by patients' worries about stigma, and avoidance on the part of individual patients.\n\nThe most common method of treatment for common mental health disorders in primary care is psychotropic medication. This is due to the limited availability of psychological interventions, despite the fact that these treatments are generally preferred by patients.\n\nSince 2004, NICE has produced a series of guidelines on the care and treatment of common mental health disorders. Some of these guidelines focus on identification and recognition (for example, the guideline on depression), whereas others give little advice on identification (for example, the guideline on generalised anxiety disorder and panic disorder). In addition to the variable advice on identification and recognition, NICE guidelines have also varied in the amount of advice they have provided on assessment and appropriate referral for the treatment of these disorders.\n\nThe intention of this guideline, which is focused on primary care, is to improve access to services (including primary care services themselves), improve identification and recognition, and provide advice on the principles that need to be adopted to develop appropriate referral and local care pathways. It brings together advice from existing guidelines and combines it with new recommendations concerning access, assessment and local care pathways for common mental health disorders.\n\nA number of the recommendations in this guideline were adapted from recommendations in other NICE guidelines for common mental health disorders. In doing so the Guideline Development Group were mindful that they had not reviewed the evidence for these recommendations and therefore when transferring them into this guideline were careful to preserve the meaning and intent of the original recommendation. Where recommendations were adapted, changes to wording or structure were made in order to fit the recommendation into this guideline; these adaptations preserved the meaning and intent of the recommendation but shifted the context in which the recommendation was made. In all cases the origin of any adapted recommendation is indicated in a note to the recommendation.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThis guideline was developed to provide an integrated approach to the identification and assessment of common mental health disorders, particularly in primary care. It draws together the recommendations from existing NICE guidance and addresses any gaps in the identification and assessment of these conditions. The guideline also provides advice for primary care and other staff on referral. Finally, it sets out guidance for the development of effective local care pathways for people with common mental health disorders.\n\nThe guideline is organised according to the principles of stepped care (see section\xa01.2).\n\n# Improving access to services\n\nPrimary and secondary care clinicians, managers and commissioners should collaborate to develop local care pathways (see also section 1.5) that promote access to services for people with common mental health disorders by:\n\nsupporting the integrated delivery of services across primary and secondary care\n\nhaving clear and explicit criteria for entry to the service\n\nfocusing on entry and not exclusion criteria\n\nhaving multiple means (including self-referral) to access the service\n\nproviding multiple points of access that facilitate links with the wider healthcare system and community in which the service is located.\n\nProvide information about the services and interventions that constitute the local care pathway, including the:\n\nrange and nature of the interventions provided\n\nsettings in which services are delivered\n\nprocesses by which a person moves through the pathway\n\nmeans by which progress and outcomes are assessed\n\ndelivery of care in related health and social care services.\n\nWhen providing information about local care pathways to people with common mental health disorders and their families and carers, all healthcare professionals should:\n\ntake into account the person's knowledge and understanding of mental health disorders and their treatment\n\nensure that such information is appropriate to the communities using the pathway.\n\nProvide all information about services in a range of languages and formats (visual, verbal and aural) and ensure that it is available from a range of settings throughout the whole community to which the service is responsible.\n\nPrimary and secondary care clinicians, managers and commissioners should collaborate to develop local care pathways (see also section 1.5) that promote access to services for people with common mental health disorders from a range of socially excluded groups including:\n\nblack and minority ethnic groups\n\nolder people\n\nthose in prison or in contact with the criminal justice system\n\nex-service personnel.\n\nSupport access to services and increase the uptake of interventions by:\n\nensuring systems are in place to provide for the overall coordination and continuity of care of people with common mental health disorders\n\ndesignating a healthcare professional to oversee the whole period of care (usually a GP in primary care settings).\n\nSupport access to services and increase the uptake of interventions by providing services for people with common mental health disorders in a variety of settings. Use an assessment of local needs as a basis for the structure and distribution of services, which should typically include delivery of:\n\nassessment and interventions outside normal working hours\n\ninterventions in the person's home or other residential settings\n\nspecialist assessment and interventions in non-traditional community-based settings (for example, community centres and social centres) and where appropriate, in conjunction with staff from those settings\n\nboth generalist and specialist assessment and intervention services in primary care settings.\n\nPrimary and secondary care clinicians, managers and commissioners should consider a range of support services to facilitate access and uptake of services. These may include providing:\n\ncrèche facilities\n\nassistance with travel\n\nadvocacy services.\n\nConsider modifications to the method and mode of delivery of assessment and treatment interventions and outcome monitoring (based on an assessment of local needs), which may typically include using:\n\ntechnology (for example, text messages, email, telephone and computers) for people who may find it difficult to, or choose not to, attend a specific service\n\nbilingual therapists or independent translators.\n\nBe respectful of, and sensitive to, diverse cultural, ethnic and religious backgrounds when working with people with common mental health disorders, and be aware of the possible variations in the presentation of these conditions. Ensure competence in:\n\nculturally sensitive assessment\n\nusing different explanatory models of common mental health disorders\n\naddressing cultural and ethnic differences when developing and implementing treatment plans\n\nworking with families from diverse ethnic and cultural backgrounds.\n\nDo not significantly vary the content and structure of assessments or interventions to address specific cultural or ethnic factors (beyond language and the cultural competence of staff), except as part of a formal evaluation of such modifications to an established intervention, as there is little evidence to support significant variations to the content and structure of assessments or interventions.\n\n# Stepped care\n\nA stepped-care model is used to organise the provision of services and to help people with common mental health disorders, their families, carers and healthcare professionals to choose the most effective interventions. The model presents an integrated overview of the key assessment and treatment interventions from this guideline. Recommendations focused solely on specialist mental health services are not included (these can be found in related guidance). Recommendation 1.5.1.3 in the section on developing local care pathways sets out the components of a stepped-care model of service delivery, which should be included in the design of local care pathways for people with common mental health disorders.\n\nFocus of the intervention\n\nNature of the intervention\n\nStep 3: Persistent subthreshold depressive symptoms or mild to moderate depression that has not responded to a low-intensity intervention; initial presentation of moderate or severe depression; GAD with marked functional impairment or that has not responded to a low-intensity intervention; moderate to severe panic disorder; OCD with moderate or severe functional impairment; PTSD.\n\nDepression: CBT, IPT, behavioural activation, behavioural couples therapy, counselling, short-term psychodynamic psychotherapy, antidepressants, combined interventions, collaborative care (for people with depression and a chronic physical health problem), self-help groups. Discuss with the person the uncertainty of the effectiveness of counselling and psychodynamic psychotherapy in treating depression.\n\nGAD: CBT, applied relaxation, drug treatment, combined interventions, self-help groups.\n\nPanic disorder: CBT, antidepressants, self-help groups.\n\nOCD: CBT (including ERP), antidepressants, combined interventions and case management, self-help groups.\n\nPTSD: Trauma-focused CBT, EMDR, drug treatment.\n\nAll disorders: Support groups, befriending, rehabilitation programmes, educational and employment support services; referral for further assessment and interventions.\n\nStep 2: Persistent subthreshold depressive symptoms or mild to moderate depression; GAD; mild to moderate panic disorder; mild to moderate OCD; PTSD (including people with mild to moderate PTSD).\n\n\n\nDepression: Individual facilitated self-help (including potentially for women during pregnancy or the postnatal period), computerised CBT, structured physical activity, group-based peer support (self-help) programmes (for people with depression and a chronic physical health problem), antidepressants, self-help groups.\n\nGAD\n and panic disorder: Individual non-facilitated and facilitated self-help, psychoeducational groups, self-help groups.\n\nOCD: Individual or group CBT (including ERP), self-help groups.\n\nPTSD: Trauma-focused CBT or EMDR.\n\nAll disorders: Support groups, educational and employment support services; referral for further assessment and interventions.\n\nStep 1: All disorders – known and suspected presentations of common mental health disorders.\n\nAll disorders: Identification, assessment, psychoeducation, active monitoring; referral for further assessment and interventions.\n\nAbbreviations: CBT, cognitive behavioural therapy; EMDR, eye movement desensitisation and reprocessing; ERP, exposure and response prevention; GAD, generalised anxiety disorder; IPT, interpersonal therapy; OCD, obsessive-compulsive disorder; PTSD, post-traumatic stress disorder.\n\n# Step 1: Identification and assessment\n\n## Identification\n\nBe alert to possible depression (particularly in people with a past history of depression, possible somatic symptoms of depression or a chronic physical health problem with associated functional impairment) and consider asking people who may have depression 2 questions, specifically:\n\nDuring the last month, have you often been bothered by feeling down, depressed or hopeless?\n\nDuring the last month, have you often been bothered by having little interest or pleasure in doing things? If a person answers 'yes' to either of the above questions, consider depression and follow the recommendations for assessment (see section\xa01.3.2).\n\nBe alert to possible anxiety disorders (particularly in people with a past history of an anxiety disorder, possible somatic symptoms of an anxiety disorder or in those who have experienced a recent traumatic event). Consider asking the person about their feelings of anxiety and their ability to stop or control worry, using the 2-item Generalized Anxiety Disorder scale (GAD-2; see the full guideline).\n\nIf the person scores 3 or more on the GAD-2 scale, consider an anxiety disorder and follow the recommendations for assessment (see section\xa01.3.2).\n\nIf the person scores less than 3 on the GAD-2 scale, but you are still concerned they may have an anxiety disorder, ask the following: 'Do you find yourself avoiding places or activities and does this cause you problems?'. If the person answers 'yes' to this question, consider an anxiety disorder and follow the recommendations for assessment (see section 1.3.2).\n\nFor people with significant language or communication difficulties, for example people with sensory impairments or a learning disability, consider using the Distress Thermometer and/or asking a family member or carer about the person's symptoms to identify a possible common mental health disorder. If a significant level of distress is identified, offer further assessment or seek the advice of a specialist.The Distress Thermometer is a single-item question screen that will identify distress coming from any source. The person places a mark on the scale answering: 'How distressed have you been during the past week on a scale of 0 to 10?' Scores of 4 or more indicate a significant level of distress that should be investigated further. (See Roth AJ et al. for more information.)\n\n## Assessment\n\nIf the identification questions (see section\xa01.3.1) indicate a possible common mental health disorder, but the practitioner is not competent to perform a mental health assessment, refer the person to an appropriate healthcare professional. If this professional is not the person's GP, inform the GP of the referral.\n\nIf the identification questions (see section\xa01.3.1) indicate a possible common mental health disorder, a practitioner who is competent to perform a mental health assessment should review the person's mental state and associated functional, interpersonal and social difficulties.\n\nWhen assessing a person with a suspected common mental health disorder, consider using:\n\na diagnostic or problem identification tool or algorithm, for example, the Improving Access to Psychological Therapies (IAPT) screening prompts tool (see appendix C of the Improving Access to Psychological Therapies Manual: appendices and helpful resources).\n\na validated measure relevant to the disorder or problem being assessed, for example, the 9-item Patient Health Questionnaire (PHQ-9), the Hospital Anxiety and Depression Scale (HADS) or the 7-item Generalized Anxiety Disorder scale (GAD-7) to inform the assessment and support the evaluation of any intervention.\n\nAll staff carrying out the assessment of suspected common mental health disorders should be competent to perform an assessment of the presenting problem in line with the service setting in which they work, and be able to:\n\ndetermine the nature, duration and severity of the presenting disorder\n\ntake into account not only symptom severity but also the associated functional impairment\n\nidentify appropriate treatment and referral options in line with relevant NICE guidance.\n\nAll staff carrying out the assessment of common mental health disorders should be competent in:\n\nrelevant verbal and non-verbal communication skills, including the ability to elicit problems, the perception of the problems and their impact, tailoring information, supporting participation in decision-making and discussing treatment options\n\nthe use of formal assessment measures and routine outcome measures in a variety of settings and environments.\n\nIn addition to assessing symptoms and associated functional impairment, consider how the following factors may have affected the development, course and severity of a person's presenting problem:\n\na history of any mental health disorder\n\na history of a chronic physical health problem\n\nany past experience of, and response to, treatments\n\nthe quality of interpersonal relationships\n\nliving conditions and social isolation\n\na family history of mental illness\n\na history of domestic violence or sexual abuse\n\nemployment and immigration status.If appropriate, the impact of the presenting problem on the care of children and young people should also be assessed, and if necessary local safeguarding procedures followed.\n\nWhen assessing a person with a suspected common mental health disorder, be aware of any learning disabilities or acquired cognitive impairments, and if necessary consider consulting with a relevant specialist when developing treatment plans and strategies.\n\nIf the presentation and history of a common mental health disorder suggest that it may be mild and self-limiting (that is, symptoms are improving) and the disorder is of recent onset, consider providing psychoeducation and active monitoring before offering or referring for further assessment or treatment. These approaches may improve less severe presentations and avoid the need for further interventions.\n\nAlways ask people with a common mental health disorder directly about suicidal ideation and intent. If there is a risk of self-harm or suicide:\n\nassess whether the person has adequate social support and is aware of sources of help\n\narrange help appropriate to the level of risk (see the section\xa0on risk assessment and monitoring)\n\nadvise the person to seek further help if the situation deteriorates.\n\nDuring pregnancy or the postnatal period, women requiring psychological interventions should be seen for treatment normally within 1\xa0month of initial assessment, and no longer than 3\xa0months afterwards. This is because of the lower threshold for access to psychological interventions during pregnancy and the postnatal period arising from the changing risk–benefit ratio for psychotropic medication at this time.\n\nWhen considering drug treatments for common mental health disorders in women who are pregnant, breastfeeding or planning a pregnancy, consult NICE's guideline on antenatal and postnatal mental health for advice on prescribing.\n\n## Risk assessment and monitoring\n\nIf a person with a common mental health disorder presents a high risk of suicide or potential harm to others, a risk of significant self-neglect, or severe functional impairment, assess and manage the immediate problem first and then refer to specialist services. Where appropriate inform families and carers.\n\nIf a person with a common mental health disorder presents considerable and immediate risk to themselves or others, refer them urgently to the emergency services or specialist mental health services.\n\nIf a person with a common mental health disorder, in particular depression, is assessed to be at risk of suicide:\n\ntake into account toxicity in overdose, if a drug is prescribed, and potential interaction with other prescribed medication; if necessary, limit the amount of drugs available\n\nconsider increasing the level of support, such as more frequent direct or telephone contacts\n\nconsider referral to specialist mental health services.\n\n# Steps 2 and 3: Treatment and referral for treatment\n\nThe recommendations for treatment and referral are also presented in table form organised by disorder in the full guideline.\n\n## Identifying the correct treatment options\n\nWhen discussing treatment options with a person with a common mental health disorder, consider:\n\ntheir past experience of the disorder\n\ntheir experience of, and response to, previous treatment\n\nthe trajectory of symptoms\n\nthe diagnosis or problem specification, severity and duration of the problem\n\nthe extent of any associated functional impairment arising from the disorder itself or any chronic physical health problem\n\nthe presence of any social or personal factors that may have a role in the development or maintenance of the disorder\n\nthe presence of any comorbid disorders.\n\nWhen discussing treatment options with a person with a common mental health disorder, provide information about:\n\nthe nature, content and duration of any proposed intervention\n\nthe acceptability and tolerability of any proposed intervention\n\npossible interactions with any current interventions\n\nthe implications for the continuing provision of any current interventions.\n\nWhen making a referral for the treatment of a common mental health disorder, take account of patient preference when choosing from a range of evidence-based treatments.\n\nWhen offering treatment for a common mental health disorder or making a referral, follow the stepped-care approach, usually offering or referring for the least intrusive, most effective intervention first (see figure\xa01 on stepped-care model: a combined summary for common mental health disorders).\n\nWhen a person presents with symptoms of anxiety and depression, assess the nature and extent of the symptoms, and if the person has:\n\ndepression that is accompanied by symptoms of anxiety, the first priority should usually be to treat the depressive disorder, in line with the NICE guideline on depression\n\nan anxiety disorder and comorbid depression or depressive symptoms, consult the NICE guidelines for the relevant anxiety disorder and consider treating the anxiety disorder first\n\nboth anxiety and depressive symptoms, with no formal diagnosis, that are associated with functional impairment, discuss with the person the symptoms to treat first and the choice of intervention.\n\nWhen a person presents with a common mental health disorder and harmful drinking or alcohol dependence, refer them for treatment of the alcohol misuse first as this may lead to significant improvement in depressive or anxiety symptoms.\n\nWhen a person presents with a common mental health disorder and a mild learning disability or mild cognitive impairment:\n\nwhere possible provide or refer for the same interventions as for other people with the same common mental health disorder\n\nif providing interventions, adjust the method of delivery or duration of the assessment or intervention to take account of the disability or impairment.\n\nWhen a person presents with a common mental health disorder and has a moderate to severe learning disability or a moderate to severe cognitive impairment, consult a specialist concerning appropriate referral and treatment options.\n\nDo not routinely vary the treatment strategies and referral practice for common mental health disorders described in this guideline either by personal characteristics (for example, sex or ethnicity) or by depression subtype (for example, atypical depression or seasonal depression) as there is no convincing evidence to support such action.\n\nIf a person with a common mental health disorder needs social, educational or vocational support, consider:\n\ninforming them about self-help groups (but not for people with PTSD), support groups and other local and national resources\n\nbefriending or a rehabilitation programme for people with long-standing moderate or severe disorders\n\neducational and employment support services.\n\n## Step 2: Treatment and referral advice for subthreshold symptoms and mild to moderate common mental health disorders\n\nFor people with persistent subthreshold depressive symptoms or mild to moderate depression:\n\noffer or refer for 1 or more of the following low-intensity interventions:\n\n\n\nindividual facilitated self-help based on the principles of cognitive behavioural therapy (CBT), except for women during pregnancy or the postnatal period (see below)\n\ncomputerised CBT\n\na structured group physical activity programme\n\na group-based peer support (self-help) programme (for those who also have a chronic physical health problem)\n\n\n\nfor women during pregnancy or the postnatal period, consider:\n\n\n\nindividual facilitated self-help based on the principles of CBT.\n\n\n\nFor pregnant women who have subthreshold symptoms of depression and/or anxiety that significantly interfere with personal and social functioning, consider providing or referring for:\n\nindividual brief psychological treatment (4 to 6 sessions), such as interpersonal therapy (IPT) or CBT for women who have had a previous episode of depression or anxiety\n\nsocial support during pregnancy and the postnatal period for women who have not had a previous episode of depression or anxiety; such support may consist of regular informal individual or group-based support.\n\nDo not offer antidepressants routinely for people with persistent subthreshold depressive symptoms or mild depression, but consider them for, or refer for an assessment, people with:\n\ninitial presentation of subthreshold depressive symptoms that have been present for a long period (typically at least 2 years) or\n\nsubthreshold depressive symptoms or mild depression that persist after other interventions or\n\na past history of moderate or severe depression or\n\nmild depression that complicates the care of a physical health problem.For guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nFor people with generalised anxiety disorder that has not improved after psychoeducation and active monitoring, offer or refer for one of the following low-intensity interventions:\n\nindividual non-facilitated self-help\n\nindividual facilitated self-help\n\npsychoeducational groups.\n\nFor people with mild to moderate panic disorder, offer or refer for 1 of the following low-intensity interventions:\n\nindividual non-facilitated self-help\n\nindividual facilitated self-help.\n\nFor people with mild to moderate OCD:\n\noffer or refer for individual CBT including exposure and response prevention (ERP) of limited duration (typically up to 10\xa0hours), which could be provided using self-help materials or by telephone or\n\nrefer for group CBT (including ERP) (note, group formats may deliver more than 10\xa0hours of therapy).\n\nFor people with PTSD, including those with mild to moderate PTSD, refer for a formal psychological intervention (trauma-focused CBT or eye movement desensitisation and reprocessing [EMDR]).\n\n## Step 3: Treatment and referral advice for persistent subthreshold depressive symptoms or mild to moderate common mental health disorders with inadequate response to initial interventions, or moderate to severe common mental health disorders\n\nFor guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nIf there has been an inadequate response following the delivery of a first-line treatment for persistent subthreshold depressive symptoms or mild to moderate common mental health disorders, a range of psychological, pharmacological or combined interventions may be considered. This section also recommends interventions or provides referral advice for first presentation of moderate to severe common mental health disorders.\n\nFor people with persistent subthreshold depressive symptoms or mild to moderate depression that has not responded to a low-intensity intervention, offer or refer for:\n\nantidepressant medication or\n\na psychological intervention (CBT, IPT, behavioural activation or behavioural couples therapy).\n\nFor people with an initial presentation of moderate or severe depression, offer or refer for a psychological intervention (CBT or IPT) in combination with an antidepressant. (Adapted from NICE's guideline on depression.)\n\nFor people with moderate to severe depression and a chronic physical health problem consider referral to collaborative care if there has been no, or only a limited, response to psychological or drug treatment alone or combined in the current or in a past episode. (Adapted from NICE's guideline on depression.)\n\nFor people with depression who decline an antidepressant, CBT, IPT, behavioural activation and behavioural couples therapy, consider providing or referring for:\n\ncounselling for people with persistent subthreshold depressive symptoms or mild to moderate depression\n\nshort-term psychodynamic psychotherapy for people with mild to moderate depression. Discuss with the person the uncertainty of the effectiveness of counselling and psychodynamic psychotherapy in treating depression.\n\nFor people with generalised anxiety disorder who have marked functional impairment or have not responded to a low-intensity intervention, offer or refer for 1 of the following:\n\nCBT or\n\napplied relaxation or\n\nif the person prefers, drug treatment.\n\nFor people with moderate to severe panic disorder (with or without agoraphobia), consider referral for:\n\nCBT or\n\nan antidepressant if the disorder is long-standing or the person has not benefitted from or has declined psychological interventions.\n\nFor people with OCD and moderate or severe functional impairment, and in particular where there is significant comorbidity with other common mental health disorders, offer or refer for:\n\nCBT (including ERP) or antidepressant medication for moderate impairment\n\nCBT (including ERP) combined with antidepressant medication and case management for severe impairment.Offer home-based treatment where the person is unable or reluctant to attend a clinic or has specific problems (for example, hoarding).\n\nFor people with long-standing OCD or with symptoms that are severely disabling and restrict their life, consider referral to a specialist mental health service.\n\nFor people with OCD who have not benefitted from 2 courses of CBT (including ERP) combined with antidepressant medication, refer to a service with specialist expertise in OCD.\n\nFor people with PTSD, offer or refer for a psychological intervention (trauma-focused CBT or EMDR). Do not delay the intervention or referral, particularly for people with severe and escalating symptoms in the first month after the traumatic event.\n\nFor people with PTSD, offer or refer for drug treatment only if a person declines an offer of a psychological intervention or expresses a preference for drug treatment.\n\n## Treatment and referral advice to help prevent relapse\n\nFor people with a common mental health disorder who are at significant risk of relapse or have a history of recurrent problems, discuss with the person the treatments that might reduce the risk of recurrence. The choice of treatment or referral for treatment should be informed by the response to previous treatment, including residual symptoms, the consequences of relapse, any discontinuation symptoms when stopping medication, and the person's preference.\n\nFor people with a previous history of depression who are currently well and who are considered at risk of relapse despite taking antidepressant medication, or those who are unable to continue or choose not to continue antidepressant medication, offer or refer for 1 of the following:\n\nindividual CBT\n\nmindfulness-based cognitive therapy (for those who have had 3 or more episodes).\n\nFor people who have had previous treatment for depression but continue to have residual depressive symptoms, offer or refer for 1 of the following:\n\nindividual CBT\n\nmindfulness-based cognitive therapy (for those who have had 3 or more episodes).\n\n# Developing local care pathways\n\nLocal care pathways should be developed to promote implementation of key principles of good care. Pathways should be:\n\nnegotiable, workable and understandable for people with common mental health disorders, their families and carers, and professionals\n\naccessible and acceptable to all people in need of the services served by the pathway\n\nresponsive to the needs of people with common mental health disorders and their families and carers\n\nintegrated so that there are no barriers to movement between different levels of the pathway\n\noutcomes focused (including measures of quality, service-user experience and harm).\n\nResponsibility for the development, management and evaluation of local care pathways should lie with a designated leadership team, which should include primary and secondary care clinicians, managers and commissioners. The leadership team should have particular responsibility for:\n\ndeveloping clear policy and protocols for the operation of the pathway\n\nproviding training and support on the operation of the pathway\n\nauditing and reviewing the performance of the pathway.\n\nPrimary and secondary care clinicians, managers and commissioners should work together to design local care pathways that promote a stepped-care model of service delivery that:\n\nprovides the least intrusive, most effective intervention first\n\nhas clear and explicit criteria for the thresholds determining access to and movement between the different levels of the pathway\n\ndoes not use single criteria such as symptom severity to determine movement between steps\n\nmonitors progress and outcomes to ensure the most effective interventions are delivered and the person moves to a higher step if needed.\n\nPrimary and secondary care clinicians, managers and commissioners should work together to design local care pathways that promote a range of evidence-based interventions at each step in the pathway and support people with common mental health disorders in their choice of interventions.\n\nAll staff should ensure effective engagement with families and carers, where appropriate, to:\n\ninform and improve the care of the person with a common mental health disorder\n\nmeet the identified needs of the families and carers.\n\nPrimary and secondary care clinicians, managers and commissioners should work together to design local care pathways that promote the active engagement of all populations served by the pathway. Pathways should:\n\noffer prompt assessments and interventions that are appropriately adapted to the cultural, gender, age and communication needs of people with common mental health disorders\n\nkeep to a minimum the number of assessments needed to access interventions.\n\nPrimary and secondary care clinicians, managers and commissioners should work together to design local care pathways that respond promptly and effectively to the changing needs of all populations served by the pathways. Pathways should have in place:\n\nclear and agreed goals for the services offered to a person with a common mental health disorder\n\nrobust and effective means for measuring and evaluating the outcomes associated with the agreed goals\n\nclear and agreed mechanisms for responding promptly to identified changes to the person's needs.\n\nPrimary and secondary care clinicians, managers and commissioners should work together to design local care pathways that provide an integrated programme of care across both primary and secondary care services. Pathways should:\n\nminimise the need for transition between different services or providers\n\nallow services to be built around the pathway and not the pathway around the services\n\nestablish clear links (including access and entry points) to other care pathways (including those for physical healthcare needs)\n\nhave designated staff who are responsible for the coordination of people's engagement with the pathway.\n\nPrimary and secondary care clinicians, managers and commissioners should work together to ensure effective communication about the functioning of the local care pathway. There should be protocols for:\n\nsharing and communicating information with people with common mental health disorders, and where appropriate families and carers, about their care\n\nsharing and communicating information about the care of service users with other professionals (including GPs)\n\ncommunicating information between the services provided within the pathway\n\ncommunicating information to services outside the pathway.\n\nPrimary and secondary care clinicians, managers and commissioners should work together to design local care pathways that have robust systems for outcome measurement in place, which should be used to inform all involved in a pathway about its effectiveness. This should include providing:\n\nindividual routine outcome measurement systems\n\neffective electronic systems for the routine reporting and aggregation of outcome measures\n\neffective systems for the audit and review of the overall clinical and cost effectiveness of the pathway.", 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Comprehensive assessment versus a brief assessment\n\nFor people with a suspected common mental health disorder, what is the clinical and cost effectiveness of using a comprehensive assessment (conducted by mental health professional) versus a brief assessment (conducted by a paraprofessional)?\n\n## Why this is important\n\nUncertainty remains about the accuracy and consequent identification of appropriate treatment by paraprofessionals in primary care. An assessment by a mental health professional is likely to result in more accurate identification of problems and appropriate treatment, but is likely to entail greater cost and potentially significant longer wait times for interventions, both of which can have deleterious effects on care.\n\nThis question should be answered using a randomised controlled design that reports short- and medium-term outcomes (including cost-effectiveness outcomes) of at least 12\xa0months' duration.\n\n# 'Walking across' from one assessment instrument to another\n\nWhat methodology should be used to allow 'walking across' from one assessment instrument for common mental health disorders to another?\n\n## Why is this important\n\nA number of different ratings scales for depression and anxiety disorders are in current use, both in research studies and clinical practice. This makes obtaining comparative estimates of clinical outcomes at the individual level difficult when moving between research and clinical settings, and also between clinical settings. A method that allows for prompt and easy 'walking across' between assessment instruments would have a potentially significant clinical benefit in routine care.\n\nThis question should be answered by developing a new method and subsequent data analysis of existing datasets to facilitate comparison between commonly used measures.\n\n# GAD-2 for people with suspected anxiety disorders\n\nIn people with suspected anxiety disorders, what is the clinical utility of using the GAD-2 compared with routine case identification to accurately identify different anxiety disorders? Should an avoidance question be added to improve case identification?\n\n## Why is this important\n\nThere is good evidence of poor detection and under-recognition in primary care of anxiety disorders. Case identification questions for anxiety disorders are not well developed. There is reasonable evidence that the GAD-2 may have clinical utility as a case identification tool for anxiety disorders, in particular generalised anxiety disorder, but there is greater uncertainly about its utility for other anxiety disorders, especially those with an element of phobic avoidance. Understanding whether the GAD-2 plus or minus an additional phobia question would improve case identification for different anxiety disorders would be an important contribution to their identification.\n\nThese questions should be answered by a well-designed cohort study in which the GAD-2 is compared with a diagnostic gold-standard for a range of anxiety disorders. The cost effectiveness of this approach should also be assessed.\n\n# Routine outcome measurement\n\nIn people with a common mental health disorder, what is the clinical utility of routine outcome measurement and is it cost effective compared with standard care?\n\n## Why is this important\n\nRoutine outcome measurement is increasingly a part of the delivery of psychological interventions, particularly in the IAPT programme. There is evidence from this programme and from other studies that routine outcome measurement may bring real benefits. However, there is much less evidence for pharmacological interventions on the cost effectiveness of routine outcome measurement. If routine outcome measurement were shown to be cost effective across the range of common mental health disorders it could be associated with improved treatment outcomes, because of its impact on healthcare professionals' behaviour and the prompter availability of appropriate treatment interventions in light of feedback from the measurement.\n\nThis should be tested in a randomised controlled trial in which different frequencies of routine outcome measurement are compared, for example at the beginning and end of treatment, at regular intervals and at every appointment.\n\n# Use of a simple algorithm compared with a standard clinical assessment\n\nFor people with a common mental health disorder, is the use of a simple algorithm (based on factors associated with treatment response), when compared with a standard clinical assessment, more clinically and cost effective?\n\n## Why is this important\n\nThere are well-established systems for the assessment of mental states, in primary and secondary care services, for common mental health disorders. One key function of such assessment is to identify both appropriate treatments and to obtain an indication of likely response to such treatments, thereby informing patient choice and leading to clinically and cost-effective interventions. Although the reliability of diagnostic systems is much improved, data on appropriate treatment response indicators remain poor, with factors such as chronicity and severity emerging as some of the most reliable indicators. Other factors may also be identified, which, if they could be developed into a simple algorithms, could inform treatment choice decisions at many levels in the healthcare system. Treatment choice can include complex assessment and discussion of options but the validity of such assessments appears to be low. Would the use of a number of simple indicators (for example, chronicity, severity and comorbidity) provide a better indication of likely treatment response? Using existing individual patient data, could a simple algorithm be developed for testing in a prospective study?\n\nThis should be tested in a 2-stage programme of research: first, a review of existing trial datasets to identify potential predictors and then to develop an algorithm; second, a randomised controlled trial in which the algorithm is tested against expert clinical prediction.\n\n# Priority of treatment for people with anxiety and depression\n\nFor people with both anxiety and depression, which disorder should be treated first to improve their outcomes?\n\n## Why is this important\n\nComorbidity between depression and anxiety disorders is common. At present there is little empirical evidence to guide healthcare professionals or patients in choosing which disorder should be treated first. Given that for many disorders the treatment strategies, particularly for psychological approaches, can be very different, guidance for healthcare professionals and patients on the appropriate sequencing of psychological interventions would be likely to significantly improve outcomes.\n\nThis should be tested in a randomised trial in which patients who have a dual diagnosis of an anxiety disorder and depression, and where there is uncertainty about the appropriate sequencing of treatment, should be randomised to different sequencing of treatment. The clinical and cost effectiveness of the interventions should be tested at the end of treatment and at 12\xa0months' follow-up.", 'Glossary': "This provides definitions of a number of terms, based on definitions from related NICE guidelines. The list aims to cover the most commonly used terms and is not intended to be exhaustive.\n\nActive monitoring: an active process of assessment, monitoring symptoms and functioning, advice and support for people with mild common mental health disorders that may spontaneously remit. It involves discussing the presenting problems and any concerns that the person may have about them, providing information about the nature and course of the disorder, arranging a further assessment, normally within 2\xa0weeks, and making contact if the person does not attend follow-up appointments. Also known as 'watchful waiting'.\n\nApplied relaxation: a psychological intervention that focuses on applying muscular relaxation in situations and occasions where the person is or might be anxious. The intervention usually consists of 12 to 15 weekly sessions (fewer if the person recovers sooner, more if clinically required), each lasting 1\xa0hour.\n\nAlcohol dependence: characterised by craving, tolerance, a preoccupation with alcohol and continued drinking in spite of harmful consequences.\n\nBefriending: meeting and talking with someone with a mental health problem usually once a week; this would be provided as an adjunct to any psychological or pharmacological intervention. The befriender may accompany the befriendee on trips to broaden their range of activities and offer practical support with ongoing difficulties.\n\nBehavioural activation: a psychological intervention for depression that aims to identify the effects of behaviour on current symptoms, mood and problem areas. It seeks to reduce symptoms and problematic behaviours through behavioural tasks related to reducing avoidance, activity scheduling, and enhancing positively reinforced behaviours. The intervention usually consists of 16 to 20 sessions over 3 to 4\xa0months.\n\nBehavioural couples therapy: a psychological intervention that aims to help people understand the effects of their interactions on each other as factors in the development and maintenance of symptoms and problems, and to change the nature of the interactions so that the person's mental health problems improve. The intervention should be based on behavioural principles and usually consists of 15 to 20 sessions over 5 to 6\xa0months.\n\nCognitive behavioural therapy (CBT): a psychological intervention where the person works collaboratively with the therapist to identify the effects of thoughts, beliefs and interpretations on current symptoms, feelings states and problems areas. They learn the skills to identity, monitor and then counteract problematic thoughts, beliefs and interpretations related to the target symptoms or problems, and appropriate coping skills. Duration of treatment varies depending on the disorder and its severity but for people with depression it should be in the range of 16 to 20 sessions over 3 to 4\xa0months; for people with GAD it should usually consist of 12 to 15 weekly sessions (fewer if the person recovers sooner, more if clinically required), each lasting 1\xa0hour.\n\nCollaborative care: in the context of this guideline, a coordinated approach to mental and physical healthcare involving the following elements: case management which is supervised and has support from a senior mental health professional; close collaboration between primary and secondary physical health services and specialist mental health services; a range of interventions consistent with those recommended in this guideline, including patient education, psychological and pharmacological interventions, and medication management; and long-term coordination of care and follow-up.\n\nComputerised cognitive behavioural therapy: a form of cognitive behavioural therapy that is provided via a stand-alone computer-based or web-based programme. It should include an explanation of the CBT model, encourage tasks between sessions, and use thought-challenging and active monitoring of behaviour, thought patterns and outcomes. It should be supported by a trained practitioner who typically provides limited facilitation of the programme and reviews progress and outcome. The intervention typically takes place over 9 to 12\xa0weeks, including follow-up.\n\nCounselling: a short-term supportive approach that aims to help people explore their feelings and problems, and make dynamic changes in their lives and relationships. The intervention usually consists of 6 to 10 sessions over 8 to 12\xa0weeks.\n\nEye movement desensitisation and reprocessing (EMDR): a psychological intervention for PTSD. During EMDR, the person is asked to concentrate on an image connected to the traumatic event and the related negative emotions, sensations and thoughts, while paying attention to something else, usually the therapist's fingers moving from side to side in front of the person's eyes. After each set of eye movements (about 20 seconds), the person is encouraged to discuss the images and emotions they felt during the eye movements. The process is repeated with a focus on any difficult, persisting memories. Once the person feels less distressed about the image, they are asked to concentrate on it while having a positive thought relating to it. The treatment should normally be 8 to 12 sessions when the PTSD results from a single event. When the trauma is discussed in the treatment session, longer sessions than usual are generally necessary (for example 90\xa0minutes). Treatment should be regular and continuous (usually at least once a week).\n\nExposure and response prevention (ERP): a psychological intervention used for people with OCD that aims to help people to overcome their need to engage in obsessional and compulsive behaviours. With the support of a practitioner, the person is exposed to whatever makes them anxious, distressed or fearful. Rather than avoiding the situation, or repeating a compulsion, the person is trained in other ways of coping with anxiety, distress or fear. The process is repeated until the person no longer feels this way.\n\nFacilitated self-help: in the context of this guideline, facilitated self-help (also known as guided self-help or bibliotherapy) is defined as a self-administered intervention, which makes use of a range of books or other self-help manuals, and electronic materials based on the principles of CBT and of an appropriate reading age. A trained practitioner typically facilitates the use of this material by introducing it, and reviewing progress and outcomes. The intervention consists of up to 6 to 8 sessions (face-to-face and via telephone) normally taking place over 9 to 12\xa0weeks, including follow-up.\n\nGroup-based peer support (self-help) programme: in the context of this guideline, a support (self-help) programme delivered to groups of patients with depression and a shared chronic physical health problem. The focus is on sharing experiences and feelings associated with having a chronic physical health problem. The programme is supported by practitioners who facilitate attendance at the meetings, have knowledge of the patients' chronic physical health problem and its relationship to depression, and review the outcomes of the intervention with the individual patients. The intervention consists typically of 1 session per week over a period of 8 to 12\xa0weeks.\n\nHarmful drinking: a pattern of alcohol consumption causing health problems directly related to alcohol. This could include psychological problems such as depression, alcohol-related accidents or physical illness such as acute pancreatitis.\n\nInterpersonal therapy (IPT): a psychological intervention that focuses on interpersonal issues. The person works with the therapist to identify the effects of problematic areas related to interpersonal conflicts, role transitions, grief and loss, and social skills, and their effects on current symptoms, feelings states and problems. They seek to reduce symptoms by learning to cope with or resolve such problems or conflicts. The intervention usually consists of 16 to 20 sessions over 3 to 4\xa0months.\n\nLow-intensity interventions: brief psychological interventions with reduced contact with a trained practitioner, where the focus is on a shared definition of the presenting problem, and the practitioner facilitates and supports the use of a range of self-help materials. The role adopted by the practitioner is one of coach or facilitator. Examples include facilitated and non-facilitated self-help, computerised CBT, physical activity programmes, group-based peer support (self-help) programmes, and psychoeducational groups.\n\nMindfulness-based cognitive therapy: a group-based skills training programme using techniques drawn from meditation and cognitive therapy designed specifically to prevent depressive relapse or recurrence of depression. Its aim is to enable people to learn to become more aware of bodily sensations, and thoughts and feelings associated with depressive relapse. The intervention usually consists of 8 weekly 2-hour sessions and 4 follow-up sessions in the 12\xa0months after the end of treatment.\n\nNon-facilitated self-help: in the context of this guideline, non-facilitated self-help (also known as pure self-help or bibliotherapy) is defined as a self-administered intervention, which makes use of written or electronic materials based on the principles of CBT and of an appropriate reading age. The intervention usually involves minimal contact with a practitioner (for example an occasional short telephone call of no more than 5\xa0minutes) and includes instructions for the person to work systematically through the materials over a period of at least 6\xa0weeks.\n\nParaprofessional: a staff member who is trained to deliver a range of specific healthcare interventions, but does not have NHS professional training, such as a psychological wellbeing practitioner.\n\nPhysical activity programme: in the context of this guideline, physical activity programmes are defined as structured and group-based (with support from a competent practitioner) and consist typically of 3 sessions per week of moderate duration (24\xa0minutes to 1\xa0hour) over 10 to 14\xa0weeks (average 12\xa0weeks).\n\nPsychoeducation: the provision of information and advice about a disorder and its treatment. It usually involves an explanatory model of the symptoms and advice on how to cope with or overcome the difficulties a person may experience. It is usually of brief duration, instigated by a healthcare professional, and supported by the use of written materials.\n\nPsychoeducational groups: a psychosocial group-based intervention based on the principles of CBT that has an interactive design and encourages observational learning. It may include presentations and self-help manuals. It is conducted by trained practitioners, with a ratio of 1 therapist to about 12\xa0participants and usually consists of 6 weekly 2-hour sessions.\n\nSomatic symptoms: physical symptoms of common mental health disorders, which form part of the cluster of symptoms that are necessary for achieving a diagnosis. They may include palpitations or muscular tension in an anxiety disorder or lethargy and sleep disturbance in depression. In some cases, they may be the main symptom with which a person first presents; they do not constitute a separate diagnosis and should be distinguished from somatoform disorders and medically unexplained symptoms.\n\nShort-term psychodynamic psychotherapy: a psychological intervention where the therapist and person explore and gain insight into conflicts and how these are represented in current situations and relationships including the therapeutic relationship. Therapy is non-directive and recipients are not taught specific skills (for example, thought monitoring, re-evaluating, and problem solving.) The intervention usually consists of 16 to 20 sessions over 4 to 6\xa0months.\n\nSeverity: see the section on assessing severity of common mental health disorders: definitions.\n\nTrauma-focused CBT: a type of CBT specifically developed for people with PTSD that focuses on memories of trauma and negative thoughts and behaviours associated with such memories. The structure and content of the intervention are based on CBT principles with an explicit focus on the traumatic event that led to the disorder. The intervention normally consists of 8 to 12 sessions when the PTSD results from a single event. When the trauma is discussed in the treatment session, longer sessions than usual are generally necessary (for example 90\xa0minutes). Treatment should be regular and continuous (usually at least once a week).\n\n# Assessing severity of common mental health disorders: definitions\n\nAssessing the severity of common mental health disorders is determined by 3 factors: symptom severity, duration of symptoms and associated functional impairment (for example, impairment of vocational, educational, social or other functioning).\n\nMild generally refers to relatively few core symptoms (although sufficient to achieve a diagnosis), a limited duration and little impact on day-to-day functioning.\n\nModerate refers to the presence of all core symptoms of the disorder plus several other related symptoms, duration beyond that required by minimum diagnostic criteria, and a clear impact on functioning.\n\nSevere refers to the presence of most or all symptoms of the disorder, often of long duration and with very marked impact on functioning (for example, an inability to participate in work-related activities and withdrawal from interpersonal activities).\n\nPersistent subthreshold refers to symptoms and associated functional impairment that do not meet full diagnostic criteria but have a substantial impact on a person's life, and which are present for a significant period of time (usually no less than 6\xa0months and up to several years)."}
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https://www.nice.org.uk/guidance/cg123
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This guideline covers care for people aged 18 and over with common mental health problems, with a focus on primary care. It aims to improve access to services for adults and how mental health problems are identified and assessed, and makes recommendations on local care pathways.
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21e2da0262b0e57fb23adb92d7387d81504ecc9c
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nice
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Endoscopic radiofrequency therapy of the anal sphincter for faecal incontinence
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Endoscopic radiofrequency therapy of the anal sphincter for faecal incontinence
# Guidance
The evidence on endoscopic radiofrequency therapy of the anal sphincter for faecal incontinence raises no major safety concerns. There is evidence of efficacy in the short term, but in a limited number of patients. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake endoscopic radiofrequency therapy of the anal sphincter for faecal incontinence should take the following actions.
Inform the clinical governance leads in their Trusts.
Ensure that patients and their carers understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended (available from www.nice.org.uk/guidance/IPG393/publicinfo).
Audit and review clinical outcomes of all patients having endoscopic radiofrequency therapy of the anal sphincter for faecal incontinence (see section 3.1).
This procedure should only be carried out in units specialising in the assessment and treatment of faecal incontinence, as one of a range of treatment options.
Further research into endoscopic radiofrequency therapy of the anal sphincter for faecal incontinence should clearly define the patient groups being treated. It should also report the clinical impact in terms of quality of life and long-term outcomes. NICE may review the procedure on publication of further evidence.# The procedure
# Indications and current treatments
Faecal incontinence occurs when a person loses the ability to control their anal sphincter and bowel movements, resulting in leakage of faeces. Causes include neurological disease and perineal injury during vaginal delivery (a relatively common cause in women).
First-line treatment is conservative, with measures such as dietary management or antidiarrhoeal medication. If these are not successful, pelvic floor muscle or anal sphincter training (sometimes including biofeedback therapy) may be used.
If conservative treatments have been unsuccessful, surgical options include sphincter repair, sacral nerve stimulation, stimulated graciloplasty (creation of a new sphincter from other suitable muscles), anorectal or transabdominal implantation of an artificial anal sphincter, or permanent colostomy.
# Outline of the procedure
The aim of endoscopic radiofrequency therapy of the anal sphincter for faecal incontinence is to cause a degree of fibrosis, so tightening the ring of muscle that forms the sphincter. It is intended to be less invasive than alternative surgical treatments.
The procedure is usually done with the patient under sedation and local anaesthesia. Under direct visualisation, a specially designed transparent catheter which houses needle electrodes is inserted into the anus. The needle electrodes deliver heat generated by radiofrequency energy to the anal sphincter muscle under temperature feedback control via temperature sensors. Radiofrequency energy is typically applied to each quadrant sequentially, starting at about the level of the dentate line and repeating this at 3 to 5 levels approximately 1 cm apart. Chilled water is used to cool the mucosa.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/878/overview
# Efficacy
A case series of 50 patients reported improved mean scores in all components of the Fecal Incontinence Quality of Life (FIQL) questionnaire (29 questions on lifestyle, coping, depression, and embarrassment, scored from 1 to 4; higher score indicates better quality of life) from baseline to 6-month follow-up (per protocol analysis: lifestyle, 2.5 to 3.1; coping, 1.9 to 2.4; depression, 2.8 to 3.3; and embarrassment, 1.9 to 2.5; p ≤ 0.0001 for each). A case series of 19 patients reported a significant improvement in mean scores in all components of the FIQL questionnaire from baseline to 5-year follow-up (lifestyle, 2.43 to 3.16, p < 0.00075; coping, 1.73 to 2.6, p < 0.00083; depression, 2.24 to 3.15, p < 0.0002; and embarrassment, 1.56 to 2.51, p < 0.0003).
The case series of 50 patients reported no differences in resting or squeeze pressure, rectal sensation, pudendal nerve motor latency, or sphincter defects on endoanal ultrasound at 6-month follow-up.
The Specialist Advisers listed key efficacy outcomes as improvement in faecal continence and improved quality of life.
# Safety
The case series of 50 patients reported mucosal ulceration in 2 patients, 2–3 weeks after treatment. In 1 patient this was superficial and settled with local care: continence was improved. In the other patient the ulceration did not involve the underlying muscle but nevertheless caused anal pain: continence was worse at 6-month follow-up.
The case series of 50 patients reported constipation in 2% (1/50) of patients (treatment and outcome not described).
The case series of 50 and 19 patients reported secondary haemorrhage in 2% (1/50) and 32% (6/19) of patients respectively. Both required suture ligation to control the bleeding (not otherwise described).
The case series of 50 patients reported postoperative anal pain in 10% (5/50) of patients.
The case series of 24 patients reported constipation and diarrhoea in 1 patient each. The first patient was treated with laxatives, and the diarrhoea in the second patient resolved spontaneously.
The Specialist Advisers listed anecdotal adverse events to include haemorrhage (acute or secondary) and anal stenosis.
# Other comments
The Committee recognised both the serious impact that faecal incontinence can have on quality of life and the potential benefits of new treatment options for carefully selected patients, provided that their efficacy has been properly demonstrated.# Further information
This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion), available from www.nice.org.uk/guidance/IPG393
For related NICE guidance see www.nice.org.uk
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG393/publicinfo
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{'Guidance': "The evidence on endoscopic radiofrequency therapy of the anal sphincter for faecal incontinence raises no major safety concerns. There is evidence of efficacy in the short term, but in a limited number of patients. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake endoscopic radiofrequency therapy of the anal sphincter for faecal incontinence should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended (available from www.nice.org.uk/guidance/IPG393/publicinfo).\n\nAudit and review clinical outcomes of all patients having endoscopic radiofrequency therapy of the anal sphincter for faecal incontinence (see section 3.1).\n\nThis procedure should only be carried out in units specialising in the assessment and treatment of faecal incontinence, as one of a range of treatment options.\n\nFurther research into endoscopic radiofrequency therapy of the anal sphincter for faecal incontinence should clearly define the patient groups being treated. It should also report the clinical impact in terms of quality of life and long-term outcomes. NICE may review the procedure on publication of further evidence.", 'The procedure': '# Indications and current treatments\n\nFaecal incontinence occurs when a person loses the ability to control their anal sphincter and bowel movements, resulting in leakage of faeces. Causes include neurological disease and perineal injury during vaginal delivery (a relatively common cause in women).\n\nFirst-line treatment is conservative, with measures such as dietary management or antidiarrhoeal medication. If these are not successful, pelvic floor muscle or anal sphincter training (sometimes including biofeedback therapy) may be used.\n\nIf conservative treatments have been unsuccessful, surgical options include sphincter repair, sacral nerve stimulation, stimulated graciloplasty (creation of a new sphincter from other suitable muscles), anorectal or transabdominal implantation of an artificial anal sphincter, or permanent colostomy.\n\n# Outline of the procedure\n\nThe aim of endoscopic radiofrequency therapy of the anal sphincter for faecal incontinence is to cause a degree of fibrosis, so tightening the ring of muscle that forms the sphincter. It is intended to be less invasive than alternative surgical treatments.\n\nThe procedure is usually done with the patient under sedation and local anaesthesia. Under direct visualisation, a specially designed transparent catheter which houses needle electrodes is inserted into the anus. The needle electrodes deliver heat generated by radiofrequency energy to the anal sphincter muscle under temperature feedback control via temperature sensors. Radiofrequency energy is typically applied to each quadrant sequentially, starting at about the level of the dentate line and repeating this at 3 to 5 levels approximately 1 cm apart. Chilled water is used to cool the mucosa.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/878/overview\n\n# Efficacy\n\nA case series of 50 patients reported improved mean scores in all components of the Fecal Incontinence Quality of Life (FIQL) questionnaire (29 questions on lifestyle, coping, depression, and embarrassment, scored from 1 to 4; higher score indicates better quality of life) from baseline to 6-month follow-up (per protocol analysis: lifestyle, 2.5 to 3.1; coping, 1.9 to 2.4; depression, 2.8 to 3.3; and embarrassment, 1.9 to 2.5; p ≤ 0.0001 for each). A case series of 19 patients reported a significant improvement in mean scores in all components of the FIQL questionnaire from baseline to 5-year follow-up (lifestyle, 2.43 to 3.16, p < 0.00075; coping, 1.73 to 2.6, p < 0.00083; depression, 2.24 to 3.15, p < 0.0002; and embarrassment, 1.56 to 2.51, p < 0.0003).\n\nThe case series of 50 patients reported no differences in resting or squeeze pressure, rectal sensation, pudendal nerve motor latency, or sphincter defects on endoanal ultrasound at 6-month follow-up.\n\nThe Specialist Advisers listed key efficacy outcomes as improvement in faecal continence and improved quality of life.\n\n# Safety\n\nThe case series of 50 patients reported mucosal ulceration in 2 patients, 2–3 weeks after treatment. In 1 patient this was superficial and settled with local care: continence was improved. In the other patient the ulceration did not involve the underlying muscle but nevertheless caused anal pain: continence was worse at 6-month follow-up.\n\nThe case series of 50 patients reported constipation in 2% (1/50) of patients (treatment and outcome not described).\n\nThe case series of 50 and 19 patients reported secondary haemorrhage in 2% (1/50) and 32% (6/19) of patients respectively. Both required suture ligation to control the bleeding (not otherwise described).\n\nThe case series of 50 patients reported postoperative anal pain in 10% (5/50) of patients.\n\nThe case series of 24 patients reported constipation and diarrhoea in 1 patient each. The first patient was treated with laxatives, and the diarrhoea in the second patient resolved spontaneously.\n\nThe Specialist Advisers listed anecdotal adverse events to include haemorrhage (acute or secondary) and anal stenosis.\n\n# Other comments\n\nThe Committee recognised both the serious impact that faecal incontinence can have on quality of life and the potential benefits of new treatment options for carefully selected patients, provided that their efficacy has been properly demonstrated.', 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion), available from www.nice.org.uk/guidance/IPG393\n\nFor related NICE guidance see www.nice.org.uk\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG393/publicinfo"}
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https://www.nice.org.uk/guidance/ipg393
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a32bad5f44a2061b39db7673a0d23053b954ec29
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nice
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Percutaneous tibial nerve stimulation for faecal incontinence
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Percutaneous tibial nerve stimulation for faecal incontinence
# Guidance
The evidence on percutaneous tibial nerve stimulation (PTNS) for faecal incontinence raises no major safety concerns. There is evidence of efficacy in the short term in a limited number of patients. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake PTNS for faecal incontinence should take the following actions.
Inform the clinical governance leads in their Trusts.
Ensure that patients and their carers understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended (available from www.nice.org.uk/guidance/IPG395/publicinfo).
Audit and review clinical outcomes of all patients having PTNS for faecal incontinence (see section 3.1).
This procedure should only be carried out in units specialising in the assessment and treatment of faecal incontinence, as one of a range of treatment options.
The Committee was advised that further research is in progress. Future research should clearly define the patient groups being treated and should explicitly address treatment schedules. Studies should report long-term outcomes and requirements for retreatment. NICE may review this guidance on publication of further evidence.# The procedure
# Indications and current treatments
Faecal incontinence occurs when a person loses the ability to control their anal sphincter and bowel movements, resulting in leakage of faeces. Causes include neurological disease and perineal injury during vaginal delivery (a relatively common cause in women).
First-line treatment is conservative, with measures such as dietary management or antidiarrhoeal medication. If these are not successful, pelvic floor muscle or anal sphincter training (sometimes including biofeedback therapy) may be used.
If conservative treatments have been unsuccessful, surgical options include sphincter repair, sacral nerve stimulation, stimulated graciloplasty (creation of a new sphincter from other suitable muscles), anorectal or transabdominal implantation of an artificial anal sphincter, or permanent colostomy.
# Outline of the procedure
The aim of PTNS is to achieve a neuromodulatory effect similar to that of sacral nerve stimulation through a less invasive route, but its exact mechanism of action is unclear.
A fine gauge needle is inserted percutaneously, just above and medial to the ankle, next to the posterior tibial nerve, and a surface electrode is placed near the arch of the foot. The needle and electrode are connected to a low-voltage stimulator. Stimulation of the posterior tibial nerve produces a motor (plantar flexion or fanning of the toes) and/or sensory (tingling in the ankle, foot or toes) response. Initial treatment usually consists of 12 outpatient sessions lasting 30 minutes each, typically a week apart. Treatment may be repeated if required.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/877/overview
# Efficacy
A non-randomised comparative study of 52 patients treated by PTNS or sham reported that 53% (17/32) had 'good' results, 31% (10/32) had 'fair' results and 16% (5/32) had 'poor' results after treatment with PTNS. No clinical improvement was reported in the 20 patients treated with sham. Clinical improvement was measured using a score ranging from 0 to 20, with 0 being perfect continence. Patients in the 'good' group had a reduction in mean score from 17.4 to 1.7 (p < 0.001), the 'fair' group had a reduction from mean 18.2 to 8.5 (p < 0.05) and the 'poor' group had a reduction from mean 18.6 to 14.8 (significance not stated).
The non-randomised comparative study of 52 patients reported that of those patients with any improvement in scores after PTNS, 30% (8/27) had a recurrence of symptoms during a mean follow-up of 22.3 months (3 and 5 patients were originally considered to have 'good' and 'fair' results respectively). Six patients had further treatment but 2 refused treatment.
The Specialist Advisers listed key efficacy outcomes as sustained improvement in continence (including where top-up therapy is required) measured as a reduction in weekly faecal incontinence episodes and quality of life.
# Safety
The case series of 22 patients reported gastrodynia (stomach ache) that lasted for several hours in 2 patients, occurring 2–3 hours after treatment sessions, and leg numbness that lasted for 2 hours in 1 patient in the first treatment session only (none required medical intervention).
Transient discomfort or throbbing pain at the insertion site, redness or inflammation at or around the needle insertion site, and transient toe numbness were all reported in a case series of 30 patients (number of cases not reported).
A case series of 13 patients reported that 1 patient stopped treatment after 7 weeks because of a swollen and painful leg (no further details).
The Specialist Advisers listed anecdotal adverse events as haematoma and nerve injury.
# Other comments
The Committee considered that PTNS could offer a simple and relatively non-invasive procedure for relieving faecal incontinence that could have a significant impact on quality of life, if further research supports its efficacy and helps to define the patients for whom it is most likely to be effective.
The Committee noted that the published studies included patients with a variety of different conditions and that not all patients had serious disability as a result of their symptoms. It also noted, however, that current research is addressing these issues.# Further information
This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion), available from www.nice.org.uk/guidance/IPG395
For related NICE guidance see www.nice.org.uk
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG395/publicinfo
|
{'Guidance': "The evidence on percutaneous tibial nerve stimulation (PTNS) for faecal incontinence raises no major safety concerns. There is evidence of efficacy in the short term in a limited number of patients. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake PTNS for faecal incontinence should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended (available from www.nice.org.uk/guidance/IPG395/publicinfo).\n\nAudit and review clinical outcomes of all patients having PTNS for faecal incontinence (see section 3.1).\n\nThis procedure should only be carried out in units specialising in the assessment and treatment of faecal incontinence, as one of a range of treatment options.\n\nThe Committee was advised that further research is in progress. Future research should clearly define the patient groups being treated and should explicitly address treatment schedules. Studies should report long-term outcomes and requirements for retreatment. NICE may review this guidance on publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nFaecal incontinence occurs when a person loses the ability to control their anal sphincter and bowel movements, resulting in leakage of faeces. Causes include neurological disease and perineal injury during vaginal delivery (a relatively common cause in women).\n\nFirst-line treatment is conservative, with measures such as dietary management or antidiarrhoeal medication. If these are not successful, pelvic floor muscle or anal sphincter training (sometimes including biofeedback therapy) may be used.\n\nIf conservative treatments have been unsuccessful, surgical options include sphincter repair, sacral nerve stimulation, stimulated graciloplasty (creation of a new sphincter from other suitable muscles), anorectal or transabdominal implantation of an artificial anal sphincter, or permanent colostomy.\n\n# Outline of the procedure\n\nThe aim of PTNS is to achieve a neuromodulatory effect similar to that of sacral nerve stimulation through a less invasive route, but its exact mechanism of action is unclear.\n\nA fine gauge needle is inserted percutaneously, just above and medial to the ankle, next to the posterior tibial nerve, and a surface electrode is placed near the arch of the foot. The needle and electrode are connected to a low-voltage stimulator. Stimulation of the posterior tibial nerve produces a motor (plantar flexion or fanning of the toes) and/or sensory (tingling in the ankle, foot or toes) response. Initial treatment usually consists of 12 outpatient sessions lasting 30 minutes each, typically a week apart. Treatment may be repeated if required.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/877/overview\n\n# Efficacy\n\nA non-randomised comparative study of 52 patients treated by PTNS or sham reported that 53% (17/32) had 'good' results, 31% (10/32) had 'fair' results and 16% (5/32) had 'poor' results after treatment with PTNS. No clinical improvement was reported in the 20 patients treated with sham. Clinical improvement was measured using a score ranging from 0 to 20, with 0 being perfect continence. Patients in the 'good' group had a reduction in mean score from 17.4 to 1.7 (p\xa0<\xa00.001), the 'fair' group had a reduction from mean 18.2 to 8.5 (p\xa0<\xa00.05) and the 'poor' group had a reduction from mean 18.6 to 14.8 (significance not stated).\n\nThe non-randomised comparative study of 52 patients reported that of those patients with any improvement in scores after PTNS, 30% (8/27) had a recurrence of symptoms during a mean follow-up of 22.3 months (3 and 5 patients were originally considered to have 'good' and 'fair' results respectively). Six patients had further treatment but 2 refused treatment.\n\nThe Specialist Advisers listed key efficacy outcomes as sustained improvement in continence (including where top-up therapy is required) measured as a reduction in weekly faecal incontinence episodes and quality of life.\n\n# Safety\n\nThe case series of 22 patients reported gastrodynia (stomach ache) that lasted for several hours in 2 patients, occurring 2–3 hours after treatment sessions, and leg numbness that lasted for 2 hours in 1 patient in the first treatment session only (none required medical intervention).\n\nTransient discomfort or throbbing pain at the insertion site, redness or inflammation at or around the needle insertion site, and transient toe numbness were all reported in a case series of 30 patients (number of cases not reported).\n\nA case series of 13 patients reported that 1 patient stopped treatment after 7 weeks because of a swollen and painful leg (no further details).\n\nThe Specialist Advisers listed anecdotal adverse events as haematoma and nerve injury.\n\n# Other comments\n\nThe Committee considered that PTNS could offer a simple and relatively non-invasive procedure for relieving faecal incontinence that could have a significant impact on quality of life, if further research supports its efficacy and helps to define the patients for whom it is most likely to be effective.\n\nThe Committee noted that the published studies included patients with a variety of different conditions and that not all patients had serious disability as a result of their symptoms. It also noted, however, that current research is addressing these issues.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion), available from www.nice.org.uk/guidance/IPG395\n\nFor related NICE guidance see www.nice.org.uk\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG395/publicinfo"}
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https://www.nice.org.uk/guidance/ipg395
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386f1c9326c04f544977a7ec2fa07aa6f7c8bef4
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nice
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Trabeculotomy ab interno for open angle glaucoma
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Trabeculotomy ab interno for open angle glaucoma
# Guidance
Current evidence on the safety and efficacy of trabeculotomy ab interno for open angle glaucoma is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.
Patient selection should be carried out in units that specialise in glaucoma treatment that can offer a range of treatment options.
NICE encourages the collection and publication of further data on long-term efficacy.# The procedure
# Indications and current treatments
Open angle glaucoma is a chronic condition associated with elevated intraocular pressure (IOP). Early stages are usually asymptomatic but as the condition progresses it leads to visual impairment and, if untreated, blindness.
Treatment usually involves eye drops containing different pharmacological agents that reduce the production or increase the absorption of aqueous humour. Surgical procedures such as trabeculectomy and laser trabeculoplasty may also be used.
# Outline of the procedure
Trabeculotomy ab interno for open angle glaucoma aims to reduce IOP by removing a portion of the trabecular meshwork to improve drainage of aqueous humour. It avoids the creation of a subconjunctival bleb associated with traditional trabeculectomy.
With the patient under local (intracameral) anaesthesia, a scleral incision is made and viscoelastic is inserted into the anterior chamber. Electrical ablation (aided by a goniolens) is used to remove a strip(s) of the trabecular meshwork. The eye is then irrigated and the viscoelastic aspirated from the anterior chamber. The incision is sutured.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/860/overview
# Efficacy
A case series of 1688 patients reported a reduction in mean IOP from 23.5 mmHg preoperatively to 16.4 mmHg at 5-year follow-up (number of patients at 5 years not stated).
A non-randomised comparative study of 828 patients treated by trabeculotomy ab interno alone (n = 538) or trabeculotomy ab interno plus phacoemulsification (n = 290) reported procedural success (defined as final IOP less than 21 mmHg and a 20% reduction in IOP in 2 consecutive visits after 3 months postoperatively and no secondary glaucoma incision surgery) in 65% (349/538) and 87% (252/290) of patients respectively at 12-month follow-up (p < 0.001).
A non-randomised comparative study of 259 patients (114 trabeculotomy ab interno with phacoemulsification and intraocular lens insertion procedures versus 145 phacoemulsification and intraocular lens insertion only procedures) reported procedural success (defined as no additional glaucoma surgery, IOP less than 21 mmHg and IOP reduced by 20% below baseline on the last 2 consecutive 3-month follow-up visits) in 80% and 46% of patients respectively at 24-month follow-up.
A case series of 53 patients reported complete overall success of the procedure (defined as IOP of 21 mmHg or less without the use of medication) in 91% of patients at 24-month follow-up (absolute figures not stated). The same study reported a significant reduction in mean IOP from 25.6 mmHg to 15.0 mmHg at 24 months (p < 0.005).
Case series of 1688, 53 and 21 patients reported reductions in the mean number of glaucoma medications used by patients after the procedure: from 3 to 1 at 5-year follow-up; 3 to less than 1 at 24-month follow-up; and 2 to less than 1 at mean follow-up of 25.3 months respectively.
The case series of 1688 patients reported that 10% (162/1688) of patients required an additional procedure during the 5-year follow-up. This included 96 trabeculectomies (6% of patients), 41 aqueous tube shunts (2%) and 14 repeat ab interno trabeculotomy procedures (1%).
The non-randomised comparative study of 828 patients treated by trabeculotomy ab interno alone (n = 538) or trabeculotomy ab interno plus phacoemulsification (n = 290) reported a need for secondary glaucoma procedures in 32% (175/538) and 8% (24/290) of patients respectively at 12-month follow-up.
The Specialist Advisers listed the key efficacy outcome as reduction in IOP.
# Safety
The case series of 1688 patients reported an increase in IOP of more than 10 mmHg after the procedure in 6% (96/1688) of patients (follow-up not stated).
The case series of 53 patients reported temporary IOP elevation (not otherwise described) in 23% (12/53) of patients.
The case series of 1688 patients reported hypotony (defined as an IOP of less than 5 mmHg) 1 day after the procedure in 1% (24/1688) of patients (follow-up not stated; not otherwise described).
The case series of 1688 patients reported corneal Descemet's limited membrane tear in 4 patients (timing of event not stated).
The case series of 53 patients reported moderate cataract with no influence on visual acuity in 11% (6/53) of patients and cataract with a loss of 1 line of visual acuity on the Snellen chart in 6% (3/53) of patients at 24-month follow-up.
The Specialist Advisers listed adverse events reported in the literature or anecdotally: hyphaema (blood in anterior chamber) and potential damage to the iris and lens (if performed on phakic eyes without concurrent cataract extraction). They considered theoretical adverse events to include trabecular meshwork scarring, which could render the procedure ineffective after 6 to 12 months.
# Other comments
The Committee noted that compliance with glaucoma medication is often poor and that the usual surgical treatment is trabeculectomy. It seemed plausible that alternative procedures, such as this one, might offer advantages to selected patients.
The Committee noted concerns about the possibility of failure of the procedure in the long term but was advised that this would not preclude further surgical treatment.# Further information
For related NICE guidance see www.nice.org.uk
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG397/publicinfo
|
{'Guidance': 'Current evidence on the safety and efficacy of trabeculotomy ab interno for open angle glaucoma is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatient selection should be carried out in units that specialise in glaucoma treatment that can offer a range of treatment options.\n\nNICE encourages the collection and publication of further data on long-term efficacy.', 'The procedure': "# Indications and current treatments\n\nOpen angle glaucoma is a chronic condition associated with elevated intraocular pressure (IOP). Early stages are usually asymptomatic but as the condition progresses it leads to visual impairment and, if untreated, blindness.\n\nTreatment usually involves eye drops containing different pharmacological agents that reduce the production or increase the absorption of aqueous humour. Surgical procedures such as trabeculectomy and laser trabeculoplasty may also be used.\n\n# Outline of the procedure\n\nTrabeculotomy ab interno for open angle glaucoma aims to reduce IOP by removing a portion of the trabecular meshwork to improve drainage of aqueous humour. It avoids the creation of a subconjunctival bleb associated with traditional trabeculectomy.\n\nWith the patient under local (intracameral) anaesthesia, a scleral incision is made and viscoelastic is inserted into the anterior chamber. Electrical ablation (aided by a goniolens) is used to remove a strip(s) of the trabecular meshwork. The eye is then irrigated and the viscoelastic aspirated from the anterior chamber. The incision is sutured.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/860/overview\n\n# Efficacy\n\nA case series of 1688 patients reported a reduction in mean IOP from 23.5\xa0mmHg preoperatively to 16.4 mmHg at 5-year follow-up (number of patients at 5 years not stated).\n\nA non-randomised comparative study of 828 patients treated by trabeculotomy ab interno alone (n = 538) or trabeculotomy ab interno plus phacoemulsification (n = 290) reported procedural success (defined as final IOP less than 21 mmHg and a 20% reduction in IOP in 2 consecutive visits after 3 months postoperatively and no secondary glaucoma incision surgery) in 65% (349/538) and 87% (252/290) of patients respectively at 12-month follow-up (p < 0.001).\n\nA non-randomised comparative study of 259 patients (114 trabeculotomy ab interno with phacoemulsification and intraocular lens insertion procedures versus 145 phacoemulsification and intraocular lens insertion only procedures) reported procedural success (defined as no additional glaucoma surgery, IOP less than 21 mmHg and IOP reduced by 20% below baseline on the last 2 consecutive 3-month follow-up visits) in 80% and 46% of patients respectively at 24-month follow-up.\n\nA case series of 53 patients reported complete overall success of the procedure (defined as IOP of 21 mmHg or less without the use of medication) in 91% of patients at 24-month follow-up (absolute figures not stated). The same study reported a significant reduction in mean IOP from 25.6 mmHg to 15.0 mmHg at 24\xa0months (p < 0.005).\n\nCase series of 1688, 53 and 21 patients reported reductions in the mean number of glaucoma medications used by patients after the procedure: from 3 to 1 at 5-year follow-up; 3 to less than 1 at 24-month follow-up; and 2 to less than 1 at mean follow-up of 25.3\xa0months respectively.\n\nThe case series of 1688 patients reported that 10% (162/1688) of patients required an additional procedure during the 5-year follow-up. This included 96 trabeculectomies (6% of patients), 41\xa0aqueous tube shunts (2%) and 14 repeat ab interno trabeculotomy procedures (1%).\n\nThe non-randomised comparative study of 828 patients treated by trabeculotomy ab interno alone (n = 538) or trabeculotomy ab interno plus phacoemulsification (n = 290) reported a need for secondary glaucoma procedures in 32% (175/538) and 8% (24/290) of patients respectively at 12-month follow-up.\n\nThe Specialist Advisers listed the key efficacy outcome as reduction in IOP.\n\n# Safety\n\nThe case series of 1688 patients reported an increase in IOP of more than 10\xa0mmHg after the procedure in 6% (96/1688) of patients (follow-up not stated).\n\nThe case series of 53 patients reported temporary IOP elevation (not otherwise described) in 23% (12/53) of patients.\n\nThe case series of 1688 patients reported hypotony (defined as an IOP of less than 5 mmHg) 1 day after the procedure in 1% (24/1688) of patients (follow-up not stated; not otherwise described).\n\nThe case series of 1688 patients reported corneal Descemet's limited membrane tear in 4 patients (timing of event not stated).\n\nThe case series of 53 patients reported moderate cataract with no influence on visual acuity in 11% (6/53) of patients and cataract with a loss of 1 line of visual acuity on the Snellen chart in 6% (3/53) of patients at 24-month follow-up.\n\nThe Specialist Advisers listed adverse events reported in the literature or anecdotally: hyphaema (blood in anterior chamber) and potential damage to the iris and lens (if performed on phakic eyes without concurrent cataract extraction). They considered theoretical adverse events to include trabecular meshwork scarring, which could render the procedure ineffective after 6 to 12\xa0months.\n\n# Other comments\n\nThe Committee noted that compliance with glaucoma medication is often poor and that the usual surgical treatment is trabeculectomy. It seemed plausible that alternative procedures, such as this one, might offer advantages to selected patients.\n\nThe Committee noted concerns about the possibility of failure of the procedure in the long term but was advised that this would not preclude further surgical treatment.", 'Further information': "For related NICE guidance see www.nice.org.uk\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG397/publicinfo"}
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https://www.nice.org.uk/guidance/ipg397
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3d232ef3940e160e3ed6b9d509901457106bfc42
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nice
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Type 2 diabetes prevention: population and community-level interventions
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Type 2 diabetes prevention: population and community-level interventions
This guideline covers preventing type 2 diabetes in adult populations and communities who are at high risk. It aims to promote a healthy diet and physical activity at community and population level, and recommends how to tailor services for people in ethnic communities and other groups who are particularly at risk of type 2 diabetes.
# Introduction
The Department of Health (DH) asked NICE to produce public health guidance on the prevention of type 2 diabetes mellitus among high-risk groups.
The referral was divided into two separate pieces of guidance. The first (this guidance) originally set out to address the prevention of 'pre-diabetes' among adults aged 18 to 74 in communities at high risk of developing type 2 diabetes. The second set out to focus on preventing the progression from 'pre-diabetes' to type 2 diabetes.
However, in January 2011 the World Health Organization (WHO) recommended that glycated haemoglobin (HbA1c) could be used as an alternative to standard glucose measures to diagnose type 2 diabetes among non-pregnant adults. HbA1c levels of 6.5% (48 mmol/mol) or above indicate that someone has type 2 diabetes – but there is no fixed point to indicate when someone has 'pre-diabetes'. (Increasing levels of HbA1c, up to the 6.5% (48 mmol/mol) cut-off point, mean someone is at increasing risk of type 2 diabetes.)
The title of this guidance has been changed since it went out for consultation to reflect this move away from recognising 'pre-diabetes' as a separate condition. However, the overall range and scope of the content remains the same. The second piece of guidance will consider the effectiveness and cost effectiveness of interventions to prevent type 2 diabetes among individuals at high-risk.
Factors which influence someone's risk of type 2 diabetes include: weight, waist circumference, age, physical activity and whether or not they have a previous history of gestational diabetes or a family history of type 2 diabetes.
In addition to these individual risk factors, people from certain communities and population groups are particularly at risk. This includes people of South Asian, African-Caribbean, black African and Chinese descent and those from lower socioeconomic groups.
The guidance is for commissioners, managers and practitioners with public health as part of their remit working within the NHS, local authorities, the national and local public health service and the wider public, private, voluntary and community sectors. It is also for national policy makers, caterers, food manufacturers and retailers.
The guidance is particularly aimed at: directors of public health, public health commissioners and all those working in national and local public health services. This includes: GPs, practice nurses, dietitians, public health nutritionists and other health professionals, as well as those involved in delivering physical activity interventions, community engagement teams and community leaders. It may also be of interest to members of the public.
The guidance complements, but does not replace, NICE guidance on: behaviour change, cardiovascular disease, community engagement, diabetes in pregnancy, management of type 2 diabetes, maternal and child nutrition, obesity, physical activity and weight management before, during and after pregnancy.
The Programme Development Group (PDG) developed these recommendations on the basis of reviews of the evidence, economic modelling, expert advice, stakeholder comments and fieldwork.
Members of the PDG are listed in appendix A. The methods used to develop the guidance are summarised in appendix B. Supporting documents used to prepare this document are listed in appendix E.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
For the research recommendations see section 4 and for gaps in research see appendix D.
# Definitions
## Type 2 diabetes
Diabetes is a group of disorders with a number of common features characterised by raised blood glucose. In England the four commonest types of diabetes are:
type 1 diabetes
type 2 diabetes
secondary diabetes (from pancreatic damage, hepatic cirrhosis, endocrinological disease/therapy, or anti-viral/anti-psychotic therapy)
gestational diabetes (diabetes of pregnancy).
The underlying disorder for type 2 diabetes is usually insulin insensitivity combined with a failure of pancreatic insulin secretion to compensate for increased glucose levels. The insulin insensitivity is usually evidenced by excess body weight or obesity, and exacerbated by over-eating and inactivity. It is commonly associated with raised blood pressure and a disturbance of blood lipid levels. The insulin deficiency is progressive over time, leading to a need for lifestyle change often combined with blood glucose lowering therapy. See NICE's guideline on managing type 2 diabetes in adults.
Type 2 diabetes is diagnosed in adults who are not pregnant by a glycated haemoglobin (HbA1c) level of 6.5% (48 mmol/mol) or above. A type 2 diabetes diagnosis can also be made by:
random venous plasma glucose concentration the same or greater than 11.1 mmol/l or
fasting venous plasma glucose concentration the same or greater than 7.0 mmol/l or
-hour venous plasma glucose concentration the same or greater than 11.1 mmol/l 2 hours after 75 g anhydrous glucose in an oral glucose tolerance test (OGTT).In patients without symptoms, the test must be repeated to confirm the diagnosis using World Health Organization criteria (see the World Health Organization's use of glycated haemoglobin in the diagnosis of diabetes mellitus and definition and diagnosis of diabetes mellitus and intermediate hyperglycemia).
## Overweight and obesity
The following table defines a healthy weight in relation to height using the body mass index (BMI). BMI is calculated from the weight in kg divided by the height in metres squared. The table also defines what it means to be overweight and different degrees of obesity (also see NICE's guideline on obesity).
Classification
BMI (kg/m2)
Healthy weight
Overweight
Obesity I
Obesity II
Obesity III
-r more
Being overweight or obese is the main contributing factor for type 2 diabetes. In addition, having a large waist circumference increases the risk of developing type 2 diabetes:
Men are at high risk if they have a waist circumference of 94 to 102 cm (37 to 40 inches). They are at very high risk if it is more than 102 cm.
Women are at high risk if they have a waist circumference of 80 to 88 cm (31.5 to 35 inches). They are at very high risk if it is more than 88 cm.
The above classification may not apply to some population groups, as noted in NICE's obesity guidance. For example, although some South Asian adults or older people may have a BMI lower than the overweight classification, they may still be at greater risk of developing conditions and diseases associated with being overweight or obese.
# Types of intervention
In this guidance, early intervention to prevent type 2 diabetes is considered as part of an integrated package of local measures to promote health and prevent a range of non-communicable diseases (including cardiovascular disease and some cancers).
The guidance also recommends national action to address the adverse environmental factors driving the increasing prevalence of type 2 diabetes.
Lifestyle interventions aimed at changing an individual's diet and increasing the amount of physical activity they do can halve the number with impaired glucose tolerance who go on to develop type 2 diabetes. However, the greatest impact on the levels – and associated costs – of type 2 diabetes is likely to be achieved by addressing these behavioural risk factors in whole communities and populations.
# Guiding principles
Type 2 diabetes shares common risk factors with other non-communicable diseases including cardiovascular disease and some cancers. This means that recommendations made in previously published NICE guidance can also help prevent it. Specifically, the following published statements underpin many of the recommendations made here.
## Supporting behaviour change
This recommendation should be read in conjunction with NICE's guideline on behaviour change: general approaches. Changing people's health-related behaviour involves:
Helping them to understand the short, medium and longer-term consequences of health-related behaviour.
Helping them to feel positive about the benefits and value of health-enhancing behaviours and changing their behaviours.
Recognising how people's social contexts and relationships may affect their behaviour.
Helping people plan changes in terms of easy sustainable steps over time.
Identifying and planning for situations that might undermine the changes people are trying to make, and planning explicit 'if–then' coping strategies to maintain changes in behaviour.
## Achieving and maintaining a healthy weight
Everyone should aim to maintain or achieve a healthy weight, to improve their health and reduce the risk of diseases associated with overweight and obesity, such as type 2 diabetes. People should follow the strategies listed below. These may make it easier to maintain a healthy weight by balancing 'calories in' (from food and drink) and 'calories out' (from being physically active):
base meals on starchy foods such as potatoes, bread, rice and pasta, choosing wholegrain where possible
eat fibre-rich foods such as oats, beans, peas, lentils, grains, seeds, fruit, vegetables, wholegrain bread and brown rice and pasta
eat at least five portions of a variety of fruit and vegetables each day, in place of foods higher in fat and calories
adopt a low-fat diet
avoid increasing fat or calorie intake
consume as little as possible of fried food; drinks and confectionery high in added sugars (such as cakes, pastries and sugar-sweetened drinks); and other food high in fat and sugar (such as some take-away and fast foods)
minimise calorie intake from alcohol
watch the portion size of meals and snacks, and how often they are eating throughout the day
eat breakfast
make activities they enjoy, such as walking, cycling, swimming, aerobics and gardening, a routine part of life and build other activity into their daily routine – for example, by taking the stairs instead of the lift or taking a walk at lunchtime
minimise sedentary activities, such as sitting for long periods watching television, at a computer or playing video games
use physically active forms of travel such as walking and cycling. (This point is adapted from NICE's guideline on physical activity in the workplace.)
## Effective weight-loss programmes
Effective weight-loss programmes should:
address the reasons why someone might find it difficult to lose weight
be tailored to individual needs and choices
be sensitive to the person's weight concerns
be based on a balanced, healthy diet
encourage regular physical activity
expect people to lose no more than 0.5 to 1 kg (1 to 2 lb) a week
identify and address barriers to change. Also see NICE's guideline on obesity.
## Physical activity
For national recommendations for physical activity in adults aged 19 to 64 and older adults (over 65) see the UK Chief Medical Officers' physical activity guidelines. For recommendations on physical activity in people who have obesity see NICE's guideline on obesity.
## Cultural appropriateness
Culturally appropriate interventions take account of the community's cultural or religious beliefs and language and literacy skills by:
Using community resources to improve awareness of, and increase access to, interventions. For example, they involve community organisations and leaders early on in the development stage, use media, plan events or make use of festivals specific to black and ethnic minority groups.
Understanding the target community and the messages that resonate with them.
Identifying and addressing barriers to access and participation, for example, by keeping costs low to ensure affordability, and by taking account of different working patterns and education levels.
Developing communication strategies which are sensitive to language use and information requirements. For example, they involve staff who can speak the languages used by the community. In addition, they may provide information in different languages and for varying levels of literacy (for example, by using colour-coded visual aids and the spoken rather than the written word).
Taking account of cultural or religious values, for example, the need for separate physical activity sessions for men and women, or in relation to body image, or beliefs and practices about hospitality and food. They also take account of religious and cultural practices that may mean certain times of the year, days of the week, settings, or timings are not suitable for community events or interventions. In addition, they provide opportunities to discuss how interventions would work in the context of people's lives.
Considering how closely aligned people are to their ethnic group or religion and whether they are exposed to influences from both the mainstream and their community in relation to diet and physical activity.
# Whose health will benefit?
Adults (aged between 18 and 74), in particular, those from:
black and minority ethnic groups
lower socioeconomic groups.
# Recommendation 1 Integrating national strategy on non-communicable diseases
## Who should take action?
Commissioners and providers of national public health services working in partnership with:
government departments
the commercial sector
local commissioners and providers of public health services
the voluntary sector, not-for-profit and non-governmental organisations.
## What action could they take?
When developing national strategy to target non-communicable diseases with a major link to diet, physical activity and obesity (for example, type 2 diabetes, cardiovascular disease, certain cancers), consider:
integrating the strategy with other relevant national actions to prevent related non-communicable diseases
addressing the key risk factors (for example, being overweight or obese, a sedentary lifestyle and an unhealthy diet)
highlighting the contribution that partners in national and local government, industry, healthcare and the voluntary sector can make by working together to reduce the risk of non-communicable diseases for the population as a whole
taking account of variations in different population subgroups (for example, by ethnicity, age or gender)
linking to targets and outcomes for reducing the key risk factors for type 2 diabetes and other non-communicable diseases.
Encourage local, regional and national monitoring of the risk factors for diabetes and other non-communicable diseases. Also encourage monitoring of age-specific incidence rates for type 2 diabetes and other non-communicable diseases.
Encourage local and national decision makers to assess the potential health impact of all new policies on the key risk factors for type 2 diabetes and other non-communicable diseases. Ensure they support any national prevention strategy.
Clearly signpost national and regional resources, including toolkits and evaluation guides, that will help local services reduce the incidence of type 2 diabetes and other non-communicable diseases.
Work with national and local commercial partners to encourage and support joint working with local public health teams to meet the national targets.
# Recommendation 2 Local joint strategic needs assessments
## Who should take action?
Commissioners and providers of local public health services in partnership with other local authority departments including:
adult social care
education
environmental health
planning
public transport.
## What action should they take?
Use national and local tools (such as the Department of Health's guidance on joint strategic needs assessment) and data from public health data collection agencies, public health reports, the census, indices of deprivation and other sources of high quality data (such as the NHS Digital website) to:
identify local communities at high risk of developing type 2 diabetes
assess their knowledge, awareness, attitudes and beliefs about the risk factors
assess their specific cultural, language and literacy needs.
Identify successful local interventions and note any gaps in service provision.
Identify local resources and existing community groups that could help promote healthy eating, physical activity and weight management, particularly within local communities at high risk of developing type 2 diabetes.
# Recommendation 3 Developing a local strategy
## Who should take action?
Commissioners and providers of local public health services in partnership with other local authority departments including:
adult social care
education
environmental health
planning
public transport.
## What action should they take?
Develop an integrated plan for local activities and programmes aimed at preventing type 2 diabetes and related non-communicable diseases (including cardiovascular disease). This should be based on the joint strategic needs assessment and relevant national strategy, targets and outcomes (such as the NHS outcomes framework).
Those developing strategic plans should consult widely with local health professionals working closely with communities at high risk of developing type 2 diabetes.
The plan should aim to increase physical activity levels and improve people's diet and weight management by:
identifying and assessing the effectiveness and cost effectiveness of existing local interventions
making recommendations for future investment and disinvestment
including action to raise awareness of type 2 diabetes and the risk factors for diabetes and other non-communicable diseases
creating local environments that encourage people to be more physically active and to adopt a healthier diet (for example, by ensuring local shops stock good quality, affordable fruit and vegetables)
targeting specific communities at high risk of developing type 2 diabetes, including people of South Asian, African-Caribbean or black African family origin, and those from lower socioeconomic groups
including interventions for individuals who are deemed at particular risk (based on clear criteria about the level of absolute risk that would trigger this provision, see also NICE's guideline on preventing type 2 diabetes in people at high risk).
Ensure local outcomes and conclusions from the strategic plan are integrated into the local commissioning strategy.
# Recommendation 4 Interventions for communities at high risk of type 2 diabetes
## Who should take action?
Commissioners and providers of local public health services in partnership with:
-ther local authority departments including: children's services, education, environmental health, leisure, planning, public transport, social housing and social services
the NHS including: GPs, practice and community nurses, dietitians, public health nutritionists, doctors and nurses working in acute and emergency care, and occupational therapists
the voluntary sector, not-for-profit and non-governmental organisations (include community leaders and trained lay workers).
## What action should they take?
Work in partnership to develop cost-effective physical activity, dietary and weight management interventions. Interventions should take into account the religious beliefs, cultural practices, age and gender, language and literacy of black, minority ethnic and lower socioeconomic groups. (Interventions costing up to £10 per head would need to achieve an average weight loss of about 0.25 kg per head to be cost effective. Those costing up to £100 per head would need to achieve an average weight loss of about 1 kg per head.)
Identify success criteria in the early stages of development to ensure interventions can be properly evaluated.
Identify any skills gaps and train or recruit staff to fill the gaps.
Identify and address barriers to participation. This includes developing communication strategies that are sensitive to the target audience's language and information requirements.
Use community resources to improve awareness of the key messages and to increase accessibility to the interventions. For example, involve community organisations and leaders at the development stage and use media, plan events or attend festivals specifically aimed at black and minority ethnic communities and lower socioeconomic groups. Also involve existing community and social groups or clubs, such as toddler groups, pubs, social clubs and local sports clubs.
Where they exist, use community links, outreach projects and lay or peer workers (from black and minority ethnic communities and from lower socioeconomic groups) to deliver interventions.
Where necessary, train lay and peer workers in how to plan, design and deliver community-based health promotion activities. Training should be based on proven training models and evaluation techniques. It should give participants the chance to practice their new skills in the community. It should also encourage them to pass on their knowledge to their peers.
Lay and peer workers and health professionals should identify and encourage community champions (for example, religious and community leaders) to promote healthy eating and physical activity.
Encourage lay and peer workers to get other members of their community involved.
Ensure lay and peer workers are part of a wider team led by health professionals. They should be involved in the planning, design and delivery of credible and culturally appropriate messages. This includes helping people to develop the practical skills they need to adopt a healthier lifestyle. For example, they should be able to run nutrition education sessions (theory and practice) or physical activity sessions. Management and supervision of these activities should be provided by the health professionals leading these teams.
Commission culturally appropriate and financially accessible weight management programmes either from the NHS or non-NHS providers, based on the guiding principles for effective weight-loss programmes. These should be provided in community settings in areas where populations at high risk of type 2 diabetes live. (For example, they could be provided in religious venues or community and social clubs.)
Ensure the systems or initiatives used to assess someone from a high-risk community are culturally appropriate.
Ensure identification and assessment systems or initiatives are linked to effective services and interventions for individuals deemed to be at high risk.See also NICE's guidelines on preventing type 2 diabetes in people at high risk and community engagement.
# Recommendation 5 Conveying messages to the whole population
## Who should take action?
Commissioners and providers of national public health services working in partnership with:
-ther government departments allied to health
local commissioners and providers of public health services
the commercial sector
national voluntary sector, not-for-profit and non-governmental organisations.
## What action should they take?
Ensure healthier lifestyle messages to prevent non-communicable diseases (including type 2 diabetes, cardiovascular disease and some cancers) are consistent, clear and culturally appropriate. Ensure they are integrated within other health promotion campaigns or interventions.
Address any misconceptions about the risk of diabetes and other non-communicable diseases that can act as barriers to change. This includes the belief that illness is inevitable (fatalism) and misconceptions about what constitutes a healthy weight. Also address any stigma surrounding the conditions.
Ensure any national media (for example, television and online social media) used to convey messages or information is culturally appropriate for the target audience.
Identify and make use of existing campaign materials, messages and resources, including those from other countries, where appropriate. Messages and materials should:
highlight the need to reduce the amount of time spent being sedentary
highlight the importance of being physically active, adopting a healthy diet and being a healthy weight
increase awareness of healthier food choices, and the calorie content and nutritional value of standard-portion size meals and drinks.
# Recommendation 6 Conveying messages to the local population
## Who should take action?
Commissioners and providers of local public health services in partnership with:
-ther local authority departments including education and leisure
the NHS including: GPs, practice and community nurses, dietitians, public health nutritionists, doctors and nurses working in acute and emergency care, and occupational therapists
the voluntary sector, not-for-profit and non-governmental organisations (including community leaders).
## What action should they take?
Work with local practitioners, role models and peers to tailor national messages for the local community about preventing type 2 diabetes and other non-communicable diseases (such as cardiovascular disease and some cancers).
Ensure healthier lifestyle messages are consistent, clear and culturally appropriate. Ensure they are integrated within other local health promotion campaigns or interventions. Provide details of the local support services available.
Address any misconceptions in the local community about the risk of diabetes and other non-communicable diseases that could act as a barrier to change. This includes the belief that illness is inevitable (fatalism) and any misconceptions about what constitutes a healthy weight. Also address any stigma surrounding these conditions.
Ensure messages and information are disseminated locally to groups at higher risk of type 2 diabetes than the general population, including black and minority ethnic and lower socioeconomic groups. Use local newspapers, online social media and local radio channels targeted at these groups. Also make use of local shops and businesses, community workers and groups, social establishments, educational institutions, workplaces, places of worship and local health care establishments, for example, hospitals.
Offer communities support to improve their diet and physical activity levels, and ensure they are aware of the importance of both.
# Recommendation 7 Promoting a healthy diet: national action
## Who should take action?
Commissioners and providers of national public health services working in partnership with:
-ther government departments
the commercial sector
the voluntary sector, not-for-profit and non-governmental organisations
local commissioners and providers of public health services.
## What action could they take?
Identify and work with a range of commercial partners to promote the provision of healthier food choices. For example:
Work with food manufacturers to improve the composition of prepared foods, where needed, to decrease calories, saturated fat and salt content. Encourage manufacturers to achieve any nationally agreed reformulation targets.
Work with caterers across the industry to help them reduce the amount of calories, saturated fat and salt in recipes and to use healthier cooking methods. They should also ensure healthier options are an integral part of all menus.
Work with food retailers to develop pricing structures that favour healthier food and drink choices.
Work with food retailers to ensure a range of portion sizes are available and that they are priced accordingly. This is particularly important for energy-dense foods and drinks.
Work with food manufacturers, caterers and retailers to provide clear, non-ambiguous and consistent nutrition information. This includes prominent displays of calorie content on the front of packaging and the use of clear signage for unpackaged food and drink. If calorie content is not known, consider indicating healthier options, such as food prepared using healthier ingredients or cooking methods.
Support the development of home-cooking resources that give information on nutritional content (for example, web-based recipe sites). Offer practical advice on preparing healthier meals, including the ingredients and cooking methods to use.
Monitor the population's diet to determine the success of national-level interventions.
Assess the health impact of all initiatives and interventions aimed at encouraging people to have a healthier diet.
# Recommendation 8 Promoting a healthy diet: local action
## Who should take action?
Commissioners and providers of local public health services in partnership with:
-ther local authority departments including: environmental health, education, leisure, social services, planning and public transport
the NHS including: dietitians and public health nutritionists
voluntary sector, not-for-profit and non-governmental organisations (include community leaders and trained lay workers)
local food retailers and caterers
large and medium-sized employers.
## What action should they take?
Make people aware of their eligibility for welfare benefits and wider schemes that will supplement the family's food budget and improve their eating patterns. This includes free school meals, free school fruit and Healthy Start food vouchers.
Provide information on how to produce healthier meals and snacks on a budget.
Work with local food retailers, caterers and workplaces to encourage local provision of affordable fruit and vegetables and other food and drinks that can contribute to a healthy, balanced diet.
Provide nutrition education sessions (theory and practice) at times to suit people with children (or provide a crèche) or to fit with working hours. Sessions should take place in acceptable, accessible venues such as children's centres.
Use existing planning mechanisms (for example, national planning guides or toolkits) to increase the opportunities available for local people to adopt a healthy, balanced diet. For example, ensure:
food retailers that provide a wide range of healthier products at reasonable cost are readily accessible locally, either on foot or via public transport
planning policies consider healthier eating when reviewing applications for new food outlets.
Encourage local retailers to use incentives (such as promotional offers) to promote healthier food and drink options. The aim should be to make the healthier choice the easiest and relatively cheaper choice. The retailers targeted may include regional and national supermarkets and convenience store chains, as well as street markets and small independent shops.
Encourage local caterers to include details in menus on the calorie content of meals to help consumers make an informed choice. If the nutritional value of recipes is not known, they should consider listing ingredients and describing the cooking methods used.
Ensure local authorities and NHS organisations develop internal policies to help prevent employees from being overweight or obese. Encourage local employers to develop similar policies. This is in line with existing NICE guidance and (in England) the local obesity strategy. For example, organisations could promote healthier food and drink choices in staff restaurants, hospitality suites, vending machines and shops by using posters, pricing and the positioning of products.
# Recommendation 9 Promoting physical activity: national action
## Who should take action?
Commissioners and providers of national public health services working in partnership with:
-ther government departments
-rganisations with a remit for town planning
-rganisations with a remit for increasing physical activity levels
commissioners and providers of local public health services
the voluntary sector, not-for-profit and non-governmental organisations.
## What action could they take?
Ensure the benefits of physical activity – and the national recommendations for physical activity – are made clear to encourage people to be more physically active.
Support a shift in the population towards being more physically active by encouraging even small changes.
Use planning regulations to maximise the opportunities available to be physically active.
Encourage the use of national and local planning guidance to ensure physical activity is a primary objective of transport policy, and when designing new buildings and the wider built environment.
Monitor the population's overall physical activity levels to determine the success of national interventions. Assess the health impact of all initiatives and interventions to encourage physical activity.
# Recommendation 10 Promoting physical activity: local action
## Who should take action?
Commissioners and providers of local public health services in partnership with:
-ther local authority departments including: planning, regeneration, public transport, leisure, sports and parks
schools with community recreation facilities (for example, as part of the extended schools programme)
the NHS including: GPs, practice and community nurses, community pharmacists and occupational therapists
voluntary sector, not-for-profit and non-governmental organisations (include community leaders and trained lay workers)
the fitness industry
large and medium-sized employers.
## What action should they take?
Ensure local planning departments use existing mechanisms (for example, national planning guides) to:
prioritise the need for people (including those whose mobility is impaired) to be physically active as a routine part of their daily life (for example, when developing the local infrastructure and when dealing with planning applications for new developments)
provide open or green spaces to give people local opportunities for walking and cycling
make sure local facilities and services are easily and safely accessible on foot, by bicycle and by other modes of transport involving physical activity (they should consider providing safe cycling routes and secure parking facilities for bikes)
provide for physical activities in safe locations that are accessible locally either on foot or via public transport
encourage people to be physically active inside buildings, for example, by using the internal infrastructure of buildings to encourage people to take the stairs rather than the lift (also see NICE's guideline on physical activity and the environment).
Enable and encourage people to achieve the national recommended levels of physical activity by including activities such as walking, cycling or climbing stairs as part of their everyday life.
Assess the type of physical activity opportunities needed locally and at what times and where. Consider social norms, family practices and any fears people may have about the safety of areas where physical activities take place (this includes fears about how safe it is to travel there and back).
Map physical activity opportunities against local needs and address any gaps in provision.
Ensure commissioned leisure services are affordable and acceptable to those at high risk of developing type 2 diabetes. This means providing affordable childcare facilities. It also means public transport links should be affordable and the environment should be culturally acceptable. For example, local authorities should consider the appropriateness of any videos and music played. They should also consider providing single-gender facilities, exercise classes, swimming sessions and walking groups – for both men and women.
Provide information on local, affordable, practical and culturally acceptable opportunities to be more active. If cultural issues affect people's ability to participate, work with them to identify activities which may be acceptable. (This may include, for example, single-gender exercise and dance classes, or swimming sessions with same-gender lifeguards.)
Encourage local employers to develop policies to encourage employees to be more physically active, for example, by using healthier modes of transport to and from work. Walking and cycling can be encouraged by providing showers and secure cycle parking. Signposting and improved decor could encourage employees to use the stairs rather than the lift. In addition, people could be encouraged to be active in lunch breaks and at other times through organised walks and subsidies for local leisure facilities Flexible working policies and incentives that promote physical activity in the workplace should be considered. (This is an extract from NICE's guidelines on obesity and promoting physical activity in the workplace; see the latter for further guidance on developing programmes and policies to encourage and support employees to be more physically active).
Ensure the basic training for professional fitness instructors covers: the role of physical activity in improving people's health, how to get marginalised groups involved and cultural issues that may prevent them from participating.
# Recommendation 11 Training those involved in promoting healthy lifestyles
## Who should take action?
Commissioners and providers of national and local public health services in partnership with:
royal colleges and professional associations, further and higher education training institutions, and other organisations responsible for competencies and continuing professional development programmes for health professionals
-ther local authority departments including education and leisure services
voluntary sector, not-for-profit and non-governmental practitioners
the commercial sector.
## What action should they take?
Ensure training programmes for those responsible for, or involved in, promoting a healthy lifestyle cover:
diversity, including cultural, religious and economic issues, delivering health promotion interventions in a non-judgemental way, and meeting age, gender, language and literacy needs
how to identify communities at increased risk of developing type 2 diabetes
strategies for changing behaviour (for those devising health promotion interventions)
how to provide advice on healthy eating, physical activity and weight management in relation to the prevention of type 2 diabetes and related non-communicable diseases
how to challenge stigma and dispel myths around type 2 diabetes.
Ensure those responsible for, or involved in, promoting healthy lifestyle choices are given time and support to develop and maintain the skills described above.
Monitor health professionals' knowledge and awareness of how to encourage people to adopt a healthy lifestyle. Use, for example, personal development plans and annual reviews. Ensure they keep their knowledge and practical skills up to date.
Ensure training programmes for all health professionals (including undergraduate, continuing professional development and, where appropriate, post-graduate training):
incorporate the knowledge and skills needed to ensure health promotion interventions are culturally sensitive
cover nutrition, physical activity and weight management in relation to the prevention of type 2 diabetes
are focused, structured and based on proven models and evaluation techniques
-ffer opportunities to practice new skills in the community
encourage the sharing of knowledge among colleagues
provide up-to-date information on topics such as nutrition advice and physical activity (information should be updated regularly).
# Public health need and practice
# Overview
On average, 100,000 people in the UK are diagnosed with diabetes every year, but in 2009 this figure reached 150,000. Many more are unaware that they have the condition (Diabetes UK 2006). It can lead to long-term complications including eye problems, kidney disease, foot ulcers and cardiovascular disease. On average at age 55, the life expectancy of people with type 2 diabetes is 5 to 7 years less than for the general population (DH 2006).
In addition to the personal cost to individuals, families and communities, diabetes is estimated to account for at least 5% of UK healthcare expenditure. For example, up to 10% of hospital budgets are spent on the condition – it is estimated that drug costs alone for people with type 2 diabetes account for about 7% of the total NHS drugs budget (Waugh et al. 2007).
In 2007, 60% of primary care trusts (PCTs) reported that programmes were in place to raise public awareness of the risk factors for type 2 diabetes – and 37% were raising awareness of its signs and symptoms. However, only 42% had assessed the needs of their population in relation to type 2 diabetes – and less than 40% had developed a type 2 diabetes strategy (Innove 2008).
# Risk factors for type 2 diabetes
Individual risk factors for type 2 diabetes include:
weight (a body mass index of 25kg/m2 or more)
a large waist circumference (more than 80 cm or 31.5 inches in women and 94 cm or 37 inches in men)
low physical activity levels
a family history of type 2 diabetes,
a history of gestational diabetes
age (being older than 40 or older than 25 for some black and minority ethnic groups).
In addition, people from the following communities are particularly at risk: those of South Asian, African-Caribbean, black African and Chinese descent and those from lower socioeconomic groups.
The more risk factors someone has, the more likely they are to develop diabetes (Harding et al. 2006).
# Vulnerable groups
People of South Asian family origin living in the UK are up to six times more likely to have type 2 diabetes than the white population (DH 2001). They are also likely to develop type 2 diabetes 10 years earlier (Nicholl et al. 1986). People of African and African-Caribbean descent are three times more likely to have type 2 diabetes than the white population. Type 2 diabetes is also more common among Chinese and other non-white groups than among white European populations (DH 2001).
The higher risk for South Asian people living in the UK is at least partly due to the fact that they may accumulate significantly more 'metabolically active' fat in the abdomen and around the waist than white European populations. (This is true even for those with a BMI in the 'healthy' range – that is, 18.5–24.9 kg/m2.) 'Metabolically active' fat is closely associated with insulin resistance, pre-diabetes and type 2 diabetes (McKeigue et al. 1991; 1992; 1993; Banerji et al. 1999).
Minority ethnic groups are less likely to participate in at least moderate-intensity physical activity (for 30 minutes continuously a week) than the general population. For example Bangladeshi men and women have the lowest levels of participation in physical activity when standardised for age (The NHS Information Centre 2006). Black Caribbean men are the only subgroup of an ethnic minority population that are not less physically active than the general population in England (The NHS Information Centre 2006).
In England, type 2 diabetes is 40% more common among those who are in social class V (people who are most socioeconomically deprived) compared with those in social class I (The NHS Information Centre 2010). In addition, people in social class V are three and a half times more likely than those in social class I to be ill as a result of diabetic complications (DH 2002).
People in social class V are also more likely to be obese than those in higher social classes. In 2004, 18% of men in social class I were obese compared to 28% in social class V. Similarly, 10% of women in social class I were obese compared with 25% of women in social class V (Foresight 2007).
In addition, there is also a clear link between physical activity and income level. For example, those on the lowest income are less likely to undertake more than 30 minutes of at least moderate-intensity activity a week compared with higher income groups (The NHS Information Centre 2008b).
The 'Low income diet and nutrition survey' found that, overall, people on lower incomes ate similar types and quantities of food as the general population. However, they were less likely to eat wholemeal bread, wholegrain and high fibre breakfast cereals and vegetables. They were also more likely to drink non-diet soft drinks and eat more processed meats, whole milk and sugar (Nelson et al. 2007).
There is overlap between the high-risk groups, that is, those who are disadvantaged and some black and minority ethnic communities, as some of the latter are more likely to live in areas of social and economic deprivation (Barakat et al. 2001).
# Tackling barriers to change
People from lower socioeconomic groups and those from black and minority ethnic communities may face economic, social and cultural barriers which prevent them from being physically active and managing their weight. Barriers include, for example, lack of funds for a healthy diet or a lack of awareness and opportunity to take part in physical activities or weight management programmes that are culturally acceptable.# Considerations
The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations.
# Individual versus population approaches
The PDG considered three types of approach to reducing population and community risk of type 2 diabetes. These were:a) Individual: focusing on people identified as being at high risk of type 2 diabetes.b) High-risk population: identifying and targeting communities of people at high risk of type 2 diabetes.c) Total population: no assessment of risk or targeting of interventions.
The PDG noted that people from lower socioeconomic groups and from some black and minority ethnic communities are at higher risk of type 2 diabetes than the general population. This is due to a set of shared characteristics and behaviours or 'determinants'. Examples include: a higher than average level of overweight and obesity, a higher than average number of people eating a less healthy diet or participating in lower than average levels of physical activity. These groups and communities would collectively benefit from interventions that target the 'shared' risk factors. In addition, more people within these groups and communities (compared with the general population) would benefit from an assessment of their individual risk – and individual interventions to alleviate that risk.
This guidance aims to reduce the risk of type 2 diabetes among populations at particularly high risk. Overweight and obesity is the single biggest risk factor for type 2 diabetes. Since recent estimates (for example, the Foresight report ) suggest that more than half of adults may be obese by 2050, the PDG noted that some of the recommendations would also have a beneficial effect on a large proportion of the general population.
The national NHS Health Check programme identifies and treats individuals at high risk of developing vascular-related diseases including type 2 diabetes. The PDG noted that not all those who are identified as being at risk will choose to change their behaviour or act on the advice. NICE guidance to prevent the progression from pre-diabetes to type 2 diabetes will aim to provide commissioners and practitioners with advice on how they can support people identified as being at high risk through this or other initiatives.
The PDG was mindful that actions to improve the health of the population overall may widen health inequalities between different groups. For example, people from higher socioeconomic groups may be more ready (or able) to change their behaviour than those on a lower income. Therefore, to address health inequalities, it may be necessary to specifically target high-risk groups – even if this is not the most cost-effective option.
Addressing the needs of high-risk communities involves working beyond geographical boundaries. A community is not necessarily a group of people living within a specific geographic location. It might, for example, involve people with shared values or a shared interest. In addition, although people may recognise themselves (and be recognised within a group) as belonging to that group or community, it may not be immediately obvious to 'outsiders'. This can make it difficult to identify and target some of those who may need help to prevent type 2 diabetes. This includes people who are homeless and those who have a disability or a long-term mental health problem. People who are unofficial migrants are another example.
Case studies of ongoing work in the UK, backed up by expert testimony, demonstrated the importance of taking the target group's needs into account from the start. This includes ensuring that any cultural sensitivities are acknowledged.
# Evidence
Trials have shown (Gillies et al. 2007) that behavioural interventions help reduce the likelihood of type 2 diabetes developing among people with pre-diabetes. For example, the Finnish diabetes prevention study (Tuomilehto et al. 2001) showed that the risk of these individuals developing type 2 diabetes is reduced if they achieve one or more of the following:
reduce their weight by more than 5%
keep their fat intake below 30% of energy intake
keep their saturated-fat intake below 10% of energy intake
eat 15 g/1000 kcal of fibre or more
are physically active for at least 4 hours per week. In addition, a population-based study (Simmons et al. 2006) found an inverse relationship between the number of these goals achieved and the risk of type 2 diabetes developing among the general population. Therefore, the PDG felt that interventions promoting these goals could significantly lower the risk of developing type 2 diabetes among people from lower socioeconomic communities and from black and minority ethnic groups.
The PDG considered systematic reviews of interventions to address the risk factors associated with type 2 diabetes, including high body mass index (BMI), high waist measurement, sedentary lifestyle or poor diet among high-risk groups. The group did not identify any evidence directly related to the prevention of 'pre-diabetes' among black and minority ethnic or lower socioeconomic groups in the UK. Overall, relevant UK-based intervention studies were scarce. Similarly, the evidence on behaviour change among minority ethnic communities was very limited. The data available tended to be based on self-reported measures related to participants' perceptions of the barriers and facilitators to behaviour change. It was not clear whether or not addressing the stated barriers and introducing facilitators would actually result in positive change.
There was no evidence of effectiveness on UK interventions aiming to raise health professionals' awareness of the risk factors for type 2 diabetes or to help them identify groups at high risk. Evidence on the effectiveness of interventions delivered by health professionals and lay workers (such as health trainers) was also lacking.
The potential effect of any intervention may vary according to the risk someone faces of developing type 2 diabetes. However, evidence was not available to assess this theory in practice.
While demonstrating promising results, most of the UK-based community projects considered by the PDG had limited reach. The group felt that they were neither large nor sustainable enough and that they would benefit from being based on established community networks. Staff training for such interventions was another issue.
The PDG developed recommendations through inductive and deductive reasoning, based on the evidence presented in the systematic reviews, expert testimony and its members' knowledge, understanding and experience of the topic area. Due to the scarcity of evidence available, the PDG also drew on existing NICE guidance on: behaviour change, community engagement, obesity, physical activity and cardiovascular disease.
The economic analysis for this work is based on a range of assumptions. The observed effect sizes for individuals, while important, are small and the confidence intervals are large. Most of the interventions considered are estimated to be cost effective (and usually very cost effective). (This assumes that the estimated effect sizes have been used to make the calculation.) The PDG recognised that the bulk of these effects were generally observed only after a number of years.
# Cost effectiveness
Economic modelling showed that weight-loss programmes in black and minority ethnic and Asian populations in England that cost £100 per head and yielded an average weight loss of at least 1 kg were cost effective at a cost per quality-adjusted life year (QALY) threshold of £20,000. Interventions that could produce an average weight loss of 3 to 4 kg would be cost-saving.
An intervention programme applied at the population level that resulted in an average weight of loss of 0.25 kg, would be cost effective at the £20,000 threshold if the cost per head of the intervention was £10. A number of the interventions reported in the literature had a per capita intervention cost of this magnitude. The PDG agreed that this analysis justified the recommendation to balance individual-level interventions of large effect aimed at high-risk individuals with cheaper interventions of small effect to individuals that could be cost effective when applied across whole populations.
# Existing NICE guidance
The PDG recognised that a number of existing activities and programmes aim to help people change their behaviour to prevent a range of diseases and conditions. It acknowledged that these activities and programmes could also help prevent type 2 diabetes and that many have been the focus of earlier NICE guidance. Similarly, the recommendations outlined in this guidance may have an impact on a range of other health conditions (including for example, cardiovascular disease, some common cancers, respiratory diseases and mental wellbeing).
There are many reasons why people who are socially and/or economically disadvantaged can find it more difficult than others to change their behaviour (Swann et al. 2009). The recommendations in this guidance draw on NICE's guideline on behaviour change: general approaches in an attempt to address this inequality. The aim is to create a local environment which encourages people in disadvantaged groups to make change.
The PDG noted the recommendations made in NICE's guideline on obesity. These focus on a range of effective, community-based programmes and stress the importance of ensuring interventions are tailored, long term and address both diet and physical activity. The guideline also outlines strategies for improving diet and increasing physical activity to help prevent obesity and minimise excess weight gain.
The PDG discussed the links between sedentary behaviour and type 2 diabetes – and the need to encourage people to be more physically active. It was aware of evidence to suggest that a sedentary lifestyle may play a more important role than diet in the higher prevalence of type 2 diabetes among black and minority ethnic groups. NICE has published a range of guidance to help the whole population be physically active. The recommendations in this guidance attempt to address specific barriers to physical activity which might face populations at high risk of developing type 2 diabetes. However, more research is needed into how to increase physical activity levels among these groups.
The PDG recognised that the success of interventions can depend on identifying local 'key players' and 'champions' and it looked to recommendations made in NICE's 2008 guideline on community engagement. It noted that, although some community leaders may be able to promote or help deliver type 2 diabetes prevention programmes, not all of them will be willing or able to do so – nor would it always be appropriate.
# Issues outside the scope
The PDG acknowledged the need to consider risk factors and vulnerability at all stages of the life course. In particular, it recognised that maternal and early infant nutrition may be important in the prevention of non-communicable diseases such as type 2 diabetes. Interventions aimed at children are also likely to be crucial in reducing the prevalence of type 2 diabetes in the longer term. For example, preventing gestational diabetes and delaying the onset of type 2 diabetes until after childbearing age would reduce the risk of a child getting type 2 diabetes later in life. These issues were beyond the remit of this guidance. However, they are addressed in other NICE guidance.
The PDG were mindful that while the scope for this guidance was adults in high-risk groups, many interventions are delivered in a family setting and these will have benefits for all family members not just adults.
The upper age cut-off point for this guidance (74 years) reflects the age limit of the national NHS Health Check programme. This programme assesses the risk of heart disease, stroke, kidney disease and type 2 diabetes among all adults aged 40–74. It aims to help them reduce or manage their risk by giving them individually tailored advice. (The second piece of guidance will consider interventions among high-risk individuals and groups.)
The PDG did not consider evidence on how specific nutrients or types of diet may reduce the risk of type 2 diabetes, as this falls under the remit of the Scientific Advisory Committee on Nutrition (SACN). As such, it was outside the scope of this guidance. However, the Group supports existing recommendations on healthy eating, as advocated in the 'Eat well' plate (Food Standards Agency 2007).
The PDG was aware of a range of factors that need to be tackled at national and international level to help high-risk groups adopt behaviours that minimise the risk of type 2 diabetes. This includes issues that could be tackled by the food industry, such as the fat content of foods, food labelling, advertising and costs. It also includes issues in relation to the built environment, such as the impact of planning decisions on physical activity levels. The PDG wholeheartedly supported existing NICE recommendations which aim to tackle these issues. It was also mindful that disadvantaged groups may be disproportionately affected and that, as such, any solutions should consider the potential impact on these groups.# Recommendations for research
The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful/negative side effects.
How effective and cost effective are interventions which use either a 'total population' or 'high-risk population' approach to preventing type 2 diabetes among people from black and minority ethnic or lower socioeconomic groups?
What are the most effective and cost effective ways of developing, implementing and assessing tailored and culturally appropriate community-level interventions to prevent type 2 diabetes among people at high risk? This includes people from a range of black and minority ethnic groups and those from lower socioeconomic communities.
Which participatory approaches are most effective and cost effective among populations at higher risk of type 2 diabetes? This should consider the awareness, knowledge, understanding and skills of the providers of interventions for people at high risk of developing type 2 diabetes?
How do socioeconomic, environmental, biological and psychosocial factors determine diet and physical activity behaviours and how do they contribute to differences in the risk of developing type 2 diabetes?
How do financial factors (including incentives, pricing and taxation of food and incentives, and pricing for physical activity opportunities) affect food and physical activity choices?
More detail on the gaps in the evidence identified during development of this guidance is provided in appendix D.# Glossary
# Body mass index
Body mass index (BMI) is commonly used to measure whether or not adults are a healthy weight or underweight, overweight or obese. It is defined as the weight in kilograms divided by the square of the height in metres (kg/m2).
# Community
A group of people who have common characteristics. Communities can be defined by location, race, ethnicity, age, occupation, a shared interest (such as using the same service), a shared belief (such as religion or faith) or other common bonds. A community can also be defined as a group of individuals living within the same geographical location (such as a hostel, a street, a ward, town or region).
# Community champions
Community champions are inspirational figures, community entrepreneurs, mentors or leaders who 'champion' the priorities and needs of their communities and help them build on their existing skills. They drive forward community activities and pass on their expertise to others. They also provide support, for example, through mentoring, helping people to get appropriate training and by helping to manage small projects.
# Diabetes
Diabetes is caused when there is too much glucose in the blood and the body cannot use it as 'fuel' because the pancreas does not produce any or sufficient insulin to help it to enter the body's cells. Alternatively, the problems may be caused because the insulin produced may not work properly ('insulin resistance'). Also see 'glucose' and 'insulin'.
# Fasting glucose sample
Glucose sample taken after a person has refrained from eating or drinking any liquids other than water for 8 hours.
# Glucose
Glucose comes from digesting carbohydrate and is also produced by the liver. Carbohydrate comes from many different kinds of food and drink, including starchy foods such as bread, potatoes and chapatis; fruit; some dairy products; sugar and other sweet foods (Diabetes UK 2010).
# HbA1c
Glycated haemoglobin (HbA1c) forms when red cells are exposed to glucose in the plasma. The HbA1c test reflects average plasma glucose over the previous eight to 12 weeks. Unlike the oral glucose tolerance test, an HbA1c test can be performed at any time of the day and does not require any special preparation such as fasting.
HbA1c is a continuous risk factor for type 2 diabetes. This means there is no fixed point when people are or are not at risk. The World Health Organization recommends a level of 6.5% (48 mmol/mol) for HbA1c as the cut-off point for diagnosing type 2 diabetes in non-pregnant adults.
# Impaired glucose tolerance
See definition below of 'pre-diabetes'.
# Insulin
Insulin is the hormone produced by the pancreas that allows glucose to enter the body's cells, where it is used as fuel for energy. It is vital for life (Diabetes UK 2010).
# Lay or community workers
People recruited from the local community or subgroup of the population to assist in the delivery of an intervention to a group of people who they identify with and are knowledgeable about. They might be peers or from the wider community but they are not professional health or public health workers.
# Oral glucose tolerance test
An oral glucose tolerance test involves measuring the blood glucose level after fasting, and then 2 hours after drinking a standard 75 g glucose drink. Fasting is defined as no calorie intake for at least 8 hours. More than one test on separate days is required for diagnosis in the absence of hyperglycaemic symptoms.
# Physical activity
The full range of human movement, from competitive sport and exercise to active hobbies, walking, cycling and the other physical activities involved in daily living.
# Pre-diabetes
Where used in this guidance, the term pre-diabetes refers to raised (but not diabetic) blood glucose levels (also known as non-diabetic hyperglycaemia, impaired glucose regulation). It indicates the presence of impaired fasting glucose and/or impaired glucose tolerance. People with pre-diabetes are at increased risk of getting type 2 diabetes. They are also at increased risk of a range of other conditions including cardiovascular disease.
# Socioeconomic group
A person's socioeconomic group is defined by a combination of their occupation, income level and education level. There is a strong relationship between socioeconomic group and health, with people from lower socioeconomic groups generally experiencing poorer health than those from higher socioeconomic groups.
# Type 2 diabetes
Type 2 diabetes (previously termed non-insulin dependent diabetes) results from reduced tissue sensitivity to insulin (insulin resistance) and/or reduced insulin production.# References
Banerji MA, Faridi N, Atluri R et al. (1999) Body composition, visceral fat leptin and insulin resistance in Asian Indian men. Journal of Clinical Endocrinology and Metabolism 84: 137–44
Barakat K, Stevenson S, Wilkinson P et al. (2001) Socio-economic differentials in recurrent ischaemia and mortality after acute myocardial infarction. Heart 85: 390–4
Department of Health (2001) Modern standards and service models – diabetes: national service framework standards. London: Department of Health
Department of Health (2002) National service framework for diabetes: standards – supplementary information. Health inequalities in diabetes. London: Department of Health
Department of Health (2006) Turning the corner: improving diabetes care. London: Department of Health
Diabetes UK (2006) Diabetes and the disadvantaged: reducing health inequalities in the UK. A report by the All Party Parliamentary Group for Diabetes and Diabetes UK
Diabetes UK (2010) Guide to diabetes: what is diabetes?
Food Standards Agency (2007) Eatwell plate.
Foresight (2007) Tackling obesities: future choices – project report. London: Government Office for Science
Forouhi NG, Luan J, Hennings S et al. (2007) Incidence of type 2 diabetes in England and its association with baseline impaired fasting glucose: The Ely study 1990–2000. Diabetic Medicine 24: 200–7
Gillies CL, Abrams KR, Lambert PC et al. (2007) Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis. BMJ 334: 299–307
Goodyear LJ, Khan BB (1998) Exercise, glucose transport, and insulin sensitivity. Annual Review of Medicine 49: 235–61
Harding A, Griffin SJ, Wareham NJ (2006) Population impact of strategies for identifying groups at high risk of type 2 diabetes. Preventative Medicine 42 (5): 364–8
Hawthorne K, Robles Y, Cannings-John R et al. (2010) Culturally appropriate health education for type 2 diabetes in ethnic minority groups: a systematic and narrative review of randomised controlled trials. Diabetic Medicine 27: 613–23
Innove (2008) Delivering performance improvement. Findings from DiabetesE third national report.
Khan BB, Flier JS (2000) Obesity and insulin resistance. The Journal of Clinical Investigation 106: 473–81
McKeigue PM, Shah B, Marmot MG (1991) Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians. Lancet 337: 382–6
McKeigue PM, Pierpont T, Ferne JM et al. (1992) Relationship of glucose intolerance and body fat pattern in South Asians and Europeans. Diabetologia 35: 785–91
McKeigue PM, Ferne JE, Pierpont T et al. (1993) Association of early onset coronary heart disease in South Asian men with glucose intolerance and hyperinsulinaemia. Circulation 87: 152–61
Nelson M, Erens B, Bates B et al. (2007) Low income diet and nutrition survey. London: The Stationery Office
Nicholl CG, Levy JC, Mohan V et al. (1986) Asian diabetes in Britain: a clinical profile. Diabetic Medicine 3: 257–60
Peel E, Parry O, Douglas M et al. (2004) Diagnosis of type 2 diabetes: a qualitative analysis of patients' emotional reactions and views about information provision. Patient Education and Counselling 53 (3): 269–75
Simmons RK, Harding AH, Jakes RW et al. (2006) How much might achievement of diabetes prevention behaviour goals reduce the incidence of diabetes if implemented at the population level? Diabetologia 49 (5): 905–11
South Asian Health Foundation (2004) The epidemic of coronary heart disease in South Asians. Birmingham: South Asian Health Foundation
Swann C, Owen L, Carmona C et al. (2009) A nudge in the right direction: developing guidance on changing behaviour. In Killoran A, Kelly MP (editors). Evidence-based public health: effectiveness and efficiency. Oxford: Oxford University Press
The NHS Information Centre (2006) Health survey for England 2004. Volume 1: the health of minority ethnic groups. Leeds: The NHS Information Centre
The NHS Information Centre (2008a). Health survey for England 2006. Volume 1: cardiovascular risk factors in adults. Leeds: The NHS Information Centre
The NHS Information Centre (2008b) Health survey for England 2006: Cardiovascular disease and risk factors: summary of the key findings. Leeds: The NHS Information Centre
The NHS Information Centre (2009) The Health survey for England 2008. Volume 1: physical activity and fitness. Leeds: The NHS Information Centre
The NHS Information Centre (2010) National diabetes audit: executive summary 2008–2009.
Tuomilehto J, Lindstrom J, Eriksson JG et al. (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. New England Journal of Medicine 344: 1343–50
Waugh N, Scotland G, McNamee P et al. (2007) Screening for type 2 diabetes literature review and economic modelling. Health technology assessment 11: 17.
World Health Organization (2006) Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation.
World Health Organization (2010) Cancer: diet and physical activity's impact .
World Health Organization (2011) Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus.# Appendix B: Summary of the methods used to develop this guidance
# Introduction
The reviews, primary research, commissioned reports and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.
The minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations.
All supporting documents are listed in appendix E.
# Key questions
The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations.
The overarching question was:
How effective and cost effective are interventions to improve the modifiable risk factors associated with pre-diabetes among black and minority ethnic groups and among lower socioeconomic groups?
The subsidiary questions were:
What are the most effective and cost-effective methods of raising health professionals' awareness of the groups at high risk of pre-diabetes?
What are the most effective and cost-effective methods of identifying communities, groups and individuals at high risk of pre-diabetes?
What are the most effective and cost-effective population-level interventions to prevent pre-diabetes?
What are the most effective and cost effective-ways of raising awareness of how to prevent pre-diabetes among high-risk groups?
What are the most effective and cost-effective ways of ensuring interventions are culturally sensitive and appropriate for use with communities at high risk of pre-diabetes?
What factors might discourage individuals, groups and communities at high risk of pre-diabetes from getting involved with preventive interventions? How might these barriers be addressed?
What are the most effective and cost-effective methods of helping people at high risk of pre-diabetes to improve their diet, be more physically active and manage their weight?
These questions were made more specific for each of the reviews (see reviews for further details).
# Reviewing the evidence
## Effectiveness reviews
Four reviews of effectiveness were conducted (reviews 1, 2, 3 and 5).
The evidence reviews for this guideline list the databases searched for each review. However, the general approach is outlined below.
The following databases were searched for reviews 1, 2 and 3 (from 1990 onwards):
British Nursing Index
Cumulative Index to Nursing and Allied Health Literature (CINAHL)
Cochrane Library
EMBASE
Evidence for Policy and Practice Information and Co-ordinating Centre Databases (EPPI Centre Databases)
MEDLINE
PsycINFO
Science Citation Index
Social Science Citation Index.
Additional searches of the grey literature were carried out and the following websites were also searched:
Association of Public Health Observatories
Diabetes UK
Joseph Rowntree Foundation
NHS Evidence
The following databases were searched for review 5 (from 1999 onwards):
Applied Social Sciences Index and Abstracts (ASSIA)
Cochrane Database of Systematic Reviews
Cumulative Index to Nursing and Allied Health Literature (CINAHL)
Database of Abstracts of Reviews of Effectiveness (DARE)
Database of Promoting Health Effectiveness Reviews (DoPHER)
Education Resources Information Centre (ERIC)
EMBASE
Health Management Information Consortium (HMIC)
HTA database (in the Cochrane Library)
MEDLINE
PsycINFO
Social Policy and Practice.
## Other reviews
Two separate sets of research were conducted to identify and describe community-level interventions to prevent type 2 diabetes (reviews 4 and 6).
Review 4 studied the search results from reviews 1 to 3. It also assessed grey literature identified via Google, the Internet search engine and via selected primary care trust (PCT) websites.
Review 6 involved searching the Internet and other networks used by managers and commissioners of community-level interventions to prevent type 2 diabetes. In addition, a referral questionnaire was sent to individuals or groups identified during the searches.
## Selection criteria
The evidence reviews for this guideline list the inclusion and exclusion criteria for each review. Details can be found within each review. However, in general, the following applied.
Studies were included in reviews 1 to 3 if they were published since 1990 and:
covered people at high risk of pre-diabetes
included interventions to prevent pre-diabetes
Included interventions to help professionals support people at high risk of developing pre-diabetes
were conducted in the UK.
Studies were excluded if they focused on:
people diagnosed with pre-diabetes (impaired fasting glucose/impaired glucose tolerance) or diabetes
pregnant women, people younger than 18 or older than 74
people taking medication that increases the risk of developing type 2 diabetes
population-level screening
diagnostic testing (such as clinical tests to identify pre-diabetes)
diabetes risk assessment tools using, for example, body mass index (BMI) and waist circumference.
Studies were included in review 5 if they were reviews published in 1999 or later and covered:
black and minority ethnic populations and groups from a low socioeconomic background in the UK, any other EU country, the USA, Canada, Australia or New Zealand
a 'general' population (but only if the ethnicity and socioeconomic status of those included in the primary studies was systematically presented)
people clinically diagnosed with pre-diabetes or obesity
interventions in a range of settings to prevent pre-diabetes or type 2 diabetes (or relevant risk factors), including those aimed at reducing or preventing obesity, promoting physical activity or reducing calorie intake
the measurement of any relevant outcome such as physical activity or dietary behaviour.
Studies were excluded if they:
focused on those aged 0–17 years
focused on minority ethnic groups not relevant to the UK (for example, American Indians or Australian Aboriginals)
covered people who were clinically diagnosed with type 2 diabetes
primarily focused on pharmacological, surgical or individual interventions (such as counselling)
did not aim to change any of the key risk factors for pre-diabetes and type 2 diabetes
were delivered in healthcare settings
were not published in English.
Broadly, interventions were included in review 4 if they:
covered activities to improve diet, increase physical activity levels or raise awareness of the risk factors for pre-diabetes
targeted adults from low socioeconomic backgrounds or from black and minority ethnic groups in the UK.
## Quality appraisal
Included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.
Study quality
++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.
- Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.
– Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.
The evidence was also assessed for its applicability to the areas (populations, settings, interventions) covered by the scope of the guidance. Each evidence statement concludes with a statement of applicability (directly applicable, partially applicable, not applicable).
## Summarising the evidence and making evidence statements
The review data was summarised in evidence tables (see full reviews).
The findings from the reviews and expert reports were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors and public health collaborating centres. The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.
# Cost effectiveness
There was a review of economic evaluations and an economic modelling exercise.
## Review of economic evaluations
Studies were identified through the effectiveness review search strategies. The following databases were searched:
EconLit
NHS Economic Evaluation Database
Public Health Interventions Cost Effectiveness Database (PHICED) (obesity and physical activity).
Previous NICE guidance on obesity and physical activity was also reviewed, as was the FORESIGHT modelling work. In addition, citation searching and reference tracking was also undertaken. The database searches followed the same inclusion and exclusion criteria as were used in the associated mapping review.
## Economic modelling
A number of assumptions were made which could underestimate or overestimate the cost effectiveness of the interventions (see review modelling report for further details).
An economic model was constructed to incorporate data from the reviews of effectiveness and cost effectiveness. The results of the economic model are reported in: 'Prevention of type 2 diabetes: preventing pre-diabetes among adults in high-risk groups. Report on cost-effectiveness evidence and methods for economic modelling'.
# Fieldwork
Fieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with practitioners and commissioners who are involved in the prevention of pre-diabetes among adults in high-risk groups, including those working in the NHS, local government, voluntary sector and private sector.
The fieldwork comprised:
two focus groups carried out nationally
telephone interviews
an online survey.
The main issues arising from this report are set out in the fieldwork findings section of appendix C.
The fieldwork was carried out by Word of Mouth Research Ltd.
# How the PDG formulated the recommendations
At its meetings during December 2009 to February 2011, the Programme Development Group (PDG) considered the evidence, expert reports and cost effectiveness to determine:
whether there was sufficient evidence (in terms of strength and applicability) to form a judgement
where relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive
where relevant, the typical size of effect (where there is one)
whether the evidence is applicable to the target groups and context covered by the guidance.
The PDG developed draft recommendations through informal consensus, based on the following criteria:
Strength (type, quality, quantity and consistency) of the evidence.
The applicability of the evidence to the populations/settings referred to in the scope.
Effect size and potential impact on the target population's health.
Impact on inequalities in health between different groups of the population.
Equality and diversity legislation.
Ethical issues and social value judgements.
Cost effectiveness (for the NHS and other public sector organisations).
Balance of harms and benefits.
Ease of implementation and any anticipated changes in practice.
Where possible, recommendations were linked to evidence statements (see appendix C). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).
The draft guidance, including the recommendations, was released for consultation in November 2010. At its meeting in February 2011, the PDG amended the guidance in light of comments from stakeholders and experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in April 2011.# Appendix C: The evidence
This appendix lists the evidence statements from six reviews provided by the public health collaborating centre and links them to the relevant recommendations. (See appendix B for the key to quality assessments.) The evidence statements are presented here without references – these can be found in the full review (see appendix E). It also lists eight expert papers and their links to the recommendations and sets out a brief summary of findings from the economic analysis.
The six reviews of effectiveness are:
Review 1: 'Prevention of type 2 diabetes: interventions to reduce risk factors for pre-diabetes among UK adults from a lower socioeconomic group'
Review 2: 'Prevention of type 2 diabetes: interventions to reduce risk factors for pre-diabetes among UK adults from black and minority ethnic groups'
Review 3: 'Prevention of type 2 diabetes: interventions to raise awareness in health professionals and assist identification of high-risk groups'
Review 4: 'Interventions for the prevention of pre-diabetes in high-risk groups: examples of current practice in relation to the UK evidence base'
Review 5: 'Review of review-level evidence to inform the development of NICE public health guidance for the prevention of pre-diabetes among adults in high-risk groups'
Review 6: 'Identification of effective community projects focused on addressing risk factors for the development of pre-diabetes in adults from black and minority ethnic groups and lower socio-economic groups'.
Evidence statement number 1.1a indicates that the linked statement is numbered 1a in review 1. Evidence statement number 3.1 indicates that the linked statement is numbered 1 in review 3. EP1 indicates that expert paper 1 is linked to the recommendation.
The reviews, expert reports and economic analysis are available. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).
Where the Programme Development Group (PDG) has considered other evidence, it is linked to the appropriate recommendation below. It is also listed in the additional evidence section of this appendix.
Recommendation 1: additional evidence NICE (2007); IDE
Recommendation 2: evidence statements 1.21a, 1.21b, 1.29, 2.5; EP9, EP10, EP13
Recommendation 3: evidence statements 1.21b, 1.29, 2.7b, 3.2, 3.6, 3.8; EP13
Recommendation 4: evidence statements 1.5, 1.21a, 1.21b, 1.21c, 1.22, 2.3, 2.9a, 3.6, 3.7, 3.8; EP8, EP9, EP10; additional evidence NICE (2006), (2008a); IDE
Recommendation 5: evidence statements 1.21a, 1.21d, 1.25, 2.4, 2.5, 2.6, 2.7a, 2.7b, 2.7c, 2.10, 3.7, 3.8; EP6, EP8, EP9, EP10
Recommendation 6: evidence statements 1.21a, 1.21d, 1.25, 2.4, 2.5, 2.6, 2.7a, 2.7b, 2.7c, 2.10, 3.7, 3.8; EP6, EP8, EP9, EP10
Recommendation 7: evidence statements 1.21b; EP7, EP8, EP11, EP12, EP14, EP15; IDE
Recommendation 8: evidence statements 1.5, 1.7, 1.21b, 1.22, 1.28, 1.29, 2.8; EP8, EP10, EP15; additional evidence NICE (2006); IDE
Recommendation 9: evidence statements 1.27, 2.5, 2.7b, 2.9b; EP13; additional evidence NICE (2008b)
Recommendation 10: evidence statements 1.21b, 1.21d, 1.27, 1.28, 1.29, 2.3, 2.4, 2.8, 2.9b EP8, EP15; additional evidence NICE (2006), (2008b), (2008c)
Recommendation 11: evidence statements 3.2, 3.3, 3.4; EP5
# Evidence statements
Please note that the wording of some evidence statements has been altered slightly from those in the evidence review(s) to make them more consistent with each other and NICE's standard house style.
## Evidence statement 1.5
Evidence of mixed effectiveness was found in relation to nutrition knowledge. One poor quality case series (-) found that a 10-week programme focused on translating dietary recommendations into practice, including guided hands-on food preparation, led to an increase in nutrition knowledge in two of the four intervention groups studied. No significant increase in nutrition knowledge was found in the other two groups.
## Evidence statement 1.7
Evidence of mixed effectiveness was found in relation to fruit and vegetable intake. One reasonable quality prospective cohort study (+) found an overall increase in overall average fruit and vegetable consumption in both the community where a new food hypermarket had opened and the comparison community with no new hypermarket over 12 months. There was however no significant change in either groups in average fruit consumption, and an increase in only the comparison community in vegetable consumption. One poor quality case series (-) examining the impact of the introduction of a new large-scale food retail outlet over a 1-year period found an increase in fruit and vegetable consumption among those who switched to the new store, but not among those who did not. Among both switchers and non-switchers, those with low pre-intervention levels significantly increased their fruit and vegetable consumption.
## Evidence statement 1.21a
There is evidence that information is more accessible and interventions more acceptable where key workers possess the appropriate knowledge, skills and personal attributes, such as empathy and trustworthiness.
One (+) evaluation found that trained lay workers were able to access and raise awareness in hard-to-reach groups through their knowledge of the community in which they were working, and their personal communication skills. Attributes of workers were found to be influential in three (all ) evaluations on the success of interventions. Other (four ) evaluations found that the skills of an intervention adviser facilitated the feeling of empowerment among participants, and that skills were learned through engaging the interest of the participants. As well as disseminating information in a meaningful way.
## Evidence statement 1.21b
Three (all ) evaluations of included intervention studies found evidence that acceptability is increased when practical demonstrations make abstract concepts and scientific language more meaningful, and when progressive small steps are taken in terms of behaviour change.
Two (both ) evaluations reported suggestions made by participants that might increase acceptability. These were: the development of women-only classes and more activities at weekends to fit in with other commitments; free sessions, free childcare (especially in school holidays), free food, individual and group tailored recipes and useful enjoyable activities.
In one (+) evaluation there was evidence that male-only classes using creative ways to conceptualise weight management increased acceptability and motivation.
One exploratory study and one evaluation (both ) found that acceptability of a food educational intervention was increased by first exploring participants' needs in terms of topic content. Three evaluations (two and one ) found that incentives such as access to free food increased motivation to participate in nutrition educational interventions. The experimental use of familiar and affordable food increased the acceptability of a food and health project.
There was evidence (one ) that interventions delivered by community members rather than health professionals tended to encourage community participation and meet local needs with an open and holistic agenda.
## Evidence statement 1.21c
There is evidence that acceptability of interventions that aim to change behaviour is enhanced by the added value of social inclusion. Social interaction has a positive subjective effect on wellbeing as well as providing a shared forum for discussion of concerns.
Evaluation of a healthy living centre (one ) found that social inclusion was stated as one aim of the intervention, while another randomised controlled trial (RCT) qualitative evaluation (+) found that interactive Internet portals increased social capital for people with shared health issues. Social interaction was a positive and facilitating factor for participation in four interventions (all ) aimed at increasing physical activity, and one aimed at improving eating behaviours. Positive social aspects of the interventions included an informal atmosphere, the opportunity to chat and discuss with other participants, as well as humour.
## Evidence statement 1.21d
There is evidence that interventions aimed at raising awareness of healthy behaviours are more acceptable when they are made appropriate to the target audience and have a positive image.
One (++) qualitative study found that young women will be less motivated to participate in sporting activities if the image associated with those activities, for example the required clothing, is perceived as negative. Two process evaluations found that participants held negative associations with the term 'healthy eating'. The group in one (++) study associated the term with government policy and the other (+) study groupregarded healthy eating as boring and not filling.
## Evidence statement 1.22
There was qualitative evidence from two (both ) multi-method evaluations of changes in participants' and their family's eating behaviour, and also of a developing interest in cooking as well as increased feelings of wellbeing. In one of these evaluations, the use of fat in cooking had reduced.
## Evidence statement 1.25
There is evidence that adopting healthy lifestyle behaviours can be influenced by existing attitudes toward health. One (++) qualitative study found evidence of a range of attitudes from actively seeking to improve health prospects to a disinterest in health issues. Another (+) interview and focus group study found a perceived lack of control over weight. Two rationales for excess weight included a flawed metabolism and genetics, neither of which were perceived as subject to change. There was evidence from one (+) interview study that for the mothers in the study, the five-a-day message was perceived as impractical and a joke. One focus group study (+) found that lack of exercise was generally not emphasised as a health risk factor by male and female blue-collar workers. In another focus group study (+), women of lower educational attainment were not clear about the links between food and health, often equating weight with health, and believed it was not good to be 'too healthy', although the long-term health of their children was considered important and related to food. Another focus group study (+) found that some mothers deliberately sought out cheap and healthy foods, however others were less concerned about the healthiness of their family meals.
## Evidence statement 1.27
There is evidence that adopting healthy lifestyle behaviours can be influenced by current lifestyle. Two evaluations (both ) and one (+) interview and focus group study found evidence that commitments and responsibilities were seen as a barrier to participation in physical activity. There was also evidence that for some, existing activity around the home is sufficient. Participants cited lack of time, particularly if employed in work or looking after children, as a barrier to physical activity. There was evidence from one (+) qualitative study that parents regard 'stress', 'comfort eating' 'being stuck in a rut' and 'embarrassment' as reasons for not carrying out sufficient physical activity. Health professionals interviewed in the same study discussed the prevalence of mental health issues such as depression in the area, and its impact on health behaviours.
## Evidence statement 1.28
There is mixed evidence that affordability has an impact on lifestyle behaviour change. One (+) qualitative study found that costs limited the extent to which deprived mothers could buy healthy food. Another (+) qualitative study exploring the beliefs of those living in new deal communities (NDCs) found a perceived lack of affordable goods in the local area, with public transport costs also regarded as prohibitive. Affordability in two studies was only an issue where buying extra food, or organic food might be considered. One (+) evaluation and one (++) qualitative study found that cooking different meals to suit the preferences of family members was considered too expensive. In one (+) evaluation there was evidence that low-income groups were resistant to change because of financial risk. In one (+) interview study with low income consumers and health professionals, both stated that pricing strategies were not regarded as helpful in encouraging healthy eating. However, health professionals held the view that healthy foods could be prioritised over convenience foods when shopping. One focus group study (+) identified the cost of food as a barrier to healthy eating due to its cost in relation to other priorities, marketing strategies and special offers not being placed on healthier foods and the waste generated by buying food that did not get eaten. Similarly, another focus group study (+) found that mothers would choose less healthy but cheaper options when shopping and wasting money on food that their families would not eat was a consideration. Expense was also reported by men as a barrier to healthy eating in another focus group study (++), although the authors did not explore this in detail.
There is evidence (one study) that affordability may be addressed by including budgeting as a topic in nutrition educational programmes. Evidence from one (+) interview study showed cost as a perceived barrier to physical activity in disadvantaged groups for both consumers and health professionals. Transport to – and use of – facilities were both perceived as costly. Physical activity referral schemes were suggested as one way of overcoming the cost of using facilities.
## Evidence statement 1.29
Evidence was found that environmental factors can be a barrier to improving nutrition. One (+) qualitative study found that a perceived lack of local amenities was a prohibiting factor in shopping for healthy foods. Access to food shopping was regarded as a barrier to healthy eating among women with lower educational attainment in one focus group study (+), in particular navigating round shops with pushchairs, coping with demanding children and bringing the shopping home on public transport and into high-rise flats. Evidence was also found that environmental factors can be a barrier to change in take-up of physical activity. One (++) qualitative evaluation found that fear of crime and feeling intimidated inhibited the motivation to participate in a new cycling initiative. One (+) qualitative study found that fear of attack prevented walking in certain areas. Another (+) evaluation showed that dark evenings and poor weather are barriers to physical exercise outdoors. One large-scale cross-sectional survey (+) found that active travel was associated with being younger, living in owner-occupied accommodation, travelling less than 4 miles to work, having access to a bicycle and not having access to a car, whereas overall physical activity was associated with living in social-rented accommodation and not being overweight.
## Evidence statement 2.3
There was evidence from one (+) focus group study that acceptability of lifestyle change interventions can be increased by raising the cultural sensitivity of delivery. For example, the importance of avoiding Ramadan needs to be considered in the timing of delivery, and separate sessions for men and women need to be considered. There was evidence that flexibility around the timing of interventions as well as the bilingual abilities of staff were important. Learning to cook traditional foods in a more healthy way was one way to preserve cultural identity. In addition, advice (particularly one-to-one) and information that takes into account literacy levels and is encouraging were crucial to sustaining motivation to adopt a healthier lifestyle.
Evidence from one (++) focus group study that included suggestions from participants, showed that acceptability of a nutritional education intervention might be increased by: including free food, timing classes to suit those with childcare responsibilities, and providing a crèche or possibly holding the classes in schools. Evidence from one (+) needs assessment study showed that cook and eat sessions and weight management classes that were made freely available on a gypsy traveller site were valued by women residents for their non-threatening environment and as a forum for discussion of health issues – as well as a way to reduce social isolation. Lack of childcare facilities, transport issues and costs were barriers to off-site activity.
Evidence from an interview-guided questionnaire study (+) and one qualitative evaluation (+) included suggestions to increase the acceptability for Muslim Bangladeshi women who may wish to access a gym. Suggestions included the provision of women-only facilities, women-only sessions, swimming facilities for women, more walking physical activity facilities, fewer aerobic classes, Sylheti-speaking assistants, better transport and childcare facilities, less loud music, no inappropriate TV programmes and provocative music videos, and access to more local gyms. Evidence from one qualitative evaluation (+) of exercise on prescription (EoP) also identified lack of access to facilities, lack of childcare arrangements, as well as a limited choice of women-only sessions as barriers to attendance.
There was evidence from one (+) mixed method study that social interaction was a motivator for South Asian women attending a healthy eating and physical activity group. Some women also stated that they ate less when attending as they were not tempted to snack in the same way as when they stayed in the house.
## Evidence statement 2.4
There was evidence from one (++) focus group study of lack of understanding between professional and lay groups in terms of Islamic teaching and its relation to healthy lifestyle practices. There was also evidence from the same study of communication difficulties arising from health literacy deficiencies in lay Bangladeshi people and cultural sensitivity deficiencies in professionals which obstruct appropriate health promotion messages.
## Evidence statement 2.5
There was evidence from four focus groups and two interview studies that religious customs can become barriers or facilitators to lifestyle change. Change was more likely where participants believed they had some degree of free will. There was conflicting evidence regarding fatalism; in one (++) study health professionals spoke of fatalism as a barrier to health prevention in some black and minority ethnic groups. However, evidence from one (+) study suggests that while the occurrence of health conditions might be regarded as God's will, it is also, according to teachings, the responsibility of the individual to attempt to maintain good health and wellbeing.
There was evidence from three focus groups (one and two ) and one (+) interview study and one qualitative evaluation (+) that healthy activities were acceptable provided they did not include aspects that were conflicting with religious teachings. One (++) focus group study showed evidence that some practices, such as eating Halal meat could limit the use of fast-food outlets.
## Evidence statement 2.6
There was evidence from nine qualitative studies that cultural influences and issues of identity can be barriers or facilitators to lifestyle change.
There is evidence from one (+) focus group study that a nomadic identity influenced dietary choices for Somalians. As descendants of camel herders, diet in the UK continued to be influenced by the staple diet of meat with rice or spaghetti and a low consumption of fruit and vegetables which were less valued.
A (+) needs assessment with gypsy travellers found that some fruit and vegetables were eaten daily, as they were seen as relatively cheap. In particular, vegetables were favoured as they could be incorporated into daily cooking. However, while 60% of participants considered themselves as 'heavy', they also stated that the meal was often followed by a take-away in the evening.
Evidence from one (+) interview study suggested that traditional South Asian beliefs regarding the preventive attributes of certain vegetables in terms of ill health are part of a cultural identity, and that this might be taken on board by professionals when discussing health promotion. Dietary practices in the UK can involve experiences that are alien to traditional culture and identity However, one (+) qualitative study showed that food choices made by South Asian women can be informed by both traditional ('our' food) and Western ('your sort of foods') explanations in terms of 'good' and 'bad' effects upon the body so long as such explanations are complementary rather than in conflict.
Evidence was found in one (+) guided interview study, one (+) focus group study and one (+) needs assessment for differences between UK culture and non-Western culture in terms of the perception of physical activity as either 'separate' or 'integral' to daily routine. Physical activity as 'separate' incurred financial costs as well as often being organised in ways that are insensitive to different cultural values.
Evidence from one (+) study highlighted the belief that expending sweat is important for increased wellbeing; this influenced the practices that might be taken up in the UK where a cold climate limits sweat production.
There was evidence from one (+) guided interview study and two (one and one ) focus group studies and one qualitative evaluation (+) that a limited command of the English language is a barrier to accessing information, as well as accessing activities and shopping facilities outside of the individual's neighbourhood.
There was evidence from one (+) interview study that some South Asians consider that nothing can be done to prevent diabetes if there is already a family history.
## Evidence statement 2.7a
There was evidence from three (two and one ) focus group studies that knowledge regarding risk factors is high in South Asian communities. However, evidence from one (+) focus group study of predominantly male Somali participants suggested a low level of knowledge. When knowledge levels were high, there was evidence from two (one and one ) focus group studies that this does not always translate to practice in terms of healthy lifestyle. Evidence from one (++) focus group study suggested that education may be one way of overcoming restrictive practices.
## Evidence statement 2.7b
Evidence from one (+) focus group study suggested that South Asian people in the UK would appreciate increased information on risk factors, advice and encouragement in order to motivate and sustain behaviour change.
There was evidence from one (+) focus group study that information and advice regarding physical activity came mainly from the media, role models, family and friends, the medical establishment (mainly hospitals) and to a limited degree, fitness campaigns.
## Evidence statement 2.7c
There was evidence from one guided interview study and two focus group studies (one and two ) and one qualitative evaluation (+) that a limited command of the English language is a barrier to accessing information, as well as activities and shopping facilities outside the neighbourhood.
## Evidence statement 2.8
For South Asian and African populations in the UK, and especially first generation migrants, there was evidence from three (two and one ) focus group studies that traditional fresh foods are not readily available locally and are expensive.
Evidence from one (++) focus group study showed that older people are less willing to travel beyond the immediate neighbourhood for food due to language barriers and fears for their safety. There is evidence from one (++) focus group study that the price of food is more of an issue for older people.
There was evidence from one (+) mixed method evaluation and one qualitative evaluation (+) that: distance from physical activities, lack of transport, fear of walking alone, having conflicting family commitments, not being able or willing to walk, ill health and cold weather were all barriers to attending a healthy eating and physical activity group. Having to travel to venues incurred extra costs even if physical exercise was on prescription, as for some South Asian women even a small financial contribution was reported as a barrier.
## Evidence statement 2.9a
There was evidence from four (two and two ) focus group studies that traditional South Asian cooking is associated with a high usage of fat, particularly for special occasions (which occur frequently) and that there is resistance to change such traditions. Indian men who wished to control their diet within a close-knit community where social events were common found it particularly difficult.
Evidence from one (+) focus group study showed that Somali cooking is associated with high meat and low fruit and vegetable content and again there is resistance to change. These traditions are part of the cultural identity and symbolic of prosperity and hospitality.
Evidence from two focus (one and one ) group studies suggested that consumption of take-away food is common in second generation South Asian males and females as a change from traditional fare. Similarly, take-away meals were commonly used by Somalian males, particularly those living alone.
Some South Asian women are beginning to cook in more healthy ways. There were suggestions from one (+) focus group study that learning to cook traditional food in healthy ways may be beneficial to South Asian groups. Another focus group study (++) suggested that women from Zimbabwe were not used to cooking for themselves as in Africa, maids had done the cooking; having to cook in the UK was seen as time consuming.
## Evidence statement 2.9b
There was evidence from two (both ) interviews and four (one and three ) focus group studies and one qualitative evaluation (+) that in South Asian groups, physical activity was perceived as a part of normal life and that there was little time for formal or 'separate' sessions, due to work or childcare commitments.
In particular, evidence from one (++) focus group study suggested women were expected to stay home and look after children rather than enrol the help of others. Evidence from one (+) interview study suggested that older participants perceived that vigorous physical activity was unnecessary in the context of advancing age and that keeping active and mobile was preferable.
There was evidence from one (+) focus group study of variation in views of South Asian and black participants regarding the appropriate level of physical activity required to obtain benefits, depending on own level of activity. There was evidence from the same study among South Asian participants that partaking in physical activity could compensate for unhealthy eating or smoking.
Evidence from two interview studies (both ), three focus group (one and two ) studies and one qualitative evaluation (+) suggests that vigorous activity such as aerobics was not acceptable to some South Asian participants, particularly females, for whom modesty and single-sex classes were important considerations. One (+) focus group study found that for some young people, however, going to the gym created a means of filling time, escape from social conditions and keeping up with fashion trends. There was evidence from one (+) focus group study of South Asian participants that partaking in physical activity could compensate for unhealthy eating or smoking.
There was also evidence from one (+) focus group study that encouraging sweating was important to some South Asian people. Evidence from one (+) focus group study and one guided interview study suggested that swimming and slow walking were preferred ways to remain active.
There is evidence from one (++) focus group study of a 'complex value hierarchy'. For example, choosing healthier options such as using less fat in cooking, and having to wear certain clothing for particular physical activities were seen as shameful and as more important than the benefits of a healthy lifestyle. In addition, as in white communities, support from families can act as a facilitator (if the new behaviour is integrated with the sense of self and one's own values without the control of others) or a barrier to changing health-related behaviours.
## Evidence statement 2.10
There was evidence from five good quality (two and three ) qualitative studies (three focus group and two interview studies) that body image expectations vary according to background and culture and often differ from those currently popular within the UK.
There is evidence from one (++) focus group study that body size can be positively or negatively associated with health and attractiveness, and attempting to reach an ideal body size can be a strong motivator for behaviour change. There was evidence from one (+) interview guided questionnaire that only 64% of overweight or obese Bangladeshi women classed themselves as overweight. There was evidence from one (+) interview study that weight management was more important for South Asian males than females, and a (+) focus group study found it important for young South Asian and black females.
Evidence was found for an association between being overweight and prosperity in one (+) focus group study with Indian, Pakistani and Indian participants. Changing dietary and physical activity patterns in old age was perceived as potentially weakening.
Having the 'right' body size was influenced by the media as well as some male views, and was important for attracting a partner for young South Asian and black females in one (+) focus group study.
In one (++) focus group study body size was found to be a stronger motivator for healthy behaviour changes than health issues.
## Evidence statement 3.2
There is evidence from one (+) study that did not focus on low income or BME groups to suggest that the process of identifying and referring high-risk patients in primary care to an exercise scheme varies between general practices. GPs and practice nurse's methods of identifying and referring patients to an exercise scheme was ad-hoc and based on: patients asking about exercise themselves, chance discussion during consultations, requests for referral by another doctor, and asking patients to choose from a variety of behaviour change activities that might produce health benefits.
Evidence from one (+) evaluation of healthy living centres acknowledges the challenges of identifying groups at risk. Hard-to-reach groups might be reached in small numbers at community events or eventually be motivated to engage with initiatives through word of mouth from relatives.
## Evidence statement 3.3
Evidence from one (+) survey study that evaluated the contribution of nurses to targeting health and social need suggests that in order to be able to empower high-risk groups to make choices about adopting healthy lifestyles, health professionals require a deep understanding of the cultural and religious beliefs and economic influences within the communities with which they are working.
One (+) evaluation highlighted the need for practitioners to take into account the realities of the people they are targeting. For example, making it clear that low-income groups do not require expensive clothing to engage in a community physical activity initiative.
## Evidence statement 3.4
Evidence from one (+) qualitative study of nurses' attitudes identified two discourses in relation to health promotion with disadvantaged groups. One was associated with the philosophy of holism that nurses were exposed to during training, resulting in empathy for the disadvantages that low-income groups face in attempting to achieve a healthy lifestyle. The other discourse reflects personal values, and beliefs that individuals must take responsibility for their own health. This tension may need addressing when practising health promotion in a culturally sensitive way.
## Evidence statement 3.6
Evidence from two evaluations (one and one ) suggests that the training of lay workers to identify and disseminate health promotion messages to members of their community is a way of reaching hard-to-reach and high-risk groups.
One (+) evaluation in which 11 women (seven of Pakistani, two of Indian and two of Chinese origin; of Muslim, Hindu and Christian religious backgrounds) undertook formal training to become community health workers (CHWs) provides evidence that lay workers trained by health professionals can identify target groups within the community and deliver health messages in a culturally sensitive way in an appropriate language. Knowledge of the communication channels in a community assisted in the success of the initiative. For example, in this study, younger women were targeted for training as they are relied upon in the community for passing on information.
Evidence from a qualitative evaluation (++) study that explores the role of the lay food and health worker suggests a consensus of opinion that the primary role for lay workers is the encouragement of dietary change by making complex messages more credible and culturally appropriate. A proactive strategy for lay workers to identify and contact at-risk individuals is to create lists of contacts within the community and introduce themselves to those on the list.
One (+) evaluation of healthy living centres highlighted a difference in focus between lay workers, who considered the larger social picture, and health professionals, whose focus was more on outcomes such as improved fruit and vegetable intake.
## Evidence statement 3.7
One (-) evaluation of peer education training as part of a community health promotion programme (Project Dil), provides evidence of a high level of uptake and enthusiasm from those engaged in peer education. The project was designed to improve the effectiveness of primary and secondary prevention of coronary heart disease in volunteer Leicestershire general practices with a high percentage of South Asian patients. Peer education was reported to facilitate health promotion within a range of organised community events.
Evidence from one (+) evaluation suggests that fostering a team spirit and sharing experiences was a key facilitator in training lay workers. However, there is evidence from the same study that scheduled activities prevented lay workers from having time to participate.
## Evidence statement 3.8
One (+) evaluation of lay worker training provides evidence that target groups within the community increased their knowledge as a result of lay worker activity, and found the cultural sensitivity of health promotion messages an important factor in helping to make changes in dietary practice.
## Expert papers
Expert paper 5: 'CPD and training, enabling professionals to practice effectively and confidently'.
Expert paper 6: 'BME groups, diet and risk of type 2 diabetes'.
Expert paper 7: 'Developing population level guidance – CVD, the Foresight Report.'
Expert paper 8: 'Dietary strategies for the prevention of pre-diabetes'.
Expert paper 9: 'Low income groups and behaviour change interventions'.
Expert paper 10: 'Adapting health promotion interventions for BME communities'.
Expert paper 11: 'Health policy and health.'
Expert paper 12: 'Ismaili Nutrition Centre'.
Expert paper 13: 'Environment and physical activity'.
Expert paper 14: 'Nutritional food labelling current thinking and practice'.
Expert paper 15: 'Fiscal policy instruments to improve diet'.
# Additional evidence
NICE's guideline on obesity.
NICE's guideline on general approaches to behaviour change: general approaches.
NICE's 2008 guideline on community engagement.
NICE's guideline on physical activity in the workplace.
NICE's 2008 guideline on physical activity and the environment.
# Cost-effectiveness evidence
The recommended interventions operate on groups of people – and often quite large groups. For most people, the amount of weight they lose, the extent of changes to their diet and any increase in the amount of exercise they take will be relatively small. In addition, a few will make changes in the wrong direction. Thus the average changes in behaviour within the group as a whole will usually be small. However, the total changes will eventually be discernable at a population level: that is, fewer people will be diagnosed with type 2 diabetes in the long run, or will be diagnosed later in life.
Modelling over the lifetime of individuals demonstrates that, if the total costs of undertaking the initial interventions are sufficiently small, these interventions will be cost effective. Some interventions will be very cost effective or, in the long run, cost saving, even after discounting future benefits at the usual rate of 3.5% per year. ('Cost saving' means that the costs saved from not having to undertake treatment later in life exceed the costs of the intervention.)
However, for a range of reasons, there is an element of uncertainty in the modelling results. This includes the possibility that better health outcomes in the future may be attributable to something other than the named interventions, or that there might be far better and cheaper treatments for type 2 diabetes in the future.
# Fieldwork findings
Fieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations. For details, see the fieldwork section in appendix B.
The guidance was welcomed by fieldwork participants. It was felt that it could help raise the profile of type 2 diabetes prevention activities, and provide renewed impetus. Many participants stated that the recommendations represented best practice in the area rather than offering a new approach. Most participants expressed the need for an integrated strategy on healthy lifestyles, covering the main related long-term conditions (such as cardiovascular disease, obesity, diabetes and hypertension) and the main lifestyle risk factors (for example, unhealthy diet and lack of physical activity). It was also felt that a better balance between recommendations for action at a local level and action at national level was important.# Appendix D: Gaps in the evidence
The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence and expert comment. These gaps are set out below.
There was not enough evidence to judge the effectiveness of interventions to reduce the risk of – and prevent – pre-diabetes. In particular, there was a lack of evidence on how effective they are with people from black and minority ethnic and lower socioeconomic communities in the UK. (Source Reviews 1–3 and 5)
There was limited evidence on how different approaches could be combined. (For example, targeting the population as whole, targeting 'high-risk' populations and other approaches, including 'individual' interventions.) (Source Reviews 1–3 and 5)
There was limited evidence on the 'cultural appropriateness' of interventions and how they could be effectively adapted or tailored to prevent pre-diabetes. (Source Reviews 1–6; Expert paper 10)
There was limited evidence on how the environment in which people live may affect their risk of developing pre-diabetes.(Source Reviews 1 and 2; Expert paper 13)
There was limited evidence on the effectiveness of interventions to develop the awareness, knowledge, understanding and skills of healthcare professionals and others responsible for people at high risk of developing pre-diabetes. (Source Review 3)
There was limited evidence on the potentially regressive effects of food taxation on health inequalities.(Source Expert paper 15)
The Group made five recommendations for research.# Appendix E: Supporting documents
Supporting documents include the following:
Evidence reviews:
Review 1: 'Prevention of type 2 diabetes: interventions to reduce risk factors for pre-diabetes among UK adults from a lower socioeconomic group'
Review 2: 'Prevention of type 2 diabetes: interventions to reduce risk factors for pre-diabetes among UK adults from black and minority ethnic groups'
Review 3: 'Prevention of type 2 diabetes: interventions to raise awareness in health professionals and assist identification of high-risk groups'
Review 4: 'Interventions for the prevention of pre-diabetes in high-risk groups: examples of current practice in relation to the UK evidence base'
Review 5: 'Review of review-level evidence to inform the development of NICE public health guidance for the prevention of pre-diabetes among adults in high-risk groups'
Review 6: 'Identification of effective community projects focused on addressing risk factors for the development of pre-diabetes in adults from black and minority ethnic groups and lower socio-economic groups'.
Economic modelling: 'Prevention of type 2 diabetes: preventing pre-diabetes among adults in high-risk groups. Report on cost-effectiveness evidence and methods for economic modelling'.
Expert papers:
Expert paper 1: 'Type 2 diabetes and pre-diabetes: diagnosis and definition'
Expert paper 2: 'Illness labelling and illness experience'
Expert paper 3: 'Socio-economic status and risk factors for type 2 diabetes'
Expert paper 4: 'Expert advice, dietary surveys and nutrition research'
Expert paper 5: 'CPD and training, enabling professionals to practice effectively and confidently'
Expert paper 6: 'BME groups, diet and risk of type 2 diabetes'
Expert paper 7: 'Developing population level guidance – CVD, the Foresight report'
Expert paper 8: 'Dietary strategies for the prevention of pre-diabetes'
Expert paper 9: 'Low income groups and behaviour change interventions'
Expert paper 10: 'Adapting health promotion interventions for BME communities'
Expert paper 11: 'Health policy and health'
Expert paper 12: 'Ismaili Nutrition Centre'
Expert paper 13: 'Environment and physical activity'
Expert paper 14: 'Nutritional food labelling: current thinking and practice'
Expert paper 15: 'Fiscal policy instruments to improve diet'.
Fieldwork report: 'Fieldwork validation report: prevention of pre-diabetes among adults in high-risk groups'.# Finding more information
You can see everything NICE says on this topic in the NICE Pathway on preventing type 2 diabetes.
To find NICE guidance on related topics, including guidance in development, see our topic page for diabetes.
For full details of the evidence and the guideline committee's discussions, see the supporting documents. You can also find information about how the guideline was developed.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.
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{'Introduction': "The Department of Health (DH) asked NICE to produce public health guidance on the prevention of type\xa02 diabetes mellitus among high-risk groups.\n\nThe referral was divided into two separate pieces of guidance. The first (this guidance) originally set out to address the prevention of 'pre-diabetes' among adults aged 18 to 74 in communities at high risk of developing type\xa02 diabetes. The second set out to focus on preventing the progression from 'pre-diabetes' to type\xa02 diabetes.\n\nHowever, in January 2011 the World Health Organization (WHO) recommended that glycated haemoglobin (HbA1c) could be used as an alternative to standard glucose measures to diagnose type\xa02 diabetes among non-pregnant adults. HbA1c levels of 6.5% (48 mmol/mol) or above indicate that someone has type\xa02 diabetes – but there is no fixed point to indicate when someone has 'pre-diabetes'. (Increasing levels of HbA1c, up to the 6.5% (48\xa0mmol/mol) cut-off point, mean someone is at increasing risk of type\xa02 diabetes.)\n\nThe title of this guidance has been changed since it went out for consultation to reflect this move away from recognising 'pre-diabetes' as a separate condition. However, the overall range and scope of the content remains the same. The second piece of guidance will consider the effectiveness and cost effectiveness of interventions to prevent type\xa02 diabetes among individuals at high-risk.\n\nFactors which influence someone's risk of type\xa02 diabetes include: weight, waist circumference, age, physical activity and whether or not they have a previous history of gestational diabetes or a family history of type\xa02 diabetes.\n\nIn addition to these individual risk factors, people from certain communities and population groups are particularly at risk. This includes people of South Asian, African-Caribbean, black African and Chinese descent and those from lower socioeconomic groups.\n\nThe guidance is for commissioners, managers and practitioners with public health as part of their remit working within the NHS, local authorities, the national and local public health service and the wider public, private, voluntary and community sectors. It is also for national policy makers, caterers, food manufacturers and retailers.\n\nThe guidance is particularly aimed at: directors of public health, public health commissioners and all those working in national and local public health services. This includes: GPs, practice nurses, dietitians, public health nutritionists and other health professionals, as well as those involved in delivering physical activity interventions, community engagement teams and community leaders. It may also be of interest to members of the public.\n\nThe guidance complements, but does not replace, NICE guidance on: behaviour change, cardiovascular disease, community engagement, diabetes in pregnancy, management of type\xa02 diabetes, maternal and child nutrition, obesity, physical activity and weight management before, during and after pregnancy.\n\nThe Programme Development Group (PDG) developed these recommendations on the basis of reviews of the evidence, economic modelling, expert advice, stakeholder comments and fieldwork.\n\nMembers of the PDG are listed in appendix A. The methods used to develop the guidance are summarised in appendix B. Supporting documents used to prepare this document are listed in appendix E.", 'Recommendations ': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nFor the research recommendations see section 4 and for gaps in research see appendix D.\n\n# Definitions\n\n## Type\xa02 diabetes\n\nDiabetes is a group of disorders with a number of common features characterised by raised blood glucose. In England the four commonest types of diabetes are:\n\ntype\xa01 diabetes\n\ntype\xa02 diabetes\n\nsecondary diabetes (from pancreatic damage, hepatic cirrhosis, endocrinological disease/therapy, or anti-viral/anti-psychotic therapy)\n\ngestational diabetes (diabetes of pregnancy).\n\nThe underlying disorder for type\xa02 diabetes is usually insulin insensitivity combined with a failure of pancreatic insulin secretion to compensate for increased glucose levels. The insulin insensitivity is usually evidenced by excess body weight or obesity, and exacerbated by over-eating and inactivity. It is commonly associated with raised blood pressure and a disturbance of blood lipid levels. The insulin deficiency is progressive over time, leading to a need for lifestyle change often combined with blood glucose lowering therapy. See NICE's guideline on managing type\xa02 diabetes in adults.\n\nType\xa02 diabetes is diagnosed in adults who are not pregnant by a glycated haemoglobin (HbA1c) level of 6.5% (48\xa0mmol/mol) or above. A type\xa02 diabetes diagnosis can also be made by:\n\nrandom venous plasma glucose concentration the same or greater than 11.1\xa0mmol/l or\n\nfasting venous plasma glucose concentration the same or greater than 7.0\xa0mmol/l or\n\n-hour venous plasma glucose concentration the same or greater than 11.1\xa0mmol/l 2\xa0hours after 75\xa0g anhydrous glucose in an oral glucose tolerance test (OGTT).In patients without symptoms, the test must be repeated to confirm the diagnosis using World Health Organization criteria (see the World Health Organization's use of glycated haemoglobin in the diagnosis of diabetes mellitus and definition and diagnosis of diabetes mellitus and intermediate hyperglycemia).\n\n## Overweight and obesity\n\nThe following table defines a healthy weight in relation to height using the body mass index (BMI). BMI is calculated from the weight in kg divided by the height in metres squared. The table also defines what it means to be overweight and different degrees of obesity (also see NICE's guideline on obesity).\n\nClassification\n\nBMI (kg/m2)\n\nHealthy weight\n\n–24.9\n\nOverweight\n\n–29.9\n\nObesity I\n\n–34.9\n\nObesity II\n\n–39.9\n\nObesity III\n\nor more\n\nBeing overweight or obese is the main contributing factor for type\xa02 diabetes. In addition, having a large waist circumference increases the risk of developing type\xa02 diabetes:\n\nMen are at high risk if they have a waist circumference of 94 to 102\xa0cm (37 to 40\xa0inches). They are at very high risk if it is more than 102\xa0cm.\n\nWomen are at high risk if they have a waist circumference of 80 to 88\xa0cm (31.5 to 35\xa0inches). They are at very high risk if it is more than 88\xa0cm.\n\nThe above classification may not apply to some population groups, as noted in NICE's obesity guidance. For example, although some South Asian adults or older people may have a BMI lower than the overweight classification, they may still be at greater risk of developing conditions and diseases associated with being overweight or obese.\n\n# Types of intervention\n\nIn this guidance, early intervention to prevent type\xa02 diabetes is considered as part of an integrated package of local measures to promote health and prevent a range of non-communicable diseases (including cardiovascular disease and some cancers).\n\nThe guidance also recommends national action to address the adverse environmental factors driving the increasing prevalence of type\xa02 diabetes.\n\nLifestyle interventions aimed at changing an individual's diet and increasing the amount of physical activity they do can halve the number with impaired glucose tolerance who go on to develop type\xa02 diabetes. However, the greatest impact on the levels – and associated costs – of type\xa02 diabetes is likely to be achieved by addressing these behavioural risk factors in whole communities and populations.\n\n# Guiding principles\n\nType\xa02 diabetes shares common risk factors with other non-communicable diseases including cardiovascular disease and some cancers. This means that recommendations made in previously published NICE guidance can also help prevent it. Specifically, the following published statements underpin many of the recommendations made here.\n\n## Supporting behaviour change\n\nThis recommendation should be read in conjunction with NICE's guideline on behaviour change: general approaches. Changing people's health-related behaviour involves:\n\nHelping them to understand the short, medium and longer-term consequences of health-related behaviour.\n\nHelping them to feel positive about the benefits and value of health-enhancing behaviours and changing their behaviours.\n\nRecognising how people's social contexts and relationships may affect their behaviour.\n\nHelping people plan changes in terms of easy sustainable steps over time.\n\nIdentifying and planning for situations that might undermine the changes people are trying to make, and planning explicit 'if–then' coping strategies to maintain changes in behaviour.\n\n## Achieving and maintaining a healthy weight\n\nEveryone should aim to maintain or achieve a healthy weight, to improve their health and reduce the risk of diseases associated with overweight and obesity, such as type\xa02 diabetes. People should follow the strategies listed below. These may make it easier to maintain a healthy weight by balancing 'calories in' (from food and drink) and 'calories out' (from being physically active):\n\nbase meals on starchy foods such as potatoes, bread, rice and pasta, choosing wholegrain where possible\n\neat fibre-rich foods such as oats, beans, peas, lentils, grains, seeds, fruit, vegetables, wholegrain bread and brown rice and pasta\n\neat at least five portions of a variety of fruit and vegetables each day, in place of foods higher in fat and calories\n\nadopt a low-fat diet\n\navoid increasing fat or calorie intake\n\nconsume as little as possible of fried food; drinks and confectionery high in added sugars (such as cakes, pastries and sugar-sweetened drinks); and other food high in fat and sugar (such as some take-away and fast foods)\n\nminimise calorie intake from alcohol\n\nwatch the portion size of meals and snacks, and how often they are eating throughout the day\n\neat breakfast\n\nmake activities they enjoy, such as walking, cycling, swimming, aerobics and gardening, a routine part of life and build other activity into their daily routine – for example, by taking the stairs instead of the lift or taking a walk at lunchtime\n\nminimise sedentary activities, such as sitting for long periods watching television, at a computer or playing video games\n\nuse physically active forms of travel such as walking and cycling. (This point is adapted from NICE's guideline on physical activity in the workplace.)\n\n## Effective weight-loss programmes\n\nEffective weight-loss programmes should:\n\naddress the reasons why someone might find it difficult to lose weight\n\nbe tailored to individual needs and choices\n\nbe sensitive to the person's weight concerns\n\nbe based on a balanced, healthy diet\n\nencourage regular physical activity\n\nexpect people to lose no more than 0.5 to 1\xa0kg (1 to 2\xa0lb) a week\n\nidentify and address barriers to change. Also see NICE's guideline on obesity.\n\n## Physical activity\n\nFor national recommendations for physical activity in adults aged 19 to 64 and older adults (over 65) see the UK Chief Medical Officers' physical activity guidelines. For recommendations on physical activity in people who have obesity see NICE's guideline on obesity.\n\n## Cultural appropriateness\n\nCulturally appropriate interventions take account of the community's cultural or religious beliefs and language and literacy skills by:\n\nUsing community resources to improve awareness of, and increase access to, interventions. For example, they involve community organisations and leaders early on in the development stage, use media, plan events or make use of festivals specific to black and ethnic minority groups.\n\nUnderstanding the target community and the messages that resonate with them.\n\nIdentifying and addressing barriers to access and participation, for example, by keeping costs low to ensure affordability, and by taking account of different working patterns and education levels.\n\nDeveloping communication strategies which are sensitive to language use and information requirements. For example, they involve staff who can speak the languages used by the community. In addition, they may provide information in different languages and for varying levels of literacy (for example, by using colour-coded visual aids and the spoken rather than the written word).\n\nTaking account of cultural or religious values, for example, the need for separate physical activity sessions for men and women, or in relation to body image, or beliefs and practices about hospitality and food. They also take account of religious and cultural practices that may mean certain times of the year, days of the week, settings, or timings are not suitable for community events or interventions. In addition, they provide opportunities to discuss how interventions would work in the context of people's lives.\n\nConsidering how closely aligned people are to their ethnic group or religion and whether they are exposed to influences from both the mainstream and their community in relation to diet and physical activity.\n\n# Whose health will benefit?\n\nAdults (aged between 18 and 74), in particular, those from:\n\nblack and minority ethnic groups\n\nlower socioeconomic groups.\n\n# Recommendation 1 Integrating national strategy on non-communicable diseases\n\n## Who should take action?\n\nCommissioners and providers of national public health services working in partnership with:\n\ngovernment departments\n\nthe commercial sector\n\nlocal commissioners and providers of public health services\n\nthe voluntary sector, not-for-profit and non-governmental organisations.\n\n## What action could they take?\n\nWhen developing national strategy to target non-communicable diseases with a major link to diet, physical activity and obesity (for example, type\xa02 diabetes, cardiovascular disease, certain cancers), consider:\n\n\n\nintegrating the strategy with other relevant national actions to prevent related non-communicable diseases\n\naddressing the key risk factors (for example, being overweight or obese, a sedentary lifestyle and an unhealthy diet)\n\nhighlighting the contribution that partners in national and local government, industry, healthcare and the voluntary sector can make by working together to reduce the risk of non-communicable diseases for the population as a whole\n\ntaking account of variations in different population subgroups (for example, by ethnicity, age or gender)\n\nlinking to targets and outcomes for reducing the key risk factors for type\xa02 diabetes and other non-communicable diseases.\n\n\n\nEncourage local, regional and national monitoring of the risk factors for diabetes and other non-communicable diseases. Also encourage monitoring of age-specific incidence rates for type\xa02 diabetes and other non-communicable diseases.\n\nEncourage local and national decision makers to assess the potential health impact of all new policies on the key risk factors for type\xa02 diabetes and other non-communicable diseases. Ensure they support any national prevention strategy.\n\nClearly signpost national and regional resources, including toolkits and evaluation guides, that will help local services reduce the incidence of type\xa02 diabetes and other non-communicable diseases.\n\nWork with national and local commercial partners to encourage and support joint working with local public health teams to meet the national targets.\n\n# Recommendation 2 Local joint strategic needs assessments\n\n## Who should take action?\n\nCommissioners and providers of local public health services in partnership with other local authority departments including:\n\nadult social care\n\neducation\n\nenvironmental health\n\nplanning\n\npublic transport.\n\n## What action should they take?\n\nUse national and local tools (such as the Department of Health's guidance on joint strategic needs assessment) and data from public health data collection agencies, public health reports, the census, indices of deprivation and other sources of high quality data (such as the NHS Digital website) to:\n\n\n\nidentify local communities at high risk of developing type\xa02 diabetes\n\nassess their knowledge, awareness, attitudes and beliefs about the risk factors\n\nassess their specific cultural, language and literacy needs.\n\n\n\nIdentify successful local interventions and note any gaps in service provision.\n\nIdentify local resources and existing community groups that could help promote healthy eating, physical activity and weight management, particularly within local communities at high risk of developing type\xa02 diabetes.\n\n# Recommendation 3 Developing a local strategy\n\n## Who should take action?\n\nCommissioners and providers of local public health services in partnership with other local authority departments including:\n\nadult social care\n\neducation\n\nenvironmental health\n\nplanning\n\npublic transport.\n\n## What action should they take?\n\nDevelop an integrated plan for local activities and programmes aimed at preventing type\xa02 diabetes and related non-communicable diseases (including cardiovascular disease). This should be based on the joint strategic needs assessment and relevant national strategy, targets and outcomes (such as the NHS outcomes framework).\n\nThose developing strategic plans should consult widely with local health professionals working closely with communities at high risk of developing type\xa02 diabetes.\n\nThe plan should aim to increase physical activity levels and improve people's diet and weight management by:\n\n\n\nidentifying and assessing the effectiveness and cost effectiveness of existing local interventions\n\nmaking recommendations for future investment and disinvestment\n\nincluding action to raise awareness of type\xa02 diabetes and the risk factors for diabetes and other non-communicable diseases\n\ncreating local environments that encourage people to be more physically active and to adopt a healthier diet (for example, by ensuring local shops stock good quality, affordable fruit and vegetables)\n\ntargeting specific communities at high risk of developing type\xa02 diabetes, including people of South Asian, African-Caribbean or black African family origin, and those from lower socioeconomic groups\n\nincluding interventions for individuals who are deemed at particular risk (based on clear criteria about the level of absolute risk that would trigger this provision, see also NICE's guideline on preventing type\xa02 diabetes in people at high risk).\n\n\n\nEnsure local outcomes and conclusions from the strategic plan are integrated into the local commissioning strategy.\n\n# Recommendation 4 Interventions for communities at high risk of type\xa02 diabetes\n\n## Who should take action?\n\nCommissioners and providers of local public health services in partnership with:\n\nother local authority departments including: children's services, education, environmental health, leisure, planning, public transport, social housing and social services\n\nthe NHS including: GPs, practice and community nurses, dietitians, public health nutritionists, doctors and nurses working in acute and emergency care, and occupational therapists\n\nthe voluntary sector, not-for-profit and non-governmental organisations (include community leaders and trained lay workers).\n\n## What action should they take?\n\nWork in partnership to develop cost-effective physical activity, dietary and weight management interventions. Interventions should take into account the religious beliefs, cultural practices, age and gender, language and literacy of black, minority ethnic and lower socioeconomic groups. (Interventions costing up to £10 per head would need to achieve an average weight loss of about 0.25\xa0kg per head to be cost effective. Those costing up to £100 per head would need to achieve an average weight loss of about 1\xa0kg per head.)\n\nIdentify success criteria in the early stages of development to ensure interventions can be properly evaluated.\n\nIdentify any skills gaps and train or recruit staff to fill the gaps.\n\nIdentify and address barriers to participation. This includes developing communication strategies that are sensitive to the target audience's language and information requirements.\n\nUse community resources to improve awareness of the key messages and to increase accessibility to the interventions. For example, involve community organisations and leaders at the development stage and use media, plan events or attend festivals specifically aimed at black and minority ethnic communities and lower socioeconomic groups. Also involve existing community and social groups or clubs, such as toddler groups, pubs, social clubs and local sports clubs.\n\nWhere they exist, use community links, outreach projects and lay or peer workers (from black and minority ethnic communities and from lower socioeconomic groups) to deliver interventions.\n\nWhere necessary, train lay and peer workers in how to plan, design and deliver community-based health promotion activities. Training should be based on proven training models and evaluation techniques. It should give participants the chance to practice their new skills in the community. It should also encourage them to pass on their knowledge to their peers.\n\nLay and peer workers and health professionals should identify and encourage community champions (for example, religious and community leaders) to promote healthy eating and physical activity.\n\nEncourage lay and peer workers to get other members of their community involved.\n\nEnsure lay and peer workers are part of a wider team led by health professionals. They should be involved in the planning, design and delivery of credible and culturally appropriate messages. This includes helping people to develop the practical skills they need to adopt a healthier lifestyle. For example, they should be able to run nutrition education sessions (theory and practice) or physical activity sessions. Management and supervision of these activities should be provided by the health professionals leading these teams.\n\nCommission culturally appropriate and financially accessible weight management programmes either from the NHS or non-NHS providers, based on the guiding principles for effective weight-loss programmes. These should be provided in community settings in areas where populations at high risk of type\xa02 diabetes live. (For example, they could be provided in religious venues or community and social clubs.)\n\nEnsure the systems or initiatives used to assess someone from a high-risk community are culturally appropriate.\n\nEnsure identification and assessment systems or initiatives are linked to effective services and interventions for individuals deemed to be at high risk.See also NICE's guidelines on preventing type\xa02 diabetes in people at high risk and community engagement.\n\n# Recommendation 5 Conveying messages to the whole population\n\n## Who should take action?\n\nCommissioners and providers of national public health services working in partnership with:\n\nother government departments allied to health\n\nlocal commissioners and providers of public health services\n\nthe commercial sector\n\nnational voluntary sector, not-for-profit and non-governmental organisations.\n\n## What action should they take?\n\nEnsure healthier lifestyle messages to prevent non-communicable diseases (including type\xa02 diabetes, cardiovascular disease and some cancers) are consistent, clear and culturally appropriate. Ensure they are integrated within other health promotion campaigns or interventions.\n\nAddress any misconceptions about the risk of diabetes and other non-communicable diseases that can act as barriers to change. This includes the belief that illness is inevitable (fatalism) and misconceptions about what constitutes a healthy weight. Also address any stigma surrounding the conditions.\n\nEnsure any national media (for example, television and online social media) used to convey messages or information is culturally appropriate for the target audience.\n\nIdentify and make use of existing campaign materials, messages and resources, including those from other countries, where appropriate. Messages and materials should:\n\n\n\nhighlight the need to reduce the amount of time spent being sedentary\n\nhighlight the importance of being physically active, adopting a healthy diet and being a healthy weight\n\nincrease awareness of healthier food choices, and the calorie content and nutritional value of standard-portion size meals and drinks.\n\n\n\n# Recommendation 6 Conveying messages to the local population\n\n## Who should take action?\n\nCommissioners and providers of local public health services in partnership with:\n\nother local authority departments including education and leisure\n\nthe NHS including: GPs, practice and community nurses, dietitians, public health nutritionists, doctors and nurses working in acute and emergency care, and occupational therapists\n\nthe voluntary sector, not-for-profit and non-governmental organisations (including community leaders).\n\n## What action should they take?\n\nWork with local practitioners, role models and peers to tailor national messages for the local community about preventing type\xa02 diabetes and other non-communicable diseases (such as cardiovascular disease and some cancers).\n\nEnsure healthier lifestyle messages are consistent, clear and culturally appropriate. Ensure they are integrated within other local health promotion campaigns or interventions. Provide details of the local support services available.\n\nAddress any misconceptions in the local community about the risk of diabetes and other non-communicable diseases that could act as a barrier to change. This includes the belief that illness is inevitable (fatalism) and any misconceptions about what constitutes a healthy weight. Also address any stigma surrounding these conditions.\n\nEnsure messages and information are disseminated locally to groups at higher risk of type\xa02 diabetes than the general population, including black and minority ethnic and lower socioeconomic groups. Use local newspapers, online social media and local radio channels targeted at these groups. Also make use of local shops and businesses, community workers and groups, social establishments, educational institutions, workplaces, places of worship and local health care establishments, for example, hospitals.\n\nOffer communities support to improve their diet and physical activity levels, and ensure they are aware of the importance of both.\n\n# Recommendation 7 Promoting a healthy diet: national action\n\n## Who should take action?\n\nCommissioners and providers of national public health services working in partnership with:\n\nother government departments\n\nthe commercial sector\n\nthe voluntary sector, not-for-profit and non-governmental organisations\n\nlocal commissioners and providers of public health services.\n\n## What action could they take?\n\nIdentify and work with a range of commercial partners to promote the provision of healthier food choices. For example:\n\n\n\nWork with food manufacturers to improve the composition of prepared foods, where needed, to decrease calories, saturated fat and salt content. Encourage manufacturers to achieve any nationally agreed reformulation targets.\n\nWork with caterers across the industry to help them reduce the amount of calories, saturated fat and salt in recipes and to use healthier cooking methods. They should also ensure healthier options are an integral part of all menus.\n\nWork with food retailers to develop pricing structures that favour healthier food and drink choices.\n\nWork with food retailers to ensure a range of portion sizes are available and that they are priced accordingly. This is particularly important for energy-dense foods and drinks.\n\nWork with food manufacturers, caterers and retailers to provide clear, non-ambiguous and consistent nutrition information. This includes prominent displays of calorie content on the front of packaging and the use of clear signage for unpackaged food and drink. If calorie content is not known, consider indicating healthier options, such as food prepared using healthier ingredients or cooking methods.\n\nSupport the development of home-cooking resources that give information on nutritional content (for example, web-based recipe sites). Offer practical advice on preparing healthier meals, including the ingredients and cooking methods to use.\n\n\n\nMonitor the population's diet to determine the success of national-level interventions.\n\nAssess the health impact of all initiatives and interventions aimed at encouraging people to have a healthier diet.\n\n# Recommendation 8 Promoting a healthy diet: local action\n\n## Who should take action?\n\nCommissioners and providers of local public health services in partnership with:\n\nother local authority departments including: environmental health, education, leisure, social services, planning and public transport\n\nthe NHS including: dietitians and public health nutritionists\n\nvoluntary sector, not-for-profit and non-governmental organisations (include community leaders and trained lay workers)\n\nlocal food retailers and caterers\n\nlarge and medium-sized employers.\n\n## What action should they take?\n\nMake people aware of their eligibility for welfare benefits and wider schemes that will supplement the family's food budget and improve their eating patterns. This includes free school meals, free school fruit and Healthy Start food vouchers.\n\nProvide information on how to produce healthier meals and snacks on a budget.\n\nWork with local food retailers, caterers and workplaces to encourage local provision of affordable fruit and vegetables and other food and drinks that can contribute to a healthy, balanced diet.\n\nProvide nutrition education sessions (theory and practice) at times to suit people with children (or provide a crèche) or to fit with working hours. Sessions should take place in acceptable, accessible venues such as children's centres.\n\nUse existing planning mechanisms (for example, national planning guides or toolkits) to increase the opportunities available for local people to adopt a healthy, balanced diet. For example, ensure:\n\n\n\nfood retailers that provide a wide range of healthier products at reasonable cost are readily accessible locally, either on foot or via public transport\n\nplanning policies consider healthier eating when reviewing applications for new food outlets.\n\n\n\nEncourage local retailers to use incentives (such as promotional offers) to promote healthier food and drink options. The aim should be to make the healthier choice the easiest and relatively cheaper choice. The retailers targeted may include regional and national supermarkets and convenience store chains, as well as street markets and small independent shops.\n\nEncourage local caterers to include details in menus on the calorie content of meals to help consumers make an informed choice. If the nutritional value of recipes is not known, they should consider listing ingredients and describing the cooking methods used.\n\nEnsure local authorities and NHS organisations develop internal policies to help prevent employees from being overweight or obese. Encourage local employers to develop similar policies. This is in line with existing NICE guidance and (in England) the local obesity strategy. For example, organisations could promote healthier food and drink choices in staff restaurants, hospitality suites, vending machines and shops by using posters, pricing and the positioning of products.\n\n# Recommendation 9 Promoting physical activity: national action\n\n## Who should take action?\n\nCommissioners and providers of national public health services working in partnership with:\n\nother government departments\n\norganisations with a remit for town planning\n\norganisations with a remit for increasing physical activity levels\n\ncommissioners and providers of local public health services\n\nthe voluntary sector, not-for-profit and non-governmental organisations.\n\n## What action could they take?\n\nEnsure the benefits of physical activity – and the national recommendations for physical activity – are made clear to encourage people to be more physically active.\n\nSupport a shift in the population towards being more physically active by encouraging even small changes.\n\nUse planning regulations to maximise the opportunities available to be physically active.\n\nEncourage the use of national and local planning guidance to ensure physical activity is a primary objective of transport policy, and when designing new buildings and the wider built environment.\n\nMonitor the population's overall physical activity levels to determine the success of national interventions. Assess the health impact of all initiatives and interventions to encourage physical activity.\n\n# Recommendation 10 Promoting physical activity: local action\n\n## Who should take action?\n\nCommissioners and providers of local public health services in partnership with:\n\nother local authority departments including: planning, regeneration, public transport, leisure, sports and parks\n\nschools with community recreation facilities (for example, as part of the extended schools programme)\n\nthe NHS including: GPs, practice and community nurses, community pharmacists and occupational therapists\n\nvoluntary sector, not-for-profit and non-governmental organisations (include community leaders and trained lay workers)\n\nthe fitness industry\n\nlarge and medium-sized employers.\n\n## What action should they take?\n\nEnsure local planning departments use existing mechanisms (for example, national planning guides) to:\n\n\n\nprioritise the need for people (including those whose mobility is impaired) to be physically active as a routine part of their daily life (for example, when developing the local infrastructure and when dealing with planning applications for new developments)\n\nprovide open or green spaces to give people local opportunities for walking and cycling\n\nmake sure local facilities and services are easily and safely accessible on foot, by bicycle and by other modes of transport involving physical activity (they should consider providing safe cycling routes and secure parking facilities for bikes)\n\nprovide for physical activities in safe locations that are accessible locally either on foot or via public transport\n\nencourage people to be physically active inside buildings, for example, by using the internal infrastructure of buildings to encourage people to take the stairs rather than the lift (also see NICE's guideline on physical activity and the environment).\n\n\n\nEnable and encourage people to achieve the national recommended levels of physical activity by including activities such as walking, cycling or climbing stairs as part of their everyday life.\n\nAssess the type of physical activity opportunities needed locally and at what times and where. Consider social norms, family practices and any fears people may have about the safety of areas where physical activities take place (this includes fears about how safe it is to travel there and back).\n\nMap physical activity opportunities against local needs and address any gaps in provision.\n\nEnsure commissioned leisure services are affordable and acceptable to those at high risk of developing type\xa02 diabetes. This means providing affordable childcare facilities. It also means public transport links should be affordable and the environment should be culturally acceptable. For example, local authorities should consider the appropriateness of any videos and music played. They should also consider providing single-gender facilities, exercise classes, swimming sessions and walking groups – for both men and women.\n\nProvide information on local, affordable, practical and culturally acceptable opportunities to be more active. If cultural issues affect people's ability to participate, work with them to identify activities which may be acceptable. (This may include, for example, single-gender exercise and dance classes, or swimming sessions with same-gender lifeguards.)\n\nEncourage local employers to develop policies to encourage employees to be more physically active, for example, by using healthier modes of transport to and from work. Walking and cycling can be encouraged by providing showers and secure cycle parking. Signposting and improved decor could encourage employees to use the stairs rather than the lift. In addition, people could be encouraged to be active in lunch breaks and at other times through organised walks and subsidies for local leisure facilities Flexible working policies and incentives that promote physical activity in the workplace should be considered. (This is an extract from NICE's guidelines on obesity and promoting physical activity in the workplace; see the latter for further guidance on developing programmes and policies to encourage and support employees to be more physically active).\n\nEnsure the basic training for professional fitness instructors covers: the role of physical activity in improving people's health, how to get marginalised groups involved and cultural issues that may prevent them from participating.\n\n# Recommendation 11 Training those involved in promoting healthy lifestyles\n\n## Who should take action?\n\nCommissioners and providers of national and local public health services in partnership with:\n\nroyal colleges and professional associations, further and higher education training institutions, and other organisations responsible for competencies and continuing professional development programmes for health professionals\n\nother local authority departments including education and leisure services\n\nvoluntary sector, not-for-profit and non-governmental practitioners\n\nthe commercial sector.\n\n## What action should they take?\n\nEnsure training programmes for those responsible for, or involved in, promoting a healthy lifestyle cover:\n\n\n\ndiversity, including cultural, religious and economic issues, delivering health promotion interventions in a non-judgemental way, and meeting age, gender, language and literacy needs\n\nhow to identify communities at increased risk of developing type\xa02 diabetes\n\nstrategies for changing behaviour (for those devising health promotion interventions)\n\nhow to provide advice on healthy eating, physical activity and weight management in relation to the prevention of type\xa02 diabetes and related non-communicable diseases\n\nhow to challenge stigma and dispel myths around type\xa02 diabetes.\n\n\n\nEnsure those responsible for, or involved in, promoting healthy lifestyle choices are given time and support to develop and maintain the skills described above.\n\nMonitor health professionals' knowledge and awareness of how to encourage people to adopt a healthy lifestyle. Use, for example, personal development plans and annual reviews. Ensure they keep their knowledge and practical skills up to date.\n\nEnsure training programmes for all health professionals (including undergraduate, continuing professional development and, where appropriate, post-graduate training):\n\n\n\nincorporate the knowledge and skills needed to ensure health promotion interventions are culturally sensitive\n\ncover nutrition, physical activity and weight management in relation to the prevention of type\xa02 diabetes\n\nare focused, structured and based on proven models and evaluation techniques\n\noffer opportunities to practice new skills in the community\n\nencourage the sharing of knowledge among colleagues\n\nprovide up-to-date information on topics such as nutrition advice and physical activity (information should be updated regularly).\n\n", 'Public health need and practice': "# Overview\n\nOn average, 100,000 people in the UK are diagnosed with diabetes every year, but in 2009 this figure reached 150,000. Many more are unaware that they have the condition (Diabetes UK 2006). It can lead to long-term complications including eye problems, kidney disease, foot ulcers and cardiovascular disease. On average at age 55, the life expectancy of people with type\xa02 diabetes is 5 to 7 years less than for the general population (DH 2006).\n\nIn addition to the personal cost to individuals, families and communities, diabetes is estimated to account for at least 5% of UK healthcare expenditure. For example, up to 10% of hospital budgets are spent on the condition – it is estimated that drug costs alone for people with type\xa02 diabetes account for about 7% of the total NHS drugs budget (Waugh et al. 2007).\n\nIn 2007, 60% of primary care trusts (PCTs) reported that programmes were in place to raise public awareness of the risk factors for type\xa02 diabetes – and 37% were raising awareness of its signs and symptoms. However, only 42% had assessed the needs of their population in relation to type\xa02 diabetes – and less than 40% had developed a type\xa02 diabetes strategy (Innove 2008).\n\n# Risk factors for type\xa02 diabetes\n\nIndividual risk factors for type\xa02 diabetes include:\n\nweight (a body mass index [BMI] of 25kg/m2 or more)\n\na large waist circumference (more than 80 cm or 31.5\xa0inches in women and 94\xa0cm or 37\xa0inches in men)\n\nlow physical activity levels\n\na family history of type\xa02 diabetes,\n\na history of gestational diabetes\n\nage (being older than 40 or older than 25 for some black and minority ethnic groups).\n\nIn addition, people from the following communities are particularly at risk: those of South Asian, African-Caribbean, black African and Chinese descent and those from lower socioeconomic groups.\n\nThe more risk factors someone has, the more likely they are to develop diabetes (Harding et al. 2006).\n\n# Vulnerable groups\n\nPeople of South Asian family origin living in the UK are up to six times more likely to have type\xa02 diabetes than the white population (DH 2001). They are also likely to develop type\xa02 diabetes 10 years earlier (Nicholl et al. 1986). People of African and African-Caribbean descent are three times more likely to have type\xa02 diabetes than the white population. Type\xa02 diabetes is also more common among Chinese and other non-white groups than among white European populations (DH 2001).\n\nThe higher risk for South Asian people living in the UK is at least partly due to the fact that they may accumulate significantly more 'metabolically active' fat in the abdomen and around the waist than white European populations. (This is true even for those with a BMI in the 'healthy' range – that is, 18.5–24.9\xa0kg/m2.) 'Metabolically active' fat is closely associated with insulin resistance, pre-diabetes and type\xa02 diabetes (McKeigue et al. 1991; 1992; 1993; Banerji et al. 1999).\n\nMinority ethnic groups are less likely to participate in at least moderate-intensity physical activity (for 30 minutes continuously a week) than the general population. For example Bangladeshi men and women have the lowest levels of participation in physical activity when standardised for age (The NHS Information Centre 2006). Black Caribbean men are the only subgroup of an ethnic minority population that are not less physically active than the general population in England (The NHS Information Centre 2006).\n\nIn England, type\xa02 diabetes is 40% more common among those who are in social class V (people who are most socioeconomically deprived) compared with those in social class I (The NHS Information Centre 2010). In addition, people in social class V are three and a half times more likely than those in social class I to be ill as a result of diabetic complications (DH 2002).\n\nPeople in social class V are also more likely to be obese than those in higher social classes. In 2004, 18% of men in social class I were obese compared to 28% in social class V. Similarly, 10% of women in social class I were obese compared with 25% of women in social class V (Foresight 2007).\n\nIn addition, there is also a clear link between physical activity and income level. For example, those on the lowest income are less likely to undertake more than 30\xa0minutes of at least moderate-intensity activity a week compared with higher income groups (The NHS Information Centre 2008b).\n\nThe 'Low income diet and nutrition survey' found that, overall, people on lower incomes ate similar types and quantities of food as the general population. However, they were less likely to eat wholemeal bread, wholegrain and high fibre breakfast cereals and vegetables. They were also more likely to drink non-diet soft drinks and eat more processed meats, whole milk and sugar (Nelson et al. 2007).\n\nThere is overlap between the high-risk groups, that is, those who are disadvantaged and some black and minority ethnic communities, as some of the latter are more likely to live in areas of social and economic deprivation (Barakat et al. 2001).\n\n# Tackling barriers to change\n\nPeople from lower socioeconomic groups and those from black and minority ethnic communities may face economic, social and cultural barriers which prevent them from being physically active and managing their weight. Barriers include, for example, lack of funds for a healthy diet or a lack of awareness and opportunity to take part in physical activities or weight management programmes that are culturally acceptable.", 'Considerations': "The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations.\n\n# Individual versus population approaches\n\nThe PDG considered three types of approach to reducing population and community risk of type\xa02 diabetes. These were:a) Individual: focusing on people identified as being at high risk of type\xa02 diabetes.b) High-risk population: identifying and targeting communities of people at high risk of type\xa02 diabetes.c) Total population: no assessment of risk or targeting of interventions.\n\nThe PDG noted that people from lower socioeconomic groups and from some black and minority ethnic communities are at higher risk of type\xa02 diabetes than the general population. This is due to a set of shared characteristics and behaviours or 'determinants'. Examples include: a higher than average level of overweight and obesity, a higher than average number of people eating a less healthy diet or participating in lower than average levels of physical activity. These groups and communities would collectively benefit from interventions that target the 'shared' risk factors. In addition, more people within these groups and communities (compared with the general population) would benefit from an assessment of their individual risk – and individual interventions to alleviate that risk.\n\nThis guidance aims to reduce the risk of type\xa02 diabetes among populations at particularly high risk. Overweight and obesity is the single biggest risk factor for type\xa02 diabetes. Since recent estimates (for example, the Foresight report ) suggest that more than half of adults may be obese by 2050, the PDG noted that some of the recommendations would also have a beneficial effect on a large proportion of the general population.\n\nThe national NHS Health Check programme identifies and treats individuals at high risk of developing vascular-related diseases including type\xa02 diabetes. The PDG noted that not all those who are identified as being at risk will choose to change their behaviour or act on the advice. NICE guidance to prevent the progression from pre-diabetes to type\xa02 diabetes will aim to provide commissioners and practitioners with advice on how they can support people identified as being at high risk through this or other initiatives.\n\nThe PDG was mindful that actions to improve the health of the population overall may widen health inequalities between different groups. For example, people from higher socioeconomic groups may be more ready (or able) to change their behaviour than those on a lower income. Therefore, to address health inequalities, it may be necessary to specifically target high-risk groups – even if this is not the most cost-effective option.\n\nAddressing the needs of high-risk communities involves working beyond geographical boundaries. A community is not necessarily a group of people living within a specific geographic location. It might, for example, involve people with shared values or a shared interest. In addition, although people may recognise themselves (and be recognised within a group) as belonging to that group or community, it may not be immediately obvious to 'outsiders'. This can make it difficult to identify and target some of those who may need help to prevent type\xa02 diabetes. This includes people who are homeless and those who have a disability or a long-term mental health problem. People who are unofficial migrants are another example.\n\nCase studies of ongoing work in the UK, backed up by expert testimony, demonstrated the importance of taking the target group's needs into account from the start. This includes ensuring that any cultural sensitivities are acknowledged.\n\n# Evidence\n\nTrials have shown (Gillies et al. 2007) that behavioural interventions help reduce the likelihood of type\xa02 diabetes developing among people with pre-diabetes. For example, the Finnish diabetes prevention study (Tuomilehto et al. 2001) showed that the risk of these individuals developing type\xa02 diabetes is reduced if they achieve one or more of the following:\n\nreduce their weight by more than 5%\n\nkeep their fat intake below 30% of energy intake\n\nkeep their saturated-fat intake below 10% of energy intake\n\neat 15\xa0g/1000\xa0kcal of fibre or more\n\nare physically active for at least 4\xa0hours per week. In addition, a population-based study (Simmons et al. 2006) found an inverse relationship between the number of these goals achieved and the risk of type\xa02 diabetes developing among the general population. Therefore, the PDG felt that interventions promoting these goals could significantly lower the risk of developing type\xa02 diabetes among people from lower socioeconomic communities and from black and minority ethnic groups.\n\nThe PDG considered systematic reviews of interventions to address the risk factors associated with type\xa02 diabetes, including high body mass index (BMI), high waist measurement, sedentary lifestyle or poor diet among high-risk groups. The group did not identify any evidence directly related to the prevention of 'pre-diabetes' among black and minority ethnic or lower socioeconomic groups in the UK. Overall, relevant UK-based intervention studies were scarce. Similarly, the evidence on behaviour change among minority ethnic communities was very limited. The data available tended to be based on self-reported measures related to participants' perceptions of the barriers and facilitators to behaviour change. It was not clear whether or not addressing the stated barriers and introducing facilitators would actually result in positive change.\n\nThere was no evidence of effectiveness on UK interventions aiming to raise health professionals' awareness of the risk factors for type\xa02 diabetes or to help them identify groups at high risk. Evidence on the effectiveness of interventions delivered by health professionals and lay workers (such as health trainers) was also lacking.\n\nThe potential effect of any intervention may vary according to the risk someone faces of developing type\xa02 diabetes. However, evidence was not available to assess this theory in practice.\n\nWhile demonstrating promising results, most of the UK-based community projects considered by the PDG had limited reach. The group felt that they were neither large nor sustainable enough and that they would benefit from being based on established community networks. Staff training for such interventions was another issue.\n\nThe PDG developed recommendations through inductive and deductive reasoning, based on the evidence presented in the systematic reviews, expert testimony and its members' knowledge, understanding and experience of the topic area. Due to the scarcity of evidence available, the PDG also drew on existing NICE guidance on: behaviour change, community engagement, obesity, physical activity and cardiovascular disease.\n\nThe economic analysis for this work is based on a range of assumptions. The observed effect sizes for individuals, while important, are small and the confidence intervals are large. Most of the interventions considered are estimated to be cost effective (and usually very cost effective). (This assumes that the estimated effect sizes have been used to make the calculation.) The PDG recognised that the bulk of these effects were generally observed only after a number of years.\n\n# Cost effectiveness\n\nEconomic modelling showed that weight-loss programmes in black and minority ethnic and Asian populations in England that cost £100 per head and yielded an average weight loss of at least 1\xa0kg were cost effective at a cost per quality-adjusted life year (QALY) threshold of £20,000. Interventions that could produce an average weight loss of 3 to 4\xa0kg would be cost-saving.\n\nAn intervention programme applied at the population level that resulted in an average weight of loss of 0.25\xa0kg, would be cost effective at the £20,000 threshold if the cost per head of the intervention was £10. A number of the interventions reported in the literature had a per capita intervention cost of this magnitude. The PDG agreed that this analysis justified the recommendation to balance individual-level interventions of large effect aimed at high-risk individuals with cheaper interventions of small effect to individuals that could be cost effective when applied across whole populations.\n\n# Existing NICE guidance\n\nThe PDG recognised that a number of existing activities and programmes aim to help people change their behaviour to prevent a range of diseases and conditions. It acknowledged that these activities and programmes could also help prevent type\xa02 diabetes and that many have been the focus of earlier NICE guidance. Similarly, the recommendations outlined in this guidance may have an impact on a range of other health conditions (including for example, cardiovascular disease, some common cancers, respiratory diseases and mental wellbeing).\n\nThere are many reasons why people who are socially and/or economically disadvantaged can find it more difficult than others to change their behaviour (Swann et al. 2009). The recommendations in this guidance draw on NICE's guideline on behaviour change: general approaches in an attempt to address this inequality. The aim is to create a local environment which encourages people in disadvantaged groups to make change.\n\nThe PDG noted the recommendations made in NICE's guideline on obesity. These focus on a range of effective, community-based programmes and stress the importance of ensuring interventions are tailored, long term and address both diet and physical activity. The guideline also outlines strategies for improving diet and increasing physical activity to help prevent obesity and minimise excess weight gain.\n\nThe PDG discussed the links between sedentary behaviour and type\xa02 diabetes – and the need to encourage people to be more physically active. It was aware of evidence to suggest that a sedentary lifestyle may play a more important role than diet in the higher prevalence of type\xa02 diabetes among black and minority ethnic groups. NICE has published a range of guidance to help the whole population be physically active. The recommendations in this guidance attempt to address specific barriers to physical activity which might face populations at high risk of developing type\xa02 diabetes. However, more research is needed into how to increase physical activity levels among these groups.\n\nThe PDG recognised that the success of interventions can depend on identifying local 'key players' and 'champions' and it looked to recommendations made in NICE's 2008 guideline on community engagement. It noted that, although some community leaders may be able to promote or help deliver type\xa02 diabetes prevention programmes, not all of them will be willing or able to do so – nor would it always be appropriate.\n\n# Issues outside the scope\n\nThe PDG acknowledged the need to consider risk factors and vulnerability at all stages of the life course. In particular, it recognised that maternal and early infant nutrition may be important in the prevention of non-communicable diseases such as type\xa02 diabetes. Interventions aimed at children are also likely to be crucial in reducing the prevalence of type\xa02 diabetes in the longer term. For example, preventing gestational diabetes and delaying the onset of type\xa02 diabetes until after childbearing age would reduce the risk of a child getting type\xa02 diabetes later in life. These issues were beyond the remit of this guidance. However, they are addressed in other NICE guidance.\n\nThe PDG were mindful that while the scope for this guidance was adults in high-risk groups, many interventions are delivered in a family setting and these will have benefits for all family members not just adults.\n\nThe upper age cut-off point for this guidance (74 years) reflects the age limit of the national NHS Health Check programme. This programme assesses the risk of heart disease, stroke, kidney disease and type\xa02 diabetes among all adults aged 40–74. It aims to help them reduce or manage their risk by giving them individually tailored advice. (The second piece of guidance will consider interventions among high-risk individuals and groups.)\n\nThe PDG did not consider evidence on how specific nutrients or types of diet may reduce the risk of type\xa02 diabetes, as this falls under the remit of the Scientific Advisory Committee on Nutrition (SACN). As such, it was outside the scope of this guidance. However, the Group supports existing recommendations on healthy eating, as advocated in the 'Eat well' plate (Food Standards Agency 2007).\n\nThe PDG was aware of a range of factors that need to be tackled at national and international level to help high-risk groups adopt behaviours that minimise the risk of type\xa02 diabetes. This includes issues that could be tackled by the food industry, such as the fat content of foods, food labelling, advertising and costs. It also includes issues in relation to the built environment, such as the impact of planning decisions on physical activity levels. The PDG wholeheartedly supported existing NICE recommendations which aim to tackle these issues. It was also mindful that disadvantaged groups may be disproportionately affected and that, as such, any solutions should consider the potential impact on these groups.", 'Recommendations for research': "The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful/negative side effects.\n\nHow effective and cost effective are interventions which use either a 'total population' or 'high-risk population' approach to preventing type\xa02 diabetes among people from black and minority ethnic or lower socioeconomic groups?\n\nWhat are the most effective and cost effective ways of developing, implementing and assessing tailored and culturally appropriate community-level interventions to prevent type\xa02 diabetes among people at high risk? This includes people from a range of black and minority ethnic groups and those from lower socioeconomic communities.\n\nWhich participatory approaches are most effective and cost effective among populations at higher risk of type\xa02 diabetes? This should consider the awareness, knowledge, understanding and skills of the providers of interventions for people at high risk of developing type\xa02 diabetes?\n\nHow do socioeconomic, environmental, biological and psychosocial factors determine diet and physical activity behaviours and how do they contribute to differences in the risk of developing type\xa02 diabetes?\n\nHow do financial factors (including incentives, pricing and taxation of food and incentives, and pricing for physical activity opportunities) affect food and physical activity choices?\n\nMore detail on the gaps in the evidence identified during development of this guidance is provided in appendix D.", 'Glossary ': "# Body mass index\n\nBody mass index (BMI) is commonly used to measure whether or not adults are a healthy weight or underweight, overweight or obese. It is defined as the weight in kilograms divided by the square of the height in metres (kg/m2).\n\n# Community\n\nA group of people who have common characteristics. Communities can be defined by location, race, ethnicity, age, occupation, a shared interest (such as using the same service), a shared belief (such as religion or faith) or other common bonds. A community can also be defined as a group of individuals living within the same geographical location (such as a hostel, a street, a ward, town or region).\n\n# Community champions\n\nCommunity champions are inspirational figures, community entrepreneurs, mentors or leaders who 'champion' the priorities and needs of their communities and help them build on their existing skills. They drive forward community activities and pass on their expertise to others. They also provide support, for example, through mentoring, helping people to get appropriate training and by helping to manage small projects.\n\n# Diabetes\n\nDiabetes is caused when there is too much glucose in the blood and the body cannot use it as 'fuel' because the pancreas does not produce any or sufficient insulin to help it to enter the body's cells. Alternatively, the problems may be caused because the insulin produced may not work properly ('insulin resistance'). Also see 'glucose' and 'insulin'.\n\n# Fasting glucose sample\n\nGlucose sample taken after a person has refrained from eating or drinking any liquids other than water for 8\xa0hours.\n\n# Glucose\n\nGlucose comes from digesting carbohydrate and is also produced by the liver. Carbohydrate comes from many different kinds of food and drink, including starchy foods such as bread, potatoes and chapatis; fruit; some dairy products; sugar and other sweet foods (Diabetes UK 2010).\n\n# HbA1c\n\nGlycated haemoglobin (HbA1c) forms when red cells are exposed to glucose in the plasma. The HbA1c test reflects average plasma glucose over the previous eight to 12 weeks. Unlike the oral glucose tolerance test, an HbA1c test can be performed at any time of the day and does not require any special preparation such as fasting.\n\nHbA1c is a continuous risk factor for type\xa02 diabetes. This means there is no fixed point when people are or are not at risk. The World Health Organization recommends a level of 6.5% (48\xa0mmol/mol) for HbA1c as the cut-off point for diagnosing type\xa02 diabetes in non-pregnant adults.\n\n# Impaired glucose tolerance\n\nSee definition below of 'pre-diabetes'.\n\n# Insulin\n\nInsulin is the hormone produced by the pancreas that allows glucose to enter the body's cells, where it is used as fuel for energy. It is vital for life (Diabetes UK 2010).\n\n# Lay or community workers\n\nPeople recruited from the local community or subgroup of the population to assist in the delivery of an intervention to a group of people who they identify with and are knowledgeable about. They might be peers or from the wider community but they are not professional health or public health workers.\n\n# Oral glucose tolerance test\n\nAn oral glucose tolerance test involves measuring the blood glucose level after fasting, and then 2 hours after drinking a standard 75\xa0g glucose drink. Fasting is defined as no calorie intake for at least 8 hours. More than one test on separate days is required for diagnosis in the absence of hyperglycaemic symptoms.\n\n# Physical activity\n\nThe full range of human movement, from competitive sport and exercise to active hobbies, walking, cycling and the other physical activities involved in daily living.\n\n# Pre-diabetes\n\nWhere used in this guidance, the term pre-diabetes refers to raised (but not diabetic) blood glucose levels (also known as non-diabetic hyperglycaemia, impaired glucose regulation). It indicates the presence of impaired fasting glucose and/or impaired glucose tolerance. People with pre-diabetes are at increased risk of getting type\xa02 diabetes. They are also at increased risk of a range of other conditions including cardiovascular disease.\n\n# Socioeconomic group\n\nA person's socioeconomic group is defined by a combination of their occupation, income level and education level. There is a strong relationship between socioeconomic group and health, with people from lower socioeconomic groups generally experiencing poorer health than those from higher socioeconomic groups.\n\n# Type\xa02 diabetes\n\nType\xa02 diabetes (previously termed non-insulin dependent diabetes)\xa0results from reduced tissue sensitivity to insulin (insulin resistance) and/or reduced insulin production.", 'References': "Banerji MA, Faridi N, Atluri R et al. (1999) Body composition, visceral fat leptin and insulin resistance in Asian Indian men. Journal of Clinical Endocrinology and Metabolism 84: 137–44\n\nBarakat K, Stevenson S, Wilkinson P et al. (2001) Socio-economic differentials in recurrent ischaemia and mortality after acute myocardial infarction. Heart 85: 390–4\n\nDepartment of Health (2001) Modern standards and service models – diabetes: national service framework standards. London: Department of Health\n\nDepartment of Health (2002) National service framework for diabetes: standards – supplementary information. Health inequalities in diabetes. London: Department of Health\n\nDepartment of Health (2006) Turning the corner: improving diabetes care. London: Department of Health\n\nDiabetes UK (2006) Diabetes and the disadvantaged: reducing health inequalities in the UK. A report by the All Party Parliamentary Group for Diabetes and Diabetes UK\n\nDiabetes UK (2010) Guide to diabetes: what is diabetes?\n\nFood Standards Agency (2007) Eatwell plate.\n\nForesight (2007) Tackling obesities: future choices – project report. London: Government Office for Science\n\nForouhi NG, Luan J, Hennings S et al. (2007) Incidence of type\xa02 diabetes in England and its association with baseline impaired fasting glucose: The Ely study 1990–2000. Diabetic Medicine 24: 200–7\n\nGillies CL, Abrams KR, Lambert PC et al. (2007) Pharmacological and lifestyle interventions to prevent or delay type\xa02 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis. BMJ 334: 299–307\n\nGoodyear LJ, Khan BB (1998) Exercise, glucose transport, and insulin sensitivity. Annual Review of Medicine 49: 235–61\n\nHarding A, Griffin SJ, Wareham NJ (2006) Population impact of strategies for identifying groups at high risk of type\xa02 diabetes. Preventative Medicine 42 (5): 364–8\n\nHawthorne K, Robles Y, Cannings-John R et al. (2010) Culturally appropriate health education for type\xa02 diabetes in ethnic minority groups: a systematic and narrative review of randomised controlled trials. Diabetic Medicine 27: 613–23\n\nInnove (2008) Delivering performance improvement. Findings from DiabetesE third national report.\n\nKhan BB, Flier JS (2000) Obesity and insulin resistance. The Journal of Clinical Investigation 106: 473–81\n\nMcKeigue PM, Shah B, Marmot MG (1991) Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians. Lancet 337: 382–6\n\nMcKeigue PM, Pierpont T, Ferne JM et al. (1992) Relationship of glucose intolerance and body fat pattern in South Asians and Europeans. Diabetologia 35: 785–91\n\nMcKeigue PM, Ferne JE, Pierpont T et al. (1993) Association of early onset coronary heart disease in South Asian men with glucose intolerance and hyperinsulinaemia. Circulation 87: 152–61\n\nNelson M, Erens B, Bates B et al. (2007) Low income diet and nutrition survey. London: The Stationery Office\n\nNicholl CG, Levy JC, Mohan V et al. (1986) Asian diabetes in Britain: a clinical profile. Diabetic Medicine 3: 257–60\n\nPeel E, Parry O, Douglas M et al. (2004) Diagnosis of type\xa02 diabetes: a qualitative analysis of patients' emotional reactions and views about information provision. Patient Education and Counselling 53 (3): 269–75\n\nSimmons RK, Harding AH, Jakes RW et al. (2006) How much might achievement of diabetes prevention behaviour goals reduce the incidence of diabetes if implemented at the population level? Diabetologia 49 (5): 905–11\n\nSouth Asian Health Foundation (2004) The epidemic of coronary heart disease in South Asians. Birmingham: South Asian Health Foundation\n\nSwann C, Owen L, Carmona C et al. (2009) A nudge in the right direction: developing guidance on changing behaviour. In Killoran A, Kelly MP (editors). Evidence-based public health: effectiveness and efficiency. Oxford: Oxford University Press\n\nThe NHS Information Centre (2006) Health survey for England 2004. Volume 1: the health of minority ethnic groups. Leeds: The NHS Information Centre\n\nThe NHS Information Centre (2008a). Health survey for England 2006. Volume 1: cardiovascular risk factors in adults. Leeds: The NHS Information Centre\n\nThe NHS Information Centre (2008b) Health survey for England 2006: Cardiovascular disease and risk factors: summary of the key findings. Leeds: The NHS Information Centre\n\nThe NHS Information Centre (2009) The Health survey for England 2008. Volume 1: physical activity and fitness. Leeds: The NHS Information Centre\n\nThe NHS Information Centre (2010) National diabetes audit: executive summary 2008–2009.\n\nTuomilehto J, Lindstrom J, Eriksson JG et al. (2001) Prevention of type\xa02 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. New England Journal of Medicine 344: 1343–50\n\nWaugh N, Scotland G, McNamee P et al. (2007) Screening for type\xa02 diabetes literature review and economic modelling. Health technology assessment 11: 17.\n\nWorld Health Organization (2006) Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation.\n\nWorld Health Organization (2010) Cancer: diet and physical activity's impact [online].\n\nWorld Health Organization (2011) Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus.", 'Appendix B: Summary of the methods used to develop this guidance': "# Introduction\n\nThe reviews, primary research, commissioned reports and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in appendix E.\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations.\n\nThe overarching question was:\n\nHow effective and cost effective are interventions to improve the modifiable risk factors associated with pre-diabetes among black and minority ethnic groups and among lower socioeconomic groups?\n\nThe subsidiary questions were:\n\nWhat are the most effective and cost-effective methods of raising health professionals' awareness of the groups at high risk of pre-diabetes?\n\nWhat are the most effective and cost-effective methods of identifying communities, groups and individuals at high risk of pre-diabetes?\n\nWhat are the most effective and cost-effective population-level interventions to prevent pre-diabetes?\n\nWhat are the most effective and cost effective-ways of raising awareness of how to prevent pre-diabetes among high-risk groups?\n\nWhat are the most effective and cost-effective ways of ensuring interventions are culturally sensitive and appropriate for use with communities at high risk of pre-diabetes?\n\nWhat factors might discourage individuals, groups and communities at high risk of pre-diabetes from getting involved with preventive interventions? How might these barriers be addressed?\n\nWhat are the most effective and cost-effective methods of helping people at high risk of pre-diabetes to improve their diet, be more physically active and manage their weight?\n\nThese questions were made more specific for each of the reviews (see reviews for further details).\n\n# Reviewing the evidence\n\n## Effectiveness reviews\n\nFour reviews of effectiveness were conducted (reviews 1, 2, 3 and 5).\n\nThe evidence reviews for this guideline list the databases searched for each review. However, the general approach is outlined below.\n\nThe following databases were searched for reviews 1, 2 and 3 (from 1990 onwards):\n\nBritish Nursing Index\n\nCumulative Index to Nursing and Allied Health Literature (CINAHL)\n\nCochrane Library\n\nEMBASE\n\nEvidence for Policy and Practice Information and Co-ordinating Centre Databases (EPPI Centre Databases)\n\nMEDLINE\n\nPsycINFO\n\nScience Citation Index\n\nSocial Science Citation Index.\n\nAdditional searches of the grey literature were carried out and the following websites were also searched:\n\nAssociation of Public Health Observatories\n\nDiabetes UK\n\nJoseph Rowntree Foundation\n\nNHS Evidence\n\nThe following databases were searched for review 5 (from 1999 onwards):\n\nApplied Social Sciences Index and Abstracts (ASSIA)\n\nCochrane Database of Systematic Reviews\n\nCumulative Index to Nursing and Allied Health Literature (CINAHL)\n\nDatabase of Abstracts of Reviews of Effectiveness (DARE)\n\nDatabase of Promoting Health Effectiveness Reviews (DoPHER)\n\nEducation Resources Information Centre (ERIC)\n\nEMBASE\n\nHealth Management Information Consortium (HMIC)\n\nHTA database (in the Cochrane Library)\n\nMEDLINE\n\nPsycINFO\n\nSocial Policy and Practice.\n\n## Other reviews\n\nTwo separate sets of research were conducted to identify and describe community-level interventions to prevent type\xa02 diabetes (reviews 4 and 6).\n\nReview 4 studied the search results from reviews 1 to 3. It also assessed grey literature identified via Google, the Internet search engine and via selected primary care trust (PCT) websites.\n\nReview 6 involved searching the Internet and other networks used by managers and commissioners of community-level interventions to prevent type\xa02 diabetes. In addition, a referral questionnaire was sent to individuals or groups identified during the searches.\n\n## Selection criteria\n\nThe evidence reviews for this guideline list the inclusion and exclusion criteria for each review. Details can be found within each review. However, in general, the following applied.\n\nStudies were included in reviews 1 to 3 if they were published since 1990 and:\n\ncovered people at high risk of pre-diabetes\n\nincluded interventions to prevent pre-diabetes\n\nIncluded interventions to help professionals support people at high risk of developing pre-diabetes\n\nwere conducted in the UK.\n\nStudies were excluded if they focused on:\n\npeople diagnosed with pre-diabetes (impaired fasting glucose/impaired glucose tolerance) or diabetes\n\npregnant women, people younger than 18 or older than 74\n\npeople taking medication that increases the risk of developing type\xa02 diabetes\n\npopulation-level screening\n\ndiagnostic testing (such as clinical tests to identify pre-diabetes)\n\ndiabetes risk assessment tools using, for example, body mass index (BMI) and waist circumference.\n\nStudies were included in review 5 if they were reviews published in 1999 or later and covered:\n\nblack and minority ethnic populations and groups from a low socioeconomic background in the UK, any other EU country, the USA, Canada, Australia or New Zealand\n\na 'general' population (but only if the ethnicity and socioeconomic status of those included in the primary studies was systematically presented)\n\npeople clinically diagnosed with pre-diabetes or obesity\n\ninterventions in a range of settings to prevent pre-diabetes or type\xa02 diabetes (or relevant risk factors), including those aimed at reducing or preventing obesity, promoting physical activity or reducing calorie intake\n\nthe measurement of any relevant outcome such as physical activity or dietary behaviour.\n\nStudies were excluded if they:\n\nfocused on those aged 0–17 years\n\nfocused on minority ethnic groups not relevant to the UK (for example, American Indians or Australian Aboriginals)\n\ncovered people who were clinically diagnosed with type\xa02 diabetes\n\nprimarily focused on pharmacological, surgical or individual interventions (such as counselling)\n\ndid not aim to change any of the key risk factors for pre-diabetes and type\xa02 diabetes\n\nwere delivered in healthcare settings\n\nwere not published in English.\n\nBroadly, interventions were included in review 4 if they:\n\ncovered activities to improve diet, increase physical activity levels or raise awareness of the risk factors for pre-diabetes\n\ntargeted adults from low socioeconomic backgrounds or from black and minority ethnic groups in the UK.\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.\n\nStudy quality\n\n++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.\n\n+ Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.\n\n– Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\n\nThe evidence was also assessed for its applicability to the areas (populations, settings, interventions) covered by the scope of the guidance. Each evidence statement concludes with a statement of applicability (directly applicable, partially applicable, not applicable).\n\n## Summarising the evidence and making evidence statements\n\nThe review data was summarised in evidence tables (see full reviews).\n\nThe findings from the reviews and expert reports were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors and public health collaborating centres. The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.\n\n# Cost effectiveness\n\nThere was a review of economic evaluations and an economic modelling exercise.\n\n## Review of economic evaluations\n\nStudies were identified through the effectiveness review search strategies. The following databases were searched:\n\nEconLit\n\nNHS Economic Evaluation Database\n\nPublic Health Interventions Cost Effectiveness Database (PHICED) (obesity and physical activity).\n\nPrevious NICE guidance on obesity and physical activity was also reviewed, as was the FORESIGHT modelling work. In addition, citation searching and reference tracking was also undertaken. The database searches followed the same inclusion and exclusion criteria as were used in the associated mapping review.\n\n## Economic modelling\n\nA number of assumptions were made which could underestimate or overestimate the cost effectiveness of the interventions (see review modelling report for further details).\n\nAn economic model was constructed to incorporate data from the reviews of effectiveness and cost effectiveness. The results of the economic model are reported in: 'Prevention of type\xa02 diabetes: preventing pre-diabetes among adults in high-risk groups. Report on cost-effectiveness evidence and methods for economic modelling'.\n\n# Fieldwork\n\nFieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with practitioners and commissioners who are involved in the prevention of pre-diabetes among adults in high-risk groups, including those working in the NHS, local government, voluntary sector and private sector.\n\nThe fieldwork comprised:\n\ntwo focus groups carried out nationally\n\ntelephone interviews\n\nan online survey.\n\nThe main issues arising from this report are set out in the fieldwork findings section of appendix C.\n\nThe fieldwork was carried out by Word of Mouth Research Ltd.\n\n# How the PDG formulated the recommendations\n\nAt its meetings during December 2009 to February 2011, the Programme Development Group (PDG) considered the evidence, expert reports and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of strength and applicability) to form a judgement\n\nwhere relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive\n\nwhere relevant, the typical size of effect (where there is one)\n\nwhether the evidence is applicable to the target groups and context covered by the guidance.\n\nThe PDG developed draft recommendations through informal consensus, based on the following criteria:\n\nStrength (type, quality, quantity and consistency) of the evidence.\n\nThe applicability of the evidence to the populations/settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nEquality and diversity legislation.\n\nEthical issues and social value judgements.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of harms and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nWhere possible, recommendations were linked to evidence statements (see appendix C). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).\n\nThe draft guidance, including the recommendations, was released for consultation in November 2010. At its meeting in February 2011, the PDG amended the guidance in light of comments from stakeholders and experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in April 2011.", 'Appendix C: The evidence ': "This appendix lists the evidence statements from six reviews provided by the public health collaborating centre and links them to the relevant recommendations. (See appendix B for the key to quality assessments.) The evidence statements are presented here without references – these can be found in the full review (see appendix E). It also lists eight expert papers and their links to the recommendations and sets out a brief summary of findings from the economic analysis.\n\nThe six reviews of effectiveness are:\n\nReview 1: 'Prevention of type\xa02 diabetes: interventions to reduce risk factors for pre-diabetes among UK adults from a lower socioeconomic group'\n\nReview 2: 'Prevention of type\xa02 diabetes: interventions to reduce risk factors for pre-diabetes among UK adults from black and minority ethnic groups'\n\nReview 3: 'Prevention of type\xa02 diabetes: interventions to raise awareness in health professionals and assist identification of high-risk groups'\n\nReview 4: 'Interventions for the prevention of pre-diabetes in high-risk groups: examples of current practice in relation to the UK evidence base'\n\nReview 5: 'Review of review-level evidence to inform the development of NICE public health guidance for the prevention of pre-diabetes among adults in high-risk groups'\n\nReview 6: 'Identification of effective community projects focused on addressing risk factors for the development of pre-diabetes in adults from black and minority ethnic groups and lower socio-economic groups'.\n\nEvidence statement number 1.1a indicates that the linked statement is numbered 1a in review 1. Evidence statement number 3.1 indicates that the linked statement is numbered 1 in review 3. EP1 indicates that expert paper 1 is linked to the recommendation.\n\nThe reviews, expert reports and economic analysis are available. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nWhere the Programme Development Group (PDG) has considered other evidence, it is linked to the appropriate recommendation below. It is also listed in the additional evidence section of this appendix.\n\nRecommendation 1: additional evidence NICE (2007); IDE\n\nRecommendation 2: evidence statements 1.21a, 1.21b, 1.29, 2.5; EP9, EP10, EP13\n\nRecommendation 3: evidence statements 1.21b, 1.29, 2.7b, 3.2, 3.6, 3.8; EP13\n\nRecommendation 4: evidence statements 1.5, 1.21a, 1.21b, 1.21c, 1.22, 2.3, 2.9a, 3.6, 3.7, 3.8; EP8, EP9, EP10; additional evidence NICE (2006), (2008a); IDE\n\nRecommendation 5: evidence statements 1.21a, 1.21d, 1.25, 2.4, 2.5, 2.6, 2.7a, 2.7b, 2.7c, 2.10, 3.7, 3.8; EP6, EP8, EP9, EP10\n\nRecommendation 6: evidence statements 1.21a, 1.21d, 1.25, 2.4, 2.5, 2.6, 2.7a, 2.7b, 2.7c, 2.10, 3.7, 3.8; EP6, EP8, EP9, EP10\n\nRecommendation 7: evidence statements 1.21b; EP7, EP8, EP11, EP12, EP14, EP15; IDE\n\nRecommendation 8: evidence statements 1.5, 1.7, 1.21b, 1.22, 1.28, 1.29, 2.8; EP8, EP10, EP15; additional evidence NICE (2006); IDE\n\nRecommendation 9: evidence statements 1.27, 2.5, 2.7b, 2.9b; EP13; additional evidence NICE (2008b)\n\nRecommendation 10: evidence statements 1.21b, 1.21d, 1.27, 1.28, 1.29, 2.3, 2.4, 2.8, 2.9b EP8, EP15; additional evidence NICE (2006), (2008b), (2008c)\n\nRecommendation 11: evidence statements 3.2, 3.3, 3.4; EP5\n\n# Evidence statements\n\nPlease note that the wording of some evidence statements has been altered slightly from those in the evidence review(s) to make them more consistent with each other and NICE's standard house style.\n\n## Evidence statement 1.5\n\nEvidence of mixed effectiveness was found in relation to nutrition knowledge. One poor quality case series (-) found that a 10-week programme focused on translating dietary recommendations into practice, including guided hands-on food preparation, led to an increase in nutrition knowledge in two of the four intervention groups studied. No significant increase in nutrition knowledge was found in the other two groups.\n\n## Evidence statement 1.7\n\nEvidence of mixed effectiveness was found in relation to fruit and vegetable intake. One reasonable quality prospective cohort study (+) found an overall increase in overall average fruit and vegetable consumption in both the community where a new food hypermarket had opened and the comparison community with no new hypermarket over 12\xa0months. There was however no significant change in either groups in average fruit consumption, and an increase in only the comparison community in vegetable consumption. One poor quality case series (-) examining the impact of the introduction of a new large-scale food retail outlet over a 1-year period found an increase in fruit and vegetable consumption among those who switched to the new store, but not among those who did not. Among both switchers and non-switchers, those with low pre-intervention levels significantly increased their fruit and vegetable consumption.\n\n## Evidence statement 1.21a\n\nThere is evidence that information is more accessible and interventions more acceptable where key workers possess the appropriate knowledge, skills and personal attributes, such as empathy and trustworthiness.\n\nOne (+) evaluation found that trained lay workers were able to access and raise awareness in hard-to-reach groups through their knowledge of the community in which they were working, and their personal communication skills. Attributes of workers were found to be influential in three (all [+]) evaluations on the success of interventions. Other (four [+]) evaluations found that the skills of an intervention adviser facilitated the feeling of empowerment among participants, and that skills were learned through engaging the interest of the participants. As well as disseminating information in a meaningful way.\n\n## Evidence statement 1.21b\n\nThree (all [+]) evaluations of included intervention studies found evidence that acceptability is increased when practical demonstrations make abstract concepts and scientific language more meaningful, and when progressive small steps are taken in terms of behaviour change.\n\nTwo (both [+]) evaluations reported suggestions made by participants that might increase acceptability. These were: the development of women-only classes and more activities at weekends to fit in with other commitments; free sessions, free childcare (especially in school holidays), free food, individual and group tailored recipes and useful enjoyable activities.\n\nIn one (+) evaluation there was evidence that male-only classes using creative ways to conceptualise weight management increased acceptability and motivation.\n\nOne exploratory study and one evaluation (both [+]) found that acceptability of a food educational intervention was increased by first exploring participants' needs in terms of topic content. Three evaluations (two [+] and one [++]) found that incentives such as access to free food increased motivation to participate in nutrition educational interventions. The experimental use of familiar and affordable food increased the acceptability of a food and health project.\n\nThere was evidence (one [+]) that interventions delivered by community members rather than health professionals tended to encourage community participation and meet local needs with an open and holistic agenda.\n\n## Evidence statement 1.21c\n\nThere is evidence that acceptability of interventions that aim to change behaviour is enhanced by the added value of social inclusion. Social interaction has a positive subjective effect on wellbeing as well as providing a shared forum for discussion of concerns.\n\nEvaluation of a healthy living centre (one [++]) found that social inclusion was stated as one aim of the intervention, while another randomised controlled trial (RCT) qualitative evaluation (+) found that interactive Internet portals increased social capital for people with shared health issues. Social interaction was a positive and facilitating factor for participation in four interventions (all [+]) aimed at increasing physical activity, and one aimed at improving eating behaviours. Positive social aspects of the interventions included an informal atmosphere, the opportunity to chat and discuss with other participants, as well as humour.\n\n## Evidence statement 1.21d\n\nThere is evidence that interventions aimed at raising awareness of healthy behaviours are more acceptable when they are made appropriate to the target audience and have a positive image.\n\nOne (++) qualitative study found that young women will be less motivated to participate in sporting activities if the image associated with those activities, for example the required clothing, is perceived as negative. Two process evaluations found that participants held negative associations with the term 'healthy eating'. The group in one (++) study associated the term with government policy and the other (+) study groupregarded healthy eating as boring and not filling.\n\n## Evidence statement 1.22\n\nThere was qualitative evidence from two (both [+]) multi-method evaluations of changes in participants' and their family's eating behaviour, and also of a developing interest in cooking as well as increased feelings of wellbeing. In one of these evaluations, the use of fat in cooking had reduced.\n\n## Evidence statement 1.25\n\nThere is evidence that adopting healthy lifestyle behaviours can be influenced by existing attitudes toward health. One (++) qualitative study found evidence of a range of attitudes from actively seeking to improve health prospects to a disinterest in health issues. Another (+) interview and focus group study found a perceived lack of control over weight. Two rationales for excess weight included a flawed metabolism and genetics, neither of which were perceived as subject to change. There was evidence from one (+) interview study that for the mothers in the study, the five-a-day message was perceived as impractical and a joke. One focus group study (+) found that lack of exercise was generally not emphasised as a health risk factor by male and female blue-collar workers. In another focus group study (+), women of lower educational attainment were not clear about the links between food and health, often equating weight with health, and believed it was not good to be 'too healthy', although the long-term health of their children was considered important and related to food. Another focus group study (+) found that some mothers deliberately sought out cheap and healthy foods, however others were less concerned about the healthiness of their family meals.\n\n## Evidence statement 1.27\n\nThere is evidence that adopting healthy lifestyle behaviours can be influenced by current lifestyle. Two evaluations (both [+]) and one (+) interview and focus group study found evidence that commitments and responsibilities were seen as a barrier to participation in physical activity. There was also evidence that for some, existing activity around the home is sufficient. Participants cited lack of time, particularly if employed in work or looking after children, as a barrier to physical activity. There was evidence from one (+) qualitative study that parents regard 'stress', 'comfort eating' 'being stuck in a rut' and 'embarrassment' as reasons for not carrying out sufficient physical activity. Health professionals interviewed in the same study discussed the prevalence of mental health issues such as depression in the area, and its impact on health behaviours.\n\n## Evidence statement 1.28\n\nThere is mixed evidence that affordability has an impact on lifestyle behaviour change. One (+) qualitative study found that costs limited the extent to which deprived mothers could buy healthy food. Another (+) qualitative study exploring the beliefs of those living in new deal communities (NDCs) found a perceived lack of affordable goods in the local area, with public transport costs also regarded as prohibitive. Affordability in two studies was only an issue where buying extra food, or organic food might be considered. One (+) evaluation and one (++) qualitative study found that cooking different meals to suit the preferences of family members was considered too expensive. In one (+) evaluation there was evidence that low-income groups were resistant to change because of financial risk. In one (+) interview study with low income consumers and health professionals, both stated that pricing strategies were not regarded as helpful in encouraging healthy eating. However, health professionals held the view that healthy foods could be prioritised over convenience foods when shopping. One focus group study (+) identified the cost of food as a barrier to healthy eating due to its cost in relation to other priorities, marketing strategies and special offers not being placed on healthier foods and the waste generated by buying food that did not get eaten. Similarly, another focus group study (+) found that mothers would choose less healthy but cheaper options when shopping and wasting money on food that their families would not eat was a consideration. Expense was also reported by men as a barrier to healthy eating in another focus group study (++), although the authors did not explore this in detail.\n\nThere is evidence (one [+] study) that affordability may be addressed by including budgeting as a topic in nutrition educational programmes. Evidence from one (+) interview study showed cost as a perceived barrier to physical activity in disadvantaged groups for both consumers and health professionals. Transport to – and use of – facilities were both perceived as costly. Physical activity referral schemes were suggested as one way of overcoming the cost of using facilities.\n\n## Evidence statement 1.29\n\nEvidence was found that environmental factors can be a barrier to improving nutrition. One (+) qualitative study found that a perceived lack of local amenities was a prohibiting factor in shopping for healthy foods. Access to food shopping was regarded as a barrier to healthy eating among women with lower educational attainment in one focus group study (+), in particular navigating round shops with pushchairs, coping with demanding children and bringing the shopping home on public transport and into high-rise flats. Evidence was also found that environmental factors can be a barrier to change in take-up of physical activity. One (++) qualitative evaluation found that fear of crime and feeling intimidated inhibited the motivation to participate in a new cycling initiative. One (+) qualitative study found that fear of attack prevented walking in certain areas. Another (+) evaluation showed that dark evenings and poor weather are barriers to physical exercise outdoors. One large-scale cross-sectional survey (+) found that active travel was associated with being younger, living in owner-occupied accommodation, travelling less than 4 miles to work, having access to a bicycle and not having access to a car, whereas overall physical activity was associated with living in social-rented accommodation and not being overweight.\n\n## Evidence statement 2.3\n\nThere was evidence from one (+) focus group study that acceptability of lifestyle change interventions can be increased by raising the cultural sensitivity of delivery. For example, the importance of avoiding Ramadan needs to be considered in the timing of delivery, and separate sessions for men and women need to be considered. There was evidence that flexibility around the timing of interventions as well as the bilingual abilities of staff were important. Learning to cook traditional foods in a more healthy way was one way to preserve cultural identity. In addition, advice (particularly one-to-one) and information that takes into account literacy levels and is encouraging were crucial to sustaining motivation to adopt a healthier lifestyle.\n\nEvidence from one (++) focus group study that included suggestions from participants, showed that acceptability of a nutritional education intervention might be increased by: including free food, timing classes to suit those with childcare responsibilities, and providing a crèche or possibly holding the classes in schools. Evidence from one (+) needs assessment study showed that cook and eat sessions and weight management classes that were made freely available on a gypsy traveller site were valued by women residents for their non-threatening environment and as a forum for discussion of health issues – as well as a way to reduce social isolation. Lack of childcare facilities, transport issues and costs were barriers to off-site activity.\n\nEvidence from an interview-guided questionnaire study (+) and one qualitative evaluation (+) included suggestions to increase the acceptability for Muslim Bangladeshi women who may wish to access a gym. Suggestions included the provision of women-only facilities, women-only sessions, swimming facilities for women, more walking physical activity facilities, fewer aerobic classes, Sylheti-speaking assistants, better transport and childcare facilities, less loud music, no inappropriate TV programmes and provocative music videos, and access to more local gyms. Evidence from one qualitative evaluation (+) of exercise on prescription (EoP) also identified lack of access to facilities, lack of childcare arrangements, as well as a limited choice of women-only sessions as barriers to attendance.\n\nThere was evidence from one (+) mixed method study that social interaction was a motivator for South Asian women attending a healthy eating and physical activity group. Some women also stated that they ate less when attending as they were not tempted to snack in the same way as when they stayed in the house.\n\n## Evidence statement 2.4\n\nThere was evidence from one (++) focus group study of lack of understanding between professional and lay groups in terms of Islamic teaching and its relation to healthy lifestyle practices. There was also evidence from the same study of communication difficulties arising from health literacy deficiencies in lay Bangladeshi people and cultural sensitivity deficiencies in professionals which obstruct appropriate health promotion messages.\n\n## Evidence statement 2.5\n\nThere was evidence from four focus groups and two interview studies that religious customs can become barriers or facilitators to lifestyle change. Change was more likely where participants believed they had some degree of free will. There was conflicting evidence regarding fatalism; in one (++) study health professionals spoke of fatalism as a barrier to health prevention in some black and minority ethnic groups. However, evidence from one (+) study suggests that while the occurrence of health conditions might be regarded as God's will, it is also, according to teachings, the responsibility of the individual to attempt to maintain good health and wellbeing.\n\nThere was evidence from three focus groups (one [++] and two [+]) and one (+) interview study and one qualitative evaluation (+) that healthy activities were acceptable provided they did not include aspects that were conflicting with religious teachings. One (++) focus group study showed evidence that some practices, such as eating Halal meat could limit the use of fast-food outlets.\n\n## Evidence statement 2.6\n\nThere was evidence from nine qualitative studies that cultural influences and issues of identity can be barriers or facilitators to lifestyle change.\n\nThere is evidence from one (+) focus group study that a nomadic identity influenced dietary choices for Somalians. As descendants of camel herders, diet in the UK continued to be influenced by the staple diet of meat with rice or spaghetti and a low consumption of fruit and vegetables which were less valued.\n\nA (+) needs assessment with gypsy travellers found that some fruit and vegetables were eaten daily, as they were seen as relatively cheap. In particular, vegetables were favoured as they could be incorporated into daily cooking. However, while 60% of participants considered themselves as 'heavy', they also stated that the meal was often followed by a take-away in the evening.\n\nEvidence from one (+) interview study suggested that traditional South Asian beliefs regarding the preventive attributes of certain vegetables in terms of ill health are part of a cultural identity, and that this might be taken on board by professionals when discussing health promotion. Dietary practices in the UK can involve experiences that are alien to traditional culture and identity However, one (+) qualitative study showed that food choices made by South Asian women can be informed by both traditional ('our' food) and Western ('your sort of foods') explanations in terms of 'good' and 'bad' effects upon the body so long as such explanations are complementary rather than in conflict.\n\nEvidence was found in one (+) guided interview study, one (+) focus group study and one (+) needs assessment for differences between UK culture and non-Western culture in terms of the perception of physical activity as either 'separate' or 'integral' to daily routine. Physical activity as 'separate' incurred financial costs as well as often being organised in ways that are insensitive to different cultural values.\n\nEvidence from one (+) study highlighted the belief that expending sweat is important for increased wellbeing; this influenced the practices that might be taken up in the UK where a cold climate limits sweat production.\n\nThere was evidence from one (+) guided interview study and two (one [+] and one [++]) focus group studies and one qualitative evaluation (+) that a limited command of the English language is a barrier to accessing information, as well as accessing activities and shopping facilities outside of the individual's neighbourhood.\n\nThere was evidence from one (+) interview study that some South Asians consider that nothing can be done to prevent diabetes if there is already a family history.\n\n## Evidence statement 2.7a\n\nThere was evidence from three (two [++] and one [+]) focus group studies that knowledge regarding risk factors is high in South Asian communities. However, evidence from one (+) focus group study of predominantly male Somali participants suggested a low level of knowledge. When knowledge levels were high, there was evidence from two (one [++] and one [+]) focus group studies that this does not always translate to practice in terms of healthy lifestyle. Evidence from one (++) focus group study suggested that education may be one way of overcoming restrictive practices.\n\n## Evidence statement 2.7b\n\nEvidence from one (+) focus group study suggested that South Asian people in the UK would appreciate increased information on risk factors, advice and encouragement in order to motivate and sustain behaviour change.\n\nThere was evidence from one (+) focus group study that information and advice regarding physical activity came mainly from the media, role models, family and friends, the medical establishment (mainly hospitals) and to a limited degree, fitness campaigns.\n\n## Evidence statement 2.7c\n\nThere was evidence from one guided interview study and two focus group studies (one [++] and two [+]) and one qualitative evaluation (+) that a limited command of the English language is a barrier to accessing information, as well as activities and shopping facilities outside the neighbourhood.\n\n## Evidence statement 2.8\n\nFor South Asian and African populations in the UK, and especially first generation migrants, there was evidence from three (two [++] and one [+]) focus group studies that traditional fresh foods are not readily available locally and are expensive.\n\nEvidence from one (++) focus group study showed that older people are less willing to travel beyond the immediate neighbourhood for food due to language barriers and fears for their safety. There is evidence from one (++) focus group study that the price of food is more of an issue for older people.\n\nThere was evidence from one (+) mixed method evaluation and one qualitative evaluation (+) that: distance from physical activities, lack of transport, fear of walking alone, having conflicting family commitments, not being able or willing to walk, ill health and cold weather were all barriers to attending a healthy eating and physical activity group. Having to travel to venues incurred extra costs even if physical exercise was on prescription, as for some South Asian women even a small financial contribution was reported as a barrier.\n\n## Evidence statement 2.9a\n\nThere was evidence from four (two [+] and two [++]) focus group studies that traditional South Asian cooking is associated with a high usage of fat, particularly for special occasions (which occur frequently) and that there is resistance to change such traditions. Indian men who wished to control their diet within a close-knit community where social events were common found it particularly difficult.\n\nEvidence from one (+) focus group study showed that Somali cooking is associated with high meat and low fruit and vegetable content and again there is resistance to change. These traditions are part of the cultural identity and symbolic of prosperity and hospitality.\n\nEvidence from two focus (one [++] and one [+]) group studies suggested that consumption of take-away food is common in second generation South Asian males and females as a change from traditional fare. Similarly, take-away meals were commonly used by Somalian males, particularly those living alone.\n\nSome South Asian women are beginning to cook in more healthy ways. There were suggestions from one (+) focus group study that learning to cook traditional food in healthy ways may be beneficial to South Asian groups. Another focus group study (++) suggested that women from Zimbabwe were not used to cooking for themselves as in Africa, maids had done the cooking; having to cook in the UK was seen as time consuming.\n\n## Evidence statement 2.9b\n\nThere was evidence from two (both [+]) interviews and four (one [++] and three [+]) focus group studies and one qualitative evaluation (+) that in South Asian groups, physical activity was perceived as a part of normal life and that there was little time for formal or 'separate' sessions, due to work or childcare commitments.\n\nIn particular, evidence from one (++) focus group study suggested women were expected to stay home and look after children rather than enrol the help of others. Evidence from one (+) interview study suggested that older participants perceived that vigorous physical activity was unnecessary in the context of advancing age and that keeping active and mobile was preferable.\n\nThere was evidence from one (+) focus group study of variation in views of South Asian and black participants regarding the appropriate level of physical activity required to obtain benefits, depending on own level of activity. There was evidence from the same study among South Asian participants that partaking in physical activity could compensate for unhealthy eating or smoking.\n\nEvidence from two interview studies (both [+]), three focus group (one [++] and two [+]) studies and one qualitative evaluation (+) suggests that vigorous activity such as aerobics was not acceptable to some South Asian participants, particularly females, for whom modesty and single-sex classes were important considerations. One (+) focus group study found that for some young people, however, going to the gym created a means of filling time, escape from social conditions and keeping up with fashion trends. There was evidence from one (+) focus group study of South Asian participants that partaking in physical activity could compensate for unhealthy eating or smoking.\n\nThere was also evidence from one (+) focus group study that encouraging sweating was important to some South Asian people. Evidence from one (+) focus group study and one guided interview study suggested that swimming and slow walking were preferred ways to remain active.\n\nThere is evidence from one (++) focus group study of a 'complex value hierarchy'. For example, choosing healthier options such as using less fat in cooking, and having to wear certain clothing for particular physical activities were seen as shameful and as more important than the benefits of a healthy lifestyle. In addition, as in white communities, support from families can act as a facilitator (if the new behaviour is integrated with the sense of self and one's own values without the control of others) or a barrier to changing health-related behaviours.\n\n## Evidence statement 2.10\n\nThere was evidence from five good quality (two [++] and three [+]) qualitative studies (three focus group and two interview studies) that body image expectations vary according to background and culture and often differ from those currently popular within the UK.\n\nThere is evidence from one (++) focus group study that body size can be positively or negatively associated with health and attractiveness, and attempting to reach an ideal body size can be a strong motivator for behaviour change. There was evidence from one (+) interview guided questionnaire that only 64% of overweight or obese Bangladeshi women classed themselves as overweight. There was evidence from one (+) interview study that weight management was more important for South Asian males than females, and a (+) focus group study found it important for young South Asian and black females.\n\nEvidence was found for an association between being overweight and prosperity in one (+) focus group study with Indian, Pakistani and Indian participants. Changing dietary and physical activity patterns in old age was perceived as potentially weakening.\n\nHaving the 'right' body size was influenced by the media as well as some male views, and was important for attracting a partner for young South Asian and black females in one (+) focus group study.\n\nIn one (++) focus group study body size was found to be a stronger motivator for healthy behaviour changes than health issues.\n\n## Evidence statement 3.2\n\nThere is evidence from one (+) study that did not focus on low income or BME groups to suggest that the process of identifying and referring high-risk patients in primary care to an exercise scheme varies between general practices. GPs and practice nurse's methods of identifying and referring patients to an exercise scheme was ad-hoc and based on: patients asking about exercise themselves, chance discussion during consultations, requests for referral by another doctor, and asking patients to choose from a variety of behaviour change activities that might produce health benefits.\n\nEvidence from one (+) evaluation of healthy living centres acknowledges the challenges of identifying groups at risk. Hard-to-reach groups might be reached in small numbers at community events or eventually be motivated to engage with initiatives through word of mouth from relatives.\n\n## Evidence statement 3.3\n\nEvidence from one (+) survey study that evaluated the contribution of nurses to targeting health and social need suggests that in order to be able to empower high-risk groups to make choices about adopting healthy lifestyles, health professionals require a deep understanding of the cultural and religious beliefs and economic influences within the communities with which they are working.\n\nOne (+) evaluation highlighted the need for practitioners to take into account the realities of the people they are targeting. For example, making it clear that low-income groups do not require expensive clothing to engage in a community physical activity initiative.\n\n## Evidence statement 3.4\n\nEvidence from one (+) qualitative study of nurses' attitudes identified two discourses in relation to health promotion with disadvantaged groups. One was associated with the philosophy of holism that nurses were exposed to during training, resulting in empathy for the disadvantages that low-income groups face in attempting to achieve a healthy lifestyle. The other discourse reflects personal values, and beliefs that individuals must take responsibility for their own health. This tension may need addressing when practising health promotion in a culturally sensitive way.\n\n## Evidence statement 3.6\n\nEvidence from two evaluations (one [+] and one [++]) suggests that the training of lay workers to identify and disseminate health promotion messages to members of their community is a way of reaching hard-to-reach and high-risk groups.\n\nOne (+) evaluation in which 11 women (seven of Pakistani, two of Indian and two of Chinese origin; of Muslim, Hindu and Christian religious backgrounds) undertook formal training to become community health workers (CHWs) provides evidence that lay workers trained by health professionals can identify target groups within the community and deliver health messages in a culturally sensitive way in an appropriate language. Knowledge of the communication channels in a community assisted in the success of the initiative. For example, in this study, younger women were targeted for training as they are relied upon in the community for passing on information.\n\nEvidence from a qualitative evaluation (++) study that explores the role of the lay food and health worker suggests a consensus of opinion that the primary role for lay workers is the encouragement of dietary change by making complex messages more credible and culturally appropriate. A proactive strategy for lay workers to identify and contact at-risk individuals is to create lists of contacts within the community and introduce themselves to those on the list.\n\nOne (+) evaluation of healthy living centres highlighted a difference in focus between lay workers, who considered the larger social picture, and health professionals, whose focus was more on outcomes such as improved fruit and vegetable intake.\n\n## Evidence statement 3.7\n\nOne (-) evaluation of peer education training as part of a community health promotion programme (Project Dil), provides evidence of a high level of uptake and enthusiasm from those engaged in peer education. The project was designed to improve the effectiveness of primary and secondary prevention of coronary heart disease in volunteer Leicestershire general practices with a high percentage of South Asian patients. Peer education was reported to facilitate health promotion within a range of organised community events.\n\nEvidence from one (+) evaluation suggests that fostering a team spirit and sharing experiences was a key facilitator in training lay workers. However, there is evidence from the same study that scheduled activities prevented lay workers from having time to participate.\n\n## Evidence statement 3.8\n\nOne (+) evaluation of lay worker training provides evidence that target groups within the community increased their knowledge as a result of lay worker activity, and found the cultural sensitivity of health promotion messages an important factor in helping to make changes in dietary practice.\n\n## Expert papers\n\nExpert paper 5: 'CPD and training, enabling professionals to practice effectively and confidently'.\n\nExpert paper 6: 'BME groups, diet and risk of type\xa02 diabetes'.\n\nExpert paper 7: 'Developing population level guidance – CVD, the Foresight Report.'\n\nExpert paper 8: 'Dietary strategies for the prevention of pre-diabetes'.\n\nExpert paper 9: 'Low income groups and behaviour change interventions'.\n\nExpert paper 10: 'Adapting health promotion interventions for BME communities'.\n\nExpert paper 11: 'Health policy and health.'\n\nExpert paper 12: 'Ismaili Nutrition Centre'.\n\nExpert paper 13: 'Environment and physical activity'.\n\nExpert paper 14: 'Nutritional food labelling current thinking and practice'.\n\nExpert paper 15: 'Fiscal policy instruments to improve diet'.\n\n# Additional evidence\n\nNICE's guideline on obesity.\n\nNICE's guideline on general approaches to behaviour change: general approaches.\n\nNICE's 2008 guideline on community engagement.\n\nNICE's guideline on physical activity in the workplace.\n\nNICE's 2008 guideline on physical activity and the environment.\n\n# Cost-effectiveness evidence\n\nThe recommended interventions operate on groups of people – and often quite large groups. For most people, the amount of weight they lose, the extent of changes to their diet and any increase in the amount of exercise they take will be relatively small. In addition, a few will make changes in the wrong direction. Thus the average changes in behaviour within the group as a whole will usually be small. However, the total changes will eventually be discernable at a population level: that is, fewer people will be diagnosed with type\xa02 diabetes in the long run, or will be diagnosed later in life.\n\nModelling over the lifetime of individuals demonstrates that, if the total costs of undertaking the initial interventions are sufficiently small, these interventions will be cost effective. Some interventions will be very cost effective or, in the long run, cost saving, even after discounting future benefits at the usual rate of 3.5% per year. ('Cost saving' means that the costs saved from not having to undertake treatment later in life exceed the costs of the intervention.)\n\nHowever, for a range of reasons, there is an element of uncertainty in the modelling results. This includes the possibility that better health outcomes in the future may be attributable to something other than the named interventions, or that there might be far better and cheaper treatments for type\xa02 diabetes in the future.\n\n# Fieldwork findings\n\nFieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations. For details, see the fieldwork section in appendix B.\n\nThe guidance was welcomed by fieldwork participants. It was felt that it could help raise the profile of type\xa02 diabetes prevention activities, and provide renewed impetus. Many participants stated that the recommendations represented best practice in the area rather than offering a new approach. Most participants expressed the need for an integrated strategy on healthy lifestyles, covering the main related long-term conditions (such as cardiovascular disease, obesity, diabetes and hypertension) and the main lifestyle risk factors (for example, unhealthy diet and lack of physical activity). It was also felt that a better balance between recommendations for action at a local level and action at national level was important.", 'Appendix D: Gaps in the evidence': "The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence and expert comment. These gaps are set out below.\n\nThere was not enough evidence to judge the effectiveness of interventions to reduce the risk of – and prevent – pre-diabetes. In particular, there was a lack of evidence on how effective they are with people from black and minority ethnic and lower socioeconomic communities in the UK. (Source Reviews 1–3 and 5)\n\nThere was limited evidence on how different approaches could be combined. (For example, targeting the population as whole, targeting 'high-risk' populations and other approaches, including 'individual' interventions.) (Source Reviews 1–3 and 5)\n\nThere was limited evidence on the 'cultural appropriateness' of interventions and how they could be effectively adapted or tailored to prevent pre-diabetes. (Source Reviews 1–6; Expert paper 10)\n\nThere was limited evidence on how the environment in which people live may affect their risk of developing pre-diabetes.(Source Reviews 1 and 2; Expert paper 13)\n\nThere was limited evidence on the effectiveness of interventions to develop the awareness, knowledge, understanding and skills of healthcare professionals and others responsible for people at high risk of developing pre-diabetes. (Source Review 3)\n\nThere was limited evidence on the potentially regressive effects of food taxation on health inequalities.(Source Expert paper 15)\n\nThe Group made five recommendations for research.", 'Appendix E: Supporting documents': "Supporting documents include the following:\n\nEvidence reviews:\n\n\n\nReview 1: 'Prevention of type\xa02 diabetes: interventions to reduce risk factors for pre-diabetes among UK adults from a lower socioeconomic group'\n\nReview 2: 'Prevention of type\xa02 diabetes: interventions to reduce risk factors for pre-diabetes among UK adults from black and minority ethnic groups'\n\nReview 3: 'Prevention of type\xa02 diabetes: interventions to raise awareness in health professionals and assist identification of high-risk groups'\n\nReview 4: 'Interventions for the prevention of pre-diabetes in high-risk groups: examples of current practice in relation to the UK evidence base'\n\nReview 5: 'Review of review-level evidence to inform the development of NICE public health guidance for the prevention of pre-diabetes among adults in high-risk groups'\n\nReview 6: 'Identification of effective community projects focused on addressing risk factors for the development of pre-diabetes in adults from black and minority ethnic groups and lower socio-economic groups'.\n\n\n\nEconomic modelling: 'Prevention of type\xa02 diabetes: preventing pre-diabetes among adults in high-risk groups. Report on cost-effectiveness evidence and methods for economic modelling'.\n\nExpert papers:\n\n\n\nExpert paper 1: 'Type\xa02 diabetes and pre-diabetes: diagnosis and definition'\n\nExpert paper 2: 'Illness labelling and illness experience'\n\nExpert paper 3: 'Socio-economic status and risk factors for type\xa02 diabetes'\n\nExpert paper 4: 'Expert advice, dietary surveys and nutrition research'\n\nExpert paper 5: 'CPD and training, enabling professionals to practice effectively and confidently'\n\nExpert paper 6: 'BME groups, diet and risk of type\xa02 diabetes'\n\nExpert paper 7: 'Developing population level guidance – CVD, the Foresight report'\n\nExpert paper 8: 'Dietary strategies for the prevention of pre-diabetes'\n\nExpert paper 9: 'Low income groups and behaviour change interventions'\n\nExpert paper 10: 'Adapting health promotion interventions for BME communities'\n\nExpert paper 11: 'Health policy and health'\n\nExpert paper 12: 'Ismaili Nutrition Centre'\n\nExpert paper 13: 'Environment and physical activity'\n\nExpert paper 14: 'Nutritional food labelling: current thinking and practice'\n\nExpert paper 15: 'Fiscal policy instruments to improve diet'.\n\n\n\nFieldwork report: 'Fieldwork validation report: prevention of pre-diabetes among adults in high-risk groups'.", 'Finding more information ': "You can see everything NICE says on this topic in the NICE Pathway on preventing type 2 diabetes.\n\nTo find NICE guidance on related topics, including guidance in development, see our topic page for diabetes.\n\nFor full details of the evidence and the guideline committee's discussions, see the supporting documents. You can also find information about how the guideline was developed.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice."}
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https://www.nice.org.uk/guidance/ph35
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This guideline covers preventing type 2 diabetes in adult populations and communities who are at high risk. It aims to promote a healthy diet and physical activity at community and population level, and recommends how to tailor services for people in ethnic communities and other groups who are particularly at risk of type 2 diabetes.
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Golimumab for the treatment of psoriatic arthritis
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Golimumab for the treatment of psoriatic arthritis
Evidence-based recommendations on golimumab (Simponi) for treating psoriatic arthritis in adults.
# Guidance
Golimumab is recommended as an option for the treatment of active and progressive psoriatic arthritis in adults only if:
it is used as described for other tumour necrosis factor (TNF) inhibitor treatments in Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (NICE technology appraisal guidance 199), and
the manufacturer provides the 100 mg dose of golimumab at the same cost as the 50 mg dose.
When using the Psoriatic Arthritis Response Criteria (PsARC; as set out in NICE technology appraisal guidance 199), healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate.# The technology
Golimumab (Simponi, Schering-Plough/Centocor) is a human monoclonal antibody that prevents the binding of tumour necrosis factor (TNF) to its receptors, thereby neutralising its activity. Golimumab has a marketing authorisation for the treatment of active and progressive psoriatic arthritis (alone or in combination with methotrexate) in adults when the response to previous disease-modifying antirheumatic drug (DMARD) therapy has been inadequate. The summary of product characteristics (SPC) notes that golimumab has also been shown to improve physical function in this population.
Golimumab is contraindicated in people with moderate to severe heart failure, hereditary problems of fructose intolerance, active tuberculosis and other severe infections. Before initiating therapy, physicians should evaluate people for prior evidence of hepatitis B virus infection, and both active and inactive (latent) tuberculosis infection. The SPC states that the needle cover on the pre-filled golimumab injection pen contains latex and therefore may cause allergic reactions in people with latex sensitivity. The SPC reports that the most common adverse reactions are upper respiratory tract infections, including nasopharyngitis, pharyngitis, laryngitis and rhinitis. For full details of adverse effects, contraindications, special warnings and precautions for use, see the SPC.
Golimumab is injected subcutaneously via a pre-filled injection pen. The recommended dose is 50 mg given once a month, on the same date each month. The SPC states that in people who weigh more than 100 kg whose psoriatic arthritis does not show an adequate clinical response after three or four doses, the dose of golimumab may be increased to 100 mg once a month. The cost of golimumab is £774.58 for a 50 mg pre-filled injection pen (excluding VAT, 'MIMS' February 2011 edition), which is equivalent to an annual cost of £9294.96 (based on the 50 mg dose). Costs may vary in different settings because of negotiated procurement discounts.
The manufacturer of golimumab has agreed a patient access scheme with the Department of Health, in which the 100 mg dose of golimumab will be available to the NHS at the same cost as the 50 mg dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of golimumab and a review of this submission by the Evidence Review Group (ERG; appendix B).
The main clinical effectiveness data were derived from a single phase III randomised controlled trial (RCT) – GO-REVEAL. The trial compared golimumab with placebo for the treatment of active and progressive psoriatic arthritis in people who had symptoms despite the use of current or previous DMARDs or non-steroidal anti-inflammatory drugs. Of the 405 trial participants, 113 were randomised to placebo, 146 were randomised to a 50 mg dose of golimumab and 146 were randomised to a 100 mg dose of golimumab. Randomisation was maintained for 24 weeks. Upward titration was allowed at week 16, such that the participants in the placebo group could switch to 50 mg golimumab and those in the 50 mg golimumab group could have their dose increased to 100 mg if their disease had failed to respond. In the placebo group 50% of participants crossed over to golimumab 50 mg treatment and in the golimumab 50 mg group 20% crossed over to golimumab 100 mg treatment. Outcomes were assessed at 14 and 24 weeks.
The primary outcomes in GO-REVEAL were American of Rheumatology (ACR) 20 response at week 14 and the change from baseline in the psoriatic arthritis modified van der Heijde-Sharp (vdH-S) score at week 24. Secondary outcomes included ACR 20 response at week 24, Psoriatic Arthritis Response Criteria (PsARC) response at weeks 14 and 24, and Psoriasis Area and Severity Index (PASI) 75 improvement at week 14 in participants with psoriasis that affected 3% or more of their body surface area at baseline. Physical functional status was measured by Health Assessment Questionnaire (HAQ) score at week 24. Health-related quality of life was measured by the Short Form 36 Health Survey (SF-36) at week 14.
The week 14 results of GO-REVEAL indicated that, compared with placebo, golimumab showed a statistically significant improvement in joint disease. An ACR 20 response was seen in 50.7% of participants in the 50 mg treatment arm compared with 8.8% in the placebo arm (relative risk 5.727, 95% confidence interval 3.24 to 10.56). A PsARC response was seen in 73.3% of participants in the 50 mg treatment arm compared with 21.2% in the placebo arm (RR 3.451, 95% CI 2.46 to 4.87). Golimumab also showed a statistically significant improvement in skin disease as measured by PASI 75 at both 14 and 24 weeks. A PASI 75 response was seen in 40.4% of participants in the 50 mg treatment arm compared with 2.5% in the placebo arm (RR 15.945, 95% CI 4.62 to 59.11) at 14 weeks, and in 55.9% of participants in the 50 mg treatment arm compared with 1.4% in the placebo arm (RR 40.794, 95% CI 7.86 to 232.88) at 24 weeks. There was also a statistically significant improvement in functional status (HAQ) at 24 weeks. A mean HAQ score change from baseline of 0.33 (standard deviation 0.55, p < 0.001) was observed in the golimumab 50 mg arm compared with −0.01 (SD 0.49) in the placebo arm. Data on HAQ score change from baseline were not available for the 14-week time point.
The manufacturer reported that golimumab 50 mg produced a statistically significant reduction from baseline in vdH-S score of 0.16 (p = 0.01) at 24 weeks compared with placebo. The reduction from baseline in vdH-S score was not statistically significant in the golimumab 100 mg group (p = 0.09). The manufacturer did not report vdH-S scores at the 14 week time point.
The Evidence Review Group (ERG) reported that the main limitation of the efficacy evaluation of golimumab was that the analyses of efficacy outcomes were restricted to the GO-REVEAL trial, which had a limited sample size and was of limited duration (see section 3.1).
The manufacturer stated that the most frequently reported adverse events associated with golimumab therapy were infections and infestations, including upper respiratory tract infections and nasopharyngitis. The manufacturer reported that the safety profile of golimumab was comparable to that of the other TNF inhibitors adalimumab, etanercept and infliximab.
The ERG reported concerns about the adverse event data presented for golimumab. It noted that no long-term adverse event data had been presented, and that in its original submission the manufacturer had not included adverse event data on golimumab from controlled studies of its use in other conditions such as rheumatoid arthritis or ankylosing spondylitis. The ERG reported that the manufacturer's conclusion that golimumab has a safety profile comparable to that of the other TNF inhibitors may be premature.
Following consultation on the Appraisal Consultation Document, the manufacturer submitted evidence on the long-term safety of golimumab. These data included 104-week results from the GO-REVEAL extension study in addition to 52- and 104-week safety data in trial participants with psoriatic arthritis, rheumatoid arthritis and ankylosing spondylitis who had received treatment with golimumab across all of the original phase III studies. These data were marked as confidential and therefore cannot be reported.
In the absence of head-to-head comparisons between golimumab and the other TNF inhibitors, the manufacturer conducted a mixed treatment comparison. The mixed treatment comparison included seven trials: the GO-REVEAL trial (golimumab versus placebo); two RCTs comparing etanercept with placebo (Mease 2000 and Mease 2004); two RCTs comparing infliximab with placebo (IMPACT and IMPACT 2); and two RCTs comparing adalimumab with placebo (ADEPT and Genovese 2007). All of the TNF inhibitors have marketing authorisations for the treatment of active and progressive psoriatic arthritis that has responded inadequately to previous DMARDs.
The trials included in the mixed treatment comparison were similar in terms of joint disease severity at baseline (for example, mean tender joint count and mean swollen joint count). There were differences, however, in the proportions of trial participants who could be evaluated for psoriasis endpoints at baseline. Most participants had received treatment with one prior DMARD, although no trial specified non-response to at least two DMARDs.
The outcomes included in the mixed treatment comparison analyses were PsARC response, change in HAQ score given PsARC response to treatment, change in HAQ score given no PsARC response, and change in PASI in people with psoriasis that affected 3% or more of their body surface area at baseline. The manufacturer selected absolute changes as the main outcomes, stating that these were the most appropriate outcomes for economic modelling. No analysis of the ACR outcomes was included in the mixed treatment comparison.
The results of the mixed treatment comparison indicated that of the four TNF inhibitors, golimumab was associated with the third highest PsARC response and absolute change in PASI from baseline. Of the four TNF inhibitors, golimumab had the lowest HAQ score change from baseline, both in people whose disease responded to treatment based on PsARC score and in those whose disease did not respond. The numerical values for each outcome derived from the mixed treatment comparison were marked as confidential and therefore cannot be reported.
The ERG reported that the network of trials included in the mixed treatment comparison was appropriately constructed, but that there were differences among the trial populations in disease severity and number of previously tried DMARDs (with many participants having received only one previous DMARD). The ERG commented that the trial populations were not precisely representative of the population with active and progressive psoriatic arthritis for whom TNF inhibitors are recommended in current British Society for Rheumatology guidelines and in Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (NICE technology appraisal guidance 199 ).
The manufacturer developed its own economic evaluation, which comprised a patient cohort model. The model compared the effects of treatment with golimumab (50 mg) in adults with active and progressive psoriatic arthritis whose disease had responded inadequately to DMARDs with the effects of treatment with infliximab, adalimumab and etanercept and with palliative care. All people entered the model with the same baseline characteristics as participants in the GO-REVEAL trial and left the model at death, irrespective of the treatment regimen. The model used a 12-week cycle for the first two cycles and annual cycles thereafter. The model captured response to treatment using HAQ score (conditional on PsARC response) as the arthritis measure and PASI score as the psoriasis measure. If there was no response to treatment at 12 weeks (according to PsARC), treatment was discontinued. The price year used for costs was not reported in the manufacturer's submission. Costs and benefits were discounted at 3.5% per annum over 40 years.
The manufacturer reported that estimates of treatment effectiveness – including PsARC response, HAQ score changes from baseline for people whose disease had responded to treatment according to PsARC at 12 weeks, HAQ score changes from baseline for those whose disease had not responded to treatment according to PsARC at 12 weeks, and PASI change from baseline in people with measurable psoriasis – were derived from the mixed treatment comparison.
The model assumed that people who continue treatment with a TNF inhibitor maintain their initial improvement in HAQ score. The same ongoing rate of withdrawal from treatment was used for all the TNF inhibitors (16.5% per annum) and represented withdrawal because of treatment failure or adverse events.
The manufacturer combined data from IMPACT2 (a study of infliximab) and GO-REVEAL using the 'Gray' algorithm to estimate utility values. The Gray algorithm converts Short Form 36 (SF-36) data to EuroQol (EQ-5D) estimates and then to utilities. The disutility of adverse events was not modelled.
The manufacturer reported that resource use associated with treatment, administration and monitoring of infliximab, etanercept and adalimumab was taken from the Assessment Group's model for TA199. In the patient access scheme (as described in section 2.4) the manufacturer provides the 100 mg dose of golimumab at the same cost as the 50 mg dose. Therefore, only the cost of the 50 mg dose of golimumab (£774.58) was included in the model. The model contained an additional 4 hours of staff nurse costs for training people to self-administer subcutaneous TNF inhibitors. The costs of infliximab were initially calculated on the assumption that vial sharing was allowed (using an average of 3.5 vials per infusion, although this assumption was later removed following a request for clarification from the ERG). The costs associated with adverse events were not included.
The manufacturer revised its original base-case estimates in response to a request from the ERG for clarification about the way utilities were calculated and for the removal of the infliximab vial sharing assumption. The revised base-case results produced total costs, total quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs, pairwise comparisons with palliative care) as follows:
palliative care: total costs of £62,224 and total QALYs of 6.61
adalimumab: total costs of £86,410 and total QALYs of 7.89, resulting in an ICER of £18,824 per QALY gained
golimumab: total costs of £94,151 and total QALYs of 8.21, resulting in an ICER of £19,993 per QALY gained
etanercept: total costs of £94,578 and total QALYs of 8.49, resulting in an ICER of £17,177 per QALY gained
infliximab: total costs of £106,620 and total QALYs of 8.49, resulting in an ICER of £23,578 per QALY gained.
The ERG reported that the manufacturer had not provided an incremental analysis in which dominated and extendedly dominated options were excluded. An option is 'dominated' if there is another option that is less costly and more effective. An option is 'extendedly dominated' when its ICER is higher than that of the next, more effective, option when compared with a common baseline (that is, it is dominated by a combination of two other alternatives). The ERG recalculated the manufacturer's base-case results by incrementally comparing each treatment with the next, more effective, option and excluding those that were extendedly dominated. The recalculated base-case results showed that both adalimumab and golimumab were extendedly dominated by a combination of etanercept and palliative care. Etanercept in comparison with palliative care was associated with an incremental cost of £32,354 and an incremental QALY gain of 1.88, resulting in an ICER of £17,209. Infliximab was dominated by etanercept.
The manufacturer conducted two subgroup analyses: one of the population with 'predominantly' rheumatic disease and one of the population with 'significant' psoriasis. The ERG recalculated the results of these analyses as described in section 3.20. The results of the recalculated subgroup analyses show adalimumab and golimumab to be extendedly dominated by a combination of etanercept and palliative care. Etanercept in comparison with palliative care was associated with an incremental cost of £34,492 and an incremental QALY gain of 2.21, resulting in an ICER of £15,607 per QALY gained in the rheumatic disease subgroup. In the psoriasis subgroup, etanercept in comparison with palliative care was associated with an incremental cost of £31,564 and an incremental QALY gain of 2.25, resulting in an ICER of £14,028 per QALY gained. Infliximab was dominated by etanercept in the rheumatic disease subgroup, and was associated with an incremental cost of £5702 and an incremental QALY gain of 0.01, resulting in an ICER of £570,200 per QALY gained in comparison with etanercept in the psoriasis subgroup.
The ERG commented that the model structure was reasonable. The ERG stated that the inclusion of costs to cover time for training in self-injection may have been unnecessary, but reported that all other included costs were appropriate. The ERG considered that it may have been appropriate to account for the possibility of dose escalation to 100 mg (as per the marketing authorisation; see section 2.3). The ERG reported that the subgroup analyses were appropriate.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of golimumab, having considered evidence on the nature of psoriatic arthritis and the value placed on the benefits of golimumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources and the impact of the patient access scheme (see section 2.4).
The Committee understood that psoriatic arthritis can cause significant distress and psychological impact on the person's life, employment and social activities. The Committee heard from a patient expert that TNF inhibitors are valued options for the treatment of psoriatic arthritis and have a positive impact on quality of life. It understood that people with the condition may prefer the option of a treatment that is self-injectable and/or has a longer retreatment interval. The Committee understood that people value having a choice of TNF inhibitors and that another treatment option will always be welcome.
The Committee considered current clinical practice for the treatment of psoriatic arthritis. It understood that TA199 recommends adalimumab, etanercept and infliximab for the treatment of psoriatic arthritis in people who have peripheral arthritis with three or more tender joints and three or more swollen joints, and when the psoriatic arthritis has not responded to adequate trials of at least two standard DMARDs (administered either individually or in combination). The Committee also noted that TA199 specifies that treatment should be with the least expensive drug, taking into account drug administration costs, required dose and product price per dose. It heard from the clinical specialists that they considered there to be little demonstrable difference between the TNF inhibitors in terms of their clinical effectiveness. The clinical experts did, however, note slight differences among the TNF inhibitors in TA199 with regard to the subjective reduction in response to treatment in the skin and joint components of the disease. The Committee heard from the commissioning expert that subtle differences in cost and administration, particularly with regard to dose escalation (as included in the marketing authorisation for infliximab) and hospitalisation, can make a big cost difference. The Committee concluded that adalimumab, etanercept and infliximab were the appropriate comparators for golimumab.
The Committee heard from the clinical specialists and the patient expert that people often prefer a less frequent dosing schedule; that is, a longer time period between treatments. However, the Committee noted that the longer retreatment interval associated with golimumab could potentially result in more discomfort because of waning efficacy before retreatment. It understood that people with psoriatic arthritis and their clinicians may therefore value the once-monthly, self-injectable administration of golimumab. The Committee concluded that golimumab could, on balance, be a valued additional treatment option for people with psoriatic arthritis.
The Committee considered the evidence on the clinical effectiveness of golimumab. It understood that the main clinical effectiveness data were derived from a single phase III RCT. The Committee noted statistically significant outcomes for the 50 mg dose compared with placebo in terms of improvements in joint disease, skin disease and functional status (see sections 3.3 and 3.4). The Committee concluded that golimumab was clinically effective compared with placebo.
The Committee discussed the 100 mg dose of golimumab, which may be considered for people who weigh more than 100 kg and whose psoriatic arthritis has not responded after three or four doses of golimumab (as stated in the SPC). It noted that neither the 100 mg arm nor dose escalation to 100 mg in the 50 mg arm in the GO-REVEAL trial was limited to people who weighed more than 100 kg, and therefore the trial population did not reflect the population in the marketing authorisation for the 100 mg dose. The Committee heard from clinical specialists that they would be more likely to select a different TNF inhibitor than to increase the dose if the 50 mg dose of golimumab failed to produce a response. The Committee concluded that it was uncertain of the extent to which the 100 mg dose would be used in clinical practice.
The Committee noted that there had been no head-to-head trials of golimumab and any of the other TNF inhibitors, and that, as a result, the manufacturer had conducted a mixed treatment comparison. The Committee recognised the limitations of mixed treatment comparisons and was aware that the associated results would need to be interpreted with caution. It also noted the manufacturer's reservations about mixed treatment comparisons and the uncertainty associated with the use of such methodologies, but noted that no alternative methods or data had been provided. Following the consultation on the Appraisal Consultation Document, the manufacturer suggested the removal of the Mease 2000 results (for etanercept) from the mixed treatment comparison, because this trial did not disaggregate HAQ scores in the same way as other trials, and showed better results for etanercept than Mease 2004 (the larger etanercept trial). The Committee had misgivings about the selective removal of individual trials, but heard from the ERG that extracting the Mease 2000 study from the mixed treatment comparison had little effect on the results. The Committee agreed it would bear this in mind when considering the results of the mixed treatment comparison.
The Committee carefully considered the results of the mixed treatment comparison. It noted that for PsARC response and absolute change in PASI from baseline, the results showed that golimumab was generally equivalent to the other TNF inhibitors. However, it also noted that golimumab had the lowest HAQ score change from baseline (both in participants whose disease responded to treatment based on PsARC score and those whose disease did not respond based on PsARC score) compared with the other TNF inhibitors.
The Committee further discussed the HAQ results from the mixed treatment comparison. The Committee understood from the clinical specialists and the patient expert that pain and disability caused by arthritis (as captured by HAQ score and reflected in the manufacturer's economic model) often have a significant impact on the person's quality of life. The Committee was concerned that, out of the four TNF inhibitors that were compared, golimumab had the lowest HAQ score change from baseline and that this might indicate inferiority of its anti-arthritic activity (see section 3.12); however, the Committee was also aware of the limitations of the mixed treatment comparison methodology. Therefore the Committee also considered the radiographic progression data, which, together with the change in HAQ score, could be used to assess the effect of a treatment on disease progression. The Committee noted the statistically significant reduction from baseline in vdH-S score (a measure of radiographic progression) for golimumab compared with placebo at 24 weeks (−0.16 for 50 mg golimumab compared with 0.27 for placebo, p = 0.01; see section 3.4). It noted that the change from baseline in vdH-S score at week 24 for golimumab was less than that for infliximab (−0.70 for 5 mg/kg infliximab compared with 0.82 for placebo, p < 0.001), which was the other TNF inhibitor for which radiographic progression was measured by vdH-S score in the trials included in the mixed treatment comparison. The Committee was aware, however, that this difference may be due to differences in the trial populations, as reflected by the respective changes from baseline with placebo. The Committee also understood that the absolute differences between the two changes from baseline were small. Although the evidence suggested that golimumab may be less effective in its anti-arthritic activity (based on the HAQ score results from the mixed treatment comparison and the data for radiographic progression), on balance the Committee concluded that the evidence was not robust enough to confirm clinically important differences in the effectiveness of golimumab compared with the other TNF inhibitors.
The Committee considered the evidence on the adverse event rates associated with the use of golimumab. It noted a number of reported 'serious' adverse events, but understood that GO-REVEAL was not powered to detect statistically significant differences in adverse event outcomes. The Committee considered the additional evidence submitted by the manufacturer on the long-term adverse event data for golimumab in people with psoriatic arthritis, and also for people with rheumatoid arthritis and ankylosing spondylitis. It concluded that although there remains uncertainty about golimumab's long-term adverse event profile, it had not been shown to be different from that of other TNF inhibitors.
The Committee considered the economic model presented by the manufacturer. The Committee noted that the model assumed people continuing on therapy maintained their initial improvement in HAQ score. The Committee considered the utility estimates incorporated in the model, and noted that the utility formula was derived from the HAQ score change and the PASI response. The HAQ score change had a greater effect on utility than the PASI response did, indicating that the calculated utility benefit was driven more by the reduction in joint symptoms than the reduction in skin disease. The Committee concluded that this was appropriate (see section 4.9).
The Committee considered the results of the manufacturer's base-case analysis, which compared each of the TNF inhibitors (including golimumab) with palliative care. The Committee heard from the ERG that the pair-wise comparisons with palliative care needed to be reworked into an incremental analysis comparing each treatment with the next most effective alternative. The ERG re-presented these results. The Committee was aware that the acquisition costs of adalimumab, etanercept and golimumab (50 mg) were similar, and that the acquisition cost of infliximab was dependent on the person's weight and the amount of the drug required, with additional administration costs for infliximab (related to intravenous infusion). The Committee noted that all alternatives to etanercept were either dominated (infliximab was more expensive but no better than etanercept) or extendedly dominated (adalimumab and golimumab were, in effect, less cost effective than etanercept; see section 3.20). The Committee agreed that golimumab was, in effect, less cost effective than etanercept.
The Committee was aware, however, that TA199 recommends adalimumab and infliximab alongside etanercept. The Committee therefore also considered whether golimumab was at least as cost effective as adalimumab and infliximab. The Committee was aware that in the incremental analysis, both adalimumab and golimumab were extendedly dominated by etanercept. However, the Committee noted that the pairwise ICER of golimumab compared with adalimumab alone would be approximately £24,000 per QALY gained. The Committee similarly noted that the pairwise ICER for golimumab compared with infliximab would be approximately £45,000, aware that in this instance the ICER would represent a 'savings per QALY lost', as golimumab was associated with both lower costs and fewer QALYs compared with infliximab (see section 3.19). Given the weaknesses of the evidence suggesting lesser clinical effectiveness of golimumab compared with the other TNF inhibitors, and the estimates of golimumab's cost effectiveness compared with adalimumab and infliximab, the Committee concluded that the 50 mg dose of golimumab was acceptable when the criteria in TA199 are met; that is, the person has peripheral arthritis with three or more tender joints and three or more swollen joints, and the psoriatic arthritis has not responded to adequate trials of at least two standard disease-modifying antirheumatic drugs (DMARDs), administered either individually or in combination.
The Committee considered the 100 mg dose of golimumab. The Committee was aware that the SPC for golimumab states that for people who weigh more than 100 kg whose disease does not show an adequate clinical response after three or four doses, the dose of golimumab may be increased to 100 mg once a month. The Committee heard two different opinions about the proportion of people who would be eligible for the higher dose. The Committee agreed that this proportion was uncertain, but that it could be substantial. The Committee noted that the 100 mg dose of golimumab was not considered in the economic model, but that, because of the patient access scheme (as described in section 2.4), the cost of the 100 mg dose would be equal to that of the 50 mg dose. In addition, the Committee acknowledged the comments from the clinical specialists that, in clinical practice, people would be more likely to be switched to a different TNF inhibitor if no response was observed with the 50 mg dose, than to have the dose increased (see section 4.6). The Committee also noted TA199 states that treatment choice should be based on cost (taking into account drug administration costs, required dose and product price per dose), with treatment initiated with the least expensive drug. Therefore the Committee concluded that with the incorporation of the patient access scheme, golimumab would be considered an acceptable option for the treatment of psoriatic arthritis if used as described for other TNF inhibitors in TA199.
The Committee discussed the discontinuation of treatment with etanercept, infliximab and adalimumab in TA199. The Committee considered that the recommendation to discontinue treatment based on an inadequate PsARC response at 12 weeks included in TA199 was also appropriate for golimumab. The Committee was aware that no evidence had been provided by the manufacturer for the use of golimumab after the failure of other TNF inhibitors. The Committee was therefore unable to make recommendations about the use of golimumab following the failure of other TNF inhibitors.
The Committee was aware that there may be some circumstances that could affect a person's responses to components of the PsARC such as any physical, sensory or learning disabilities, or communication difficulties. The Committee concluded that in such cases, healthcare professionals should make any adjustments they consider appropriate.
The Committee was aware of registries that collect data on the long-term outcomes of treatment with TNF inhibitors for rheumatoid arthritis. The Committee noted the importance of registries in gathering data and supported the inclusion of outcomes specific to psoriatic arthritis in a suitable registry so that specific information about treatments and treatment-related adverse events in psoriatic arthritis can be collected.
In summary, the Committee considered the clinical and cost effectiveness of golimumab in the light of the submitted evidence and the comments of the clinical specialists, the commissioning expert and the patient expert. The Committee noted that although the evidence suggested that golimumab may be less effective in its anti-arthritic activity (based on the HAQ score results from the mixed treatment comparison and the data for radiographic progression), the evidence was not robust enough to confirm clinically important differences in the effectiveness of golimumab compared with the other TNF inhibitors. The Committee further noted that golimumab was, in effect, not cost effective when compared with etanercept, but may be cost effective when compared with adalimumab and infliximab. The Committee was aware that the patient access scheme (as described in section 2.4) would provide the 100 mg dose of golimumab at the same cost as the 50 mg dose. The Committee concluded that, with the incorporation of the patient access scheme and if the criteria specified in TA199 were met, golimumab should be recommended as an option for the treatment of active and progressive psoriatic arthritis in adults, as described for other TNF inhibitor treatments in TA199.
# Summary of the Appraisal Committee's key conclusions
TA220 (STA)
Golimumab for the treatment of psoriatic arthritis
FAD section
Key conclusions
Golimumab is recommended as an option for the treatment of active and progressive psoriatic arthritis in adults only if:
it is used as described for other tumour necrosis factor (TNF) inhibitor treatments in 'Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis' (NICE technology appraisal guidance 199)and
the manufacturer provides the 100 mg dose of golimumab at the same cost as the 50 mg dose.
When using the Psoriatic Arthritis Response Criteria (PsARC; as set out in NICE technology appraisal guidance 199), healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate.
The key drivers for these recommendations were:
that the evidence was not robust enough to confirm clinically important differences in the effectiveness of golimumab compared with the other TNF inhibitors recommended in NICE technology appraisal guidance 199
that although golimumab was not as cost effective as etanercept, the cost-effectiveness estimates of the 50 mg dose of golimumab compared with adalimumab and infliximab were acceptable.
Current practice
Clinical need of patients
Psoriatic arthritis can cause significant distress and psychological impact on the person's life. People with psoriatic arthritis value a choice among treatments, and may prefer the option of a treatment that is self-injectable and/or has a longer retreatment interval.
The Committee noted that the pain and disability of the arthritis component of the disease often have a significant impact on the person's quality of life.
Availability of alternative treatments
NICE technology appraisal guidance 199 recommends adalimumab, etanercept and infliximab for the treatment of psoriatic arthritis when the person has peripheral arthritis with three or more tender joints and three or more swollen joints, and when the psoriatic arthritis has not responded to adequate trials of at least two standard DMARDs (administered either individually or in combination). NICE technology appraisal guidance 199 specifies that treatment should be with the least expensive drug, taking into account drug administration costs, required dose and product price per dose.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits and how it might improve the way that current need is met (i.e., is this a 'step-change' in the management of the condition)?
Clinical specialists and the patient expert emphasised that people often prefer a less frequent dosing schedule. The Committee understood that people with psoriatic arthritis and clinicians may therefore value the once-monthly, self-injectable administration of golimumab.
What is the position of the treatment in the pathway of care for the condition?
The Committee concluded that adalimumab, etanercept and infliximab as recommended in NICE technology appraisal guidance 199 were the appropriate comparators for golimumab.
Adverse effects
There were a number of 'serious' adverse events reported with the use of golimumab. However, the pivotal trial was not powered to detect statistically significant differences in adverse event outcomes. The Committee concluded that although there remains uncertainty about golimumab's long-term adverse event profile, it had not been shown to be different from that of other TNF inhibitors.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The main clinical effectiveness data were derived from a single phase III RCT. The Committee noted statistically significant outcomes for the 50 mg dose of golimumab compared with placebo for improvements in joint disease, skin disease and functional status. The Committee concluded that golimumab was clinically effective compared with placebo.
The Committee noted there had been no head-to-head trials between golimumab and any of the other TNF inhibitors. As a result, the manufacturer had conducted a mixed treatment comparison. The Committee recognised the limitations of mixed treatment comparisons and was aware that the associated results would need to be interpreted with caution.
The Committee noted that for PsARC response and absolute change in PASI from baseline, the results of the mixed treatment comparison suggested golimumab was generally equivalent to the other TNF inhibitors. However, the Committee also noted that golimumab had the lowest HAQ score change from baseline compared with the other TNF inhibitors.
The Committee was concerned that, out of the four TNF inhibitors that were compared, golimumab had the lowest HAQ score change from baseline and that this might indicate inferiority of its anti-arthritic activity; however, the Committee was also aware of the limitations of the mixed treatment comparison methodology. With regard to the data for radiographic progression, no mixed treatment comparison had been provided. Using a raw comparison of data from separate trials, the Committee understood that absolute differences between golimumab and infliximab in the respective change from baseline in vdH-S score were small, and may be due to differences in the trial populations.
Relevance to general clinical practice in the NHS
Clinical specialists stated that they would be more likely to select a different TNF inhibitor than to increase the dose if the 50 mg dose of golimumab failed to produce a response.
Uncertainties generated by the evidence
The main clinical trial evidence was derived from a single phase III, randomised controlled study. Because there had been no head-to-head trials between golimumab and any of the other TNF inhibitors, the manufacturer had conducted a mixed treatment comparison.
Based on a raw comparison of golimumab trial data with that of infliximab, the change from baseline in vdH-S score (which is a measure of radiographic progression) at week 24 for golimumab was less than that for infliximab. The Committee was aware, however, that this difference may be due to differences in the trial populations, as reflected by the difference between the trials in the respective changes from baseline with placebo.
The 100 mg dose in the pivotal trial was not limited to people weighing over 100 kg, and was therefore not reflective of the population in the marketing authorisation for that dose.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
No subgroups were identified for which there is evidence of differential effectiveness.
N/A
Estimate of the size of the clinical effectiveness including strength of supporting evidence
Although the evidence suggested that golimumab may be less effective in its anti-arthritic activity (based on the HAQ score results from the mixed treatment comparison and the data for radiographic progression), on balance the Committee concluded that the evidence was not robust enough to confirm clinically important differences in the effectiveness of golimumab compared with the other TNF inhibitors.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee heard from the ERG that the pair-wise comparisons of each of the TNF inhibitors with palliative care needed to be reworked into an incremental analysis, comparing each treatment with the next most effective alternative. The ERG re-presented these results.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted that the 100 mg dose of golimumab was not considered in the economic model, but that, because of the patient access scheme (as described in section 2.4), the cost of the 100 mg dose of golimumab would be equal to that of the 50 mg dose.
Incorporation of health-related quality of life benefits and utility values
The utility formula was derived from the HAQ score change and the PASI response. The HAQ score change had a greater effect on utility than the PASI response did, indicating that the utility benefit was driven more by the reduction in joint symptoms than the reduction in skin disease. The Committee concluded that this was appropriate.
Have any potential significant and substantial health-related benefits been identified that were not included in the QALY calculation, and how have these been separately evaluated and what is the impact (if any) on the judgement of the most plausible ICER?
There were no material claims made by the manufacturer regarding any health-related benefits of the technology that were not included in the QALY calculation. None were identified or considered by the Committee.
N/A
Are there specific groups of people for whom the technology is particularly cost effective?
No subgroups were identified for whom golimumab is particularly cost effective.
N/A
What are the key drivers of cost effectiveness?
When each TNF inhibitor was compared with the next most effective alternative, all alternatives to etanercept were either dominated (infliximab) or extendedly-dominated (adalimumab and golimumab).
As NICE technology appraisal guidance 199 recommends adalimumab and infliximab alongside etanercept, the Committee considered whether golimumab was at least as cost effective as adalimumab and infliximab. The Committee noted the weaknesses of the evidence suggesting clinically important differences in the effectiveness of golimumab compared with the other TNF inhibitors.
Given the weaknesses of the evidence suggesting lesser clinical effectiveness of golimumab compared with the other TNF inhibitors, and the estimates of golimumab's cost effectiveness compared with adalimumab and infliximab, the Committee concluded that the 50 mg dose of golimumab was acceptable when the criteria in NICE technology appraisal guidance 199 are met.
Most likely cost-effectiveness estimate (given as an ICER)
When each TNF inhibitor was compared with the next most effective alternative, all alternatives to etanercept were either dominated (infliximab) or extendedly-dominated (adalimumab and golimumab). The Committee concluded that golimumab was, in effect, less cost effective than etanercept.
The ICER of golimumab compared with adalimumab alone would be approximately £24,000 per QALY gained. The ICER for golimumab compared with infliximab would be approximately £45,000, noting that in this instance the ICER would represent a 'savings per QALY lost', as golimumab was associated with both lower costs and fewer QALYs compared with infliximab.
Additional factors taken into account
Patient Access Schemes
(PPRS)
The manufacturer of golimumab has agreed a patient access scheme with the Department of Health, in which the 100 mg dose of golimumab will be available to the NHS at the same cost as the 50 mg dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.
End-of-life considerations
(Supplementary advice on end-of-life)
The supplementary advice was not relevant to this appraisal.
N/A
Equalities considerations
The Committee concluded that, when using the PsARC, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate.
, 4.16# Recommendation for further research
The Committee highlighted the importance of collecting further data within registries of patients receiving biological treatments for psoriatic arthritis to obtain information on long-term outcomes, including adverse events.# Related NICE guidance
Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis.NICE technology appraisal guidance 199 (August 2010).# Review of guidance
The guidance on this technology will be considered for review by the Guidance Executive alongside NICE technology appraisal guidance 199 ('Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis', review date June 2013). The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveApril 2011# Changes after publication
February 2014: implementation section updated to clarify that golimumab is recommended as an option for treating psoriatic arthritis. Additional minor maintenance update also carried out.
March 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': "Golimumab is recommended as an option for the treatment of active and progressive psoriatic arthritis in adults only if:\n\nit is used as described for other tumour necrosis factor (TNF) inhibitor treatments in Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (NICE technology appraisal guidance 199), and\n\nthe manufacturer provides the 100\xa0mg dose of golimumab at the same cost as the 50\xa0mg dose.\n\nWhen using the Psoriatic Arthritis Response Criteria (PsARC; as set out in NICE technology appraisal guidance 199), healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate.", 'The technology ': "Golimumab (Simponi, Schering-Plough/Centocor) is a human monoclonal antibody that prevents the binding of tumour necrosis factor (TNF) to its receptors, thereby neutralising its activity. Golimumab has a marketing authorisation for the treatment of active and progressive psoriatic arthritis (alone or in combination with methotrexate) in adults when the response to previous disease-modifying antirheumatic drug (DMARD) therapy has been inadequate. The summary of product characteristics (SPC) notes that golimumab has also been shown to improve physical function in this population.\n\nGolimumab is contraindicated in people with moderate to severe heart failure, hereditary problems of fructose intolerance, active tuberculosis and other severe infections. Before initiating therapy, physicians should evaluate people for prior evidence of hepatitis B virus infection, and both active and inactive (latent) tuberculosis infection. The SPC states that the needle cover on the pre-filled golimumab injection pen contains latex and therefore may cause allergic reactions in people with latex sensitivity. The SPC reports that the most common adverse reactions are upper respiratory tract infections, including nasopharyngitis, pharyngitis, laryngitis and rhinitis. For full details of adverse effects, contraindications, special warnings and precautions for use, see the SPC.\n\nGolimumab is injected subcutaneously via a pre-filled injection pen. The recommended dose is 50\xa0mg given once a month, on the same date each month. The SPC states that in people who weigh more than 100\xa0kg whose psoriatic arthritis does not show an adequate clinical response after three or four\xa0doses, the dose of golimumab may be increased to 100\xa0mg once a month. The cost of golimumab is £774.58 for a 50\xa0mg pre-filled injection pen (excluding VAT, 'MIMS' February 2011 edition), which is equivalent to an annual cost of £9294.96 (based on the 50\xa0mg dose). Costs may vary in different settings because of negotiated procurement discounts.\n\nThe manufacturer of golimumab has agreed a patient access scheme with the Department of Health, in which the 100\xa0mg dose of golimumab will be available to the NHS at the same cost as the 50\xa0mg dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of golimumab and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe main clinical effectiveness data were derived from a single phase III randomised controlled trial (RCT) – GO-REVEAL. The trial compared golimumab with placebo for the treatment of active and progressive psoriatic arthritis in people who had symptoms despite the use of current or previous DMARDs or non-steroidal anti-inflammatory drugs. Of the 405\xa0trial participants, 113 were randomised to placebo, 146 were randomised to a 50\xa0mg dose of golimumab and 146 were randomised to a 100\xa0mg dose of golimumab. Randomisation was maintained for 24\xa0weeks. Upward titration was allowed at week\xa016, such that the participants in the placebo group could switch to 50\xa0mg golimumab and those in the 50\xa0mg golimumab group could have their dose increased to 100\xa0mg if their disease had failed to respond. In the placebo group 50% of participants crossed over to golimumab 50\xa0mg treatment and in the golimumab 50\xa0mg group 20% crossed over to golimumab 100\xa0mg treatment. Outcomes were assessed at 14 and 24\xa0weeks.\n\nThe primary outcomes in GO-REVEAL were American of Rheumatology (ACR)\xa020 response at week\xa014 and the change from baseline in the psoriatic arthritis modified van der Heijde-Sharp (vdH-S) score at week\xa024. Secondary outcomes included ACR\xa020 response at week\xa024, Psoriatic Arthritis Response Criteria (PsARC) response at weeks\xa014 and 24, and Psoriasis Area and Severity Index (PASI)\xa075 improvement at week\xa014 in participants with psoriasis that affected 3% or more of their body surface area at baseline. Physical functional status was measured by Health Assessment Questionnaire (HAQ) score at week\xa024. Health-related quality of life was measured by the Short Form 36 Health Survey (SF-36) at week\xa014.\n\nThe week\xa014 results of GO-REVEAL indicated that, compared with placebo, golimumab showed a statistically significant improvement in joint disease. An ACR\xa020 response was seen in 50.7% of participants in the 50\xa0mg treatment arm compared with 8.8% in the placebo arm (relative risk [RR]\xa05.727, 95%\xa0confidence interval [CI]\xa03.24 to 10.56). A PsARC response was seen in 73.3% of participants in the 50\xa0mg treatment arm compared with 21.2% in the placebo arm (RR\xa03.451, 95%\xa0CI\xa02.46 to 4.87). Golimumab also showed a statistically significant improvement in skin disease as measured by PASI\xa075 at both 14 and 24\xa0weeks. A PASI\xa075 response was seen in 40.4% of participants in the 50\xa0mg treatment arm compared with 2.5% in the placebo arm (RR\xa015.945, 95%\xa0CI\xa04.62 to 59.11) at 14\xa0weeks, and in 55.9% of participants in the 50\xa0mg treatment arm compared with 1.4% in the placebo arm (RR\xa040.794, 95%\xa0CI\xa07.86 to 232.88) at 24\xa0weeks. There was also a statistically significant improvement in functional status (HAQ) at 24\xa0weeks. A mean HAQ score change from baseline of 0.33 (standard deviation [SD]\xa00.55, p\xa0<\xa00.001) was observed in the golimumab 50\xa0mg arm compared with −0.01 (SD\xa00.49) in the placebo arm. Data on HAQ score change from baseline were not available for the 14-week time point.\n\nThe manufacturer reported that golimumab 50\xa0mg produced a statistically significant reduction from baseline in vdH-S score of 0.16 (p\xa0=\xa00.01) at 24\xa0weeks compared with placebo. The reduction from baseline in vdH-S score was not statistically significant in the golimumab 100\xa0mg group (p\xa0=\xa00.09). The manufacturer did not report vdH-S scores at the 14\xa0week time point.\n\nThe Evidence Review Group (ERG) reported that the main limitation of the efficacy evaluation of golimumab was that the analyses of efficacy outcomes were restricted to the GO-REVEAL trial, which had a limited sample size and was of limited duration (see section 3.1).\n\nThe manufacturer stated that the most frequently reported adverse events associated with golimumab therapy were infections and infestations, including upper respiratory tract infections and nasopharyngitis. The manufacturer reported that the safety profile of golimumab was comparable to that of the other TNF inhibitors adalimumab, etanercept and infliximab.\n\nThe ERG reported concerns about the adverse event data presented for golimumab. It noted that no long-term adverse event data had been presented, and that in its original submission the manufacturer had not included adverse event data on golimumab from controlled studies of its use in other conditions such as rheumatoid arthritis or ankylosing spondylitis. The ERG reported that the manufacturer's conclusion that golimumab has a safety profile comparable to that of the other TNF inhibitors may be premature.\n\nFollowing consultation on the Appraisal Consultation Document, the manufacturer submitted evidence on the long-term safety of golimumab. These data included 104-week results from the GO-REVEAL extension study in addition to 52- and 104-week safety data in trial participants with psoriatic arthritis, rheumatoid arthritis and ankylosing spondylitis who had received treatment with golimumab across all of the original phase III studies. These data were marked as confidential and therefore cannot be reported.\n\nIn the absence of head-to-head comparisons between golimumab and the other TNF inhibitors, the manufacturer conducted a mixed treatment comparison. The mixed treatment comparison included seven trials: the GO-REVEAL trial (golimumab versus placebo); two RCTs comparing etanercept with placebo (Mease 2000 and Mease 2004); two RCTs comparing infliximab with placebo (IMPACT and IMPACT 2); and two RCTs comparing adalimumab with placebo (ADEPT and Genovese 2007). All of the TNF inhibitors have marketing authorisations for the treatment of active and progressive psoriatic arthritis that has responded inadequately to previous DMARDs.\n\nThe trials included in the mixed treatment comparison were similar in terms of joint disease severity at baseline (for example, mean tender joint count and mean swollen joint count). There were differences, however, in the proportions of trial participants who could be evaluated for psoriasis endpoints at baseline. Most participants had received treatment with one prior DMARD, although no trial specified non-response to at least two DMARDs.\n\nThe outcomes included in the mixed treatment comparison analyses were PsARC response, change in HAQ score given PsARC response to treatment, change in HAQ score given no PsARC response, and change in PASI in people with psoriasis that affected 3% or more of their body surface area at baseline. The manufacturer selected absolute changes as the main outcomes, stating that these were the most appropriate outcomes for economic modelling. No analysis of the ACR outcomes was included in the mixed treatment comparison.\n\nThe results of the mixed treatment comparison indicated that of the four TNF inhibitors, golimumab was associated with the third highest PsARC response and absolute change in PASI from baseline. Of the four TNF inhibitors, golimumab had the lowest HAQ score change from baseline, both in people whose disease responded to treatment based on PsARC score and in those whose disease did not respond. The numerical values for each outcome derived from the mixed treatment comparison were marked as confidential and therefore cannot be reported.\n\nThe ERG reported that the network of trials included in the mixed treatment comparison was appropriately constructed, but that there were differences among the trial populations in disease severity and number of previously tried DMARDs (with many participants having received only one previous DMARD). The ERG commented that the trial populations were not precisely representative of the population with active and progressive psoriatic arthritis for whom TNF inhibitors are recommended in current British Society for Rheumatology guidelines and in Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (NICE technology appraisal guidance\xa0199 [TA199]).\n\nThe manufacturer developed its own economic evaluation, which comprised a patient cohort model. The model compared the effects of treatment with golimumab (50\xa0mg) in adults with active and progressive psoriatic arthritis whose disease had responded inadequately to DMARDs with the effects of treatment with infliximab, adalimumab and etanercept and with palliative care. All people entered the model with the same baseline characteristics as participants in the GO-REVEAL trial and left the model at death, irrespective of the treatment regimen. The model used a 12-week cycle for the first two cycles and annual cycles thereafter. The model captured response to treatment using HAQ score (conditional on PsARC response) as the arthritis measure and PASI score as the psoriasis measure. If there was no response to treatment at 12\xa0weeks (according to PsARC), treatment was discontinued. The price year used for costs was not reported in the manufacturer's submission. Costs and benefits were discounted at 3.5% per annum over 40\xa0years.\n\nThe manufacturer reported that estimates of treatment effectiveness – including PsARC response, HAQ score changes from baseline for people whose disease had responded to treatment according to PsARC at 12\xa0weeks, HAQ score changes from baseline for those whose disease had not responded to treatment according to PsARC at 12\xa0weeks, and PASI change from baseline in people with measurable psoriasis – were derived from the mixed treatment comparison.\n\nThe model assumed that people who continue treatment with a TNF inhibitor maintain their initial improvement in HAQ score. The same ongoing rate of withdrawal from treatment was used for all the TNF inhibitors (16.5% per annum) and represented withdrawal because of treatment failure or adverse events.\n\nThe manufacturer combined data from IMPACT2 (a study of infliximab) and GO-REVEAL using the 'Gray' algorithm to estimate utility values. The Gray algorithm converts Short Form 36 (SF-36) data to EuroQol (EQ-5D) estimates and then to utilities. The disutility of adverse events was not modelled.\n\nThe manufacturer reported that resource use associated with treatment, administration and monitoring of infliximab, etanercept and adalimumab was taken from the Assessment Group's model for TA199. In the patient access scheme (as described in section 2.4) the manufacturer provides the 100\xa0mg dose of golimumab at the same cost as the 50\xa0mg dose. Therefore, only the cost of the 50\xa0mg dose of golimumab (£774.58) was included in the model. The model contained an additional 4\xa0hours of staff nurse costs for training people to self-administer subcutaneous TNF inhibitors. The costs of infliximab were initially calculated on the assumption that vial sharing was allowed (using an average of 3.5\xa0vials per infusion, although this assumption was later removed following a request for clarification from the ERG). The costs associated with adverse events were not included.\n\nThe manufacturer revised its original base-case estimates in response to a request from the ERG for clarification about the way utilities were calculated and for the removal of the infliximab vial sharing assumption. The revised base-case results produced total costs, total quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs, pairwise comparisons with palliative care) as follows:\n\npalliative care: total costs of £62,224 and total QALYs of 6.61\n\nadalimumab: total costs of £86,410 and total QALYs of 7.89, resulting in an ICER of £18,824 per QALY gained\n\ngolimumab: total costs of £94,151 and total QALYs of 8.21, resulting in an ICER of £19,993 per QALY gained\n\netanercept: total costs of £94,578 and total QALYs of 8.49, resulting in an ICER of £17,177 per QALY gained\n\ninfliximab: total costs of £106,620 and total QALYs of 8.49, resulting in an ICER of £23,578 per QALY gained.\n\nThe ERG reported that the manufacturer had not provided an incremental analysis in which dominated and extendedly dominated options were excluded. An option is 'dominated' if there is another option that is less costly and more effective. An option is 'extendedly dominated' when its ICER is higher than that of the next, more effective, option when compared with a common baseline (that is, it is dominated by a combination of two other alternatives). The ERG recalculated the manufacturer's base-case results by incrementally comparing each treatment with the next, more effective, option and excluding those that were extendedly dominated. The recalculated base-case results showed that both adalimumab and golimumab were extendedly dominated by a combination of etanercept and palliative care. Etanercept in comparison with palliative care was associated with an incremental cost of £32,354 and an incremental QALY gain of 1.88, resulting in an ICER of £17,209. Infliximab was dominated by etanercept.\n\nThe manufacturer conducted two subgroup analyses: one of the population with 'predominantly' rheumatic disease and one of the population with 'significant' psoriasis. The ERG recalculated the results of these analyses as described in section 3.20. The results of the recalculated subgroup analyses show adalimumab and golimumab to be extendedly dominated by a combination of etanercept and palliative care. Etanercept in comparison with palliative care was associated with an incremental cost of £34,492 and an incremental QALY gain of 2.21, resulting in an ICER of £15,607 per QALY gained in the rheumatic disease subgroup. In the psoriasis subgroup, etanercept in comparison with palliative care was associated with an incremental cost of £31,564 and an incremental QALY gain of 2.25, resulting in an ICER of £14,028 per QALY gained. Infliximab was dominated by etanercept in the rheumatic disease subgroup, and was associated with an incremental cost of £5702 and an incremental QALY gain of 0.01, resulting in an ICER of £570,200 per QALY gained in comparison with etanercept in the psoriasis subgroup.\n\nThe ERG commented that the model structure was reasonable. The ERG stated that the inclusion of costs to cover time for training in self-injection may have been unnecessary, but reported that all other included costs were appropriate. The ERG considered that it may have been appropriate to account for the possibility of dose escalation to 100\xa0mg (as per the marketing authorisation; see section 2.3). The ERG reported that the subgroup analyses were appropriate.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of golimumab, having considered evidence on the nature of psoriatic arthritis and the value placed on the benefits of golimumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources and the impact of the patient access scheme (see section 2.4).\n\nThe Committee understood that psoriatic arthritis can cause significant distress and psychological impact on the person's life, employment and social activities. The Committee heard from a patient expert that TNF inhibitors are valued options for the treatment of psoriatic arthritis and have a positive impact on quality of life. It understood that people with the condition may prefer the option of a treatment that is self-injectable and/or has a longer retreatment interval. The Committee understood that people value having a choice of TNF inhibitors and that another treatment option will always be welcome.\n\nThe Committee considered current clinical practice for the treatment of psoriatic arthritis. It understood that TA199 recommends adalimumab, etanercept and infliximab for the treatment of psoriatic arthritis in people who have peripheral arthritis with three or more tender joints and three or more swollen joints, and when the psoriatic arthritis has not responded to adequate trials of at least two standard DMARDs (administered either individually or in combination). The Committee also noted that TA199 specifies that treatment should be with the least expensive drug, taking into account drug administration costs, required dose and product price per dose. It heard from the clinical specialists that they considered there to be little demonstrable difference between the TNF inhibitors in terms of their clinical effectiveness. The clinical experts did, however, note slight differences among the TNF inhibitors in TA199 with regard to the subjective reduction in response to treatment in the skin and joint components of the disease. The Committee heard from the commissioning expert that subtle differences in cost and administration, particularly with regard to dose escalation (as included in the marketing authorisation for infliximab) and hospitalisation, can make a big cost difference. The Committee concluded that adalimumab, etanercept and infliximab were the appropriate comparators for golimumab.\n\nThe Committee heard from the clinical specialists and the patient expert that people often prefer a less frequent dosing schedule; that is, a longer time period between treatments. However, the Committee noted that the longer retreatment interval associated with golimumab could potentially result in more discomfort because of waning efficacy before retreatment. It understood that people with psoriatic arthritis and their clinicians may therefore value the once-monthly, self-injectable administration of golimumab. The Committee concluded that golimumab could, on balance, be a valued additional treatment option for people with psoriatic arthritis.\n\nThe Committee considered the evidence on the clinical effectiveness of golimumab. It understood that the main clinical effectiveness data were derived from a single phase III RCT. The Committee noted statistically significant outcomes for the 50\xa0mg dose compared with placebo in terms of improvements in joint disease, skin disease and functional status (see sections 3.3 and 3.4). The Committee concluded that golimumab was clinically effective compared with placebo.\n\nThe Committee discussed the 100\xa0mg dose of golimumab, which may be considered for people who weigh more than 100\xa0kg and whose psoriatic arthritis has not responded after three or four doses of golimumab (as stated in the SPC). It noted that neither the 100\xa0mg arm nor dose escalation to 100\xa0mg in the 50\xa0mg arm in the GO-REVEAL trial was limited to people who weighed more than 100\xa0kg, and therefore the trial population did not reflect the population in the marketing authorisation for the 100\xa0mg dose. The Committee heard from clinical specialists that they would be more likely to select a different TNF inhibitor than to increase the dose if the 50\xa0mg dose of golimumab failed to produce a response. The Committee concluded that it was uncertain of the extent to which the 100\xa0mg dose would be used in clinical practice.\n\nThe Committee noted that there had been no head-to-head trials of golimumab and any of the other TNF inhibitors, and that, as a result, the manufacturer had conducted a mixed treatment comparison. The Committee recognised the limitations of mixed treatment comparisons and was aware that the associated results would need to be interpreted with caution. It also noted the manufacturer's reservations about mixed treatment comparisons and the uncertainty associated with the use of such methodologies, but noted that no alternative methods or data had been provided. Following the consultation on the Appraisal Consultation Document, the manufacturer suggested the removal of the Mease 2000 results (for etanercept) from the mixed treatment comparison, because this trial did not disaggregate HAQ scores in the same way as other trials, and showed better results for etanercept than Mease 2004 (the larger etanercept trial). The Committee had misgivings about the selective removal of individual trials, but heard from the ERG that extracting the Mease 2000 study from the mixed treatment comparison had little effect on the results. The Committee agreed it would bear this in mind when considering the results of the mixed treatment comparison.\n\nThe Committee carefully considered the results of the mixed treatment comparison. It noted that for PsARC response and absolute change in PASI from baseline, the results showed that golimumab was generally equivalent to the other TNF inhibitors. However, it also noted that golimumab had the lowest HAQ score change from baseline (both in participants whose disease responded to treatment based on PsARC score and those whose disease did not respond based on PsARC score) compared with the other TNF inhibitors.\n\nThe Committee further discussed the HAQ results from the mixed treatment comparison. The Committee understood from the clinical specialists and the patient expert that pain and disability caused by arthritis (as captured by HAQ score and reflected in the manufacturer's economic model) often have a significant impact on the person's quality of life. The Committee was concerned that, out of the four TNF inhibitors that were compared, golimumab had the lowest HAQ score change from baseline and that this might indicate inferiority of its anti-arthritic activity (see section 3.12); however, the Committee was also aware of the limitations of the mixed treatment comparison methodology. Therefore the Committee also considered the radiographic progression data, which, together with the change in HAQ score, could be used to assess the effect of a treatment on disease progression. The Committee noted the statistically significant reduction from baseline in vdH-S score (a measure of radiographic progression) for golimumab compared with placebo at 24\xa0weeks (−0.16 for 50\xa0mg golimumab compared with 0.27 for placebo, p\xa0=\xa00.01; see section 3.4). It noted that the change from baseline in vdH-S score at week\xa024 for golimumab was less than that for infliximab (−0.70 for 5\xa0mg/kg infliximab compared with 0.82 for placebo, p\xa0<\xa00.001), which was the other TNF inhibitor for which radiographic progression was measured by vdH-S score in the trials included in the mixed treatment comparison. The Committee was aware, however, that this difference may be due to differences in the trial populations, as reflected by the respective changes from baseline with placebo. The Committee also understood that the absolute differences between the two changes from baseline were small. Although the evidence suggested that golimumab may be less effective in its anti-arthritic activity (based on the HAQ score results from the mixed treatment comparison and the data for radiographic progression), on balance the Committee concluded that the evidence was not robust enough to confirm clinically important differences in the effectiveness of golimumab compared with the other TNF inhibitors.\n\nThe Committee considered the evidence on the adverse event rates associated with the use of golimumab. It noted a number of reported 'serious' adverse events, but understood that GO-REVEAL was not powered to detect statistically significant differences in adverse event outcomes. The Committee considered the additional evidence submitted by the manufacturer on the long-term adverse event data for golimumab in people with psoriatic arthritis, and also for people with rheumatoid arthritis and ankylosing spondylitis. It concluded that although there remains uncertainty about golimumab's long-term adverse event profile, it had not been shown to be different from that of other TNF inhibitors.\n\nThe Committee considered the economic model presented by the manufacturer. The Committee noted that the model assumed people continuing on therapy maintained their initial improvement in HAQ score. The Committee considered the utility estimates incorporated in the model, and noted that the utility formula was derived from the HAQ score change and the PASI response. The HAQ score change had a greater effect on utility than the PASI response did, indicating that the calculated utility benefit was driven more by the reduction in joint symptoms than the reduction in skin disease. The Committee concluded that this was appropriate (see section 4.9).\n\nThe Committee considered the results of the manufacturer's base-case analysis, which compared each of the TNF inhibitors (including golimumab) with palliative care. The Committee heard from the ERG that the pair-wise comparisons with palliative care needed to be reworked into an incremental analysis comparing each treatment with the next most effective alternative. The ERG re-presented these results. The Committee was aware that the acquisition costs of adalimumab, etanercept and golimumab (50\xa0mg) were similar, and that the acquisition cost of infliximab was dependent on the person's weight and the amount of the drug required, with additional administration costs for infliximab (related to intravenous infusion). The Committee noted that all alternatives to etanercept were either dominated (infliximab was more expensive but no better than etanercept) or extendedly dominated (adalimumab and golimumab were, in effect, less cost effective than etanercept; see section 3.20). The Committee agreed that golimumab was, in effect, less cost effective than etanercept.\n\nThe Committee was aware, however, that TA199 recommends adalimumab and infliximab alongside etanercept. The Committee therefore also considered whether golimumab was at least as cost effective as adalimumab and infliximab. The Committee was aware that in the incremental analysis, both adalimumab and golimumab were extendedly dominated by etanercept. However, the Committee noted that the pairwise ICER of golimumab compared with adalimumab alone would be approximately £24,000 per QALY gained. The Committee similarly noted that the pairwise ICER for golimumab compared with infliximab would be approximately £45,000, aware that in this instance the ICER would represent a 'savings per QALY lost', as golimumab was associated with both lower costs and fewer QALYs compared with infliximab (see section 3.19). Given the weaknesses of the evidence suggesting lesser clinical effectiveness of golimumab compared with the other TNF inhibitors, and the estimates of golimumab's cost effectiveness compared with adalimumab and infliximab, the Committee concluded that the 50\xa0mg dose of golimumab was acceptable when the criteria in TA199 are met; that is, the person has peripheral arthritis with three or more tender joints and three or more swollen joints, and the psoriatic arthritis has not responded to adequate trials of at least two standard disease-modifying antirheumatic drugs (DMARDs), administered either individually or in combination.\n\nThe Committee considered the 100\xa0mg dose of golimumab. The Committee was aware that the SPC for golimumab states that for people who weigh more than 100\xa0kg whose disease does not show an adequate clinical response after three or four\xa0doses, the dose of golimumab may be increased to 100\xa0mg once a month. The Committee heard two different opinions about the proportion of people who would be eligible for the higher dose. The Committee agreed that this proportion was uncertain, but that it could be substantial. The Committee noted that the 100\xa0mg dose of golimumab was not considered in the economic model, but that, because of the patient access scheme (as described in section 2.4), the cost of the 100\xa0mg dose would be equal to that of the 50\xa0mg dose. In addition, the Committee acknowledged the comments from the clinical specialists that, in clinical practice, people would be more likely to be switched to a different TNF inhibitor if no response was observed with the 50\xa0mg dose, than to have the dose increased (see section 4.6). The Committee also noted TA199 states that treatment choice should be based on cost (taking into account drug administration costs, required dose and product price per dose), with treatment initiated with the least expensive drug. Therefore the Committee concluded that with the incorporation of the patient access scheme, golimumab would be considered an acceptable option for the treatment of psoriatic arthritis if used as described for other TNF inhibitors in TA199.\n\nThe Committee discussed the discontinuation of treatment with etanercept, infliximab and adalimumab in TA199. The Committee considered that the recommendation to discontinue treatment based on an inadequate PsARC response at 12\xa0weeks included in TA199 was also appropriate for golimumab. The Committee was aware that no evidence had been provided by the manufacturer for the use of golimumab after the failure of other TNF inhibitors. The Committee was therefore unable to make recommendations about the use of golimumab following the failure of other TNF inhibitors.\n\nThe Committee was aware that there may be some circumstances that could affect a person's responses to components of the PsARC such as any physical, sensory or learning disabilities, or communication difficulties. The Committee concluded that in such cases, healthcare professionals should make any adjustments they consider appropriate.\n\nThe Committee was aware of registries that collect data on the long-term outcomes of treatment with TNF inhibitors for rheumatoid arthritis. The Committee noted the importance of registries in gathering data and supported the inclusion of outcomes specific to psoriatic arthritis in a suitable registry so that specific information about treatments and treatment-related adverse events in psoriatic arthritis can be collected.\n\nIn summary, the Committee considered the clinical and cost effectiveness of golimumab in the light of the submitted evidence and the comments of the clinical specialists, the commissioning expert and the patient expert. The Committee noted that although the evidence suggested that golimumab may be less effective in its anti-arthritic activity (based on the HAQ score results from the mixed treatment comparison and the data for radiographic progression), the evidence was not robust enough to confirm clinically important differences in the effectiveness of golimumab compared with the other TNF inhibitors. The Committee further noted that golimumab was, in effect, not cost effective when compared with etanercept, but may be cost effective when compared with adalimumab and infliximab. The Committee was aware that the patient access scheme (as described in section 2.4) would provide the 100\xa0mg dose of golimumab at the same cost as the 50\xa0mg dose. The Committee concluded that, with the incorporation of the patient access scheme and if the criteria specified in TA199 were met, golimumab should be recommended as an option for the treatment of active and progressive psoriatic arthritis in adults, as described for other TNF inhibitor treatments in TA199.\n\n# Summary of the Appraisal Committee's key conclusions\n\nTA220 (STA)\n\n\n\nGolimumab for the treatment of psoriatic arthritis\n\nFAD section\n\n\n\nKey conclusions\n\nGolimumab is recommended as an option for the treatment of active and progressive psoriatic arthritis in adults only if:\n\nit is used as described for other tumour necrosis factor (TNF) inhibitor treatments in 'Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis' (NICE technology appraisal guidance 199)and\n\nthe manufacturer provides the 100\xa0mg dose of golimumab at the same cost as the 50\xa0mg dose.\n\n\n\n\n\n\n\n\n\n\n\n\n\nWhen using the Psoriatic Arthritis Response Criteria (PsARC; as set out in NICE technology appraisal guidance\xa0199), healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate.\n\n\n\n\n\n\n\nThe key drivers for these recommendations were:\n\nthat the evidence was not robust enough to confirm clinically important differences in the effectiveness of golimumab compared with the other TNF inhibitors recommended in NICE technology appraisal guidance\xa0199\n\n\n\n\n\n\n\nthat although golimumab was not as cost effective as etanercept, the cost-effectiveness estimates of the 50\xa0mg dose of golimumab compared with adalimumab and infliximab were acceptable.\n\n\n\n\n\n\n\n\n\nCurrent practice\n\nClinical need of patients\n\n\n\n\n\n\n\nPsoriatic arthritis can cause significant distress and psychological impact on the person's life. People with psoriatic arthritis value a choice among treatments, and may prefer the option of a treatment that is self-injectable and/or has a longer retreatment interval.\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee noted that the pain and disability of the arthritis component of the disease often have a significant impact on the person's quality of life.\n\n\n\nAvailability of alternative treatments\n\n\n\n\n\nNICE technology appraisal guidance\xa0199 recommends adalimumab, etanercept and infliximab for the treatment of psoriatic arthritis when the person has peripheral arthritis with three or more tender joints and three or more swollen joints, and when the psoriatic arthritis has not responded to adequate trials of at least two standard DMARDs (administered either individually or in combination). NICE technology appraisal guidance\xa0199 specifies that treatment should be with the least expensive drug, taking into account drug administration costs, required dose and product price per dose.\n\n\n\n\n\n\n\nThe technology\n\n\n\nProposed benefits of the technology\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits and how it might improve the way that current need is met (i.e., is this a 'step-change' in the management of the condition)?\n\nClinical specialists and the patient expert emphasised that people often prefer a less frequent dosing schedule. The Committee understood that people with psoriatic arthritis and clinicians may therefore value the once-monthly, self-injectable administration of golimumab.\n\n\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\n\n\n\n\nThe Committee concluded that adalimumab, etanercept and infliximab as recommended in NICE technology appraisal guidance\xa0199 were the appropriate comparators for golimumab.\n\n\n\n\n\nAdverse effects\n\n\n\n\n\nThere were a number of 'serious' adverse events reported with the use of golimumab. However, the pivotal trial was not powered to detect statistically significant differences in adverse event outcomes. The Committee concluded that although there remains uncertainty about golimumab's long-term adverse event profile, it had not been shown to be different from that of other TNF inhibitors.\n\n\n\n\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\n\n\n\n\nThe main clinical effectiveness data were derived from a single phase III RCT. The Committee noted statistically significant outcomes for the 50\xa0mg dose of golimumab compared with placebo for improvements in joint disease, skin disease and functional status. The Committee concluded that golimumab was clinically effective compared with placebo.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee noted there had been no head-to-head trials between golimumab and any of the other TNF inhibitors. As a result, the manufacturer had conducted a mixed treatment comparison. The Committee recognised the limitations of mixed treatment comparisons and was aware that the associated results would need to be interpreted with caution.\n\n\n\nThe Committee noted that for PsARC response and absolute change in PASI from baseline, the results of the mixed treatment comparison suggested golimumab was generally equivalent to the other TNF inhibitors. However, the Committee also noted that golimumab had the lowest HAQ score change from baseline compared with the other TNF inhibitors.\n\n\n\n\n\nThe Committee was concerned that, out of the four TNF inhibitors that were compared, golimumab had the lowest HAQ score change from baseline and that this might indicate inferiority of its anti-arthritic activity; however, the Committee was also aware of the limitations of the mixed treatment comparison methodology. With regard to the data for radiographic progression, no mixed treatment comparison had been provided. Using a raw comparison of data from separate trials, the Committee understood that absolute differences between golimumab and infliximab in the respective change from baseline in vdH-S score were small, and may be due to differences in the trial populations.\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\n\n\n\n\nClinical specialists stated that they would be more likely to select a different TNF inhibitor than to increase the dose if the 50\xa0mg dose of golimumab failed to produce a response.\n\n\n\n\n\nUncertainties generated by the evidence\n\n\n\nThe main clinical trial evidence was derived from a single phase III, randomised controlled study. Because there had been no head-to-head trials between golimumab and any of the other TNF inhibitors, the manufacturer had conducted a mixed treatment comparison.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nBased on a raw comparison of golimumab trial data with that of infliximab, the change from baseline in vdH-S score (which is a measure of radiographic progression) at week\xa024 for golimumab was less than that for infliximab. The Committee was aware, however, that this difference may be due to differences in the trial populations, as reflected by the difference between the trials in the respective changes from baseline with placebo.\n\n\n\n\n\n\n\nThe 100\xa0mg dose in the pivotal trial was not limited to people weighing over 100\xa0kg, and was therefore not reflective of the population in the marketing authorisation for that dose.\n\n\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\n\n\nNo subgroups were identified for which there is evidence of differential effectiveness.\n\nN/A\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\n\n\nAlthough the evidence suggested that golimumab may be less effective in its anti-arthritic activity (based on the HAQ score results from the mixed treatment comparison and the data for radiographic progression), on balance the Committee concluded that the evidence was not robust enough to confirm clinically important differences in the effectiveness of golimumab compared with the other TNF inhibitors.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\n\n\nThe Committee heard from the ERG that the pair-wise comparisons of each of the TNF inhibitors with palliative care needed to be reworked into an incremental analysis, comparing each treatment with the next most effective alternative. The ERG re-presented these results.\n\n\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\n\n\nThe Committee noted that the 100\xa0mg dose of golimumab was not considered in the economic model, but that, because of the patient access scheme (as described in section 2.4), the cost of the 100\xa0mg dose of golimumab would be equal to that of the 50\xa0mg dose.\n\n\n\n\n\nIncorporation of health-related quality of life benefits and utility values\n\n\n\nThe utility formula was derived from the HAQ score change and the PASI response. The HAQ score change had a greater effect on utility than the PASI response did, indicating that the utility benefit was driven more by the reduction in joint symptoms than the reduction in skin disease. The Committee concluded that this was appropriate.\n\n\n\n\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the QALY calculation, and how have these been separately evaluated and what is the impact (if any) on the judgement of the most plausible ICER?\n\n\n\nThere were no material claims made by the manufacturer regarding any health-related benefits of the technology that were not included in the QALY calculation. None were identified or considered by the Committee.\n\nN/A\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\n\n\nNo subgroups were identified for whom golimumab is particularly cost effective.\n\nN/A\n\nWhat are the key drivers of cost effectiveness?\n\n\n\nWhen each TNF inhibitor was compared with the next most effective alternative, all alternatives to etanercept were either dominated (infliximab) or extendedly-dominated (adalimumab and golimumab).\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAs NICE technology appraisal guidance\xa0199 recommends adalimumab and infliximab alongside etanercept, the Committee considered whether golimumab was at least as cost effective as adalimumab and infliximab. The Committee noted the weaknesses of the evidence suggesting clinically important differences in the effectiveness of golimumab compared with the other TNF inhibitors.\n\n\n\n\n\nGiven the weaknesses of the evidence suggesting lesser clinical effectiveness of golimumab compared with the other TNF inhibitors, and the estimates of golimumab's cost effectiveness compared with adalimumab and infliximab, the Committee concluded that the 50\xa0mg dose of golimumab was acceptable when the criteria in NICE technology appraisal guidance\xa0199 are met.\n\n\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nWhen each TNF inhibitor was compared with the next most effective alternative, all alternatives to etanercept were either dominated (infliximab) or extendedly-dominated (adalimumab and golimumab). The Committee concluded that golimumab was, in effect, less cost effective than etanercept.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe ICER of golimumab compared with adalimumab alone would be approximately £24,000 per QALY gained. The ICER for golimumab compared with infliximab would be approximately £45,000, noting that in this instance the ICER would represent a 'savings per QALY lost', as golimumab was associated with both lower costs and fewer QALYs compared with infliximab.\n\n\n\n\n\nAdditional factors taken into account\n\nPatient Access Schemes\n\n(PPRS)\n\n\n\nThe manufacturer of golimumab has agreed a patient access scheme with the Department of Health, in which the 100\xa0mg dose of golimumab will be available to the NHS at the same cost as the 50\xa0mg dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\n\n\n\n\n\nEnd-of-life considerations\n\n(Supplementary advice on end-of-life)\n\nThe supplementary advice was not relevant to this appraisal.\n\nN/A\n\nEqualities considerations\n\nThe Committee concluded that, when using the PsARC, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate.\n\n, 4.16", 'Recommendation for further research ': 'The Committee highlighted the importance of collecting further data within registries of patients receiving biological treatments for psoriatic arthritis to obtain information on long-term outcomes, including adverse events.', 'Related NICE guidance': 'Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis.NICE technology appraisal guidance 199 (August 2010).', 'Review of guidance': "The guidance on this technology will be considered for review by the Guidance Executive alongside NICE technology appraisal guidance\xa0199 ('Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis', review date June 2013). The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveApril 2011", 'Changes after publication': 'February 2014: implementation section updated to clarify that golimumab is recommended as an option for treating psoriatic arthritis. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta220
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Evidence-based recommendations on golimumab (Simponi) for treating psoriatic arthritis in adults.
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23ec1c895160e3eb5a55dfe60ae8d2b5d4765ebc
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nice
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Ovarian cancer: recognition and initial management
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Ovarian cancer: recognition and initial management
This guideline covers detecting, diagnosing and treating women (18 years and older) who have, or are suspected of having, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer or borderline ovarian cancer. It aims to enable earlier detection of ovarian cancer and improve initial treatment.
# Introduction
Ovarian cancer is the leading cause of death from gynaecological cancer in the UK, and its incidence is rising. It is the fifth most common cancer in women, with a lifetime risk of about 2% in England and Wales.
The outcome for women with ovarian cancer is generally poor, with an overall 5-year survival rate of less than 35%. This is because most women who have ovarian cancer present with advanced disease. The stage of the disease is the most important factor affecting outcome. The woman's general health at the time of presentation is also important because it affects what treatments can be used. Most women have had symptoms for months before presentation, and there are often delays between presentation and specialist referral. There is a need for greater awareness of the disease and also for initial investigations in primary and secondary care that enable earlier referral and optimum treatment.
Despite the relatively poor overall survival rates for ovarian cancer, there has been a two-fold increase in survival over the last 30 years. This has coincided with the advent of effective chemotherapy, and the introduction of platinum-based agents in particular, as well as changes in surgical practice. More recently, there has been a significant shift towards greater specialisation in the delivery of care, resulting from the implementation of the Department of Health's cancer service guidance 'Improving outcomes in gynaecological cancers'. It is likely that some or all of these changes have contributed to the improved survival rates, emphasising the need to ensure that women with diagnosed ovarian cancer are treated in specialist centres that can provide comprehensive cancer care.
This guideline does not cover the entire care pathway for ovarian cancer. It focuses on areas where there is uncertainty or wide variation in clinical practice with regard to the detection, diagnosis and initial management of ovarian cancer. The guideline recommendations are applicable to women with epithelial ovarian cancer (the most common type of ovarian cancer), as well as women with fallopian tube carcinoma, primary peritoneal carcinoma or borderline ovarian cancer (see research recommendations for further details).
The guideline assumes that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.# Guidance
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Detection in primary care
Recommendations in this section have been incorporated into the NICE guideline on suspected cancer.
## Awareness of symptoms and signs
Refer the woman urgently if physical examination identifies ascites and/or a pelvic or abdominal mass (which is not obviously uterine fibroids).An urgent referral means that the woman is referred to a gynaecological cancer service within the national target in England and Wales for referral for suspected cancer, which is currently 2 weeks. See also the NICE guideline on suspected cancer: recognition and referral.
Carry out tests in primary care (see section on asking the right question – first tests) if a woman (especially if 50 or over) reports having any of the following symptoms on a persistent or frequent basis – particularly more than 12 times per month:
persistent abdominal distension (women often refer to this as 'bloating')
feeling full (early satiety) and/or loss of appetite
pelvic or abdominal pain
increased urinary urgency and/or frequency.See also the NICE guideline on suspected cancer: recognition and referral.
Consider carrying out tests in primary care (see section on asking the right question – first tests) if a woman reports unexplained weight loss, fatigue or changes in bowel habit.
Advise any woman who is not suspected of having ovarian cancer to return to her GP if her symptoms become more frequent and/or persistent.
Carry out appropriate tests for ovarian cancer (see section on asking the right question – first tests) in any woman of 50 or over who has experienced symptoms within the last 12 months that suggest irritable bowel syndrome (IBS), because IBS rarely presents for the first time in women of this age.See NICE's clinical guideline on irritable bowel syndrome in adults.
## Asking the right question – first tests
Measure serum CA125 in primary care in women with symptoms that suggest ovarian cancer (see section on awareness of symptoms and signs).
If serum CA125 is 35 IU/ml or greater, arrange an ultrasound scan of the abdomen and pelvis.
If the ultrasound suggests ovarian cancer, refer the woman urgently for further investigation.An urgent referral means that the woman is referred to a gynaecological cancer service within the national target in England and Wales for referral for suspected cancer, which is currently 2 weeks. See also the NICE guideline on suspected cancer: recognition and referral.
For any woman who has normal serum CA125 (less than 35 IU/ml), or CA125 of 35 IU/ml or greater but a normal ultrasound:
assess her carefully for other clinical causes of her symptoms and investigate if appropriate
if no other clinical cause is apparent, advise her to return to her GP if her symptoms become more frequent and/or persistent.
# Establishing the diagnosis in secondary care
## Tumour markers: which to use?
Measure serum CA125 in secondary care in all women with suspected ovarian cancer, if this has not already been done in primary care.
In women under 40 with suspected ovarian cancer, measure levels of alpha fetoprotein (AFP) and beta human chorionic gonadotrophin (beta-hCG) as well as serum CA125, to identify women who may not have epithelial ovarian cancer.
## Malignancy indices
Calculate a risk of malignancy index I (RMI I) score (after performing an ultrasound; see recommendation 1.2.3.1) and refer all women with an RMI I score of 250 or greater to a specialist multidisciplinary team.See the appendix for details of how to calculate an RMI I score.
## Imaging in the diagnostic pathway: which procedures?
Perform an ultrasound of the abdomen and pelvis as the first imaging test in secondary care for women with suspected ovarian cancer, if this has not already been done in primary care.
If the ultrasound, serum CA125 and clinical status suggest ovarian cancer, perform a CT scan of the pelvis and abdomen to establish the extent of disease. Include the thorax if clinically indicated.
Do not use MRI routinely for assessing women with suspected ovarian cancer.
## Tissue diagnosis
Requirement for tissue diagnosis
If offering cytotoxic chemotherapy to women with suspected advanced ovarian cancer, first obtain a confirmed tissue diagnosis by histology (or by cytology if histology is not appropriate) in all but exceptional cases.
Offer cytotoxic chemotherapy for suspected advanced ovarian cancer without a tissue diagnosis (histology or cytology) only:
in exceptional cases, after discussion at the multidisciplinary team and
after discussing with the woman the possible benefits and risks of starting chemotherapy without a tissue diagnosis.
Methods of tissue diagnosis other than laparotomy
If surgery has not been performed, use histology rather than cytology to obtain a tissue diagnosis. To obtain tissue for histology:
use percutaneous image-guided biopsy if this is feasible
consider laparoscopic biopsy if percutaneous image-guided biopsy is not feasible or has not produced an adequate sample.Use cytology if histology is not appropriate.
# Management of suspected early (stage I) ovarian cancer
## The role of systematic retroperitoneal lymphadenectomy
Perform retroperitoneal lymph node assessment as part of optimal surgical staging in women with suspected ovarian cancer whose disease appears to be confined to the ovaries (that is, who appear to have stage I disease).Lymph node assessment involves sampling of retroperitoneal lymphatic tissue from the para-aortic area and pelvic side walls if there is a palpable abnormality, or random sampling if there is no palpable abnormality. Optimal surgical staging constitutes: midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and infracolic omentectomy; biopsies of any peritoneal deposits; random biopsies of the pelvic and abdominal peritoneum; and retroperitoneal lymph node assessment (Winter-Roach et al. ).
Do not include systematic retroperitoneal lymphadenectomy (block dissection of lymph nodes from the pelvic side walls to the level of the renal veins) as part of standard surgical treatment in women with suspected ovarian cancer whose disease appears to be confined to the ovaries (that is, who appear to have stage I disease).
## Adjuvant systemic chemotherapy for stage I disease
Do not offer adjuvant chemotherapy to women who have had optimal surgical staging and have low-risk stage I disease (grade 1 or 2, stage Ia or Ib).
Offer women with high-risk stage I disease (grade 3 or stage Ic) adjuvant chemotherapy consisting of 6 cycles of carboplatin.
Discuss the possible benefits and side effects of adjuvant chemotherapy with women who have had suboptimal surgical staging and appear to have stage I disease.Optimal surgical staging constitutes: midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and infracolic omentectomy; biopsies of any peritoneal deposits; random biopsies of the pelvic and abdominal peritoneum; and retroperitoneal lymph node assessment (Winter-Roach et al. ).
# Management of advanced (stage II to IV) ovarian cancer
For NICE technology appraisal guidance on first-line chemotherapy see the NICE topic page on ovarian cancer.
## Primary surgery
If performing surgery for women with ovarian cancer, whether before chemotherapy or after neoadjuvant chemotherapy, the objective should be complete resection of all macroscopic disease.
## Intraperitoneal chemotherapy
Do not offer intraperitoneal chemotherapy to women with ovarian cancer, except as part of a clinical trial.
## Second-line and subsequent treatment
For NICE technology appraisal guidance on second-line and subsequent treatment for ovarian cancer, including genomic biomarker-based therapy, see the NICE topic page on ovarian cancer.
The point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based cancer treatments.
# Support needs of women with newly diagnosed ovarian cancer
Offer all women with newly diagnosed ovarian cancer information about their disease, including psychosocial and psychosexual issues, that:
is available at the time they want it
includes the amount of detail that they want and are able to deal with
is in a suitable format, including written information.
Ensure that information is available about:
the stage of the disease, treatment options and prognosis
how to manage the side effects of both the disease and its treatments in order to maximise wellbeing
sexuality and sexual activity
fertility and hormone treatment
symptoms and signs of disease recurrence
genetics, including the chances of family members developing ovarian cancer
self-help strategies to optimise independence and coping
where to go for support, including support groups
how to deal with emotions such as sadness, depression, anxiety and a feeling of a lack of control over the outcome of the disease and treatment.# Research recommendations
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.
# Relationship between duration of symptoms of ovarian cancer and stage at diagnosis
Further research should be undertaken on the relationship between the duration and frequency of symptoms in women with ovarian cancer before diagnosis, the stage of disease at diagnosis and subsequent survival.
## Why this is important
Most women presenting with ovarian cancer have advanced disease and have had symptoms for months. Greater awareness among both women and healthcare professionals might result in women presenting earlier with less advanced disease, leading to better outcomes. There is insufficient understanding of the factors that influence earlier diagnosis in women with ovarian cancer, especially the relationship between duration of symptoms and stage at diagnosis. Data demonstrating benefits from earlier presentation will justify investment in raising awareness among women and healthcare professionals. This is likely to be a population-based study that records both the duration and frequency of symptoms.
# Imaging in the diagnostic pathway for women with ovarian cancer
Large multicentre case–control studies should be conducted to compare the accuracy of CT versus MRI for staging and for predicting optimal cytoreduction in women with ovarian cancer.
## Why this is important
Currently most women with ovarian cancer will undergo a CT scan before surgery to assess the extent and resectability of disease. CT and MRI are complementary in their abilities to detect disease, but no adequate studies have been performed that compare their effectiveness in women with suspected ovarian cancer. No comparative studies have been undertaken evaluating surgical outcome. A prospective study in women undergoing primary surgery would be feasible.
# The value of primary surgery for women with advanced ovarian cancer
Research should be undertaken to determine the effectiveness of primary surgery for women with advanced ovarian cancer whose tumour cannot be fully excised.
## Why this is important
Most women with advanced ovarian cancer undergo surgery at some point. Previous studies have shown that surgery after the completion of chemotherapy has no therapeutic value. Studies are being performed to investigate whether the timing of surgery during primary chemotherapy influences outcome. No studies have evaluated whether primary surgery itself has any therapeutic value when compared with chemotherapy alone. The potential advantages of surgery have to be offset against the morbidity, occasional mortality and undoubted costs associated with it. This would be a prospective randomised clinical trial recruiting women who have biopsy-proven advanced ovarian cancer and who are fit enough to receive surgery and chemotherapy. Women would be randomised to either chemotherapy and surgery (conventional arm) or chemotherapy alone (experimental arm). Primary outcome measures would be survival at 1 and 5 years.# Appendix: Risk of malignancy index (RMI I)
RMI I combines 3 pre-surgical features: serum CA125 (CA125), menopausal status (M) and ultrasound score (U). The RMI is a product of the ultrasound scan score, the menopausal status and the serum CA125 level (IU/ml).
RMI = U x M x CA125
The ultrasound result is scored 1 point for each of the following characteristics: multilocular cysts, solid areas, metastases, ascites and bilateral lesions. U = 0 (for an ultrasound score of 0), U = 1 (for an ultrasound score of 1), U = 3 (for an ultrasound score of 2 to 5).
The menopausal status is scored as 1 = pre-menopausal and 3 = post-menopausal.
The classification of 'post-menopausal' is a woman who has had no period for more than 1 year or a woman over 50 who has had a hysterectomy.
Serum CA125 is measured in IU/ml and can vary between 0 and hundreds or even thousands of units.
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{'Introduction': "Ovarian cancer is the leading cause of death from gynaecological cancer in the UK, and its incidence is rising. It is the fifth most common cancer in women, with a lifetime risk of about 2% in England and Wales.\n\nThe outcome for women with ovarian cancer is generally poor, with an overall 5-year survival rate of less than 35%. This is because most women who have ovarian cancer present with advanced disease. The stage of the disease is the most important factor affecting outcome. The woman's general health at the time of presentation is also important because it affects what treatments can be used. Most women have had symptoms for months before presentation, and there are often delays between presentation and specialist referral. There is a need for greater awareness of the disease and also for initial investigations in primary and secondary care that enable earlier referral and optimum treatment.\n\nDespite the relatively poor overall survival rates for ovarian cancer, there has been a two-fold increase in survival over the last 30 years. This has coincided with the advent of effective chemotherapy, and the introduction of platinum-based agents in particular, as well as changes in surgical practice. More recently, there has been a significant shift towards greater specialisation in the delivery of care, resulting from the implementation of the Department of Health's cancer service guidance 'Improving outcomes in gynaecological cancers'. It is likely that some or all of these changes have contributed to the improved survival rates, emphasising the need to ensure that women with diagnosed ovarian cancer are treated in specialist centres that can provide comprehensive cancer care.\n\nThis guideline does not cover the entire care pathway for ovarian cancer. It focuses on areas where there is uncertainty or wide variation in clinical practice with regard to the detection, diagnosis and initial management of ovarian cancer. The guideline recommendations are applicable to women with epithelial ovarian cancer (the most common type of ovarian cancer), as well as women with fallopian tube carcinoma, primary peritoneal carcinoma or borderline ovarian cancer (see research recommendations for further details).\n\nThe guideline assumes that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.", 'Guidance': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Detection in primary care\n\nRecommendations in this section have been incorporated into the NICE guideline on suspected cancer.\n\n## Awareness of symptoms and signs\n\nRefer the woman urgently if physical examination identifies ascites and/or a pelvic or abdominal mass (which is not obviously uterine fibroids).An urgent referral means that the woman is referred to a gynaecological cancer service within the national target in England and Wales for referral for suspected cancer, which is currently 2\xa0weeks. See also the NICE guideline on suspected cancer: recognition and referral.\n\nCarry out tests in primary care (see section on asking the right question – first tests) if a woman (especially if 50 or over) reports having any of the following symptoms on a persistent or frequent basis – particularly more than 12 times per month:\n\npersistent abdominal distension (women often refer to this as 'bloating')\n\nfeeling full (early satiety) and/or loss of appetite\n\npelvic or abdominal pain\n\nincreased urinary urgency and/or frequency.See also the NICE guideline on suspected cancer: recognition and referral.\n\nConsider carrying out tests in primary care (see section on asking the right question – first tests) if a woman reports unexplained weight loss, fatigue or changes in bowel habit.\n\nAdvise any woman who is not suspected of having ovarian cancer to return to her GP if her symptoms become more frequent and/or persistent.\n\nCarry out appropriate tests for ovarian cancer (see section on asking the right question – first tests) in any woman of 50 or over who has experienced symptoms within the last 12 months that suggest irritable bowel syndrome (IBS), because IBS rarely presents for the first time in women of this age.See NICE's clinical guideline on irritable bowel syndrome in adults.\n\n## Asking the right question – first tests\n\nMeasure serum CA125 in primary care in women with symptoms that suggest ovarian cancer (see section on awareness of symptoms and signs).\n\nIf serum CA125 is 35 IU/ml or greater, arrange an ultrasound scan of the abdomen and pelvis.\n\nIf the ultrasound suggests ovarian cancer, refer the woman urgently for further investigation.An urgent referral means that the woman is referred to a gynaecological cancer service within the national target in England and Wales for referral for suspected cancer, which is currently 2\xa0weeks. See also the NICE guideline on suspected cancer: recognition and referral.\n\nFor any woman who has normal serum CA125 (less than 35\xa0IU/ml), or CA125 of 35 IU/ml or greater but a normal ultrasound:\n\nassess her carefully for other clinical causes of her symptoms and investigate if appropriate\n\nif no other clinical cause is apparent, advise her to return to her GP if her symptoms become more frequent and/or persistent.\n\n# Establishing the diagnosis in secondary care\n\n## Tumour markers: which to use?\n\nMeasure serum CA125 in secondary care in all women with suspected ovarian cancer, if this has not already been done in primary care.\n\nIn women under 40 with suspected ovarian cancer, measure levels of alpha fetoprotein (AFP) and beta human chorionic gonadotrophin (beta-hCG) as well as serum CA125, to identify women who may not have epithelial ovarian cancer.\n\n## Malignancy indices\n\nCalculate a risk of malignancy index I (RMI I) score (after performing an ultrasound; see recommendation 1.2.3.1) and refer all women with an RMI I score of 250 or greater to a specialist multidisciplinary team.See the appendix for details of how to calculate an RMI\xa0I score.\n\n## Imaging in the diagnostic pathway: which procedures?\n\nPerform an ultrasound of the abdomen and pelvis as the first imaging test in secondary care for women with suspected ovarian cancer, if this has not already been done in primary care.\n\nIf the ultrasound, serum CA125 and clinical status suggest ovarian cancer, perform a CT scan of the pelvis and abdomen to establish the extent of disease. Include the thorax if clinically indicated.\n\nDo not use MRI routinely for assessing women with suspected ovarian cancer.\n\n## Tissue diagnosis\n\nRequirement for tissue diagnosis\n\nIf offering cytotoxic chemotherapy to women with suspected advanced ovarian cancer, first obtain a confirmed tissue diagnosis by histology (or by cytology if histology is not appropriate) in all but exceptional cases.\n\nOffer cytotoxic chemotherapy for suspected advanced ovarian cancer without a tissue diagnosis (histology or cytology) only:\n\nin exceptional cases, after discussion at the multidisciplinary team and\n\nafter discussing with the woman the possible benefits and risks of starting chemotherapy without a tissue diagnosis.\n\nMethods of tissue diagnosis other than laparotomy\n\nIf surgery has not been performed, use histology rather than cytology to obtain a tissue diagnosis. To obtain tissue for histology:\n\nuse percutaneous image-guided biopsy if this is feasible\n\nconsider laparoscopic biopsy if percutaneous image-guided biopsy is not feasible or has not produced an adequate sample.Use cytology if histology is not appropriate.\n\n# Management of suspected early (stage I) ovarian cancer\n\n## The role of systematic retroperitoneal lymphadenectomy\n\nPerform retroperitoneal lymph node assessment as part of optimal surgical staging in women with suspected ovarian cancer whose disease appears to be confined to the ovaries (that is, who appear to have stage I disease).Lymph node assessment involves sampling of retroperitoneal lymphatic tissue from the para-aortic area and pelvic side walls if there is a palpable abnormality, or random sampling if there is no palpable abnormality. Optimal surgical staging constitutes: midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and infracolic omentectomy; biopsies of any peritoneal deposits; random biopsies of the pelvic and abdominal peritoneum; and retroperitoneal lymph node assessment (Winter-Roach et al. ).\n\nDo not include systematic retroperitoneal lymphadenectomy (block dissection of lymph nodes from the pelvic side walls to the level of the renal veins) as part of standard surgical treatment in women with suspected ovarian cancer whose disease appears to be confined to the ovaries (that is, who appear to have stage I disease).\n\n## Adjuvant systemic chemotherapy for stage I disease\n\nDo not offer adjuvant chemotherapy to women who have had optimal surgical staging and have low-risk stage I disease (grade 1 or 2, stage Ia or Ib).\n\nOffer women with high-risk stage I disease (grade 3 or stage Ic) adjuvant chemotherapy consisting of 6 cycles of carboplatin.\n\nDiscuss the possible benefits and side effects of adjuvant chemotherapy with women who have had suboptimal surgical staging and appear to have stage I disease.Optimal surgical staging constitutes: midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and infracolic omentectomy; biopsies of any peritoneal deposits; random biopsies of the pelvic and abdominal peritoneum; and retroperitoneal lymph node assessment (Winter-Roach et al. ).\n\n# Management of advanced (stage II to IV) ovarian cancer\n\nFor NICE technology appraisal guidance on first-line chemotherapy see the NICE topic page on ovarian cancer.\n\n## Primary surgery\n\nIf performing surgery for women with ovarian cancer, whether before chemotherapy or after neoadjuvant chemotherapy, the objective should be complete resection of all macroscopic disease.\n\n## Intraperitoneal chemotherapy\n\nDo not offer intraperitoneal chemotherapy to women with ovarian cancer, except as part of a clinical trial.\n\n## Second-line and subsequent treatment\n\nFor NICE technology appraisal guidance on second-line and subsequent treatment for ovarian cancer, including genomic biomarker-based therapy, see the NICE topic page on ovarian cancer.\n\nThe point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based cancer treatments.\n\n# Support needs of women with newly diagnosed ovarian cancer\n\nOffer all women with newly diagnosed ovarian cancer information about their disease, including psychosocial and psychosexual issues, that:\n\nis available at the time they want it\n\nincludes the amount of detail that they want and are able to deal with\n\nis in a suitable format, including written information.\n\nEnsure that information is available about:\n\nthe stage of the disease, treatment options and prognosis\n\nhow to manage the side effects of both the disease and its treatments in order to maximise wellbeing\n\nsexuality and sexual activity\n\nfertility and hormone treatment\n\nsymptoms and signs of disease recurrence\n\ngenetics, including the chances of family members developing ovarian cancer\n\nself-help strategies to optimise independence and coping\n\nwhere to go for support, including support groups\n\nhow to deal with emotions such as sadness, depression, anxiety and a feeling of a lack of control over the outcome of the disease and treatment.", 'Research recommendations': 'The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Relationship between duration of symptoms of ovarian cancer and stage at diagnosis\n\nFurther research should be undertaken on the relationship between the duration and frequency of symptoms in women with ovarian cancer before diagnosis, the stage of disease at diagnosis and subsequent survival.\n\n## Why this is important\n\nMost women presenting with ovarian cancer have advanced disease and have had symptoms for months. Greater awareness among both women and healthcare professionals might result in women presenting earlier with less advanced disease, leading to better outcomes. There is insufficient understanding of the factors that influence earlier diagnosis in women with ovarian cancer, especially the relationship between duration of symptoms and stage at diagnosis. Data demonstrating benefits from earlier presentation will justify investment in raising awareness among women and healthcare professionals. This is likely to be a population-based study that records both the duration and frequency of symptoms.\n\n# Imaging in the diagnostic pathway for women with ovarian cancer\n\nLarge multicentre case–control studies should be conducted to compare the accuracy of CT versus MRI for staging and for predicting optimal cytoreduction in women with ovarian cancer.\n\n## Why this is important\n\nCurrently most women with ovarian cancer will undergo a CT scan before surgery to assess the extent and resectability of disease. CT and MRI are complementary in their abilities to detect disease, but no adequate studies have been performed that compare their effectiveness in women with suspected ovarian cancer. No comparative studies have been undertaken evaluating surgical outcome. A prospective study in women undergoing primary surgery would be feasible.\n\n# The value of primary surgery for women with advanced ovarian cancer\n\nResearch should be undertaken to determine the effectiveness of primary surgery for women with advanced ovarian cancer whose tumour cannot be fully excised.\n\n## Why this is important\n\nMost women with advanced ovarian cancer undergo surgery at some point. Previous studies have shown that surgery after the completion of chemotherapy has no therapeutic value. Studies are being performed to investigate whether the timing of surgery during primary chemotherapy influences outcome. No studies have evaluated whether primary surgery itself has any therapeutic value when compared with chemotherapy alone. The potential advantages of surgery have to be offset against the morbidity, occasional mortality and undoubted costs associated with it. This would be a prospective randomised clinical trial recruiting women who have biopsy-proven advanced ovarian cancer and who are fit enough to receive surgery and chemotherapy. Women would be randomised to either chemotherapy and surgery (conventional arm) or chemotherapy alone (experimental arm). Primary outcome measures would be survival at 1 and 5 years.', 'Appendix: Risk of malignancy index (RMI I)': "RMI I combines 3 pre-surgical features: serum CA125 (CA125), menopausal status (M) and ultrasound score (U). The RMI is a product of the ultrasound scan score, the menopausal status and the serum CA125 level (IU/ml).\n\nRMI\xa0=\xa0U\xa0x\xa0M\xa0x\xa0CA125\n\nThe ultrasound result is scored 1 point for each of the following characteristics: multilocular cysts, solid areas, metastases, ascites and bilateral lesions. U\xa0=\xa00 (for an ultrasound score of 0), U\xa0=\xa01 (for an ultrasound score of 1), U\xa0=\xa03 (for an ultrasound score of 2 to 5).\n\nThe menopausal status is scored as 1\xa0=\xa0pre-menopausal and 3\xa0=\xa0post-menopausal.\n\nThe classification of 'post-menopausal' is a woman who has had no period for more than 1\xa0year or a woman over 50 who has had a hysterectomy.\n\nSerum CA125 is measured in IU/ml and can vary between 0 and hundreds or even thousands of units."}
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https://www.nice.org.uk/guidance/cg122
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This guideline covers detecting, diagnosing and treating women (18 years and older) who have, or are suspected of having, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer or borderline ovarian cancer. It aims to enable earlier detection of ovarian cancer and improve initial treatment.
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2557c7e264ddb8dc27067a875c1c635323fb2e97
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nice
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Carotid artery stent placement for asymptomatic extracranial carotid stenosis
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Carotid artery stent placement for asymptomatic extracranial carotid stenosis
# Guidance
This document replaces previous guidance on carotid artery stent placement for carotid stenosis (interventional procedure guidance 191).
Current evidence on the safety of carotid artery stent placement for asymptomatic extracranial carotid stenosis shows well-documented risks, in particular the risk of stroke. The evidence on efficacy is inadequate in quantity. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake carotid artery stent placement for asymptomatic extracranial carotid stenosis should take the following actions.
Ensure that patients and their carers understand the uncertainty about the procedure's efficacy, the risk of stroke and other complications, and the reasons for advising stenting rather than endarterectomy or best medical treatment alone in their particular case. Patients should be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.
Patient selection should be carried out by a multidisciplinary team, which should include an interventional radiologist or a neuroradiologist, a vascular surgeon and a physician with specialist interest in stroke. Cardiac surgeons and cardiologists should liaise with the multidisciplinary team in relation to patients being considered for this procedure as a prelude to cardiac surgery.
This procedure should only be carried out by clinicians with specific training and expertise in the technique who regularly perform complex endovascular interventions. The Royal College of Radiologists has produced training standards.
NICE encourages clinicians either to enter patients into the ACST-2 trial (Asymptomatic Carotid Artery Surgery Trial 2) or to submit data to the Endovascular Carotid Register, run by the British Society of Interventional Radiology and the Vascular Society of Great Britain and Ireland. NICE may review this procedure on publication of further evidence.# The procedure
# Indications and current treatments
Asymptomatic stenosis of the extracranial carotid arteries may be identified incidentally through imaging – for example, before cardiac surgery. Patients with carotid stenosis are at an increased risk of transient ischaemic attack (TIA) or stroke; but the risk is lower compared with patients with symptomatic stenosis.
Good medical control of cardiovascular risk factors is essential. Severe asymptomatic stenoses are sometimes treated by carotid endarterectomy.
# Outline of the procedure
Carotid stenting is carried out with the patient under local anaesthesia using a percutaneous transfemoral approach. A guidewire is passed into the carotid artery, commonly with a cerebral protection device at its tip, which is designed to prevent any debris from passing into the cerebral circulation during the procedure. The carotid stenosis is then usually pre-dilated using a balloon catheter. A metal mesh (stent) is inserted to treat the stenosis, with the aim of preventing both embolism and restenosis.
Carotid stenting is a less invasive percutaneous procedure than carotid endarterectomy which aims to avoid wound complications associated with that procedure.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
The efficacy outcomes described below include stroke or death that occurred more than 30 days after the procedure (unless specified otherwise). Stroke or death occurring on or before 30 days were considered to represent safety outcomes.
A randomised controlled trial (RCT) of 2522 patients reported that among asymptomatic patients there was no significant difference in the rate of stroke or death following stenting or endarterectomy (5% vs 3%; hazard ratio 1.86, 95% confidence interval 0.95 to 3.66; p = 0.07) at a median 2.5-year follow-up (absolute figures not stated). A non-randomised controlled study including 8706 asymptomatic patients reported no significant difference in stroke or death rate following carotid stenting (2%) and endarterectomy (2%) in asymptomatic patients (p = 0.16) (absolute figures and follow-up not stated).
A UK national register of 291 asymptomatic patients reported 5-year event rates as follows: stroke 4%; stroke or TIA 8%; mortality or disabling stroke 19%; and mortality 18%.
The Specialist Advisers listed key efficacy outcomes as long-term patency and freedom from stroke or death.
# Safety
The UK national register of 291 asymptomatic patients reported a mortality rate of < 1% (1/181) at 30-day follow-up.
A meta-analysis of 2 studies including 140 asymptomatic patients reported no significant difference in stroke or death rate at 30-day follow-up between the stenting group (4% ) and the endarterectomy group (3% ) (odds ratio 1.06, 95% CI 0.16 to 6.94; p = 0.96). The UK national register of 291 asymptomatic patients reported death or disabling stroke rate of 1% (2/181) by 30-day follow-up.
The UK national register of 291 asymptomatic patients reported the following event rates: disabling stroke < 1% (1/181), non-disabling stroke 1% (2/181), TIA 2% (4/181) and myocardial infarction < 1% (1/181) at 30-day follow-up. The RCT of 85 asymptomatic patients reported no perioperative strokes or TIAs in either the stenting group or the endarterectomy group.
The RCT of 2252 patients with either symptomatic or asymptomatic stenosis reported that there was a significantly lower incidence of perioperative myocardial infarction following carotid stenting (1% ) than following endarterectomy (2% ) (HR 0.50, 95% CI 0.26 to 0.94; p = 0.03).
The Specialist Advisers listed anecdotal or reported adverse events related to this procedure as femoral artery damage and renal failure. They considered theoretical adverse events to be dissection, restenosis or contrast allergy/nephrotoxicity.
# Committee comments
The Committee noted that the case mix in recent observational studies from the US is substantially different to that in the UK.
The Committee noted uncertainties about the benefits of carotid stenting before cardiac surgery.# Further information
For related NICE guidance see our website.
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
It updates and replaces NICE interventional procedure guidance 191.
We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.
Changes since publication
December 2011: minor maintenance
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': "This document replaces previous guidance on carotid artery stent placement for carotid stenosis (interventional procedure guidance 191).\n\nCurrent evidence on the safety of carotid artery stent placement for asymptomatic extracranial carotid stenosis shows well-documented risks, in particular the risk of stroke. The evidence on efficacy is inadequate in quantity. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake carotid artery stent placement for asymptomatic extracranial carotid stenosis should take the following actions.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's efficacy, the risk of stroke and other complications, and the reasons for advising stenting rather than endarterectomy or best medical treatment alone in their particular case. Patients should be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nPatient selection should be carried out by a multidisciplinary team, which should include an interventional radiologist or a neuroradiologist, a vascular surgeon and a physician with specialist interest in stroke. Cardiac surgeons and cardiologists should liaise with the multidisciplinary team in relation to patients being considered for this procedure as a prelude to cardiac surgery.\n\nThis procedure should only be carried out by clinicians with specific training and expertise in the technique who regularly perform complex endovascular interventions. The Royal College of Radiologists has produced training standards.\n\nNICE encourages clinicians either to enter patients into the ACST-2 trial (Asymptomatic Carotid Artery Surgery Trial 2) or to submit data to the Endovascular Carotid Register, run by the British Society of Interventional Radiology and the Vascular Society of Great Britain and Ireland. NICE may review this procedure on publication of further evidence.", 'The procedure': '# Indications and current treatments\n\nAsymptomatic stenosis of the extracranial carotid arteries may be identified incidentally through imaging – for example, before cardiac surgery. Patients with carotid stenosis are at an increased risk of transient ischaemic attack (TIA) or stroke; but the risk is lower compared with patients with symptomatic stenosis.\n\nGood medical control of cardiovascular risk factors is essential. Severe asymptomatic stenoses are sometimes treated by carotid endarterectomy.\n\n# Outline of the procedure\n\nCarotid stenting is carried out with the patient under local anaesthesia using a percutaneous transfemoral approach. A guidewire is passed into the carotid artery, commonly with a cerebral protection device at its tip, which is designed to prevent any debris from passing into the cerebral circulation during the procedure. The carotid stenosis is then usually pre-dilated using a balloon catheter. A metal mesh (stent) is inserted to treat the stenosis, with the aim of preventing both embolism and restenosis.\n\nCarotid stenting is a less invasive percutaneous procedure than carotid endarterectomy which aims to avoid wound complications associated with that procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nThe efficacy outcomes described below include stroke or death that occurred more than 30 days after the procedure (unless specified otherwise). Stroke or death occurring on or before 30\xa0days were considered to represent safety outcomes.\n\nA randomised controlled trial (RCT) of 2522 patients reported that among asymptomatic patients there was no significant difference in the rate of stroke or death following stenting or endarterectomy (5% vs 3%; hazard ratio [HR] 1.86, 95% confidence interval [CI] 0.95 to 3.66; p\xa0=\xa00.07) at a median 2.5-year follow-up (absolute figures not stated). A non-randomised controlled study including 8706 asymptomatic patients reported no significant difference in stroke or death rate following carotid stenting (2%) and endarterectomy (2%) in asymptomatic patients (p\xa0=\xa00.16) (absolute figures and follow-up not stated).\n\nA UK national register of 291 asymptomatic patients reported 5-year event rates as follows: stroke 4%; stroke or TIA 8%; mortality or disabling stroke 19%; and mortality 18%.\n\nThe Specialist Advisers listed key efficacy outcomes as long-term patency and freedom from stroke or death.\n\n# Safety\n\nThe UK national register of 291 asymptomatic patients reported a mortality rate of < 1% (1/181) at 30-day follow-up.\n\nA meta-analysis of 2 studies including 140 asymptomatic patients reported no significant difference in stroke or death rate at 30-day follow-up between the stenting group (4% [3/73]) and the endarterectomy group (3% [2/63]) (odds ratio 1.06, 95% CI 0.16 to 6.94; p\xa0=\xa00.96). The UK national register of 291 asymptomatic patients reported death or disabling stroke rate of 1% (2/181) by 30-day follow-up.\n\nThe UK national register of 291 asymptomatic patients reported the following event rates: disabling stroke < 1% (1/181), non-disabling stroke 1% (2/181), TIA 2% (4/181) and myocardial infarction < 1% (1/181) at 30-day follow-up. The RCT of 85 asymptomatic patients reported no perioperative strokes or TIAs in either the stenting group or the endarterectomy group.\n\nThe RCT of 2252 patients with either symptomatic or asymptomatic stenosis reported that there was a significantly lower incidence of perioperative myocardial infarction following carotid stenting (1% [14/1262]) than following endarterectomy (2% [28/1240]) (HR 0.50, 95% CI 0.26 to 0.94; p = 0.03).\n\nThe Specialist Advisers listed anecdotal or reported adverse events related to this procedure as femoral artery damage and renal failure. They considered theoretical adverse events to be dissection, restenosis or contrast allergy/nephrotoxicity.\n\n# Committee comments\n\nThe Committee noted that the case mix in recent observational studies from the US is substantially different to that in the UK.\n\nThe Committee noted uncertainties about the benefits of carotid stenting before cardiac surgery.', 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 191.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nDecember 2011: minor maintenance\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg388
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e888313edcfdaf8b645ad183fcbc5c225d21b18a
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nice
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Stent insertion for bleeding oesophageal varices
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Stent insertion for bleeding oesophageal varices
# Guidance
This document replaces previous guidance on stent insertion for bleeding oesophageal varices (interventional procedure guidance 265).
Current evidence on stent insertion for bleeding oesophageal varices is from small numbers of patients, but shows no major safety concerns. There is evidence to show that this procedure is efficacious in selected patients in whom other methods of treatment have failed to control bleeding. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.# The procedure
# Indications and current treatments
Oesophageal varices are enlarged veins within the lower oesophagus and the oesophagogastric junction which develop in patients with portal hypertension, often as a result of cirrhosis. Bleeding from varices has a significant risk of death and the risk of re-bleeding is high.
The management of bleeding oesophageal varices commonly requires blood transfusion. Measures aimed at arresting the bleeding include vasoactive medication, balloon tamponade, endoscopic variceal band ligation or sclerotherapy. In patients with refractory bleeding, transjugular intrahepatic portosystemic shunts (TIPSS), and shunt or devascularisation surgery, may be required.
# Outline of the procedure
The aim of this procedure is to apply pressure to the bleeding oesophageal varices to induce haemostasis.
A coated metal stent supplied on a delivery system is inserted with the aim of compressing the bleeding varices in the oesophageal wall. The stent is usually inserted with the aid of an endoscope (but can be inserted without), and appropriate positioning may be confirmed endoscopically, fluoroscopically or by chest X-ray.
The stent maintains a patent oesophageal lumen for passage of food, saliva and other fluids. It is left in position for up to 2 weeks and is then removed endoscopically.
Further procedures, such as TIPSS or surgery, may be done to reduce the risk of further bleeds.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/690/overview
# Efficacy
Case series of 34 and 20 patients reported that stent insertion stopped the bleeding in all patients and that no re-bleeding occurred in any patients (60-day follow-up). A case series of 10 patients reported immediate control of bleeding in 78% (7/9) of patients who had successful stent insertion (stent insertion was unsuccessful in 1 patient). Re-bleeding, which was successfully treated by TIPSS, occurred in 1 patient.
Case series of 34, 20 and 10 patients treated with stent insertion reported 10, 2 and 5 deaths respectively during follow-up of between 42 and 60 days. Of the 17 deaths, 2 resulted from exsanguination, 1 was caused by multi-organ failure and failure to control the bleeding, and the remainder were as a result of hepatic or multi-organ failure.
The case series of 34 patients reported that 32% (11/34) of patients required endoscopic band ligation, 24% (8/34) required radiologic TIPSS insertion and 15% (5/34) required laparoscopic azygoportal disconnection after stent removal (timing of events not stated).
The case series of 20 patients reported that after stent removal 25% (5/20) of patients required TIPSS insertion, 25% (5/20) required laparoscopic azygoportal disconnection and 20% (4/20) required embolotherapy with sclerosing agents combined with coils (timing of events not stated).
The Specialist Advisers listed key efficacy outcomes as control of bleeding, reduction in risk of re-bleeding, avoidance of using blood products and survival.
# Safety
A case report described acute bronchial obstruction at day 6 caused by stent-related compression of the left main bronchus (confirmed by computed tomography scan) which was relieved by stent removal.
Migration of the stent into the stomach was reported in 21% (7/34) of patients during 60-day follow-up in the case series of 34 patients. All stents were successfully repositioned within 24–48 hours. In the case series of 20 patients, stent migration into the stomach was reported in 25% (5/20) of patients: all stents were repositioned endoscopically. Three of the 5 migrations were in the first 5 patients in the series.
Slight oesophageal ulceration at the distal end of the stent was reported in 1 patient within 60-day follow-up in the case series of 34 patients.
The Specialist Advisers listed adverse events reported in the literature or from their own experience as mucosal trauma on withdrawal, oesophageal perforation, oesophageal pressure ulceration, fistula formation, worsening of bleeding, failure of removal of the device and aspiration pneumonia. They considered theoretical adverse events to include dysphagia.
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG392/publicinfo
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{'Guidance': 'This document replaces previous guidance on stent insertion for bleeding oesophageal varices (interventional procedure guidance 265).\n\nCurrent evidence on stent insertion for bleeding oesophageal varices is from small numbers of patients, but shows no major safety concerns. There is evidence to show that this procedure is efficacious in selected patients in whom other methods of treatment have failed to control bleeding. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.', 'The procedure': "# Indications and current treatments\n\nOesophageal varices are enlarged veins within the lower oesophagus and the oesophagogastric junction which develop in patients with portal hypertension, often as a result of cirrhosis. Bleeding from varices has a significant risk of death and the risk of re-bleeding is high.\n\nThe management of bleeding oesophageal varices commonly requires blood transfusion. Measures aimed at arresting the bleeding include vasoactive medication, balloon tamponade, endoscopic variceal band ligation or sclerotherapy. In patients with refractory bleeding, transjugular intrahepatic portosystemic shunts (TIPSS), and shunt or devascularisation surgery, may be required.\n\n# Outline of the procedure\n\nThe aim of this procedure is to apply pressure to the bleeding oesophageal varices to induce haemostasis.\n\nA coated metal stent supplied on a delivery system is inserted with the aim of compressing the bleeding varices in the oesophageal wall. The stent is usually inserted with the aid of an endoscope (but can be inserted without), and appropriate positioning may be confirmed endoscopically, fluoroscopically or by chest X-ray.\n\nThe stent maintains a patent oesophageal lumen for passage of food, saliva and other fluids. It is left in position for up to 2\xa0weeks and is then removed endoscopically.\n\nFurther procedures, such as TIPSS or surgery, may be done to reduce the risk of further bleeds.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/690/overview\n\n# Efficacy\n\nCase series of 34 and 20 patients reported that stent insertion stopped the bleeding in all patients and that no re-bleeding occurred in any patients (60-day follow-up). A case series of 10 patients reported immediate control of bleeding in 78% (7/9) of patients who had successful stent insertion (stent insertion was unsuccessful in 1 patient). Re-bleeding, which was successfully treated by TIPSS, occurred in 1 patient.\n\nCase series of 34, 20 and 10 patients treated with stent insertion reported 10, 2 and 5 deaths respectively during follow-up of between 42 and 60 days. Of the 17 deaths, 2 resulted from exsanguination, 1 was caused by multi-organ failure and failure to control the bleeding, and the remainder were as a result of hepatic or multi-organ failure.\n\nThe case series of 34 patients reported that 32% (11/34) of patients required endoscopic band ligation, 24% (8/34) required radiologic TIPSS insertion and 15% (5/34) required laparoscopic azygoportal disconnection after stent removal (timing of events not stated).\n\nThe case series of 20 patients reported that after stent removal 25% (5/20) of patients required TIPSS insertion, 25% (5/20) required laparoscopic azygoportal disconnection and 20% (4/20) required embolotherapy with sclerosing agents combined with coils (timing of events not stated).\n\nThe Specialist Advisers listed key efficacy outcomes as control of bleeding, reduction in risk of re-bleeding, avoidance of using blood products and survival.\n\n# Safety\n\nA case report described acute bronchial obstruction at day 6 caused by stent-related compression of the left main bronchus (confirmed by computed tomography scan) which was relieved by stent removal.\n\nMigration of the stent into the stomach was reported in 21% (7/34) of patients during 60-day follow-up in the case series of 34 patients. All stents were successfully repositioned within 24–48 hours. In the case series of 20 patients, stent migration into the stomach was reported in 25% (5/20) of patients: all stents were repositioned endoscopically. Three of the 5 migrations were in the first 5 patients in the series.\n\nSlight oesophageal ulceration at the distal end of the stent was reported in 1 patient within 60-day follow-up in the case series of 34 patients.\n\nThe Specialist Advisers listed adverse events reported in the literature or from their own experience as mucosal trauma on withdrawal, oesophageal perforation, oesophageal pressure ulceration, fistula formation, worsening of bleeding, failure of removal of the device and aspiration pneumonia. They considered theoretical adverse events to include dysphagia.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG392/publicinfo"}
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https://www.nice.org.uk/guidance/ipg392
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8c34d57bf2a8a0244aef7fe44e84e8b85bc6ef3d
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nice
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Carotid artery stent placement for symptomatic extracranial carotid stenosis
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Carotid artery stent placement for symptomatic extracranial carotid stenosis
# Guidance
This document replaces previous guidance on carotid artery stent placement for carotid stenosis (interventional procedure guidance 191).
Current evidence on the safety and efficacy of carotid artery stent placement for symptomatic extracranial carotid stenosis is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance and audit or research.
During the consent process, clinicians should ensure that patients understand the risk of stroke and other complications associated with this procedure. Clinicians should also ensure that patients understand the reasons for advising carotid artery stent placement rather than endarterectomy in their particular case.
Patient selection should be carried out by a multidisciplinary team, which should include an interventional radiologist or a neuroradiologist, a vascular surgeon and a physician with a specialist interest in stroke.
This procedure should only be carried out by clinicians with specific training and expertise in the technique who regularly perform complex endovascular interventions. The Royal College of Radiologists has produced training standards.# The procedure
# Indications and current treatments
Stenosis of the extracranial carotid arteries due to atherosclerosis can cause transient ischaemic attacks (TIAs) or stroke. Patients with symptomatic carotid stenosis are at increased risk of stroke.
Good medical control of cardiovascular risk factors is essential. Prompt treatment of the carotid stenosis is carried out in selected patients: carotid endarterectomy is the standard treatment.
# Outline of the procedure
Carotid stenting is usually carried out with the patient under local anaesthesia using a percutaneous transfemoral approach. A guidewire is passed into the carotid artery, commonly with a cerebral protection device at its tip, which is designed to prevent any debris from passing into the cerebral circulation during the procedure. The carotid stenosis is then usually pre-dilated using a balloon catheter. A metal mesh (stent) is inserted to treat the stenosis, with the aim of preventing both embolism and restenosis.
Carotid stenting is a less invasive percutaneous procedure than carotid endarterectomy which aims to avoid wound complications associated with that procedure.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/8/overview
# Efficacy
The efficacy outcomes described below include stroke or death that occurred more than 30 days after the procedure (unless specified otherwise). Stroke or death occurring on or before 30 days were considered to represent safety outcomes.
A meta-analysis of 3433 symptomatic patients reported no significant difference in mortality between patients treated by stenting (2% ) and endarterectomy (1% ) (relative risk 1.44, 95% confidence interval 0.84 to 2.47; p = 0.18) at 120-day follow-up. A randomised controlled trial (RCT) of 2522 patients reported no significant difference in mortality between patients treated by stenting (11%) and those treated by endarterectomy (13%) (hazard ratio 1.12, 95% CI 0.83 to 1.51; p = 0.45) at median 2.5-year follow-up (absolute figures not stated).
A UK national register of 953 symptomatic patients treated by stenting reported a 5-year rate of mortality, disabling stroke or mortality, and stroke of 19%, 21% and 7% respectively (data on 173, 167 and 156 patients respectively were available for analysis).
An RCT of 1713 symptomatic patients reported no significant difference in the rate of disabling stroke or death between the stenting group (5% ) and the endarterectomy group (3% ) (HR 1.28, 95% CI 0.77 to 2.11) at 120-day follow-up.
The RCT of 2522 patients reported that among symptomatic patients there was no significant difference in the rate of stroke or death following stenting (8%) and endarterectomy (6%) (HR 1.37, 95% CI 0.90 to 2.00; p = 0.14) at 2.5-year follow-up (absolute figures not stated). A non-randomised controlled study including 1086 symptomatic patients reported a significant difference in the rate of stroke or death following carotid stenting (8%) and endarterectomy (5%) in symptomatic patients (p = 0.01) (absolute figures and follow-up not stated).
An RCT of 1214 symptomatic patients treated by stenting or endarterectomy reported that both groups had a 2% rate of ipsilateral stroke during 31-day to 2-year follow-up (HR 1.17, 95% CI 0.51 to 2.70; p = not significant).
The Specialist Advisers listed a key efficacy outcome as long-term stroke prevention.
# Safety
The meta-analysis of 3433 symptomatic patients reported no significant difference in mortality at 30-day follow-up between patients treated by stenting (1% ) and those treated by endarterectomy (< 1% ) (RR 1.86, 95% CI 0.87 to 4.00; p = 0.10). In the UK national register of 953 symptomatic patients treated by stenting, 30-day post-procedural mortality was 2%.
The meta-analysis of 3433 symptomatic patients reported that the rate of stroke at 30-day follow-up was significantly higher following stenting (7% ) than following endarterectomy (4% ) (RR 1.74, 95% CI 1.31 to 2.32; p = 0.0001): this excess was attributable largely to patients older than 70 years. The UK national register of 953 symptomatic patients treated by stenting reported disabling stroke in 1% (8/829) of patients, non-disabling stroke in 3% (26/829) and TIA in 4% (32/829) at 30-day follow-up.
An RCT of 2252 patients reported that there was a significantly lower incidence of perioperative myocardial infarction following carotid stenting (1% ) than following endarterectomy (2% ) (HR 0.50, 95% CI 0.26 to 0.94, p = 0.03).
The Specialist Advisers listed known adverse events as access site complications, peripheral emboli, carotid artery rupture, femoral catheter access site damage and reactions to contrast material. They considered radiation-induced neoplasia to be a theoretical adverse event.
# Committee comments
The Committee noted recent observational studies were from the US where case mix is different from the UK.# Further information
For related NICE guidance see www.nice.org.uk
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG389/publicinfo
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{'Guidance': 'This document replaces previous guidance on carotid artery stent placement for carotid stenosis (interventional procedure guidance 191).\n\nCurrent evidence on the safety and efficacy of carotid artery stent placement for symptomatic extracranial carotid stenosis is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance and audit or research.\n\nDuring the consent process, clinicians should ensure that patients understand the risk of stroke and other complications associated with this procedure. Clinicians should also ensure that patients understand the reasons for advising carotid artery stent placement rather than endarterectomy in their particular case.\n\nPatient selection should be carried out by a multidisciplinary team, which should include an interventional radiologist or a neuroradiologist, a vascular surgeon and a physician with a specialist interest in stroke.\n\nThis procedure should only be carried out by clinicians with specific training and expertise in the technique who regularly perform complex endovascular interventions. The Royal College of Radiologists has produced training standards.', 'The procedure': '# Indications and current treatments\n\nStenosis of the extracranial carotid arteries due to atherosclerosis can cause transient ischaemic attacks (TIAs) or stroke. Patients with symptomatic carotid stenosis are at increased risk of stroke.\n\nGood medical control of cardiovascular risk factors is essential. Prompt treatment of the carotid stenosis is carried out in selected patients: carotid endarterectomy is the standard treatment.\n\n# Outline of the procedure\n\nCarotid stenting is usually carried out with the patient under local anaesthesia using a percutaneous transfemoral approach. A guidewire is passed into the carotid artery, commonly with a cerebral protection device at its tip, which is designed to prevent any debris from passing into the cerebral circulation during the procedure. The carotid stenosis is then usually pre-dilated using a balloon catheter. A metal mesh (stent) is inserted to treat the stenosis, with the aim of preventing both embolism and restenosis.\n\nCarotid stenting is a less invasive percutaneous procedure than carotid endarterectomy which aims to avoid wound complications associated with that procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/8/overview\n\n# Efficacy\n\nThe efficacy outcomes described below include stroke or death that occurred more than 30\xa0days after the procedure (unless specified otherwise). Stroke or death occurring on or before 30\xa0days were considered to represent safety outcomes.\n\nA meta-analysis of 3433 symptomatic patients reported no significant difference in mortality between patients treated by stenting (2% [32/1725]) and endarterectomy (1% [22/1708]) (relative risk [RR] 1.44, 95% confidence interval [CI] 0.84 to 2.47; p\xa0=\xa00.18) at 120-day follow-up. A randomised controlled trial (RCT) of 2522 patients reported no significant difference in mortality between patients treated by stenting (11%) and those treated by endarterectomy (13%) (hazard ratio [HR] 1.12, 95% CI 0.83 to 1.51; p\xa0=\xa00.45) at median 2.5-year follow-up (absolute figures not stated).\n\nA UK national register of 953 symptomatic patients treated by stenting reported a 5-year rate of mortality, disabling stroke or mortality, and stroke of 19%, 21% and 7% respectively (data on 173, 167 and 156 patients respectively were available for analysis).\n\nAn RCT of 1713 symptomatic patients reported no significant difference in the rate of disabling stroke or death between the stenting group (5% [43/853]) and the endarterectomy group (3% [27/857]) (HR 1.28, 95% CI 0.77 to 2.11) at 120-day follow-up.\n\nThe RCT of 2522 patients reported that among symptomatic patients there was no significant difference in the rate of stroke or death following stenting (8%) and endarterectomy (6%) (HR 1.37, 95% CI 0.90 to 2.00; p\xa0=\xa00.14) at 2.5-year follow-up (absolute figures not stated). A non-randomised controlled study including 1086 symptomatic patients reported a significant difference in the rate of stroke or death following carotid stenting (8%) and endarterectomy (5%) in symptomatic patients (p\xa0=\xa00.01) (absolute figures and follow-up not stated).\n\nAn RCT of 1214 symptomatic patients treated by stenting or endarterectomy reported that both groups had a 2% rate of ipsilateral stroke during 31-day to 2-year follow-up (HR 1.17, 95% CI 0.51 to 2.70; p\xa0=\xa0not significant).\n\nThe Specialist Advisers listed a key efficacy outcome as long-term stroke prevention.\n\n# Safety\n\nThe meta-analysis of 3433 symptomatic patients reported no significant difference in mortality at 30-day follow-up between patients treated by stenting (1% [19/1679]) and those treated by endarterectomy (< 1% [10/1645]) (RR 1.86, 95% CI 0.87 to 4.00; p\xa0=\xa00.10). In the UK national register of 953 symptomatic patients treated by stenting, 30-day post-procedural mortality was 2%.\n\nThe meta-analysis of 3433 symptomatic patients reported that the rate of stroke at 30-day follow-up was significantly higher following stenting (7% [125/1679]) than following endarterectomy (4% [70/1645]) (RR 1.74, 95% CI 1.31 to 2.32; p\xa0=\xa00.0001): this excess was attributable largely to patients older than 70\xa0years. The UK national register of 953 symptomatic patients treated by stenting reported disabling stroke in 1% (8/829) of patients, non-disabling stroke in 3% (26/829) and TIA in 4% (32/829) at 30-day follow-up.\n\nAn RCT of 2252 patients reported that there was a significantly lower incidence of perioperative myocardial infarction following carotid stenting (1% [14/1262]) than following endarterectomy (2% [28/1240]) (HR 0.50, 95% CI 0.26 to 0.94, p\xa0=\xa00.03).\n\nThe Specialist Advisers listed known adverse events as access site complications, peripheral emboli, carotid artery rupture, femoral catheter access site damage and reactions to contrast material. They considered radiation-induced neoplasia to be a theoretical adverse event.\n\n# Committee comments\n\nThe Committee noted recent observational studies were from the US where case mix is different from the UK.', 'Further information': "For related NICE guidance see www.nice.org.uk\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG389/publicinfo"}
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https://www.nice.org.uk/guidance/ipg389
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5ff961b6ae12611e293d4abb3fd3f491080b2ed9
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nice
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Endovascular stent-grafting of popliteal aneurysms
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Endovascular stent-grafting of popliteal aneurysms
# Guidance
Current evidence on endovascular stent-grafting of popliteal aneurysms is limited in quantity but shows no major safety concerns. Evidence on efficacy is inadequate because it is limited to the short-term. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake endovascular stent-grafting of popliteal aneurysms should take the following actions
Inform the clinical governance leads in their Trusts.
Ensure that patients and their carers understand the uncertainty about the procedure's long-term efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended (available from www.nice.org.uk/guidance/IPG390/publicinfo).
Audit and review clinical outcomes of all patients having endovascular stent-grafting of popliteal aneurysms (see section 3.1).
Patient selection for this procedure should be carried out by a multidisciplinary team which should include a vascular surgeon and an interventional radiologist with specific training and experience in the technique.
NICE encourages further research into endovascular stent-grafting of popliteal aneurysms and may review this procedure on publication of further evidence.# The procedure
# Indications and current treatments
Popliteal artery aneurysms are the most common peripheral aneurysms. They can cause leg ischaemia by embolism or thrombosis and may rupture. Current treatment is usually by open surgical bypass grafting. Postoperative antiplatelet therapy is generally given.
# Outline of the procedure
Endovascular repair stent-grafting of popliteal aneurysms is carried out with the patient under local or general anaesthesia. Under fluoroscopic guidance, a stent-graft device is inserted into the femoral artery using standard catheter and guidewire techniques. Care is taken to ensure adequate length of anchoring stent in the normal vessel, both proximally and distally, to bridge the popliteal aneurysm and fully exclude the aneurysm from the circulation.
A range of different stents are available for this procedure.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/817/overview
# Efficacy
A meta-analysis of 320 patients treated by endovascular repair reported primary and secondary patency rates at 1 year of 83% (95% CI 79% to 88%) and 86% (95% CI 82% to 91%) respectively. In the same meta-analysis, comparative data were available for 159 patients: the primary patency rate at 1 year for endovascular repair was 84% (36/43), compared with 85%) 99/116) for open repair (p = 0.46). Secondary patency rates at 1 year were 86% (37/43) for endovascular repair and 95% (110/116) for open repair (p = 0.07). A non-randomised comparative study of 43 patients (56 limbs; 15 endovascular and 41 open repair) reported primary patency rates of 83% and 88% respectively at 24-month follow-up (p = not significant). A case series of 60 patients at 24 months were 100% and 92% for endovascular and open repair respectively (p = not significant). A case series of 60 patients reported that the primary patency rate was 77% at 3 years and 70% at 5 years. Primary patency is defined as uninterrupted patency following revascularisation. Secondary patency implies that re-intervention has been required to restore patency.
A case series of 50 patients reported that 98% (56/57) of aneurysms were completely excluded after endovascular repair.
The case series of 50 patients reported a limb salvage rate of 97% (55/57).
A randomised controlled trial (RCT) of 42 patients treated by endovascular or open repair reported that 14% (3/21) of patients in the endovascular group required open repair because of endograft occlusion during a mean follow-up of 47 months. In the case series of 50 patients, stent-graft occlusion occurred in 16% (9.57) of aneurysms (2 were successfully treated by thrombolysis, 5 were treated by femoropopliteal bypass, 1 patient was asymptomatic and was not treated, and in the remaining patient, treatment of the occlusion was delayed leading to severe limb ischaemia requiring amputation).
The Specialist Advisers listed key efficacy outcomes as successful exclusion of the aneurysm, long-term prevention of thrombosis and distal emoblisation, prevention of rupture, and limb salvage.
# Safety
Endograft thrombosis occurred in 10% (2/21) of patients treated by endovascular repair the day after the procedure in the RCT of 42 patients. In 1 patient, intra-arterial thombolytic therapy followed by an additional endovascular procedure was successful. The other patient required open repair after 72 hours. Acute thrombosis was reported in 6% (2/23) of aneurysms within 24 hours of the procedure in the case series of 29 patients; both aneurysms were successfully recanalised with catheter-directed thrombolysis and balloon angioplasty or rheolytic thrombectomy. In this study, a further 4 patients were diagnosed with thrombosis during follow-up (1 was described as acute and 3 as subacute).
Stent fracture in 4% (3/73) of aneurysms (2 leading to occlusion) and stent migration in 12% (9/73) of aneurysms were reported in the case series of 60 patients. Stent migration was reported in 7% (4/57) of procedures in the case series of 50 patients.
Stenosis was reported in 3% (2/73) of procedures (timing of events not stated) in the case series of 60 patients. These were treated by percutaneous transluminal angioplasty.
There was 1 report of distal embolsiation necessitating amputation in the case series of 50 patients.
The Specialist Advisers listed anecdotal adverse events as stent occlusion leading to acute limb ischaemia, stent-graft thrombosis, graft failure due to repeated mechanical stress, endoleak and puncture-site arterial bleeding. They considered theoretical adverse events to include stent-graft infection and loss of aneurysm control.# Further information
This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion), available from www.nice.org.uk/guidance/IPG390
For related NICE guidance see www.nice.org.uk
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG390/publicinfo
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{'Guidance': "Current evidence on endovascular stent-grafting of popliteal aneurysms is limited in quantity but shows no major safety concerns. Evidence on efficacy is inadequate because it is limited to the short-term. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake endovascular stent-grafting of popliteal aneurysms should take the following actions\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's long-term efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended (available from www.nice.org.uk/guidance/IPG390/publicinfo).\n\nAudit and review clinical outcomes of all patients having endovascular stent-grafting of popliteal aneurysms (see section 3.1).\n\nPatient selection for this procedure should be carried out by a multidisciplinary team which should include a vascular surgeon and an interventional radiologist with specific training and experience in the technique.\n\nNICE encourages further research into endovascular stent-grafting of popliteal aneurysms and may review this procedure on publication of further evidence.", 'The procedure': '# Indications and current treatments\n\nPopliteal artery aneurysms are the most common peripheral aneurysms. They can cause leg ischaemia by embolism or thrombosis and may rupture. Current treatment is usually by open surgical bypass grafting. Postoperative antiplatelet therapy is generally given.\n\n# Outline of the procedure\n\nEndovascular repair stent-grafting of popliteal aneurysms is carried out with the patient under local or general anaesthesia. Under fluoroscopic guidance, a stent-graft device is inserted into the femoral artery using standard catheter and guidewire techniques. Care is taken to ensure adequate length of anchoring stent in the normal vessel, both proximally and distally, to bridge the popliteal aneurysm and fully exclude the aneurysm from the circulation.\n\nA range of different stents are available for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/guidance/IP/817/overview\n\n# Efficacy\n\nA meta-analysis of 320 patients treated by endovascular repair reported primary and secondary patency rates at 1 year of 83% (95% CI 79% to 88%) and 86% (95% CI 82% to 91%) respectively. In the same meta-analysis, comparative data were available for 159 patients: the primary patency rate at 1 year for endovascular repair was 84% (36/43), compared with 85%) 99/116) for open repair (p = 0.46). Secondary patency rates at 1 year were 86% (37/43) for endovascular repair and 95% (110/116) for open repair (p = 0.07). A non-randomised comparative study of 43 patients (56 limbs; 15 endovascular and 41 open repair) reported primary patency rates of 83% and 88% respectively at 24-month follow-up (p = not significant). A case series of 60 patients at 24 months were 100% and 92% for endovascular and open repair respectively (p = not significant). A case series of 60 patients reported that the primary patency rate was 77% at 3 years and 70% at 5 years. Primary patency is defined as uninterrupted patency following revascularisation. Secondary patency implies that re-intervention has been required to restore patency.\n\nA case series of 50 patients reported that 98% (56/57) of aneurysms were completely excluded after endovascular repair.\n\nThe case series of 50 patients reported a limb salvage rate of 97% (55/57).\n\nA randomised controlled trial (RCT) of 42 patients treated by endovascular or open repair reported that 14% (3/21) of patients in the endovascular group required open repair because of endograft occlusion during a mean follow-up of 47 months. In the case series of 50 patients, stent-graft occlusion occurred in 16% (9.57) of aneurysms (2 were successfully treated by thrombolysis, 5 were treated by femoropopliteal bypass, 1 patient was asymptomatic and was not treated, and in the remaining patient, treatment of the occlusion was delayed leading to severe limb ischaemia requiring amputation).\n\nThe Specialist Advisers listed key efficacy outcomes as successful exclusion of the aneurysm, long-term prevention of thrombosis and distal emoblisation, prevention of rupture, and limb salvage.\n\n# Safety\n\nEndograft thrombosis occurred in 10% (2/21) of patients treated by endovascular repair the day after the procedure in the RCT of 42 patients. In 1 patient, intra-arterial thombolytic therapy followed by an additional endovascular procedure was successful. The other patient required open repair after 72 hours. Acute thrombosis was reported in 6% (2/23) of aneurysms within 24 hours of the procedure in the case series of 29 patients; both aneurysms were successfully recanalised with catheter-directed thrombolysis and balloon angioplasty or rheolytic thrombectomy. In this study, a further 4 patients were diagnosed with thrombosis during follow-up (1 was described as acute and 3 as subacute).\n\nStent fracture in 4% (3/73) of aneurysms (2 leading to occlusion) and stent migration in 12% (9/73) of aneurysms were reported in the case series of 60 patients. Stent migration was reported in 7% (4/57) of procedures in the case series of 50 patients.\n\nStenosis was reported in 3% (2/73) of procedures (timing of events not stated) in the case series of 60 patients. These were treated by percutaneous transluminal angioplasty.\n\nThere was 1 report of distal embolsiation necessitating amputation in the case series of 50 patients.\n\nThe Specialist Advisers listed anecdotal adverse events as stent occlusion leading to acute limb ischaemia, stent-graft thrombosis, graft failure due to repeated mechanical stress, endoleak and puncture-site arterial bleeding. They considered theoretical adverse events to include stent-graft infection and loss of aneurysm control.', 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion), available from www.nice.org.uk/guidance/IPG390\n\nFor related NICE guidance see www.nice.org.uk\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG390/publicinfo"}
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https://www.nice.org.uk/guidance/ipg390
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a61e94fb38459018c9c3abd56321eede494002bf
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nice
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Extracorporeal membrane oxygenation for severe acute respiratory failure in adults
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Extracorporeal membrane oxygenation for severe acute respiratory failure in adults
# Guidance
This document replaces previous guidance on extracorporeal membrane oxygenation in adults (interventional procedure guidance 39).
Evidence on the safety of extracorporeal membrane oxygenation (ECMO) for severe acute respiratory failure in adults is adequate but shows that there is a risk of serious side effects. Evidence on its efficacy is inadequate to draw firm conclusions: data from the recent CESAR (Conventional ventilation or extracorporeal membrane oxygenation for severe adult respiratory failure) trial were difficult to interpret because different management strategies were applied among many different hospitals in the control group and a single centre was used for the ECMO treatment group. Therefore this procedure should only be used with special arrangements for clinical governance, consent and research.
Clinicians wishing to undertake ECMO for severe acute respiratory failure in adults should take the following actions.
Inform the clinical governance leads in their Trusts.
Whenever possible, ensure that patients and their carers understand the uncertainty about the procedure's efficacy and its risks and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended (available from www.nice.org.uk/IPG391/publicinfo).
Extracorporeal membrane oxygenation for severe acute respiratory failure in adults should only be carried out by clinical teams with specific training and expertise in the procedure.
Clinicians are encouraged to submit data on all adults undergoing ECMO for severe acute respiratory failure to the international Extracorporeal Life Support Organization register (www.elso.med.umich.edu).
NICE encourages further research into the use of innovative technologies for the management of severe acute respiratory failure, and may review this guidance on publication of further evidence.# The procedure
# Indications and current treatments
Extracorporeal membrane oxygenation is a supportive therapy for adults with severe acute respiratory failure from a potentially reversible cause. Extracorporeal membrane systems mimic gas exchange in the lungs by eliminating some carbon dioxide from the blood and adding oxygen.
There are many causes of severe acute respiratory failure, including acute respiratory distress syndrome, pneumonia, and chest trauma.
Conventional treatment involves maximum medical support, including mechanical ventilation. Arteriovenous extracorporeal membrane carbon dioxide removal, also known as pumpless extracorporeal lung assist, can also be used to support gas exchange.
# Outline of the procedure
Extracorporeal membrane oxygenation for severe acute respiratory failure in adults aims to reduce ventilator-induced lung injuries and improve patient outcomes.
There are two main types of ECMO: venovenous ECMO (for respiratory support) and venoarterial ECMO (for cardiac and mixed cardiac and respiratory support). In venovenous ECMO desaturated blood is withdrawn from the venae cavae and pumped through an oxygenator, where gas exchange of oxygen and carbon dioxide takes place. The oxygenated blood is then returned to the venous system. In venoarterial ECMO, blood is withdrawn via the venous system and returned to the arterial system. In both systems patients are given a continuous infusion of an anticoagulant, usually heparin, to prevent blood clotting in the external system.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at
# Efficacy
A randomised controlled trial (RCT) of 180 patients treated by ECMO or conventional management reported death or severe disability in 37% (33/90) and 53% (46/87; there was no information about 3 patients) of patients respectively at 6-month follow-up (relative risk 0.69, 95% confidence interval 0.05 to 0.97).
A non-randomised comparative study of 245 patients treated by ECMO or conventional treatment reported survival to hospital discharge in 55% (34/62) and 61% (absolute figures not stated) of patients respectively (p = not significant). A non-randomised comparative study of 150 patients treated by ECMO or conventional treatment reported survival rates of 53% (17/32) and 71% (84/118) respectively (p = 0.06). All patients in these studies treated by ECMO had more severe disease than controls.
The RCT of 180 patients treated by ECMO or conventional management reported similar levels of overall health status scores in both groups at 6 months (67.9 versus 65.9; measured on a visual analogue scale from 0 to 100, where a higher score indicates a better health status).
The Specialist Advisers listed key efficacy outcomes as successful weaning from ECMO, successful weaning from ventilation, improved survival and quality of life.
# Safety
The non-randomised comparative study of 245 patients and the case series of 255 patients both reported that 5% of patients (3/62 in the comparative study, no actual figures were given for the case series) developed disseminated intravascular coagulation.
Vessel perforation during cannulation contributed to the deathof 1 patient out of 68 treated by ECMO in the RCT of 180 patients.
Difficulties and/or injuries during cannulation were reported in 8% (5/62) of patients in the non-randomised comparative study of 245 patients; 1 patient required surgical intervention to repair an injury to the carotid artery.
The non-randomised comparative study of 245 patients and case series of 1473 and 255 patients reported rupture of the ECMO tubing system in 5% (3/62), 4% (64/1473) and 3% (actual numbers not stated) of patients respectively. Of the patients in the non‑randomised comparative study, brain death was diagnosed in 1 patient after resuscitation and reinstitution of ECMO.
The Specialist Advisers listed anecdotal adverse events as air embolism, thromboembolic events, sepsis, multi‑organ failure and mechanical failure.
# Other comments
The Committee recognised the importance of the CESAR trial and the reasons for its pragmatic design.# Further information
NHS Specialised Services has developed 'Standards for Nationally Designated Centres for Extracorporeal Membrane Oxygenation (ECMO) for Adults with Severe Potentially Reversible Respiratory Failure'.
For related NICE guidance see www.nice.org.uk.
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG391/publicinfo
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{'Guidance': "This document replaces previous guidance on extracorporeal membrane oxygenation in adults (interventional procedure guidance 39).\n\nEvidence on the safety of extracorporeal membrane oxygenation (ECMO) for severe acute respiratory failure in adults is adequate but shows that there is a risk of serious side effects. Evidence on its efficacy is inadequate to draw firm conclusions: data from the recent CESAR (Conventional ventilation or extracorporeal membrane oxygenation for severe adult respiratory failure) trial were difficult to interpret because different management strategies were applied among many different hospitals in the control group and a single centre was used for the ECMO treatment group. Therefore this procedure should only be used with special arrangements for clinical governance, consent and research.\n\nClinicians wishing to undertake ECMO for severe acute respiratory failure in adults should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nWhenever possible, ensure that patients and their carers understand the uncertainty about the procedure's efficacy and its risks and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended (available from www.nice.org.uk/IPG391/publicinfo).\n\nExtracorporeal membrane oxygenation for severe acute respiratory failure in adults should only be carried out by clinical teams with specific training and expertise in the procedure.\n\nClinicians are encouraged to submit data on all adults undergoing ECMO for severe acute respiratory failure to the international Extracorporeal Life Support Organization register (www.elso.med.umich.edu).\n\nNICE encourages further research into the use of innovative technologies for the management of severe acute respiratory failure, and may review this guidance on publication of further evidence.", 'The procedure': '# Indications and current treatments\n\nExtracorporeal membrane oxygenation is a supportive therapy for adults with severe acute respiratory failure from a potentially reversible cause. Extracorporeal membrane systems mimic gas exchange in the lungs by eliminating some carbon dioxide from the blood and adding oxygen.\n\nThere are many causes of severe acute respiratory failure, including acute respiratory distress syndrome, pneumonia, and chest trauma.\n\nConventional treatment involves maximum medical support, including mechanical ventilation. Arteriovenous extracorporeal membrane carbon dioxide removal, also known as pumpless extracorporeal lung assist, can also be used to support gas exchange.\n\n# Outline of the procedure\n\nExtracorporeal membrane oxygenation for severe acute respiratory failure in adults aims to reduce ventilator-induced lung injuries and improve patient outcomes.\n\nThere are two main types of ECMO: venovenous ECMO (for respiratory support) and venoarterial ECMO (for cardiac and mixed cardiac and respiratory support). In venovenous ECMO desaturated blood is withdrawn from the venae cavae and pumped through an oxygenator, where gas exchange of oxygen and carbon dioxide takes place. The oxygenated blood is then returned to the venous system. In venoarterial ECMO, blood is withdrawn via the venous system and returned to the arterial system. In both systems patients are given a continuous infusion of an anticoagulant, usually heparin, to prevent blood clotting in the external system.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at http://www.nice.org.uk/guidance/index.jsp?action=download&o=56402\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 180 patients treated by ECMO or conventional management reported death or severe disability in 37% (33/90) and 53% (46/87; there was no information about 3 patients) of patients respectively at 6-month follow-up (relative risk [RR] 0.69, 95% confidence interval [CI] 0.05 to 0.97).\n\nA non-randomised comparative study of 245 patients treated by ECMO or conventional treatment reported survival to hospital discharge in 55% (34/62) and 61% (absolute figures not stated) of patients respectively (p\xa0=\xa0not significant). A non-randomised comparative study of 150 patients treated by ECMO or conventional treatment reported survival rates of 53% (17/32) and 71% (84/118) respectively (p\xa0=\xa00.06). All patients in these studies treated by ECMO had more severe disease than controls.\n\nThe RCT of 180 patients treated by ECMO or conventional management reported similar levels of overall health status scores in both groups at 6\xa0months (67.9 versus 65.9; measured on a visual analogue scale from 0 to 100, where a higher score indicates a better health status).\n\nThe Specialist Advisers listed key efficacy outcomes as successful weaning from ECMO, successful weaning from ventilation, improved survival and quality of life.\n\n# Safety\n\nThe non-randomised comparative study of 245 patients and the case series of 255 patients both reported that 5% of patients (3/62 in the comparative study, no actual figures were given for the case series) developed disseminated intravascular coagulation.\n\nVessel perforation during cannulation contributed to the deathof 1 patient out of 68 treated by ECMO in the RCT of 180 patients.\n\nDifficulties and/or injuries during cannulation were reported in 8% (5/62) of patients in the non-randomised comparative study of 245\xa0patients; 1 patient required surgical intervention to repair an injury to the carotid artery.\n\nThe non-randomised comparative study of 245 patients and case series of 1473 and 255 patients reported rupture of the ECMO tubing system in 5% (3/62), 4% (64/1473) and 3% (actual numbers not stated) of patients respectively. Of the patients in the non‑randomised comparative study, brain death was diagnosed in 1 patient after resuscitation and reinstitution of ECMO.\n\nThe Specialist Advisers listed anecdotal adverse events as air embolism, thromboembolic events, sepsis, multi‑organ failure and mechanical failure.\n\n# Other comments\n\nThe Committee recognised the importance of the CESAR trial and the reasons for its pragmatic design.', 'Further information': "NHS Specialised Services has developed 'Standards for Nationally Designated Centres for Extracorporeal Membrane Oxygenation (ECMO) for Adults with Severe Potentially Reversible Respiratory Failure'.\n\nFor related NICE guidance see www.nice.org.uk.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. See www.nice.org.uk/guidance/IPG391/publicinfo"}
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https://www.nice.org.uk/guidance/ipg391
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b320782348f87c9ce42d3c2fc3e67439a0e8eb54
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nice
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Azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia
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Azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia
Evidence-based recommendations on azacitidine (Vidaza) for treating myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia in adults.
# Guidance
Azacitidine is recommended as a treatment option for adults who are not eligible for haematopoietic stem cell transplantation and have:
intermediate-2 and high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS) or
chronic myelomonocytic leukaemia with 10–29% marrow blasts without myeloproliferative disorder or
acute myeloid leukaemia with 20–30% blasts and multilineage dysplasia, according to the World Health Organization classification and
if the manufacturer provides azacitidine with the discount agreed as part of the patient access scheme.# The technology
Azacitidine (Vidaza, Celgene) is an anticancer drug that is thought to work by re-establishing cells' natural mechanisms to control abnormal growth. Azacitidine has a UK marketing authorisation for the treatment of adult patients who are not eligible for haematopoietic stem cell transplantation with:
intermediate-2 and high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS)
chronic myelomonocytic leukaemia with 10–29% marrow blasts without myeloproliferative disorder or
acute myeloid leukaemia with 20–30% blasts and multilineage dysplasia, according to World Health Organization classification.
Azacitidine is contraindicated in patients who have known hypersensitivity to azacitidine or to any of its excipients; in women who are breastfeeding; and in patients with advanced malignant hepatic tumours. The summary of product characteristics (SPC) states that complete blood counts should be performed before starting therapy, and as often as needed, to monitor response and toxicity. The SPC lists precautions for use in patients with liver or kidney impairment, and cardiac or pulmonary disease. The SPC reports that the most common adverse reactions are thrombocytopenia, neutropenia, leukopenia, nausea, vomiting and injection site reactions. For full details of side effects and contraindications, see the SPC.
Azacitidine is injected subcutaneously daily for 7 days, followed by a rest period of 21 days. The SPC states that patients should be treated for a minimum of six cycles. The recommended dose is 75 mg/m2 of body surface area. The SPC states that patients should be pre-medicated with anti-emetics to prevent nausea and vomiting. The list price of azacitidine is £321 for a 100-mg vial (excluding VAT; 'British national formulary' edition 60). Based on a body surface area of 1.7 m2 and a dose of 75 mg/m2, fourteen vials would be required for one cycle (two vials for each day of treatment). Costs may vary in different settings because of negotiated procurement discounts.
The manufacturer had agreed a patient access scheme with the Department of Health in which azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia would be available with a discount applied to all invoices (referred to as the 'original' patient access scheme in this document). The manufacturer subsequently proposed a revised patient access scheme, in which the discount level is revised and is commercial-in-confidence. The Department of Health has agreed that the revised patient access scheme can be included in this appraisal in January 2011. The manufacturer has agreed that the revised patient access scheme will remain in place until the publication of reviewed NICE guidance.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of azacitidine and a review of these submissions by the Evidence Review Group (ERG) and the Decision Support Unit (DSU; appendix B).
The main evidence for the efficacy of azacitidine in patients with high- and intermediate-2 risk myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia in the manufacturer's submission was obtained from a phase III, open-label, multicentre, randomised controlled trial (AZA-001; n = 358). Supplementary data from an open-label extension trial of AZA-001 were also provided. Before randomisation, patients were preselected by the investigator (on the basis of age, general condition, comorbidities and patient preference) for treatment with one of three conventional care regimens: best supportive care alone, low-dose chemotherapy plus best supportive care or standard-dose chemotherapy plus best supportive care. Patients were then randomised to receive either azacitidine or the preselected conventional care regimen. Patients receiving a particular conventional care regimen were compared with patients who had been preselected for the same care regimen but were then randomised to treatment with azacitidine. The manufacturer reported that patients randomised to either azacitidine or one of the conventional care regimens were comparable in terms of age, baseline severity of myelodysplastic syndrome, Eastern Cooperative Oncology Group (ECOG) performance status and time since original diagnosis. However, within the conventional care regimens, patients preselected to receive low- or standard-dose chemotherapy tended to be younger and have a higher ECOG performance status than patients preselected to receive best supportive care alone. Randomisation and subsequent analyses were stratified according to the French–American–British classification (FAB) subtype and IPSS group. Of the 179 patients receiving a conventional care regimen, 105 (59%) were preselected for best supportive care alone, 49 (27%) for low-dose chemotherapy and 25 (14%) for standard-dose chemotherapy. Of the 179 patients receiving azacitidine, 117 (65%) had been preselected for best supportive care alone, 45 (25%) for low-dose chemotherapy and 17 (9%; percentages do not add up to 100% because of rounding) for standard-dose chemotherapy.
The primary endpoint in AZA-001 was overall survival. Secondary endpoints included time to transformation to acute myeloid leukaemia, haematological response, independence from red blood cell transfusions for 56 consecutive days or more, number of infections needing intravenous antibiotics and occurrence of adverse events.
The manufacturer's submission stated that the intention-to-treat median overall survival was 24.5 months for patients receiving azacitidine compared with 15.0 months for patients receiving conventional care regimens (p = 0.0001, hazard ratio 0.58, 95% confidence interval 0.43 to 0.77). The median time to transformation to acute myeloid leukaemia was 17.8 months (interquartile range 8.6 to 36.8, 95% CI 13.6 to 23.6) with azacitidine compared with 11.5 months (interquartile range 4.9 to not reached, 95% CI 8.3 to 14.5) with conventional care regimens (p < 0.0001, hazard ratio 0.50, 95% CI 0.35 to 0.70). The manufacturer also reported results within each of the preselection groups. Treatment with azacitidine led to statistically significant improvements in overall survival in the group preselected for best supportive care alone and in the group preselected for low-dose chemotherapy plus best supportive care, but not in the group preselected for standard-dose chemotherapy plus best-supportive care. Only patients preselected for best supportive care alone had statistically significant improvement with azacitidine in time to transformation to acute myeloid leukaemia. Of the patients who were dependent on red blood cell transfusions at baseline, 45% of patients treated with azacitidine no longer needed transfusions during treatment compared with 11.8% of patients receiving conventional care regimens (p < 0.0001). The manufacturer reported that in a subgroup analysis of patients with the –7/del(7q) chromosomal abnormality, median overall survival was higher in patients receiving azacitidine than in patients receiving conventional care regimens.
The ERG considered the results from AZA-001 to be robust and to show clinical benefit for patients treated with azacitidine. The ERG noted that the open-label design of the study meant that the results could be subject to bias and that there was an imbalance in the numbers lost to follow-up. The ERG considered that this means that the effectiveness of azacitidine in clinical practice could be lower than that seen in AZA-001. In addition, the ERG noted that the results for the comparison with low- and standard-dose chemotherapy were less robust because of the small numbers of patients included.
The manufacturer developed an economic evaluation, comprising a two-arm health-state transition model. One arm estimated the costs and outcomes associated with treatment with azacitidine; the other arm estimated the costs and outcomes associated with treatment with the conventional care regimens in AZA-001 (see section 3.1). Patients entered the model in the myelodysplastic syndromes health state at the start of treatment and left the model at death. The model used a 35-day cycle with a lifetime horizon.
The manufacturer's economic model used data from AZA-001 and its open-label extension trial to estimate effectiveness. The economic model underwent a number of iterations after clarification requests from the Committee, the ERG and the DSU. The manufacturer's base-case analysis used a lognormal parametric function to extrapolate the overall survival from the data observed in the trial. Survival data from a myelodysplastic syndromes registry in Düsseldorf were presented in support of the selection of the lognormal function. Sensitivity analyses explored the use of alternative parametric functions. Time to progression was modelled in such a way that progression to the acute myeloid leukaemia health state occurred eight cycles before death to reflect the mean length of time patients had acute myeloid leukaemia in AZA-001.
The manufacturer reported that no quality of life data were collected in AZA-001 that could be used to populate the economic model. Utility value estimates for patients treated with azacitidine and best supportive care were taken from the prospective, open-label, multicentre randomised controlled trial CALGB 9221 (n = 191). In this trial, patients with myelodysplastic syndromes were treated with either azacitidine or best supportive care, and European Organisation for Research and Treatment of Cancer (EORTC) quality of life data were collected. This trial was excluded from the clinical-effectiveness analysis because the patient population was of a lower IPSS risk category than the population specified in the marketing authorisation for azacitidine. The manufacturer converted the EORTC quality of life data into EQ-5D values using an algorithm developed using data from a study in patients with oesophageal cancer. Utility value estimates for patients treated with chemotherapy were mapped to the EQ-5D from SF-12 scores published in a report about patients receiving low-dose and standard-dose chemotherapy.
The manufacturer reported that, when possible, healthcare resource use was determined from AZA-001 protocol regimens. When data were not available from the trial, resource use estimates were based on expert opinion obtained through a questionnaire. Drug costs were taken from the BNF (edition 57). The majority of treatment costs were determined using the NHS 2009/10 tariff. Personal and Social Services Research Unit costs and NHS reference costs (2006/07) were used for resources if a tariff cost was not available. Because azacitidine requires a 7-day continuous treatment cycle, the additional cost of weekend administration was modelled as a two-fold increase in administration cost for 2 days of each treatment cycle. The manufacturer estimated that vial sharing, which involves treating multiple patients on the same day, could be used for 49% of patients. The reduction in unused vials and consequent savings in drug costs resulting from vial sharing were explored in a scenario analysis.
The manufacturer's base-case results (using the lognormal parametric function to extrapolate overall survival and excluding any patient access scheme; see section 3.6) gave incremental cost-effectiveness ratios (ICERs) for treatment with azacitidine compared with each of the conventional care regimens of £47,432 per quality-adjusted life year (QALY) gained for patients in the best supportive care alone group, £40,754 per QALY gained for patients in the low-dose chemotherapy group, and £37,105 per QALY gained for patients in the standard-dose chemotherapy group. The scenario analysis that explored vial sharing decreased the base-case ICERs to £44,440, £37,929 and £34,366 per QALY gained for the best supportive care alone, low-dose chemotherapy and standard-dose chemotherapy groups respectively. Incorporating the original patient access scheme reduced the base-case ICERs (and those with vial sharing) to £45,538 (£42,756), £38,966 (£36,399) and £35,371 (£32,823) per QALY gained for the best supportive care alone, low-dose chemotherapy and standard-dose chemotherapy groups respectively.
The manufacturer provided cost-effectiveness analyses for each of the parametric survival functions explored. The ICERs referred to below incorporate the original patient access scheme. For the analyses using the Weibull survival function, the ICERs were £63,177 per QALY gained for the best supportive care alone group, £49,030 per QALY gained for the low-dose chemotherapy group, and £51,252 per QALY gained for the standard-dose chemotherapy group. For the analyses using the exponential survival function, the ICERs were £67,203 per QALY gained for the best supportive care alone group, £58,418 per QALY gained for the low-dose chemotherapy group, and £60,097 per QALY gained for the standard-dose chemotherapy group. For the analyses using the lognormal survival function, the ICERs were £45,538 per QALY gained for the best supportive care alone group, £38,996 per QALY gained for the low-dose chemotherapy group, and £35,371 per QALY gained for the standard-dose chemotherapy group.For analyses using the baseline survival from the Düsseldorf registry data and applying the respective hazard ratios associated with treatment, the ICERs were £71,522 per QALY gained for the best supportive care alone group, £58,282 per QALY gained for the low-dose chemotherapy group, and £85,790 per QALY gained for the standard-dose chemotherapy group.
The ERG expressed concerns about the analyses of the preselected conventional care groups in AZA-001. It noted that two of the groups, particularly the standard-dose chemotherapy group, consisted of very small numbers of patients, and that to consider the arms of the trial in isolation effectively breaks randomisation.
The ERG raised concerns about the parametric function selected to model overall survival. It noted that the selection of the lognormal function was not strongly supported by evidence from AZA-001, its open-label extension trial or the Düsseldorf registry data. The ERG reported that when various parametric functions were compared with the individual patient data from the Düsseldorf registry, an exponential survival function underestimated long-term survival, while log-logistic and lognormal survival functions overestimated long-term survival. The ERG noted that the use of log-logistic and lognormal functions estimated a percentage of patients would survive into their nineties, which the ERG considered unrealistic, given the nature of the condition. The ERG reported that of the functions explored, the Weibull survival function provided the best fit to the Düsseldorf registry data.
The ERG commented that the time to transformation to acute myeloid leukaemia in AZA-001 was subject to considerable censoring from loss of patients to follow-up. It therefore considered that the modelled time to transformation was subject to uncertainty.
The ERG noted several issues with the conversion of EORTC quality of life data into utility values. The ERG reported that the algorithm used to derive the utility values was considered by its developers to be less reliable for patients in more severe health states than alternative algorithms that were explored and rejected by the manufacturer. The ERG noted that this could bias the results. It also reported that the algorithm had been developed using data from patients with oesophageal cancer, and that patients eligible for azacitidine were of a similar age to these patients. However, the underlying conditions and comorbidities were potentially very different. The ERG stated that the utility values resulting from the algorithm should be treated with caution.
The manufacturer explored the impact of adjusting the utility values to account for the differences in the baseline patient characteristics. This was shown to have little impact on the ICERs.
After the appeal, the manufacturer submitted information on the proportions of patients with high-risk myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia receiving low-dose chemotherapy plus best supportive care and the proportions of patients receiving best supportive care alone. This information included:
a survey of 72 UK haematologists, with the proportions of patients treated with each conventional care regimen between 2008 and 2010 who were eligible for azacitidine according to the marketing authorisation
a survey of 23 UK hospitals, with the proportions of patients treated with each conventional care regimen and
data from the Haematological Malignancy Research Network registry (HMRN; collecting data from 22 hospitals in the Yorkshire and Humber and Yorkshire Coast cancer networks) on the first-line treatment of patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia between September 2004 and August 2009. The hospital survey and HMRN registry data included all patients with high-risk myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia, not just patients who would be eligible for azacitidine according to the marketing authorisation. The haematologist survey data and hospital survey data were presented graphically and indicated that the majority of patients received best supportive care alone, although this proportion appeared lower among the haematologists identified as specialist consultants and among the hospitals identified as specialist centres. The audit of the HMRN registry data showed that of those patients considered as IPSS intermediate-2 or IPSS high risk, 58% received best supportive care alone (including observation only), 12% received low-dose chemotherapy and 28% received standard-dose chemotherapy (2% of patients died before treatment).
The DSU provided a critique of the three sources of information. The survey of 72 UK haematologists was based on clinicians' estimates of patients receiving each conventional care regimen, rather than the proportions of patients who were eligible for each regimen. Because it was not clear whether the data provided were from case note review or from clinician self-reporting, the DSU considered that the survey was subject to a high risk of bias. For this reason the DSU considered that this survey did not provide reliable data to inform the Committee's considerations about the conventional care regimens. Regarding the survey from 23 UK hospitals, the DSU commented that because the data had been presented graphically it was difficult to estimate the exact proportions of patients treated with each care regimen. The survey was considered to offer limited information because:
patients who would not be eligible to receive azacitidine were included and
there was a lack of information about whether the sample of hospitals was representative of all UK hospitals and about the methods of data collection. In the DSU's view, the HMRN registry provided the most objective and reliable data for the numbers of patients receiving conventional care regimens. In summary, the DSU expressed the view that the three sources of information provided only a limited evidence base for the use of low-dose chemotherapy and confirmed the current variation in clinical practice.
After the appeal, the manufacturer also submitted information about the clinical characteristics of patients receiving each of the conventional care regimens in routine clinical practice. This included the results of an 'informal literature review' by the manufacturer and the clinical characteristics of patients receiving low-dose chemotherapy from the survey of UK haematologists. The manufacturer reported that among patients who were eligible for azacitidine according to the marketing authorisation, low-dose chemotherapy was most widely used in the UK in patients with the following characteristics:
symptomatic cytopenias:
anaemia requiring transfusion
neutropenia 0.5–1.0 × 109/litre (with or without infectious episodes)
thrombocytopenia 30–100 × 109/litre
normal karyotype (or one cytogenetic abnormality)
limited comorbidities, with Haematopoietic Cell Transplantation-specific Comorbidity Index (HCTCI) score 0–2
ECOG performance status 0–2
logistically able to undergo treatment.
The DSU commented that only two of the eleven studies provided by the manufacturer after the appeal were conducted in the UK and only one had been published since 1991. It was not clear how the characteristics had been selected from these studies; in particular toxicity and administration had been identified in the literature review but did not appear in the final list of characteristics. However, the HCTCI score, which the manufacturer previously reported was not in routine clinical use in the UK, was included in the list. In summary, the DSU considered that the literature review offered limited evidence on eligibility criteria for patients receiving the conventional care regimens.
After the appeal, the manufacturer also submitted additional cost-effectiveness analyses incorporating health-related quality of life data from the patient group MDS UK. The manufacturer provided analyses:
separately comparing azacitidine with each conventional care regimen specified by the Appeal Panel (that is, compared with best supportive care alone and compared with low-dose chemotherapy plus best supportive care) and
comparing azacitidine with usual care (that is, a single estimate representing a weighted average of all the conventional care regimens together). Each analysis used a Weibull parametric function to extrapolate overall survival, assumed no vial sharing, and included the original patient access scheme.
The manufacturer's analyses submitted after the appeal indicated that azacitidine compared with best supportive care alone was associated with an incremental cost of £63,756 and an incremental QALY gain of 1.01, producing an ICER of £63,177 per QALY gained. Azacitidine compared with low-dose chemotherapy was associated with an incremental cost of £65,671 and an incremental QALY gain of 1.34, giving an ICER of £49,030 per QALY gained. Azacitidine compared with usual care (a weighted average of all the conventional care regimens together) was associated with an incremental cost of £61,801 and an incremental QALY gain of 1.09, giving an ICER of £56,945 per QALY gained. The manufacturer's submission stated that this weighted average was calculated using the proportion of patients receiving each of the conventional care regimens in AZA-001 (that is, 62% for best supportive care alone, 26% for low-dose chemotherapy plus best supportive care and 12% for standard-dose chemotherapy plus best supportive care).
The DSU commented that the utility values used in the revised economic evaluation were based on descriptions of health states that included dependence or independence from transfusion as a feature and did not separate the specific utility value of dependence or independence from transfusion from that of associated symptoms. It noted the small numbers of patients in the study (n = 47) and patients from the UK (n = 21). The DSU further noted that the data did not capture adverse events, in contrast with the utility value estimates used in the manufacturer's original base case. The DSU commented that constant utility values had been applied over the time horizon of the model, assuming that a patient's dependence on transfusion would remain constant throughout their treatment period. It considered that this was an unreasonable assumption. The DSU concluded that the MDS utility data did not provide more appropriate information for the economic evaluation than the data used in the manufacturer's base case. However, the DSU ran exploratory analyses using data from all patients in the MDS UK study and then with only data from the UK patients. None of these exploratory analyses resulted in significant changes to the cost-effectiveness estimates provided by the manufacturer.
The DSU considered that the analysis using a weighted average (see section 3.21) was not an appropriate measure of the cost effectiveness of azacitidine. The DSU took the view that the appropriate approach would be to consider all the treatment options in a single incremental analysis, comparing each treatment with the next most effective alternative, and excluding any dominated (that is, more costly and less effective) treatments from the analysis.
In response to the appraisal consultation document produced after the appeal, the manufacturer submitted updated cost-effectiveness analyses. Each analysis was deterministic, used a Weibull parametric function to extrapolate overall survival, assumed no vial sharing, and included the revised patient access scheme (see section 2.4). These analyses estimated the following ICERs for azacitidine, compared with three alternative weighted averages of the conventional care regimens:
£49,405 per QALY gained, based on the proportions of patients that had received one of the conventional care regimens after randomisation in AZA-001 (of which 59% patients received best supportive care alone, 27% received low-dose chemotherapy and 14% received standard-dose chemotherapy)
£49,837 per QALY gained, based on the proportions of IPSS intermediate-2 or high-risk patients that had received one of the conventional care regimens in the HMRN registry (of which 59% patients received best supportive care alone, 12% received low-dose chemotherapy and 28% received standard-dose chemotherapy)
£50,920 per QALY gained, based on the proportions of patients with the 'refractory anaemia with excess blasts' (RAEB) disease subtype that had received one of the conventional care regimens in the HMRN registry (of which 69% patients received best supportive care alone, 13% received low-dose chemotherapy and 18% received standard-dose chemotherapy).
The DSU considered that the most generalisable estimates for conventional care patterns from AZA-001 should be taken from the pre-randomisation proportions (that is, the whole trial population), instead of the proportions of patients (50% of the trial population) randomised to one of the conventional care regimens (as presented by the manufacturer). Before randomisation, 62% of patients were preselected to receive best supportive care alone, 26% received low-dose chemotherapy and 12% received standard-dose chemotherapy. The weighted average ICER associated with these proportions was £49,808 per QALY gained.
The DSU further considered that probabilistic analyses (instead of the deterministic analyses presented by the manufacturer) would be more robust, and therefore more appropriate for the Committee's consideration. The probabilistic ICERs associated with each of the weighted averages were:
£47,336 per QALY gained, based on the proportions of patients that had received one of the conventional care regimens after randomisation in AZA-001
£47,782 per QALY gained, based on the proportions of patients preselected (that is, prior to randomisation) to receive one of the conventional care regimens in AZA-001
£47,224 per QALY gained, based on the proportions of IPSS intermediate-2 or high-risk patients allocated to conventional care regimens in the HMRN registry
£48,581 per QALY gained, based on the proportions of patients with the RAEB disease subtype allocated to conventional care regimens in the HMRN registry.
Full details of all the evidence are in the manufacturer's submissions, the ERG report and the DSU reports.# Consideration of the evidence
The Appraisal Committee (appendix A) reviewed the data available on the clinical and cost effectiveness of azacitidine, having considered evidence on the nature of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia and the value placed on the benefits of azacitidine by patients with the conditions, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee heard from the clinical specialists that current practice includes the use of best supportive care and, for some patients who are able to tolerate it, low- or standard-dose chemotherapy. However, the Committee heard from the clinical specialists that there was no nationally recognised standard of care for patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia, particularly regarding patients' eligibility for chemotherapy. The Committee noted survey and HMRN registry data provided by the manufacturer, which together showed variations in treatment patterns among UK haematologists. The survey data showed a wide variation in clinicians' views about what determines a patient's eligibility for chemotherapy. The Committee heard from the clinical specialists that the group of patients eligible for chemotherapy could only be broadly described because of the current lack of consensus among UK haematologists about whether chemotherapy is appropriate for patients with certain comorbidities or disease-specific characteristics, and because of the inability to quantify clinician and patient preference for treatment. The Committee concluded that while best supportive care, low-dose and standard-dose chemotherapy were currently being used to treat patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia, there was no consensus among clinicians on the set of clinical characteristics that could identify patients for whom chemotherapy should be a treatment option.
The Committee considered the quality of life of patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia. The Committee understood from the evidence submitted, and from the evidence of clinical specialists and patient experts, that fatigue and a reduced ability to carry out day-to-day activities are common in these conditions and have a negative impact on patients' quality of life. The Committee noted information from patient groups, who reported that dependence on blood transfusions is an important aspect of these conditions and also has a negative impact on quality of life. The Committee concluded that having myelodysplastic syndromes decreases quality of life, and aspects of current conventional care (such as the need for blood transfusions) have a further negative impact on quality of life.
# Clinical effectiveness
The Committee considered the clinical-effectiveness evidence from AZA-001 presented by the manufacturer. The Committee understood that patients were preselected for treatment with one of the conventional care regimens before randomisation, and this was based on age, ECOG performance status, the presence of comorbidities and patient preference. It also understood that patients randomised to treatment with azacitidine were compared with patients in their respective pre-randomisation regimen. The Committee also heard from the clinical specialists that the proportion of patients in each preselection group in AZA-001 broadly represented the treatment patients with these conditions receive in the UK (that is, treatment with chemotherapy plus best supportive care is appropriate for considerably fewer patients than treatment with best supportive care alone).
The Committee noted that the median overall survival for patients receiving azacitidine was longer than for patients receiving the conventional care regimens. The Committee further noted that median time to transformation to acute myeloid leukaemia was longer for patients receiving azacitidine and the percentage of patients becoming independent of blood transfusions was higher for patients receiving azacitidine than for patients receiving the conventional care regimens. The Committee noted that when outcomes were analysed separately for each conventional care regimen, the difference in overall survival between the treatment arms in the standard-dose chemotherapy group was not statistically significant, and the differences between the treatment arms in the estimates of time to transformation to acute myeloid leukaemia for either the low-dose or standard-dose chemotherapy groups were not statistically significant. The Committee was aware that the small patient numbers limited the precision and certainty of the outcome estimates in these groups, but concluded that the estimates of total overall survival compared with conventional care appeared robust. The Committee noted that the problems relating to loss of patients to follow-up, as described by the ERG (see section 3.13), may have introduced bias into estimates of relative effectiveness, but concluded that this effect was likely to be minimal.
The Committee considered the role of patient preference in the design and analysis of AZA-001. The Committee heard from the DSU and the manufacturer that the term 'patient preference trial' is used to describe trial designs that take account of a patient's preference to receive either the study treatment (for example, azacitidine) or the comparator (for example, conventional care). It noted that in AZA-001, patient preference informed preselection to one of the conventional care regimens before randomisation, but did not inform randomisation to either azacitidine or conventional care. The Committee concluded that the role of patient preference in AZA-001 did not affect the way in which the trial results or subsequent analyses should be considered.
The Committee considered the potential adverse effects associated with treatments for myelodysplastic syndromes and the impact of these effects on quality of life. The Committee heard from the clinical specialists that common adverse effects of treatment with azacitidine include peripheral blood cytopenias, myelosuppression, nausea, vomiting and injection site reactions. The patient experts and clinical specialists agreed that these adverse effects are generally well tolerated. The Committee heard from the patient experts that compared with other treatment options, azacitidine was associated with relief from fatigue, fewer infection-related hospitalisations, a decreased need for blood and platelet transfusion, and increased ability to perform day-to-day activities. The Committee noted that no quality of life data were collected in AZA-001, although EORTC data collected in CALGB 9221 suggested improvements in overall health with azacitidine.
The Committee concluded on the basis of the clinical-effectiveness evidence and the evidence from the clinical specialists and patient experts that azacitidine is a clinically effective treatment for myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia.
# Cost effectiveness
The Committee considered evidence on the cost effectiveness of azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia. It discussed the likelihood of vial sharing, noting that because of the small number of patients, it may be difficult to implement a vial-sharing scheme. It concluded that the manufacturer's estimate of 49% of patients being able to receive treatment at the same time (and therefore share vials) seemed optimistic. The Committee concluded that the analyses incorporating estimated vial sharing did not produce plausible results and therefore would not form the basis for its decision on the use of azacitidine in the NHS.
The Committee noted the ERG's concerns about the manufacturer's initial model, mainly relating to the selection of the parametric function to model overall survival. The ERG stated that the most important influence on the model's outputs was overall survival, and that the choice of parametric distribution used to extrapolate estimates of overall survival from AZA-001 greatly influenced the results. The Committee noted that the manufacturer's initial base case used the lognormal function to extrapolate overall survival from the trial data, which the manufacturer justified with supporting data from a Düsseldorf myelodysplastic syndromes registry. The Committee understood that the use of the lognormal distribution modelled survival in such a way that some patients were predicted to live to an unrealistic age given the nature of the condition (see section 3.12), that is the use of lognormal distribution led to an overestimation of survival. The Committee concluded that the Weibull distribution generally provided the best overall fit to the Düsseldorf registry long-term survival data, and that modelling that incorporated the Weibull distribution should be used to inform a decision on the use of azacitidine in the NHS.
The Committee considered the estimates of quality of life included in the model (see also sections 4.12 and 4.13). The Committee first considered the derivation of the utility values. It was aware of the ERG's concerns about the mapping of EORTC values to the EQ-5D (see section 3.14). The Committee concluded that because the algorithm had been developed using data from patients with oesophageal cancer, the values would be associated with greater uncertainty than if a validated algorithm based on patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia had been used.
The Committee then considered the face validity of the quality of life gains attributed to azacitidine in the model. The patient experts and clinical specialists stated that treatment with azacitidine reduces symptoms (such as fatigue) and the need for blood transfusions. The Committee agreed that the associated utility gains of these should ideally be reflected in the model. The Committee noted that greater independence from blood transfusions was not explicitly included in the utility value estimate. It was aware that the manufacturer estimated the utility value by mapping to the EQ-5D. The Committee understood that the EQ-5D does not include fatigue as a dimension, although it would capture some of the effects of fatigue on the patient's ability to undertake day-to-day activities. The Committee also understood that the EORTC measure includes a domain that captures the impact of treatment on quality of life, and that dependence on transfusion could be expected to affect this. It considered that reduced fatigue after azacitidine treatment may not have been completely captured in the modelled utility values. The Committee noted the alternative utility values provided by MDS UK after the appeal, which were meant to better reflect the utility values associated with dependence on or independence from blood transfusions. However, the Committee noted the DSU's concern that the alternative utility values did not separate dependence or independence from transfusion from associated symptoms (see section 3.22) and it did not accept these in preference to the manufacturer's previous estimates. The Committee also noted that the model applied constant utility values within each health state, therefore assuming quality of life gains from the first day of treatment, which it considered unrealistic. Taking all these points into account, the Committee concluded that it was uncertain whether the utility values used in the model under- or over-estimated the true utility values associated with myelodysplastic syndromes.
The Committee considered the uncertainty around the quality of life estimates included in the model (see sections 4.11 and 4.12). The Committee noted that sensitivity analyses carried out by the manufacturer showed that variations in the utility values had relatively little impact on the ICERs. It concluded that because the ICER estimate was largely driven by the incremental life years gained and the acquisition cost of azacitidine, and was only minimally affected by the changes in health-related quality of life, the impact of any over- or underestimation of quality of life gains was likely to be small.
The Committee considered the inclusion of costs in the economic model. The Committee noted the use of the NHS 2009/2010 tariff. It considered that using the NHS 2009/10 tariff was appropriate because it could provide a more precise estimate of hospital costs by breaking down costs attributable to adverse events. The Committee also noted the assumed increase in the cost for treatment received at the weekend. The Committee concluded that the modelled increased costs of weekend administration were reasonable, aware that the associated impact on the ICERs was relatively small. On balance, the Committee concluded that costs included in the model were acceptable.
The Committee considered the estimated cost effectiveness of azacitidine. The Committee noted that the manufacturer had submitted two approaches to estimating the ICERs for azacitidine:
-ne analysis comparing azacitidine separately with each of the conventional care regimens specified by the Appeal Panel (that is, compared with best supportive care alone and compared with low-dose chemotherapy plus best supportive care) and
three analyses comparing azacitidine with usual care (that is, a single estimate representing a weighted average of all the conventional care regimens together), with each analysis using different proportions of conventional care to form the weighted average. The Committee noted that no cost-effectiveness evidence was presented for the subgroup of patients with the –7/del(7q) chromosomal abnormality.
The Committee considered the two approaches to estimating the cost effectiveness of azacitidine. The Committee first considered the separate conventional care regimen analyses. The Committee noted that patients randomised to receive azacitidine in the group preselected to receive low-dose chemotherapy plus best supportive care incurred higher total costs (£101,100) than those randomised to azacitidine who had been preselected to receive best supportive care alone (£91,800). It further noted that the number of total QALYs (that is, not the incremental QALY gain) was greater in those randomised to azacitidine who had been preselected to receive low-dose chemotherapy (2.44) than in those randomised to azacitidine who had been preselected to receive best supportive care alone (2.04). The Committee also noted that in the analyses presented before the appeal comparing azacitidine with standard-dose chemotherapy, the number of QALYs associated with those randomised to azacitidine who had been preselected to receive standard-dose chemotherapy in the azacitidine arm was 1.91. The Committee concluded that there appeared to be no reason, other than differences in baseline patient characteristics, why those who were randomised to azacitidine but were preselected to receive low-dose chemotherapy should have gained greater benefit than those who were randomised to azacitidine but were preselected to receive standard-dose chemotherapy plus best supportive care or best supportive care alone. The Committee agreed that this uncertainty should be noted when considering the most appropriate analyses on which to base its recommendations.
The Committee then considered the analyses of azacitidine compared with a weighted average of usual care (see sections 3.24 to 3.26). The Committee understood that the weighted ICERs had each been calculated by combining the individual ICERs for the respective conventional care regimens, each weighted by the proportion of patients receiving these regimens in AZA-001 and in the HMRN registry respectively. The Committee understood the significant methodological limitations associated with analyses involving the use of such a weighted average, in particular the need for equivalent patient characteristics (such as age or disease severity) at baseline among any of the groups being combined (see section 4.16). It also acknowledged the importance of ensuring that the full range of appropriate comparators was considered within these groups. It noted that because of differences in the baseline patient characteristics of the conventional care regimen subgroups (see section 3.1) the patient populations and associated population-specific results may not necessarily be appropriate for statistical analysis, which combines estimates across the groups using a simple weighted average.
The Committee then considered which of the two analytical approaches to considering cost effectiveness provided the most appropriate basis for its decision. It agreed that the most important consideration in whether a decision should be based on the separate comparisons with the different conventional care regimens was the need for a clear definition of the groups of patients eligible to receive each of the conventional care regimens. The Committee agreed that because a set of clear and objective clinical characteristics defining the eligibility of patients to receive chemotherapy had not been agreed among haematologists, it could not make recommendations based on any of the separate conventional care regimen groups (see section 4.2).
The Committee was aware of the significant methodological limitations with using weighted averages. The Committee understood that weighted averages can mask differences in the incremental costs and/or QALYs of the technologies being combined. The Committee was aware that the NICE 'Guide to the methods of technology appraisal' states that best practice should be considered as a comparator for appraisal of health technologies. If best practice is defined as a cost-effective treatment option, the standard approach to assessing the cost effectiveness of azacitidine in this context would be to consider all treatment options (that is, each of the conventional care regimens) in an iterative incremental analysis (that is, assessing the ratio of the additional cost and benefit of each technology compared with the next best alternative) to identify the most cost-effective strategy. The Committee understood that the weighted average approach assumes that each conventional care regimen is the most cost-effective treatment option available for the patient group for whom it is used. It heard from the DSU that the necessary evidence to test this assumption is not available, given the remit of this appraisal, and therefore the use of a weighted average would result in some uncertainty in the ICER produced. It further heard from the DSU that if the cost effectiveness of each of the individual conventional care regimens was not established, the magnitude and direction of uncertainty in the weighted average ICER is unknown. The Committee also understood that because the populations eligible for each of the conventional care regimens cannot be clearly defined (see section 4.2), an incremental analysis (as preferred by the DSU) is not possible in this case. Taking into account the limitations of the available evidence and in the absence of a satisfactory alternative, the Committee hesitantly concluded that any decision on the cost effectiveness of azacitidine would need to be made using the weighted average.
The Committee considered the proportions of each conventional care regimen used to calculate the weighted average. It understood that the manufacturer's base-case estimate was based on the proportions of people receiving each conventional care regimen in AZA-001, but that alternative analyses used the HMRN registry data submitted by the manufacturer (see section 3.25). The Committee heard from the clinical specialists that the HMRN registry, a UK database of over 600 patients, provided a representative estimate of the management of myelodysplastic syndromes in the UK. It noted that the HMRN registry includes a wider range of patients than those covered by the marketing authorisation for azacitidine but acknowledged clinical advice that within the HMRN registry, the subset of patients classified as having IPSS intermediate-2 or high-risk myelodysplastic syndromes provided the best available estimate of the proportion of patients receiving each of the conventional care regimens in the patient population for whom azacitidine is licensed. The Committee concluded that a weighted average of conventional care regimens should be calculated using the HMRN registry data (for the subset of patients having IPSS intermediate-2 or high-risk myelodysplastic syndromes) rather than the AZA-001 data.
The Committee considered the ICERs calculated using a weighted average of the proportions receiving conventional care regimens in the HMRN registry for patients classified as IPSS intermediate-2 or high risk. It understood that in this patient population approximately 59% of patients received best supportive care alone, 12% received low-dose chemotherapy plus best supportive care and 29% received standard-dose chemotherapy plus best supportive care. The Committee noted that the manufacturer's deterministic ICER using these proportions of patients was £49,800 per QALY gained. The Committee heard from the DSU that the probabilistic estimate of the ICER associated with these proportions was approximately £47,200 per QALY gained (see section 3.27). The Committee considered that the probabilistic ICER was a more valid estimate than the deterministic estimate because it takes account of joint parameter uncertainty. The Committee noted that because the incremental cost-effectiveness estimates of each respective conventional care regimen that comprise the weighted average were not known (see section 4.19), uncertainty about the true ICER for azacitidine compared with usual care remained. Taking into account the limitations associated with the use of a weighted average and the uncertainty associated with the cost effectiveness of each individual conventional care regimen, the Committee concluded that £47,200 per QALY gained represented the best available estimate of the cost effectiveness of azacitidine.
The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met.
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust.
The Committee discussed whether the benefit provided by azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee understood that there are approximately 700 patients with IPSS intermediate-2 and high-risk myelodysplastic syndromes in England and Wales. The Committee considered that life expectancy with best supportive care alone was likely to be approximately 11.5 months. It considered the evidence from AZA-001 and noted that the median overall survival for patients treated with azacitidine in the best supportive care preselection group was 21.1 months. The Committee agreed that azacitidine would improve the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia and that it was likely that azacitidine would increase overall survival by approximately 9.6 months. The Committee agreed that the estimates of clinical effectiveness informing the best available estimate of the ICER were sufficiently robust and concluded that azacitidine meets the criteria for being a life-extending, end-of-life treatment.
The Committee then considered the ICER taking into account the end-of-life considerations. It considered that the best available estimate of the base-case ICER was approximately £47,200 per QALY gained (see section 4.21). The Committee accepted the uncertainty associated with this estimate and acknowledged the difficulty of assessing the impact of uncertainty on the best estimate of the ICER (see section 4.19). The Committee was aware that other technologies had been recommended using the end-of-life criteria with ICERs as high as the one in this appraisal, but was conscious of the increasing cost pressures in the NHS and the opportunity costs that would result from a recommendation to fund a technology with an ICER of this magnitude. However, the Committee recognised that azacitidine represents an important change in the treatment of patients with myelodysplastic syndromes, noting the substantial benefits associated with its use. The Committee considered that on balance, the additional weight that would need to be assigned to the QALY benefits for the cost effectiveness of azacitidine to fall within the current threshold range was acceptable on this occasion. Therefore the Committee considered that azacitidine when provided by the manufacturer with the discount agreed in the revised patient access scheme agreed by the Department of Health in January 2011 was a cost-effective use of NHS resources as a treatment option for people with myelodysplastic syndromes, as stated in the marketing authorisation. This includes adults who are not eligible for haematopoietic stem cell transplantation with intermediate-2 and high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS), chronic myelomonocytic leukaemia with 10–29% marrow blasts without myeloproliferative disorder or acute myeloid leukaemia with 20–30% blasts and multilineage dysplasia, according to World Health Organization classification.
The Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations in any way. At an earlier meeting, the Committee noted that azacitidine may be of specific benefit to those who, for clinical or religious reasons, are unable to receive blood transfusions, because patients treated with azacitidine require fewer blood transfusions than patients treated with best supportive care. However, the Committee noted that no representations had been made or evidence received about the pathway of care for this particular group of patients, or about the effectiveness of azacitidine in this patient population. Therefore the Committee agreed that it would not be appropriate to make recommendations for a subgroup of patients unable to receive blood transfusions. Because the final recommendations (see section 4.24) do not restrict access to azacitidine for any particular group of patients, the Committee concluded that there was now no need to alter or add to its recommendations in any case.
# Summary of Appraisal Committee's key conclusions
TA218
Azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia
Section
Key conclusion
Azacitidine is recommended as a treatment option for adults who are not eligible for haematopoietic stem cell transplantation and have:
intermediate-2 and high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS) or
chronic myelomonocytic leukaemia with 10–29% marrow blasts without myeloproliferative disorder or
acute myeloid leukaemia with 20–30% blasts and multilineage dysplasia, according to the World Health Organization classification and
if the manufacturer provides azacitidine with the discount agreed as part of the patient access scheme.
The key drivers for this recommendation were as follows:
Taking into account the end-of-life considerations, the Committee recognised that azacitidine represents an important change in the treatment of patients with myelodysplastic syndromes.
The Committee considered that on balance, with the addition of the revised patient access scheme, azacitidine represented a cost-effective use of NHS resources.
Current practice
Clinical need of patients, including the availability of alternative treatments
Best supportive care, low-dose and standard-dose chemotherapy are currently being used to treat patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia who are not eligible for stem cell transplantation. However, there was no consensus among clinicians on the set of clinical characteristics that could identify patients for whom chemotherapy should be a treatment option.
Fatigue and a reduced ability to carry out day-to-day activities are common in these conditions and have a negative impact on patients' quality of life. Dependence on blood transfusions is an important aspect of these conditions and also has a negative impact on quality of life.
The technology
Proposed benefits of the technology
The Committee concluded on the basis of the clinical-effectiveness evidence and the evidence from the clinical specialists and patient experts that azacitidine is a clinically effective treatment for myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia.
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
Compared with other treatment options, azacitidine was associated with relief from fatigue, fewer hospitalisations because of infections, a decreased need for blood and platelet transfusion, and increased ability to perform day-to-day activities.
What is the position of the treatment in the pathway of care for the condition?
Azacitidine is licensed as first-line treatment for myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia and would replace best supportive care, low-dose and standard-dose chemotherapy.
Adverse effects
Common adverse events associated with azacitidine include peripheral blood cytopenias, myelosuppression, nausea, vomiting and injection site reactions. The patient experts and clinical specialists agreed that these adverse events are generally well tolerated.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee noted that the problems relating to loss of patients to follow-up in the pivotal trial (AZA-001) may have introduced bias into the estimates of relative effectiveness, but concluded that this effect was likely to be minimal.
The Committee concluded that the estimates of total overall survival compared with conventional care appeared robust.
The role of patient preference in the pre-randomisation of the pivotal trial did not affect the way in which the trial results or subsequent analyses should be considered.
Relevance to general clinical practice in the NHS
The comparator therapies used in the pivotal trial broadly represented the treatment patients with these conditions receive in the UK.
Uncertainties generated by the evidence
The small patient numbers limited the precision and certainty of the outcome estimates in the low-dose and standard-dose chemotherapy groups. However the Committee concluded that the estimates of total overall survival compared with conventional care appeared robust.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The manufacturer reported that in a subgroup analysis of patients with the –7/del(7q) chromosomal abnormality, median overall survival was higher in patients receiving azacitidine than in patients receiving conventional care regimens.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded on the basis of the clinical-effectiveness evidence and the evidence from the clinical specialists and patient experts that azacitidine is a clinically effective treatment for myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia.
Evidence for cost effectiveness
Availability and nature of evidence
No quality of life data were collected in the pivotal trial, although EORTC data collected in the CALGB 9221 trial suggested improvements in overall health with azacitidine.
The use of a weighted average for the comparator was associated with significant methodological limitations. However, taking into account the limitations of the available evidence and in the absence of a satisfactory alternative, the Committee hesitantly concluded that any decision on the cost effectiveness of azacitidine would need to be made using the weighted average.
The HMRN registry provided the best available estimate of the proportion of patients receiving each of the conventional care regimens to use in the calculation of the weighted average, namely those patients classified as having IPSS intermediate-2 or high-risk myelodysplastic syndromes.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee concluded that the analyses incorporating estimated vial sharing did not produce plausible results and therefore would not form the basis for its decision on the use of azacitidine in the NHS.
The Committee concluded that the Weibull distribution generally provided the best overall fit to the Düsseldorf registry long-term survival data.
The Committee concluded that it was uncertain whether the utility values used in the model under- or over-estimated the true utility values associated with myelodysplastic syndromes.
The Committee noted that the total costs and total QALY gain for azacitidine differed depending on which care regimen it was being compared with. It considered that this variation added to the uncertainty in the model.
Because the cost effectiveness of each of the individual conventional care regimens was not established the magnitude and direction of uncertainty in the weighted average ICER was unknown.
Incorporation of health-related quality of life benefits and utility values
The Committee concluded that because the algorithm had been developed using data from patients with oesophageal cancer, the values would be associated with greater uncertainty than if a validated algorithm based on patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia had been used.
The Committee agreed that the utility values provided by MDS UK after the appeal did not provide better estimates of the gains in health-related quality of life than the manufacturer's previous estimates.
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee noted that the model applied constant utility values within each health state, therefore assuming quality of life gains from the first day of treatment, which it considered unrealistic.
The Committee concluded that the utility values used in manufacturer's base case may not have captured the effects of transfusion dependence and fatigue. However, the ICER was only minimally affected by changes in the utility values.
to
Are there specific groups of people for whom the technology is particularly cost effective?
No cost-effectiveness evidence was presented for the subgroup of patients with the –7/del(7q) chromosomal abnormality.
What are the key drivers of cost effectiveness?
The Committee concluded that the ICER estimate was largely driven by the incremental life years gained (that is, the extrapolated survival) and the acquisition cost of azacitidine, and that the ICER was only minimally affected by the changes in health-related quality of life.
Most likely cost-effectiveness estimate (given as an ICER)
Taking into account the limitations associated with the use of a weighted average and the uncertainty associated with the cost effectiveness of each individual conventional care regimen, the Committee concluded that £47,200 per QALY gained represented the best available estimate of the cost effectiveness of azacitidine.
Additional factors taken into account
Patient access schemes
(PPRS)
The manufacturer agreed a revised patient access scheme with the Department of Health in January 2011 (which replaces an earlier patient access scheme), in which azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia will be available to the NHS with a discount, the level of which is commercial-in-confidence.
End-of-life considerations
The Committee concluded that azacitidine met the criteria for being a life-extending, end-of-life treatment. The Committee recognised that azacitidine represents an important change in the treatment of patients with myelodysplastic syndromes. The Committee considered that on balance, the additional weight that would need to be assigned to the QALY benefits in this patient group for the cost effectiveness of azacitidine to fall within the current threshold range was acceptable.
Equalities considerations and social value judgements
The Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations in any way. At an earlier meeting, the Committee noted that azacitidine may be of specific benefit to those who, for clinical or religious reasons, are unable to receive blood transfusions, because patients treated with azacitidine require fewer blood transfusions than patients treated with best supportive care. However, the Committee noted that no representations had been made or evidence received about the pathway of care for this particular group of patients, or about the effectiveness of azacitidine in this patient population. Therefore the Committee agreed that it would not be appropriate to make recommendations for a subgroup of patients unable to receive blood transfusions. Because the final recommendations (see section 4.24) do not restrict access to azacitidine for any particular group of patients, the Committee concluded that there was now no need to alter or add to its recommendations in any case.
# Recommendations for further research
The Committee recommends that a study estimating utility values using directly observed health-related quality of life values (such as EQ-5D scores) in patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia is conducted.# Related NICE guidance
Improving outcomes in haematological cancers. NICE cancer service guidance (2003).# Review of guidance
The guidance on this technology will be considered for review in February 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveMarch 2011# Changes after publication
February 2014: implementation section updated to clarify that azacitidine is recommended as an option for treating myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia. Additional minor maintenance update also carried out.
ISBN: 978-1-4731-3448-5
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{'Guidance': 'Azacitidine is recommended as a treatment option for adults who are not eligible for haematopoietic stem cell transplantation and have:\n\nintermediate-2 and high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS) or\n\nchronic myelomonocytic leukaemia with 10–29% marrow blasts without myeloproliferative disorder or\n\nacute myeloid leukaemia with 20–30% blasts and multilineage dysplasia, according to the World Health Organization classification and\n\nif the manufacturer provides azacitidine with the discount agreed as part of the patient access scheme.', 'The technology': "Azacitidine (Vidaza, Celgene) is an anticancer drug that is thought to work by re-establishing cells' natural mechanisms to control abnormal growth. Azacitidine has a UK marketing authorisation for the treatment of adult patients who are not eligible for haematopoietic stem cell transplantation with:\n\nintermediate-2 and high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS)\n\nchronic myelomonocytic leukaemia with 10–29% marrow blasts without myeloproliferative disorder or\n\nacute myeloid leukaemia with 20–30% blasts and multilineage dysplasia, according to World Health Organization classification.\n\nAzacitidine is contraindicated in patients who have known hypersensitivity to azacitidine or to any of its excipients; in women who are breastfeeding; and in patients with advanced malignant hepatic tumours. The summary of product characteristics (SPC) states that complete blood counts should be performed before starting therapy, and as often as needed, to monitor response and toxicity. The SPC lists precautions for use in patients with liver or kidney impairment, and cardiac or pulmonary disease. The SPC reports that the most common adverse reactions are thrombocytopenia, neutropenia, leukopenia, nausea, vomiting and injection site reactions. For full details of side effects and contraindications, see the SPC.\n\nAzacitidine is injected subcutaneously daily for 7\xa0days, followed by a rest period of 21\xa0days. The SPC states that patients should be treated for a minimum of six cycles. The recommended dose is 75\xa0mg/m2 of body surface area. The SPC states that patients should be pre-medicated with anti-emetics to prevent nausea and vomiting. The list price of azacitidine is £321 for a 100-mg vial (excluding VAT; 'British national formulary' [BNF] edition 60). Based on a body surface area of 1.7\xa0m2 and a dose of 75\xa0mg/m2, fourteen vials would be required for one cycle (two vials for each day of treatment). Costs may vary in different settings because of negotiated procurement discounts.\n\nThe manufacturer had agreed a patient access scheme with the Department of Health in which azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia would be available with a discount applied to all invoices (referred to as the 'original' patient access scheme in this document). The manufacturer subsequently proposed a revised patient access scheme, in which the discount level is revised and is commercial-in-confidence. The Department of Health has agreed that the revised patient access scheme can be included in this appraisal in January 2011. The manufacturer has agreed that the revised patient access scheme will remain in place until the publication of reviewed NICE guidance.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of azacitidine and a review of these submissions by the Evidence Review Group (ERG) and the Decision Support Unit (DSU; appendix B).\n\nThe main evidence for the efficacy of azacitidine in patients with high- and intermediate-2 risk myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia in the manufacturer's submission was obtained from a phase III, open-label, multicentre, randomised controlled trial (AZA-001; n\xa0=\xa0358). Supplementary data from an open-label extension trial of AZA-001 were also provided. Before randomisation, patients were preselected by the investigator (on the basis of age, general condition, comorbidities and patient preference) for treatment with one of three conventional care regimens: best supportive care alone, low-dose chemotherapy plus best supportive care or standard-dose chemotherapy plus best supportive care. Patients were then randomised to receive either azacitidine or the preselected conventional care regimen. Patients receiving a particular conventional care regimen were compared with patients who had been preselected for the same care regimen but were then randomised to treatment with azacitidine. The manufacturer reported that patients randomised to either azacitidine or one of the conventional care regimens were comparable in terms of age, baseline severity of myelodysplastic syndrome, Eastern Cooperative Oncology Group (ECOG) performance status and time since original diagnosis. However, within the conventional care regimens, patients preselected to receive low- or standard-dose chemotherapy tended to be younger and have a higher ECOG performance status than patients preselected to receive best supportive care alone. Randomisation and subsequent analyses were stratified according to the French–American–British classification (FAB) subtype and IPSS group. Of the 179 patients receiving a conventional care regimen, 105 (59%) were preselected for best supportive care alone, 49 (27%) for low-dose chemotherapy and 25 (14%) for standard-dose chemotherapy. Of the 179 patients receiving azacitidine, 117 (65%) had been preselected for best supportive care alone, 45 (25%) for low-dose chemotherapy and 17 (9%; percentages do not add up to 100% because of rounding) for standard-dose chemotherapy.\n\nThe primary endpoint in AZA-001 was overall survival. Secondary endpoints included time to transformation to acute myeloid leukaemia, haematological response, independence from red blood cell transfusions for 56 consecutive days or more, number of infections needing intravenous antibiotics and occurrence of adverse events.\n\nThe manufacturer's submission stated that the intention-to-treat median overall survival was 24.5\xa0months for patients receiving azacitidine compared with 15.0\xa0months for patients receiving conventional care regimens (p\xa0=\xa00.0001, hazard ratio 0.58, 95% confidence interval [CI] 0.43 to 0.77). The median time to transformation to acute myeloid leukaemia was 17.8\xa0months (interquartile range 8.6 to 36.8, 95% CI 13.6 to 23.6) with azacitidine compared with 11.5\xa0months (interquartile range 4.9 to not reached, 95% CI 8.3 to 14.5) with conventional care regimens (p\xa0<\xa00.0001, hazard ratio 0.50, 95% CI 0.35 to 0.70). The manufacturer also reported results within each of the preselection groups. Treatment with azacitidine led to statistically significant improvements in overall survival in the group preselected for best supportive care alone and in the group preselected for low-dose chemotherapy plus best supportive care, but not in the group preselected for standard-dose chemotherapy plus best-supportive care. Only patients preselected for best supportive care alone had statistically significant improvement with azacitidine in time to transformation to acute myeloid leukaemia. Of the patients who were dependent on red blood cell transfusions at baseline, 45% of patients treated with azacitidine no longer needed transfusions during treatment compared with 11.8% of patients receiving conventional care regimens (p\xa0<\xa00.0001). The manufacturer reported that in a subgroup analysis of patients with the –7/del(7q) chromosomal abnormality, median overall survival was higher in patients receiving azacitidine than in patients receiving conventional care regimens.\n\nThe ERG considered the results from AZA-001 to be robust and to show clinical benefit for patients treated with azacitidine. The ERG noted that the open-label design of the study meant that the results could be subject to bias and that there was an imbalance in the numbers lost to follow-up. The ERG considered that this means that the effectiveness of azacitidine in clinical practice could be lower than that seen in AZA-001. In addition, the ERG noted that the results for the comparison with low- and standard-dose chemotherapy were less robust because of the small numbers of patients included.\n\nThe manufacturer developed an economic evaluation, comprising a two-arm health-state transition model. One arm estimated the costs and outcomes associated with treatment with azacitidine; the other arm estimated the costs and outcomes associated with treatment with the conventional care regimens in AZA-001 (see section 3.1). Patients entered the model in the myelodysplastic syndromes health state at the start of treatment and left the model at death. The model used a 35-day cycle with a lifetime horizon.\n\nThe manufacturer's economic model used data from AZA-001 and its open-label extension trial to estimate effectiveness. The economic model underwent a number of iterations after clarification requests from the Committee, the ERG and the DSU. The manufacturer's base-case analysis used a lognormal parametric function to extrapolate the overall survival from the data observed in the trial. Survival data from a myelodysplastic syndromes registry in Düsseldorf were presented in support of the selection of the lognormal function. Sensitivity analyses explored the use of alternative parametric functions. Time to progression was modelled in such a way that progression to the acute myeloid leukaemia health state occurred eight cycles before death to reflect the mean length of time patients had acute myeloid leukaemia in AZA-001.\n\nThe manufacturer reported that no quality of life data were collected in AZA-001 that could be used to populate the economic model. Utility value estimates for patients treated with azacitidine and best supportive care were taken from the prospective, open-label, multicentre randomised controlled trial CALGB 9221 (n\xa0=\xa0191). In this trial, patients with myelodysplastic syndromes were treated with either azacitidine or best supportive care, and European Organisation for Research and Treatment of Cancer (EORTC) quality of life data were collected. This trial was excluded from the clinical-effectiveness analysis because the patient population was of a lower IPSS risk category than the population specified in the marketing authorisation for azacitidine. The manufacturer converted the EORTC quality of life data into EQ-5D values using an algorithm developed using data from a study in patients with oesophageal cancer. Utility value estimates for patients treated with chemotherapy were mapped to the EQ-5D from SF-12 scores published in a report about patients receiving low-dose and standard-dose chemotherapy.\n\nThe manufacturer reported that, when possible, healthcare resource use was determined from AZA-001 protocol regimens. When data were not available from the trial, resource use estimates were based on expert opinion obtained through a questionnaire. Drug costs were taken from the BNF (edition 57). The majority of treatment costs were determined using the NHS 2009/10 tariff. Personal and Social Services Research Unit costs and NHS reference costs (2006/07) were used for resources if a tariff cost was not available. Because azacitidine requires a 7-day continuous treatment cycle, the additional cost of weekend administration was modelled as a two-fold increase in administration cost for 2\xa0days of each treatment cycle. The manufacturer estimated that vial sharing, which involves treating multiple patients on the same day, could be used for 49% of patients. The reduction in unused vials and consequent savings in drug costs resulting from vial sharing were explored in a scenario analysis.\n\nThe manufacturer's base-case results (using the lognormal parametric function to extrapolate overall survival and excluding any patient access scheme; see section 3.6) gave incremental cost-effectiveness ratios (ICERs) for treatment with azacitidine compared with each of the conventional care regimens of £47,432 per quality-adjusted life year (QALY) gained for patients in the best supportive care alone group, £40,754 per QALY gained for patients in the low-dose chemotherapy group, and £37,105 per QALY gained for patients in the standard-dose chemotherapy group. The scenario analysis that explored vial sharing decreased the base-case ICERs to £44,440, £37,929 and £34,366 per QALY gained for the best supportive care alone, low-dose chemotherapy and standard-dose chemotherapy groups respectively. Incorporating the original patient access scheme reduced the base-case ICERs (and those with vial sharing) to £45,538 (£42,756), £38,966 (£36,399) and £35,371 (£32,823) per QALY gained for the best supportive care alone, low-dose chemotherapy and standard-dose chemotherapy groups respectively.\n\nThe manufacturer provided cost-effectiveness analyses for each of the parametric survival functions explored. The ICERs referred to below incorporate the original patient access scheme. For the analyses using the Weibull survival function, the ICERs were £63,177 per QALY gained for the best supportive care alone group, £49,030 per QALY gained for the low-dose chemotherapy group, and £51,252 per QALY gained for the standard-dose chemotherapy group. For the analyses using the exponential survival function, the ICERs were £67,203 per QALY gained for the best supportive care alone group, £58,418 per QALY gained for the low-dose chemotherapy group, and £60,097 per QALY gained for the standard-dose chemotherapy group. For the analyses using the lognormal survival function, the ICERs were £45,538 per QALY gained for the best supportive care alone group, £38,996 per QALY gained for the low-dose chemotherapy group, and £35,371 per QALY gained for the standard-dose chemotherapy group.For analyses using the baseline survival from the Düsseldorf registry data and applying the respective hazard ratios associated with treatment, the ICERs were £71,522 per QALY gained for the best supportive care alone group, £58,282 per QALY gained for the low-dose chemotherapy group, and £85,790 per QALY gained for the standard-dose chemotherapy group.\n\nThe ERG expressed concerns about the analyses of the preselected conventional care groups in AZA-001. It noted that two of the groups, particularly the standard-dose chemotherapy group, consisted of very small numbers of patients, and that to consider the arms of the trial in isolation effectively breaks randomisation.\n\nThe ERG raised concerns about the parametric function selected to model overall survival. It noted that the selection of the lognormal function was not strongly supported by evidence from AZA-001, its open-label extension trial or the Düsseldorf registry data. The ERG reported that when various parametric functions were compared with the individual patient data from the Düsseldorf registry, an exponential survival function underestimated long-term survival, while log-logistic and lognormal survival functions overestimated long-term survival. The ERG noted that the use of log-logistic and lognormal functions estimated a percentage of patients would survive into their nineties, which the ERG considered unrealistic, given the nature of the condition. The ERG reported that of the functions explored, the Weibull survival function provided the best fit to the Düsseldorf registry data.\n\nThe ERG commented that the time to transformation to acute myeloid leukaemia in AZA-001 was subject to considerable censoring from loss of patients to follow-up. It therefore considered that the modelled time to transformation was subject to uncertainty.\n\nThe ERG noted several issues with the conversion of EORTC quality of life data into utility values. The ERG reported that the algorithm used to derive the utility values was considered by its developers to be less reliable for patients in more severe health states than alternative algorithms that were explored and rejected by the manufacturer. The ERG noted that this could bias the results. It also reported that the algorithm had been developed using data from patients with oesophageal cancer, and that patients eligible for azacitidine were of a similar age to these patients. However, the underlying conditions and comorbidities were potentially very different. The ERG stated that the utility values resulting from the algorithm should be treated with caution.\n\nThe manufacturer explored the impact of adjusting the utility values to account for the differences in the baseline patient characteristics. This was shown to have little impact on the ICERs.\n\nAfter the appeal, the manufacturer submitted information on the proportions of patients with high-risk myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia receiving low-dose chemotherapy plus best supportive care and the proportions of patients receiving best supportive care alone. This information included:\n\na survey of 72 UK haematologists, with the proportions of patients treated with each conventional care regimen between 2008 and 2010 who were eligible for azacitidine according to the marketing authorisation\n\na survey of 23 UK hospitals, with the proportions of patients treated with each conventional care regimen and\n\ndata from the Haematological Malignancy Research Network registry (HMRN; collecting data from 22 hospitals in the Yorkshire and Humber and Yorkshire Coast cancer networks) on the first-line treatment of patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia between September 2004 and August 2009. The hospital survey and HMRN registry data included all patients with high-risk myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia, not just patients who would be eligible for azacitidine according to the marketing authorisation. The haematologist survey data and hospital survey data were presented graphically and indicated that the majority of patients received best supportive care alone, although this proportion appeared lower among the haematologists identified as specialist consultants and among the hospitals identified as specialist centres. The audit of the HMRN registry data showed that of those patients considered as IPSS intermediate-2 or IPSS high risk, 58% received best supportive care alone (including observation only), 12% received low-dose chemotherapy and 28% received standard-dose chemotherapy (2% of patients died before treatment).\n\nThe DSU provided a critique of the three sources of information. The survey of 72 UK haematologists was based on clinicians' estimates of patients receiving each conventional care regimen, rather than the proportions of patients who were eligible for each regimen. Because it was not clear whether the data provided were from case note review or from clinician self-reporting, the DSU considered that the survey was subject to a high risk of bias. For this reason the DSU considered that this survey did not provide reliable data to inform the Committee's considerations about the conventional care regimens. Regarding the survey from 23 UK hospitals, the DSU commented that because the data had been presented graphically it was difficult to estimate the exact proportions of patients treated with each care regimen. The survey was considered to offer limited information because:\n\npatients who would not be eligible to receive azacitidine were included and\n\nthere was a lack of information about whether the sample of hospitals was representative of all UK hospitals and about the methods of data collection. In the DSU's view, the HMRN registry provided the most objective and reliable data for the numbers of patients receiving conventional care regimens. In summary, the DSU expressed the view that the three sources of information provided only a limited evidence base for the use of low-dose chemotherapy and confirmed the current variation in clinical practice.\n\nAfter the appeal, the manufacturer also submitted information about the clinical characteristics of patients receiving each of the conventional care regimens in routine clinical practice. This included the results of an 'informal literature review' by the manufacturer and the clinical characteristics of patients receiving low-dose chemotherapy from the survey of UK haematologists. The manufacturer reported that among patients who were eligible for azacitidine according to the marketing authorisation, low-dose chemotherapy was most widely used in the UK in patients with the following characteristics:\n\nsymptomatic cytopenias:\n\n\n\nanaemia requiring transfusion\n\nneutropenia 0.5–1.0\xa0×\xa0109/litre (with or without infectious episodes)\n\nthrombocytopenia 30–100\xa0×\xa0109/litre\n\n\n\nnormal karyotype (or one cytogenetic abnormality)\n\nlimited comorbidities, with Haematopoietic Cell Transplantation-specific Comorbidity Index (HCTCI) score 0–2\n\nECOG performance status 0–2\n\nlogistically able to undergo treatment.\n\nThe DSU commented that only two of the eleven studies provided by the manufacturer after the appeal were conducted in the UK and only one had been published since 1991. It was not clear how the characteristics had been selected from these studies; in particular toxicity and administration had been identified in the literature review but did not appear in the final list of characteristics. However, the HCTCI score, which the manufacturer previously reported was not in routine clinical use in the UK, was included in the list. In summary, the DSU considered that the literature review offered limited evidence on eligibility criteria for patients receiving the conventional care regimens.\n\nAfter the appeal, the manufacturer also submitted additional cost-effectiveness analyses incorporating health-related quality of life data from the patient group MDS UK. The manufacturer provided analyses:\n\nseparately comparing azacitidine with each conventional care regimen specified by the Appeal Panel (that is, compared with best supportive care alone and compared with low-dose chemotherapy plus best supportive care) and\n\ncomparing azacitidine with usual care (that is, a single estimate representing a weighted average of all the conventional care regimens together). Each analysis used a Weibull parametric function to extrapolate overall survival, assumed no vial sharing, and included the original patient access scheme.\n\nThe manufacturer's analyses submitted after the appeal indicated that azacitidine compared with best supportive care alone was associated with an incremental cost of £63,756 and an incremental QALY gain of 1.01, producing an ICER of £63,177 per QALY gained. Azacitidine compared with low-dose chemotherapy was associated with an incremental cost of £65,671 and an incremental QALY gain of 1.34, giving an ICER of £49,030 per QALY gained. Azacitidine compared with usual care (a weighted average of all the conventional care regimens together) was associated with an incremental cost of £61,801 and an incremental QALY gain of 1.09, giving an ICER of £56,945 per QALY gained. The manufacturer's submission stated that this weighted average was calculated using the proportion of patients receiving each of the conventional care regimens in AZA-001 (that is, 62% for best supportive care alone, 26% for low-dose chemotherapy plus best supportive care and 12% for standard-dose chemotherapy plus best supportive care).\n\nThe DSU commented that the utility values used in the revised economic evaluation were based on descriptions of health states that included dependence or independence from transfusion as a feature and did not separate the specific utility value of dependence or independence from transfusion from that of associated symptoms. It noted the small numbers of patients in the study (n\xa0=\xa047) and patients from the UK (n\xa0=\xa021). The DSU further noted that the data did not capture adverse events, in contrast with the utility value estimates used in the manufacturer's original base case. The DSU commented that constant utility values had been applied over the time horizon of the model, assuming that a patient's dependence on transfusion would remain constant throughout their treatment period. It considered that this was an unreasonable assumption. The DSU concluded that the MDS utility data did not provide more appropriate information for the economic evaluation than the data used in the manufacturer's base case. However, the DSU ran exploratory analyses using data from all patients in the MDS UK study and then with only data from the UK patients. None of these exploratory analyses resulted in significant changes to the cost-effectiveness estimates provided by the manufacturer.\n\nThe DSU considered that the analysis using a weighted average (see section 3.21) was not an appropriate measure of the cost effectiveness of azacitidine. The DSU took the view that the appropriate approach would be to consider all the treatment options in a single incremental analysis, comparing each treatment with the next most effective alternative, and excluding any dominated (that is, more costly and less effective) treatments from the analysis.\n\nIn response to the appraisal consultation document produced after the appeal, the manufacturer submitted updated cost-effectiveness analyses. Each analysis was deterministic, used a Weibull parametric function to extrapolate overall survival, assumed no vial sharing, and included the revised patient access scheme (see section 2.4). These analyses estimated the following ICERs for azacitidine, compared with three alternative weighted averages of the conventional care regimens:\n\n£49,405 per QALY gained, based on the proportions of patients that had received one of the conventional care regimens after randomisation in AZA-001 (of which 59% patients received best supportive care alone, 27% received low-dose chemotherapy and 14% received standard-dose chemotherapy)\n\n£49,837 per QALY gained, based on the proportions of IPSS intermediate-2 or high-risk patients that had received one of the conventional care regimens in the HMRN registry (of which 59% patients received best supportive care alone, 12% received low-dose chemotherapy and 28% received standard-dose chemotherapy)\n\n£50,920 per QALY gained, based on the proportions of patients with the 'refractory anaemia with excess blasts' (RAEB) disease subtype that had received one of the conventional care regimens in the HMRN registry (of which 69% patients received best supportive care alone, 13% received low-dose chemotherapy and 18% received standard-dose chemotherapy).\n\nThe DSU considered that the most generalisable estimates for conventional care patterns from AZA-001 should be taken from the pre-randomisation proportions (that is, the whole trial population), instead of the proportions of patients (50% of the trial population) randomised to one of the conventional care regimens (as presented by the manufacturer). Before randomisation, 62% of patients were preselected to receive best supportive care alone, 26% received low-dose chemotherapy and 12% received standard-dose chemotherapy. The weighted average ICER associated with these proportions was £49,808 per QALY gained.\n\nThe DSU further considered that probabilistic analyses (instead of the deterministic analyses presented by the manufacturer) would be more robust, and therefore more appropriate for the Committee's consideration. The probabilistic ICERs associated with each of the weighted averages were:\n\n£47,336 per QALY gained, based on the proportions of patients that had received one of the conventional care regimens after randomisation in AZA-001\n\n£47,782 per QALY gained, based on the proportions of patients preselected (that is, prior to randomisation) to receive one of the conventional care regimens in AZA-001\n\n£47,224 per QALY gained, based on the proportions of IPSS intermediate-2 or high-risk patients allocated to conventional care regimens in the HMRN registry\n\n£48,581 per QALY gained, based on the proportions of patients with the RAEB disease subtype allocated to conventional care regimens in the HMRN registry.\n\nFull details of all the evidence are in the manufacturer's submissions, the ERG report and the DSU reports.", 'Consideration of the evidence': "The Appraisal Committee (appendix A) reviewed the data available on the clinical and cost effectiveness of azacitidine, having considered evidence on the nature of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia and the value placed on the benefits of azacitidine by patients with the conditions, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee heard from the clinical specialists that current practice includes the use of best supportive care and, for some patients who are able to tolerate it, low- or standard-dose chemotherapy. However, the Committee heard from the clinical specialists that there was no nationally recognised standard of care for patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia, particularly regarding patients' eligibility for chemotherapy. The Committee noted survey and HMRN registry data provided by the manufacturer, which together showed variations in treatment patterns among UK haematologists. The survey data showed a wide variation in clinicians' views about what determines a patient's eligibility for chemotherapy. The Committee heard from the clinical specialists that the group of patients eligible for chemotherapy could only be broadly described because of the current lack of consensus among UK haematologists about whether chemotherapy is appropriate for patients with certain comorbidities or disease-specific characteristics, and because of the inability to quantify clinician and patient preference for treatment. The Committee concluded that while best supportive care, low-dose and standard-dose chemotherapy were currently being used to treat patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia, there was no consensus among clinicians on the set of clinical characteristics that could identify patients for whom chemotherapy should be a treatment option.\n\nThe Committee considered the quality of life of patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia. The Committee understood from the evidence submitted, and from the evidence of clinical specialists and patient experts, that fatigue and a reduced ability to carry out day-to-day activities are common in these conditions and have a negative impact on patients' quality of life. The Committee noted information from patient groups, who reported that dependence on blood transfusions is an important aspect of these conditions and also has a negative impact on quality of life. The Committee concluded that having myelodysplastic syndromes decreases quality of life, and aspects of current conventional care (such as the need for blood transfusions) have a further negative impact on quality of life.\n\n# Clinical effectiveness\n\nThe Committee considered the clinical-effectiveness evidence from AZA-001 presented by the manufacturer. The Committee understood that patients were preselected for treatment with one of the conventional care regimens before randomisation, and this was based on age, ECOG performance status, the presence of comorbidities and patient preference. It also understood that patients randomised to treatment with azacitidine were compared with patients in their respective pre-randomisation regimen. The Committee also heard from the clinical specialists that the proportion of patients in each preselection group in AZA-001 broadly represented the treatment patients with these conditions receive in the UK (that is, treatment with chemotherapy plus best supportive care is appropriate for considerably fewer patients than treatment with best supportive care alone).\n\nThe Committee noted that the median overall survival for patients receiving azacitidine was longer than for patients receiving the conventional care regimens. The Committee further noted that median time to transformation to acute myeloid leukaemia was longer for patients receiving azacitidine and the percentage of patients becoming independent of blood transfusions was higher for patients receiving azacitidine than for patients receiving the conventional care regimens. The Committee noted that when outcomes were analysed separately for each conventional care regimen, the difference in overall survival between the treatment arms in the standard-dose chemotherapy group was not statistically significant, and the differences between the treatment arms in the estimates of time to transformation to acute myeloid leukaemia for either the low-dose or standard-dose chemotherapy groups were not statistically significant. The Committee was aware that the small patient numbers limited the precision and certainty of the outcome estimates in these groups, but concluded that the estimates of total overall survival compared with conventional care appeared robust. The Committee noted that the problems relating to loss of patients to follow-up, as described by the ERG (see section 3.13), may have introduced bias into estimates of relative effectiveness, but concluded that this effect was likely to be minimal.\n\nThe Committee considered the role of patient preference in the design and analysis of AZA-001. The Committee heard from the DSU and the manufacturer that the term 'patient preference trial' is used to describe trial designs that take account of a patient's preference to receive either the study treatment (for example, azacitidine) or the comparator (for example, conventional care). It noted that in AZA-001, patient preference informed preselection to one of the conventional care regimens before randomisation, but did not inform randomisation to either azacitidine or conventional care. The Committee concluded that the role of patient preference in AZA-001 did not affect the way in which the trial results or subsequent analyses should be considered.\n\nThe Committee considered the potential adverse effects associated with treatments for myelodysplastic syndromes and the impact of these effects on quality of life. The Committee heard from the clinical specialists that common adverse effects of treatment with azacitidine include peripheral blood cytopenias, myelosuppression, nausea, vomiting and injection site reactions. The patient experts and clinical specialists agreed that these adverse effects are generally well tolerated. The Committee heard from the patient experts that compared with other treatment options, azacitidine was associated with relief from fatigue, fewer infection-related hospitalisations, a decreased need for blood and platelet transfusion, and increased ability to perform day-to-day activities. The Committee noted that no quality of life data were collected in AZA-001, although EORTC data collected in CALGB 9221 suggested improvements in overall health with azacitidine.\n\nThe Committee concluded on the basis of the clinical-effectiveness evidence and the evidence from the clinical specialists and patient experts that azacitidine is a clinically effective treatment for myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia.\n\n# Cost effectiveness\n\nThe Committee considered evidence on the cost effectiveness of azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia. It discussed the likelihood of vial sharing, noting that because of the small number of patients, it may be difficult to implement a vial-sharing scheme. It concluded that the manufacturer's estimate of 49% of patients being able to receive treatment at the same time (and therefore share vials) seemed optimistic. The Committee concluded that the analyses incorporating estimated vial sharing did not produce plausible results and therefore would not form the basis for its decision on the use of azacitidine in the NHS.\n\nThe Committee noted the ERG's concerns about the manufacturer's initial model, mainly relating to the selection of the parametric function to model overall survival. The ERG stated that the most important influence on the model's outputs was overall survival, and that the choice of parametric distribution used to extrapolate estimates of overall survival from AZA-001 greatly influenced the results. The Committee noted that the manufacturer's initial base case used the lognormal function to extrapolate overall survival from the trial data, which the manufacturer justified with supporting data from a Düsseldorf myelodysplastic syndromes registry. The Committee understood that the use of the lognormal distribution modelled survival in such a way that some patients were predicted to live to an unrealistic age given the nature of the condition (see section 3.12), that is the use of lognormal distribution led to an overestimation of survival. The Committee concluded that the Weibull distribution generally provided the best overall fit to the Düsseldorf registry long-term survival data, and that modelling that incorporated the Weibull distribution should be used to inform a decision on the use of azacitidine in the NHS.\n\nThe Committee considered the estimates of quality of life included in the model (see also sections 4.12 and 4.13). The Committee first considered the derivation of the utility values. It was aware of the ERG's concerns about the mapping of EORTC values to the EQ-5D (see section 3.14). The Committee concluded that because the algorithm had been developed using data from patients with oesophageal cancer, the values would be associated with greater uncertainty than if a validated algorithm based on patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia had been used.\n\nThe Committee then considered the face validity of the quality of life gains attributed to azacitidine in the model. The patient experts and clinical specialists stated that treatment with azacitidine reduces symptoms (such as fatigue) and the need for blood transfusions. The Committee agreed that the associated utility gains of these should ideally be reflected in the model. The Committee noted that greater independence from blood transfusions was not explicitly included in the utility value estimate. It was aware that the manufacturer estimated the utility value by mapping to the EQ-5D. The Committee understood that the EQ-5D does not include fatigue as a dimension, although it would capture some of the effects of fatigue on the patient's ability to undertake day-to-day activities. The Committee also understood that the EORTC measure includes a domain that captures the impact of treatment on quality of life, and that dependence on transfusion could be expected to affect this. It considered that reduced fatigue after azacitidine treatment may not have been completely captured in the modelled utility values. The Committee noted the alternative utility values provided by MDS UK after the appeal, which were meant to better reflect the utility values associated with dependence on or independence from blood transfusions. However, the Committee noted the DSU's concern that the alternative utility values did not separate dependence or independence from transfusion from associated symptoms (see section 3.22) and it did not accept these in preference to the manufacturer's previous estimates. The Committee also noted that the model applied constant utility values within each health state, therefore assuming quality of life gains from the first day of treatment, which it considered unrealistic. Taking all these points into account, the Committee concluded that it was uncertain whether the utility values used in the model under- or over-estimated the true utility values associated with myelodysplastic syndromes.\n\nThe Committee considered the uncertainty around the quality of life estimates included in the model (see sections 4.11 and 4.12). The Committee noted that sensitivity analyses carried out by the manufacturer showed that variations in the utility values had relatively little impact on the ICERs. It concluded that because the ICER estimate was largely driven by the incremental life years gained and the acquisition cost of azacitidine, and was only minimally affected by the changes in health-related quality of life, the impact of any over- or underestimation of quality of life gains was likely to be small.\n\nThe Committee considered the inclusion of costs in the economic model. The Committee noted the use of the NHS 2009/2010 tariff. It considered that using the NHS 2009/10 tariff was appropriate because it could provide a more precise estimate of hospital costs by breaking down costs attributable to adverse events. The Committee also noted the assumed increase in the cost for treatment received at the weekend. The Committee concluded that the modelled increased costs of weekend administration were reasonable, aware that the associated impact on the ICERs was relatively small. On balance, the Committee concluded that costs included in the model were acceptable.\n\nThe Committee considered the estimated cost effectiveness of azacitidine. The Committee noted that the manufacturer had submitted two approaches to estimating the ICERs for azacitidine:\n\none analysis comparing azacitidine separately with each of the conventional care regimens specified by the Appeal Panel (that is, compared with best supportive care alone and compared with low-dose chemotherapy plus best supportive care) and\n\nthree analyses comparing azacitidine with usual care (that is, a single estimate representing a weighted average of all the conventional care regimens together), with each analysis using different proportions of conventional care to form the weighted average. The Committee noted that no cost-effectiveness evidence was presented for the subgroup of patients with the –7/del(7q) chromosomal abnormality.\n\nThe Committee considered the two approaches to estimating the cost effectiveness of azacitidine. The Committee first considered the separate conventional care regimen analyses. The Committee noted that patients randomised to receive azacitidine in the group preselected to receive low-dose chemotherapy plus best supportive care incurred higher total costs (£101,100) than those randomised to azacitidine who had been preselected to receive best supportive care alone (£91,800). It further noted that the number of total QALYs (that is, not the incremental QALY gain) was greater in those randomised to azacitidine who had been preselected to receive low-dose chemotherapy (2.44) than in those randomised to azacitidine who had been preselected to receive best supportive care alone (2.04). The Committee also noted that in the analyses presented before the appeal comparing azacitidine with standard-dose chemotherapy, the number of QALYs associated with those randomised to azacitidine who had been preselected to receive standard-dose chemotherapy in the azacitidine arm was 1.91. The Committee concluded that there appeared to be no reason, other than differences in baseline patient characteristics, why those who were randomised to azacitidine but were preselected to receive low-dose chemotherapy should have gained greater benefit than those who were randomised to azacitidine but were preselected to receive standard-dose chemotherapy plus best supportive care or best supportive care alone. The Committee agreed that this uncertainty should be noted when considering the most appropriate analyses on which to base its recommendations.\n\nThe Committee then considered the analyses of azacitidine compared with a weighted average of usual care (see sections 3.24 to 3.26). The Committee understood that the weighted ICERs had each been calculated by combining the individual ICERs for the respective conventional care regimens, each weighted by the proportion of patients receiving these regimens in AZA-001 and in the HMRN registry respectively. The Committee understood the significant methodological limitations associated with analyses involving the use of such a weighted average, in particular the need for equivalent patient characteristics (such as age or disease severity) at baseline among any of the groups being combined (see section 4.16). It also acknowledged the importance of ensuring that the full range of appropriate comparators was considered within these groups. It noted that because of differences in the baseline patient characteristics of the conventional care regimen subgroups (see section 3.1) the patient populations and associated population-specific results may not necessarily be appropriate for statistical analysis, which combines estimates across the groups using a simple weighted average.\n\nThe Committee then considered which of the two analytical approaches to considering cost effectiveness provided the most appropriate basis for its decision. It agreed that the most important consideration in whether a decision should be based on the separate comparisons with the different conventional care regimens was the need for a clear definition of the groups of patients eligible to receive each of the conventional care regimens. The Committee agreed that because a set of clear and objective clinical characteristics defining the eligibility of patients to receive chemotherapy had not been agreed among haematologists, it could not make recommendations based on any of the separate conventional care regimen groups (see section 4.2).\n\nThe Committee was aware of the significant methodological limitations with using weighted averages. The Committee understood that weighted averages can mask differences in the incremental costs and/or QALYs of the technologies being combined. The Committee was aware that the NICE 'Guide to the methods of technology appraisal' states that best practice should be considered as a comparator for appraisal of health technologies. If best practice is defined as a cost-effective treatment option, the standard approach to assessing the cost effectiveness of azacitidine in this context would be to consider all treatment options (that is, each of the conventional care regimens) in an iterative incremental analysis (that is, assessing the ratio of the additional cost and benefit of each technology compared with the next best alternative) to identify the most cost-effective strategy. The Committee understood that the weighted average approach assumes that each conventional care regimen is the most cost-effective treatment option available for the patient group for whom it is used. It heard from the DSU that the necessary evidence to test this assumption is not available, given the remit of this appraisal, and therefore the use of a weighted average would result in some uncertainty in the ICER produced. It further heard from the DSU that if the cost effectiveness of each of the individual conventional care regimens was not established, the magnitude and direction of uncertainty in the weighted average ICER is unknown. The Committee also understood that because the populations eligible for each of the conventional care regimens cannot be clearly defined (see section 4.2), an incremental analysis (as preferred by the DSU) is not possible in this case. Taking into account the limitations of the available evidence and in the absence of a satisfactory alternative, the Committee hesitantly concluded that any decision on the cost effectiveness of azacitidine would need to be made using the weighted average.\n\nThe Committee considered the proportions of each conventional care regimen used to calculate the weighted average. It understood that the manufacturer's base-case estimate was based on the proportions of people receiving each conventional care regimen in AZA-001, but that alternative analyses used the HMRN registry data submitted by the manufacturer (see section 3.25). The Committee heard from the clinical specialists that the HMRN registry, a UK database of over 600 patients, provided a representative estimate of the management of myelodysplastic syndromes in the UK. It noted that the HMRN registry includes a wider range of patients than those covered by the marketing authorisation for azacitidine but acknowledged clinical advice that within the HMRN registry, the subset of patients classified as having IPSS intermediate-2 or high-risk myelodysplastic syndromes provided the best available estimate of the proportion of patients receiving each of the conventional care regimens in the patient population for whom azacitidine is licensed. The Committee concluded that a weighted average of conventional care regimens should be calculated using the HMRN registry data (for the subset of patients having IPSS intermediate-2 or high-risk myelodysplastic syndromes) rather than the AZA-001 data.\n\nThe Committee considered the ICERs calculated using a weighted average of the proportions receiving conventional care regimens in the HMRN registry for patients classified as IPSS intermediate-2 or high risk. It understood that in this patient population approximately 59% of patients received best supportive care alone, 12% received low-dose chemotherapy plus best supportive care and 29% received standard-dose chemotherapy plus best supportive care. The Committee noted that the manufacturer's deterministic ICER using these proportions of patients was £49,800 per QALY gained. The Committee heard from the DSU that the probabilistic estimate of the ICER associated with these proportions was approximately £47,200 per QALY gained (see section 3.27). The Committee considered that the probabilistic ICER was a more valid estimate than the deterministic estimate because it takes account of joint parameter uncertainty. The Committee noted that because the incremental cost-effectiveness estimates of each respective conventional care regimen that comprise the weighted average were not known (see section 4.19), uncertainty about the true ICER for azacitidine compared with usual care remained. Taking into account the limitations associated with the use of a weighted average and the uncertainty associated with the cost effectiveness of each individual conventional care regimen, the Committee concluded that £47,200 per QALY gained represented the best available estimate of the cost effectiveness of azacitidine.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met.\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust.\n\nThe Committee discussed whether the benefit provided by azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee understood that there are approximately 700\xa0patients with IPSS intermediate-2 and high-risk myelodysplastic syndromes in England and Wales. The Committee considered that life expectancy with best supportive care alone was likely to be approximately 11.5\xa0months. It considered the evidence from AZA-001 and noted that the median overall survival for patients treated with azacitidine in the best supportive care preselection group was 21.1\xa0months. The Committee agreed that azacitidine would improve the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia and that it was likely that azacitidine would increase overall survival by approximately 9.6\xa0months. The Committee agreed that the estimates of clinical effectiveness informing the best available estimate of the ICER were sufficiently robust and concluded that azacitidine meets the criteria for being a life-extending, end-of-life treatment.\n\nThe Committee then considered the ICER taking into account the end-of-life considerations. It considered that the best available estimate of the base-case ICER was approximately £47,200 per QALY gained (see section\xa04.21). The Committee accepted the uncertainty associated with this estimate and acknowledged the difficulty of assessing the impact of uncertainty on the best estimate of the ICER (see section 4.19). The Committee was aware that other technologies had been recommended using the end-of-life criteria with ICERs as high as the one in this appraisal, but was conscious of the increasing cost pressures in the NHS and the opportunity costs that would result from a recommendation to fund a technology with an ICER of this magnitude. However, the Committee recognised that azacitidine represents an important change in the treatment of patients with myelodysplastic syndromes, noting the substantial benefits associated with its use. The Committee considered that on balance, the additional weight that would need to be assigned to the QALY benefits for the cost effectiveness of azacitidine to fall within the current threshold range was acceptable on this occasion. Therefore the Committee considered that azacitidine when provided by the manufacturer with the discount agreed in the revised patient access scheme agreed by the Department of Health in January 2011 was a cost-effective use of NHS resources as a treatment option for people with myelodysplastic syndromes, as stated in the marketing authorisation. This includes adults who are not eligible for haematopoietic stem cell transplantation with intermediate-2 and high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS), chronic myelomonocytic leukaemia with 10–29% marrow blasts without myeloproliferative disorder or acute myeloid leukaemia with 20–30% blasts and multilineage dysplasia, according to World Health Organization classification.\n\nThe Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations in any way. At an earlier meeting, the Committee noted that azacitidine may be of specific benefit to those who, for clinical or religious reasons, are unable to receive blood transfusions, because patients treated with azacitidine require fewer blood transfusions than patients treated with best supportive care. However, the Committee noted that no representations had been made or evidence received about the pathway of care for this particular group of patients, or about the effectiveness of azacitidine in this patient population. Therefore the Committee agreed that it would not be appropriate to make recommendations for a subgroup of patients unable to receive blood transfusions. Because the final recommendations (see section 4.24) do not restrict access to azacitidine for any particular group of patients, the Committee concluded that there was now no need to alter or add to its recommendations in any case.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA218\n\n\n\nAzacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia\n\nSection\n\nKey conclusion\n\nAzacitidine is recommended as a treatment option for adults who are not eligible for haematopoietic stem cell transplantation and have:\n\nintermediate-2 and high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS) or\n\nchronic myelomonocytic leukaemia with 10–29% marrow blasts without myeloproliferative disorder or\n\nacute myeloid leukaemia with 20–30% blasts and multilineage dysplasia, according to the World Health Organization classification and\n\nif the manufacturer provides azacitidine with the discount agreed as part of the patient access scheme.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe key drivers for this recommendation were as follows:\n\nTaking into account the end-of-life considerations, the Committee recognised that azacitidine represents an important change in the treatment of patients with myelodysplastic syndromes.\n\nThe Committee considered that on balance, with the addition of the revised patient access scheme, azacitidine represented a cost-effective use of NHS resources.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\n\n\nBest supportive care, low-dose and standard-dose chemotherapy are currently being used to treat patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia who are not eligible for stem cell transplantation. However, there was no consensus among clinicians on the set of clinical characteristics that could identify patients for whom chemotherapy should be a treatment option.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nFatigue and a reduced ability to carry out day-to-day activities are common in these conditions and have a negative impact on patients' quality of life. Dependence on blood transfusions is an important aspect of these conditions and also has a negative impact on quality of life.\n\n,\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\n\n\nThe Committee concluded on the basis of the clinical-effectiveness evidence and the evidence from the clinical specialists and patient experts that azacitidine is a clinically effective treatment for myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nCompared with other treatment options, azacitidine was associated with relief from fatigue, fewer hospitalisations because of infections, a decreased need for blood and platelet transfusion, and increased ability to perform day-to-day activities.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\n\n\nAzacitidine is licensed as first-line treatment for myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia and would replace best supportive care, low-dose and standard-dose chemotherapy.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAdverse effects\n\n\n\nCommon adverse events associated with azacitidine include peripheral blood cytopenias, myelosuppression, nausea, vomiting and injection site reactions. The patient experts and clinical specialists agreed that these adverse events are generally well tolerated.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\n\n\nThe Committee noted that the problems relating to loss of patients to follow-up in the pivotal trial (AZA-001) may have introduced bias into the estimates of relative effectiveness, but concluded that this effect was likely to be minimal.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee concluded that the estimates of total overall survival compared with conventional care appeared robust.\n\n\n\n\n\n\n\nThe role of patient preference in the pre-randomisation of the pivotal trial did not affect the way in which the trial results or subsequent analyses should be considered.\n\n\n\nRelevance to general clinical practice in the NHS\n\n\n\nThe comparator therapies used in the pivotal trial broadly represented the treatment patients with these conditions receive in the UK.\n\n\n\n\n\n\n\nUncertainties generated by the evidence\n\n\n\nThe small patient numbers limited the precision and certainty of the outcome estimates in the low-dose and standard-dose chemotherapy groups. However the Committee concluded that the estimates of total overall survival compared with conventional care appeared robust.\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\n\n\nThe manufacturer reported that in a subgroup analysis of patients with the –7/del(7q) chromosomal abnormality, median overall survival was higher in patients receiving azacitidine than in patients receiving conventional care regimens.\n\n\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\n\n\nThe Committee concluded on the basis of the clinical-effectiveness evidence and the evidence from the clinical specialists and patient experts that azacitidine is a clinically effective treatment for myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia.\n\n\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nNo quality of life data were collected in the pivotal trial, although EORTC data collected in the CALGB 9221 trial suggested improvements in overall health with azacitidine.\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe use of a weighted average for the comparator was associated with significant methodological limitations. However, taking into account the limitations of the available evidence and in the absence of a satisfactory alternative, the Committee hesitantly concluded that any decision on the cost effectiveness of azacitidine would need to be made using the weighted average.\n\n\n\n\n\n\n\nThe HMRN registry provided the best available estimate of the proportion of patients receiving each of the conventional care regimens to use in the calculation of the weighted average, namely those patients classified as having IPSS intermediate-2 or high-risk myelodysplastic syndromes.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee concluded that the analyses incorporating estimated vial sharing did not produce plausible results and therefore would not form the basis for its decision on the use of azacitidine in the NHS.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee concluded that the Weibull distribution generally provided the best overall fit to the Düsseldorf registry long-term survival data.\n\n\n\n\n\nThe Committee concluded that it was uncertain whether the utility values used in the model under- or over-estimated the true utility values associated with myelodysplastic syndromes.\n\n\n\n\n\nThe Committee noted that the total costs and total QALY gain for azacitidine differed depending on which care regimen it was being compared with. It considered that this variation added to the uncertainty in the model.\n\n\n\n\n\nBecause the cost effectiveness of each of the individual conventional care regimens was not established the magnitude and direction of uncertainty in the weighted average ICER was unknown.\n\n\n\nIncorporation of health-related quality of life benefits and utility values\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee concluded that because the algorithm had been developed using data from patients with oesophageal cancer, the values would be associated with greater uncertainty than if a validated algorithm based on patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia had been used.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee agreed that the utility values provided by MDS UK after the appeal did not provide better estimates of the gains in health-related quality of life than the manufacturer's previous estimates.\n\n\n\n\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\n\n\nThe Committee noted that the model applied constant utility values within each health state, therefore assuming quality of life gains from the first day of treatment, which it considered unrealistic.\n\n\n\n\n\n\n\nThe Committee concluded that the utility values used in manufacturer's base case may not have captured the effects of transfusion dependence and fatigue. However, the ICER was only minimally affected by changes in the utility values.\n\nto\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo cost-effectiveness evidence was presented for the subgroup of patients with the –7/del(7q) chromosomal abnormality.\n\n\n\n\n\nWhat are the key drivers of cost effectiveness?\n\n\n\nThe Committee concluded that the ICER estimate was largely driven by the incremental life years gained (that is, the extrapolated survival) and the acquisition cost of azacitidine, and that the ICER was only minimally affected by the changes in health-related quality of life.\n\n\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nTaking into account the limitations associated with the use of a weighted average and the uncertainty associated with the cost effectiveness of each individual conventional care regimen, the Committee concluded that £47,200 per QALY gained represented the best available estimate of the cost effectiveness of azacitidine.\n\n\n\n\n\nAdditional factors taken into account\n\nPatient access schemes\n\n(PPRS)\n\nThe manufacturer agreed a revised patient access scheme with the Department of Health in January 2011 (which replaces an earlier patient access scheme), in which azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia will be available to the NHS with a discount, the level of which is commercial-in-confidence.\n\n\n\n\n\nEnd-of-life considerations\n\n\n\nThe Committee concluded that azacitidine met the criteria for being a life-extending, end-of-life treatment. The Committee recognised that azacitidine represents an important change in the treatment of patients with myelodysplastic syndromes. The Committee considered that on balance, the additional weight that would need to be assigned to the QALY benefits in this patient group for the cost effectiveness of azacitidine to fall within the current threshold range was acceptable.\n\n\n\n,\n\n\n\nEqualities considerations and social value judgements\n\n\n\nThe Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations in any way. At an earlier meeting, the Committee noted that azacitidine may be of specific benefit to those who, for clinical or religious reasons, are unable to receive blood transfusions, because patients treated with azacitidine require fewer blood transfusions than patients treated with best supportive care. However, the Committee noted that no representations had been made or evidence received about the pathway of care for this particular group of patients, or about the effectiveness of azacitidine in this patient population. Therefore the Committee agreed that it would not be appropriate to make recommendations for a subgroup of patients unable to receive blood transfusions. Because the final recommendations (see section 4.24) do not restrict access to azacitidine for any particular group of patients, the Committee concluded that there was now no need to alter or add to its recommendations in any case.\n\n\n\n", 'Recommendations for further research ': 'The Committee recommends that a study estimating utility values using directly observed health-related quality of life values (such as EQ-5D scores) in patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia is conducted.', 'Related NICE guidance': 'Improving outcomes in haematological cancers. NICE cancer service guidance (2003).', 'Review of guidance': 'The guidance on this technology will be considered for review in February 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveMarch 2011', 'Changes after publication': 'February 2014: implementation section updated to clarify that azacitidine is recommended as an option for treating myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia. Additional minor maintenance update also carried out.\n\nISBN: 978-1-4731-3448-5'}
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https://www.nice.org.uk/guidance/ta218
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Evidence-based recommendations on azacitidine (Vidaza) for treating myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia in adults.
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afa55970d80df84e38f645f50f561d0efeba9f56
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nice
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Coexisting severe mental illness (psychosis) and substance misuse: assessment and management in healthcare settings
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Coexisting severe mental illness (psychosis) and substance misuse: assessment and management in healthcare settings
This guideline covers assessing and managing people aged 14 years and over with coexisting severe mental illness (psychosis) and substance misuse. It aims to help healthcare professionals guide people with psychosis with coexisting substance misuse to stabilise, reduce or stop their substance misuse, to improve treatment adherence and outcomes, and to enhance their lives.
# Introduction
This guideline covers the assessment and management of adults and young people (aged 14 years and older) who have a clinical diagnosis of psychosis with coexisting substance misuse.
The term psychosis is used to describe a group of severe mental health disorders characterised by the presence of delusions and hallucinations that disrupt a person's perception, thoughts, emotions and behaviour. The main forms of psychosis are schizophrenia (including schizoaffective disorder, schizophreniform disorder and delusional disorder), bipolar disorder or other affective psychosis.
Substance misuse is a broad term encompassing, in this guideline, the harmful use of any psychotropic substance, including alcohol and either legal or illicit drugs. Such use is usually, but not always, regarded as a problem if there is evidence of dependence, characterised by psychological reinforcement of repeated substance-taking behaviour and, in some cases, a withdrawal syndrome. However, substance misuse can be harmful without dependence, especially among people with a coexisting psychosis.
Approximately 40% of people with psychosis misuse substances at some point in their lifetime, at least double the rate seen in the general population. In addition, people with coexisting substance misuse have a higher risk of relapse and hospitalisation, and have higher levels of unmet needs compared with other inpatients with psychosis who do not misuse substances.
Substance misuse among individuals with psychiatric disorders is associated with significantly poorer outcomes than for individuals with a single disorder. These outcomes include worsening psychiatric symptoms, poorer physical health, increased use of institutional services, poor medication adherence, homelessness, increased risk of HIV infection, greater dropout from services and higher overall treatment costs. Social outcomes are also significantly worse, including greater homelessness and rooflessness, a higher impact on families and carers, and increased contact with the criminal justice system.
Rooflessness here refers to living rough or on the streets, whereas homelessness encompasses people who are living in shelters.
People with psychosis commonly take various non-prescribed substances as a way of coping with their symptoms, and in a third of people with psychosis, this amounts to harmful or dependent use. The outcome for people with psychosis and coexisting substance misuse is worse than for people without coexisting substance misuse, partly because the substances used may exacerbate the psychosis and partly because substances often interfere with pharmacological or psychological treatment. This guideline aims to help healthcare professionals guide people with psychosis and coexisting substance misuse to stabilise, reduce or stop their substance misuse, to improve treatment adherence and outcomes, and to enhance their lives.
As well as primary and secondary services, this guideline also applies to services that are delivered by the third sector and commissioned by the NHS.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Definitions of depression and severity
Depression refers to a wide range of mental health problems characterised by the absence of a positive affect (a loss of interest and enjoyment in ordinary things and experiences), low mood and a range of associated emotional, cognitive, physical and behavioural symptoms. For more detail, see the International Classification of Diseases-11 (ICD-11) or the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria for depression.
Depression severity exists along a continuum and is essentially composed of 3 elements:
symptoms (which may vary in frequency and intensity)
duration of the disorder
the impact on personal and social functioning.
Severity of depression is therefore a consequence of the contribution of all of these elements.
Traditionally, depression severity has been grouped under 4 categories (subthreshold, mild, moderate and severe) but in the development of this guideline the committee wanted to develop a way of representing the severity of depression which best represents the available evidence on the classification and would help the uptake of the recommendations in routine clinical practice. This guideline has therefore defined new episodes of depression as less severe or more severe depression.
Less severe depression encompasses subthreshold and mild depression, and more severe depression encompasses moderate and severe depression. Thresholds on validated scales were used in this guideline as an indicator of severity. For example, a score 16 on the PHQ-9 scale was used, with scores less than 16 defined as less severe depression, and scores of 16 or more defined as more severe depression.
The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.
# Principles of care
## Working with adults and young people with psychosis and coexisting substance misuse
When working with adults and young people with known or suspected psychosis and coexisting substance misuse, take time to engage the person from the start, and build a respectful, trusting, non-judgemental relationship in an atmosphere of hope and optimism. Be direct in your communications, use a flexible and motivational approach, and take into account that:
stigma and discrimination are associated with both psychosis and substance misuse
some people will try to conceal either one or both of their conditions
many people with psychosis and coexisting substance misuse fear being detained or imprisoned, being given psychiatric medication forcibly or having their children taken into care, and some fear that they may be 'mad'.
When working with adults and young people with known or suspected psychosis and coexisting substance misuse:
ensure that discussions take place in settings in which confidentiality, privacy and dignity can be maintained
avoid clinical language without adequate explanation
provide independent interpreters (who are not related to the person) if needed
aim to preserve continuity of care and minimise changes of key workers in order to foster a therapeutic relationship.
## Race and culture
Healthcare professionals working with adults and young people with psychosis and coexisting substance misuse should ensure that they are competent to engage, assess, and negotiate with service users from diverse cultural and ethnic backgrounds and their families, carers or significant others.'Significant other' refers not just to a partner but also to friends and any person the service user considers to be important to them.
Work with local black and minority ethnic organisations and groups to help support and engage adults and young people with psychosis and coexisting substance misuse. Offer organisations and groups information and training about how to recognise psychosis with coexisting substance misuse and access treatment and care locally.
## Providing information
Offer written and verbal information to adults and young people appropriate to their level of understanding about the nature and treatment of both their psychosis and substance misuse. Written information should:
include the information for the public (available in English and Welsh), which contains a list of organisations that can provide more information
be available in the appropriate language or, for those who cannot use written text, in an alternative format (audio or video).
All healthcare professionals in primary, secondary or specialist substance misuse services working with adults and young people with psychosis should offer information and advice about the risks associated with substance misuse and the negative impact that it can have on the experience and management of psychosis.
## Working with and supporting families, carers and significant others
Encourage families, carers or significant others to be involved in the treatment of adults and young people with psychosis and coexisting substance misuse to help support treatment and care and promote recovery.
When families, carers or significant others live or are in close contact with the person with psychosis and coexisting substance misuse, offer family intervention as recommended in NICE guideline on psychosis and schizophrenia in adults.
When families, carers or significant others are involved in supporting the person with psychosis and coexisting substance misuse, discuss with them any concerns about the impact of these conditions on them and on other family members.
Offer families, carers or significant others a carer's assessment of their caring, physical, social, and mental health needs. Where needs are identified, develop a care plan for the family member or carer.
Offer written and verbal information to families, carers or significant others appropriate to their level of understanding about the nature and treatment of psychosis and substance misuse, including how they can help to support the person. Written information should be available in the appropriate language or, for those who cannot use written text, in an accessible format (audio or video).
Offer information to families, carers or significant others about local family or carer support groups and voluntary organisations, including those for psychosis and for substance misuse, and help families, carers or significant others to access these.
Negotiate confidentiality and sharing of information between the person with psychosis and coexisting substance misuse and their family, carer or a significant other.'Significant other' refers not just to a partner but also to friends and any person the service user considers to be important to them.
Ensure the needs of young carers or dependent adults of the person with psychosis and coexisting substance misuse are assessed. Initiate safeguarding procedures where appropriate (see recommendations 1.1.16 to 1.1.20 on safeguarding issues).
## Support for healthcare professionals
Working with people with psychosis and coexisting substance misuse can be challenging and healthcare professionals should seek effective support – for example, through professional supervision or staff support groups.
## Safeguarding issues
If people with psychosis and coexisting substance misuse are parents or carers of children or young people, ensure that the child's or young person's needs are assessed according to local safeguarding procedures. See also, safeguarding children on the Gov.uk website.
If children or young people being cared for by people with psychosis and coexisting substance misuse are referred to CAMHS under local safeguarding procedures:
use a multi-agency approach, including social care and education, to ensure that various perspectives on the child's life are considered
consider using the Common Assessment Framework (CAF); advice on this can be sought from the local named lead for safeguarding.
If serious concerns are identified, health or social care professionals working with the child or young person (see recommendation 1.1.17) should develop a child protection plan.
When working with people with psychosis and coexisting substance misuse who are responsible for vulnerable adults, ensure that the home situation is risk assessed and that safeguarding procedures are in place for the vulnerable adult. Advice on safeguarding vulnerable adults can be sought from the local named lead for safeguarding.
Consider adults with psychosis and coexisting substance misuse for assessment according to local safeguarding procedures for vulnerable adults if there are concerns regarding exploitation or self-care, or if they have been in contact with the criminal justice system.
## Consent, capacity and treatment decisions
Before undertaking any investigations for substance misuse, and before each treatment decision is taken:
provide service users with full information appropriate to their needs about psychosis and substance misuse and the management of both conditions, to ensure informed consent
understand and apply the principles underpinning the Mental Capacity Act (2005), and be aware that mental capacity is decision-specific (that is, if there is doubt about mental capacity, assessment of mental capacity should be made in relation to each decision)
be able to assess mental capacity using the test set out in the Mental Capacity Act (2005).These principles should apply whether or not people are being detained or treated under the Mental Health Act (1983; amended 1995 and 2007).
## Advance decisions and statements
Develop advance decisions and advance statements in collaboration with adults with psychosis and coexisting substance misuse, especially if their condition is severe and they have been treated under the Mental Health Act (1983; amended 1995 and 2007). Record the decisions and statements and include copies in the care plan in primary and secondary care. Give copies to the person, their care coordinator, and their family, carer or a significant other if the person agrees.'Significant other' refers not just to a partner but also to friends and any person the service user considers to be important to them.
Take advance decisions and advance statements into account in accordance with the Mental Capacity Act (2005). Although advance decisions and advance statements can be overridden using the Mental Health Act (1983; amended 1995 and 2007), try to honour them wherever possible.
## Working with the voluntary sector
Healthcare professionals in primary care and secondary care mental health services, and in specialist substance misuse services, should work collaboratively with voluntary sector organisations that provide help and support for adults and young people with psychosis and coexisting substance misuse. Ensure that advocates from such organisations are included in the care planning and care programming process wherever this is possible and agreed by the person with psychosis and coexisting substance misuse.
Healthcare professionals in primary care and secondary care mental health services, and in specialist substance misuse services, should work collaboratively with voluntary sector organisations providing services for adults and young people with psychosis and coexisting substance misuse to develop agreed protocols for routine and crisis care.
# Recognition of psychosis with coexisting substance misuse
Healthcare professionals in all settings, including primary care, secondary care mental health services, CAMHS and accident and emergency departments, and those in prisons and criminal justice mental health liaison schemes, should routinely ask adults and young people with known or suspected psychosis about their use of alcohol and/or prescribed and non-prescribed (including illicit) drugs. If the person has used substances ask them about all of the following:
particular substance(s) used
quantity, frequency and pattern of use
route of administration
duration of current level of use.In addition, conduct an assessment of dependency (see NICE guidelines on drug misuse in over 16s: opioid detoxification and alcohol-use disorders: diagnosis, assessment and management of harmful drinking (high-risk drinking) and alcohol dependence) and also seek corroborative evidence from families, carers or significant others, where this is possible and permission is given.
Healthcare professionals in all settings, including primary care, secondary care mental health services, CAMHS and accident and emergency departments, and those in prisons and criminal justice mental health liaison schemes, should routinely assess adults and young people with known or suspected substance misuse for possible psychosis. Seek corroborative evidence from families, carers or significant others, where this is possible and permission is given.'Significant other' refers not just to a partner but also to friends and any person the service user considers to be important to them.
# Primary care
## Referral from primary care
Refer all adults and young people with psychosis or suspected psychosis, including those who are suspected of coexisting substance misuse, to either secondary care mental health services or CAMHS for assessment and further management.
Refer all adults and young people with substance misuse or suspected substance misuse who are suspected of having coexisting psychosis to secondary care mental health services or CAMHS for assessment and further management.
## Physical healthcare
Monitor the physical health of adults and young people with psychosis and coexisting substance misuse, as described in the NICE guideline on psychosis and schizophrenia in adults. Pay particular attention to the impact of alcohol and drugs (prescribed and non-prescribed) on physical health. Monitoring should be conducted at least once a year or more frequently if the person has a significant physical illness or there is a risk of physical illness because of substance misuse.
# Secondary care mental health services
## Competence
Healthcare professionals working within secondary care mental health services should ensure they are competent in the recognition, treatment and care of adults and young people with psychosis and coexisting substance misuse.
Healthcare professionals working within secondary care mental health services with adults and young people with psychosis and coexisting substance misuse should consider having supervision, advice, consultation and/or training from specialists in substance misuse services. This is to aid in the development and implementation of treatment plans for substance misuse within CAMHS or adult community mental health services.
## Pathways into care
Do not exclude adults and young people with psychosis and coexisting substance misuse from age-appropriate mental healthcare because of their substance misuse.
Do not exclude adults and young people with psychosis and coexisting substance misuse from age-appropriate substance misuse services because of a diagnosis of psychosis.
For most adults with psychosis and coexisting substance misuse, treatment for both conditions should be provided by healthcare professionals in secondary care mental health services such as community-based mental health teams.
## Coordinating care
Consider seeking specialist advice and initiating joint working arrangements with specialist substance misuse services for adults and young people with psychosis being treated by community mental health teams, and known to be:
severely dependent on alcohol or
dependent on both alcohol and benzodiazepines or
dependent on opioids and/or cocaine or crack cocaine.Adult community mental health services or CAMHS should continue to provide care coordination and treatment for the psychosis within joint working arrangements.
Consider seeking specialist advice and initiate joint working arrangements with specialist substance misuse services if the person's substance misuse:
is difficult to control and/or
leads to significant impairment of functioning, family breakdown or significant social disruption such as homelessness.
If a person with psychosis and coexisting substance misuse requires planned detoxification from either drugs or alcohol, this should take place in an inpatient setting (see section 1.6).
Delivery of care and transfer between services for adults and young people with psychosis and coexisting substance misuse should include a care coordinator and use the Care Programme Approach.
## Assessment
Adults and young people with psychosis and coexisting substance misuse attending secondary care mental health services should be offered a comprehensive, multidisciplinary assessment, including assessment of all of the following:
personal history
mental, physical and sexual health
social, family and economic situation
accommodation, including history of homelessness and stability of current living arrangements
current and past substance misuse and its impact upon their life, health and response to treatment
criminal justice history and current status
personal strengths and weaknesses and readiness to change their substance use and other aspects of their lives. The assessment may need to take place over several meetings to gain a full understanding of the person and the range of problems they experience, and to promote engagement.
When assessing adults and young people with psychosis and coexisting substance misuse, seek corroborative evidence from families, carers or significant others where this is possible and permission is given. Summarise the findings, share this with the person and record it in their care plan.'Significant other' refers not just to a partner but also to friends and any person the service user considers to be important to them.
Review any changes in the person's use of substances. This should include changes in:
the way the use of substances affects the person over time
patterns of use
mental and physical state
circumstances and treatment. Share the summary with the person and record it in their care plan.
When assessing adults and young people with psychosis and coexisting substance misuse, be aware that low levels of substance use that would not usually be considered harmful or problematic in people without psychosis, can have a significant impact on the mental health of people with psychosis.
Regularly assess and monitor risk of harm to self and/or others and develop and implement a risk management plan to be reviewed when the service users' circumstances or levels of risk change. Specifically consider additional risks associated with substance misuse, including:
physical health risks (for example, withdrawal seizures, delirium tremens, blood-borne viruses, accidental overdose, and interactions with prescribed medication) and
the impact that substance use may have on other risks such as self-harm, suicide, self-neglect, violence, abuse of or by others, exploitation, accidental injury and offending behaviour.
## Biological/physical testing
Biological or physical tests for substance use (such as blood and urine tests or hair analysis) may be useful in the assessment, treatment and management of substance misuse for adults and young people with psychosis. However, this should be agreed with the person first as part of their care plan. Do not use biological or physical tests in routine screening for substance misuse in adults and young people with psychosis.
## Treatment
Before starting treatment for adults and young people with psychosis and coexisting substance misuse, review:
the diagnosis of psychosis and of the coexisting substance misuse, especially if either diagnosis has been made during a crisis or emergency presentation and
the effectiveness of previous and current treatments and their acceptability to the person; discontinue ineffective treatments.
When developing a care plan for an adult or young person with psychosis and coexisting substance misuse, take account of the complex and individual relationships between substance misuse, psychotic symptoms, emotional state, behaviour and the person's social context.
Ensure that adults and young people with psychosis and coexisting substance misuse are offered evidence-based treatments for both conditions (see recommendations 1.4.19 and 1.4.20).
For the treatment of psychosis, see NICE guideline on bipolar disorder or the guideline on NICE guideline on psychosis and schizophrenia in adults.
For the treatment of substance misuse, see:
NICE guidelines on alcohol-use disorders: diagnosis and clinical management of alcohol-related physical complications and alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence and/or
NICE guidelines on drug misuse in over 16s: psychosocial interventions and opioid detoxification.
When developing a treatment plan for a person with psychosis and coexisting substance misuse, tailor the plan and the sequencing of treatments to the person and take account of:
the relative severity of both the psychosis and the substance misuse at different times and
the person's social and treatment context and
the person's readiness for change.
Do not exclude adults and young people with psychosis and coexisting substance misuse from contingency management programmes because of their psychosis.
Use antipsychotics according to the guideline on NICE guidelines on psychosis and schizophrenia in adults or bipolar disorder because there is no evidence for any differential benefit for one antipsychotic over another for people with psychosis and coexisting substance misuse.
Use depot/long-acting injectable antipsychotics according to the NICE guideline on psychosis and schizophrenia in managing covert non-adherence with treatment for psychosis and not as a specific treatment for psychosis and coexisting substance misuse.
When prescribing medication for adults and young people with psychosis and coexisting substance misuse:
take into account the level and type of substance misuse, especially of alcohol, as this may alter the metabolism of prescribed medication, decrease its effectiveness and/or increase the risk of side effects
warn the person about potential interactions between substances of misuse and prescribed medication
discuss the problems and potential dangers of using non-prescribed substances and alcohol to counteract the effects or side effects of prescribed medication.
# Substance misuse services
## Competence
Healthcare professionals in substance misuse services should be competent to:
recognise the signs and symptoms of psychosis
undertake a mental health needs and risk assessment sufficient to know how and when to refer to secondary care mental health services.
## Assessment
Adults and young people with psychosis and coexisting substance misuse attending substance misuse services should be offered a comprehensive, multidisciplinary mental health assessment in addition to an assessment of their substance misuse.
## Joint working
Healthcare professionals in substance misuse services should be present at Care Programme Approach meetings for adults and young people with psychosis and coexisting substance misuse within their service who are also receiving treatment and support in other health services.
Specialist substance misuse services should provide advice, consultation, and training for healthcare professionals in adult mental health services and CAMHS regarding the assessment and treatment of substance misuse, and of substance misuse with coexisting psychosis.
Specialist substance misuse services should work closely with secondary care mental health services to develop local protocols derived from this guideline for adults and young people with psychosis and coexisting substance misuse. The agreed local protocols should set out responsibilities and processes for assessment, referral, treatment and shared care across the whole care pathway.
# Inpatient mental health services
## Substance misuse
All inpatient mental health services should ensure that they have policies and procedures for promoting a therapeutic environment free from drugs and alcohol that have been developed together with service users and their families, carers or significant others. These should include: search procedures, visiting arrangements, planning and reviewing leave, drug and alcohol testing, disposal of legal and illicit substances, and other security measures. Soon after admission, provide all service users, and their families, carers or significant others, with information about the policies and procedures.'Significant other' refers not just to a partner but also to friends and any person the service user considers to be important to them.
When carrying out a comprehensive assessment for all adults and young people admitted to inpatient mental health services, ensure that they are assessed for current substance misuse and evidence of withdrawal symptoms at the point of admission.
Biological or physical tests for substance use should only be considered in inpatient services as part of the assessment and treatment planning for adults and young people with psychosis and coexisting substance misuse. Obtain consent for these tests and inform the person of the results as part of an agreed treatment plan. Where mental capacity is lacking, refer to the Mental Capacity Act (2005).
Ensure that planned detoxification from either drugs or alcohol is undertaken only:
with the involvement and advice of substance misuse services
in an inpatient setting, preferably in specialist detoxification units, or designated detoxification beds within inpatient mental health services and
as part of an overall treatment plan. For the further management of opioid detoxification see the NICE guideline on drug misuse in over 16s: opioid detoxification. For the further management of assisted alcohol withdrawal see the NICE guideline on alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence.
## Discharge
Do not discharge adults and young people with psychosis and coexisting substance misuse from an inpatient mental health service solely because of their substance misuse.
When adults and young people with psychosis and coexisting substance misuse are discharged from an inpatient mental health service, ensure that they have:
an identified care coordinator and
a care plan that includes a consideration of needs associated with both their psychosis and their substance misuse and
been informed of the risks of overdose if they start reusing substances, especially opioids, that have been reduced or discontinued during the inpatient stay.
# Staffed accommodation
## Exclusion from services
Do not exclude people with psychosis and coexisting substance misuse from staffed accommodation (such as supported or residential care) solely because of their substance misuse
Do not exclude people with psychosis and coexisting substance misuse from staffed accommodation aimed at addressing substance misuse solely because of their diagnosis of psychosis.
## Aims of treatment
Ensure that people with psychosis and coexisting substance misuse who live in staffed accommodation receive treatment for both their psychosis and their substance misuse with the explicit aim of helping the person remain in stable accommodation.
# Specific issues for young people with psychosis and coexisting substance misuse
## Competence
Professionals in Tier 1 (primary care and educational settings) should be competent to recognise early signs of psychosis and substance misuse in young people.
Healthcare professionals in Tier 3 (community mental health teams) and Tier 4 (specialist inpatient and regional services) CAMHS, and in early intervention in psychosis services, should be competent in the management of psychosis and substance misuse in young people.
## Identification and referral
Professionals in Tier 1 (primary care and educational settings) should seek advice or consultation from Tier 2 CAMHS (primary care) when signs of psychosis are detected in young people. If healthcare professionals in Tier 2 CAMHS detect signs of psychosis in young people, a referral to Tier 3 CAMHS or early intervention in psychosis services for young people should be made according to local protocols.
Ask all young people seen in Tier 3 and Tier 4 CAMHS and in early intervention in psychosis services who have psychosis or suspected psychosis about substance misuse (see recommendation 1.2.1).
Children and young people who, after comprehensive assessment, are considered to be at high risk of harm to themselves or others, should be referred directly to Tier 4 CAMHS including inpatient services where necessary.
## Assessment and treatment
Healthcare professionals working with young people with psychosis and coexisting substance misuse should ensure they are familiar with the legal framework that applies to young people including the Mental Health Act (1983; amended 1995 and 2007), the Mental Capacity Act (2005), and the Children Act (2004).
For psychological, psychosocial, family and medical interventions for young people, follow the recommendations for adults in this guideline; they may need to be adapted according to the young person's circumstances and age. In addition, other agencies, including children's services, should be involved to ensure that the young person's educational, employment, family and housing needs are met.
When prescribing medication, take into account the young person's age and weight when determining the dose. If it is appropriate to prescribe unlicensed medication, explain to the young person and/or their parents or carers the reasons for doing this.
Those providing and commissioning services should ensure that:
age-appropriate mental health services are available for young people with psychosis and coexisting substance misuse and
transition arrangements to adult mental health services are in place where appropriate.# Recommendations for research
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline.
# Determining prevalence, risk and protective factors, and course of illness
What are the prevalence, risk and protective factors, and course of illness for different combinations of psychosis and coexisting substance misuse (for example, schizophrenia and cannabis misuse or bipolar disorder and alcohol misuse)?
## Why this is important
Studies vary in terms of the definitions and diagnosis of psychosis and substance misuse, and how they are conducted. This makes it difficult to draw conclusions about prevalence and patterns in patient groups differentiated by diagnosis, ethnicity and other demographics. Additionally, most studies are cross-sectional, so little is known about how both conditions change over time. Moreover, there is little guidance about which levels and patterns of substance misuse in which patient groups are associated with the worst clinical and social outcomes. Such information is necessary to target resources at groups most at risk of very poor outcomes.
This question should be answered using a longitudinal study design with a representative sample large enough to establish the prevalence, pattern, and epidemiology of different combinations of psychosis and coexisting substance misuse, associated social determinants, treatment and outcome. The study should also collect information that could inform the development of new interventions or the modification of existing interventions to improve prognosis.
# Predicting the onset of substance misuse in young people with psychosis
What risk factors predict the onset of substance misuse in young people with psychosis?
## Why this is important
People with psychosis and coexisting substance misuse are more likely to be non-adherent to prescribed medication, and have poor engagement with treatment programmes, increased risk of suicide, more and longer inpatient stays, increased risk of violence and time spent in the criminal justice system, and poorer overall prognosis. Because the onset of psychosis at a younger age is also an indicator of poor prognosis, people with a combination of younger age of onset and coexisting substance misuse may have a particularly poor prognosis. A clearer understanding of the risk and protective factors for substance misuse in young people with psychosis, and the interrelationship of the two conditions over time, may facilitate the development of treatment approaches for the coexisting conditions in this group. This may then improve the longer term outcome for a group of people who tend to have a poor prognosis.
This question should be answered using a prospective cohort study design.
# Psychosocial interventions versus standard care
Are psychosocial interventions clinically and cost effective when compared with standard care for people with psychosis and coexisting substance misuse?
## Why this is important
Psychosocial interventions are recommended for the treatment of substance misuse, with contingency management showing particular promise. However, they have not been adequately tested in people who also have psychosis.
This question should be answered using a randomised controlled trial that examines short- and medium-term outcomes over at least 18 months. Studies should focus on people whose misuse of substances is most often encountered in clinical practice and has the greatest impact on mental health (such as cannabis and polysubstance misuse) and on those interventions – such as contingency management, cognitive therapy and relapse prevention – that show most promise in people with substance misuse without psychosis. Those providing the intervention should be trained and supervised to ensure that the results are robust and generalisable. Outcomes should reflect both observer and service user-rated assessments of improvement (including mental health and social functioning) and the intervention's acceptability. Studies need to be large enough to determine the intervention's costs and cost effectiveness.
# Environmental interventions versus standard care
Are environmental interventions clinically and cost effective when compared with standard care for people with psychosis and coexisting substance misuse?
## Why this is important
Social and other environmental factors can play a role in triggering and maintaining substance misuse in people with psychosis, and in reducing the likelihood of progress and recovery. Evidence suggests that when the primary focus of management involves improving the environment, both conditions may improve.
This question should be answered using a randomised controlled trial that examines short- and medium-term outcomes over at least 12 months. Studies should focus on people with psychosis whose misuse of substances is most often encountered in clinical practice and has the greatest impact on mental health (such as cannabis and polysubstance misuse), and on interventions that take a collaborative approach to identifying and modifying social and environmental factors that may trigger substance misuse. Those providing the intervention should be trained and supervised to ensure that the results are robust and generalisable. Outcomes should reflect both observer and service user-rated assessments of improvement (including mental health and social functioning) and the intervention's acceptability. Studies need to be large enough to determine the intervention's costs and cost effectiveness.
# Clozapine versus other pharmacological interventions
Is clozapine clinically and cost effective when compared with other pharmacological interventions for people with psychosis and coexisting substance misuse?
## Why this is important
The NICE guideline on psychosis and schizophrenia states that clozapine should be offered to people with schizophrenia whose illness has not responded adequately to treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs. However, there is insufficient evidence to guide healthcare professionals about the use of clozapine in people with psychosis and coexisting substance misuse. Expert opinion often advocates clozapine as having a particular role in this population, but the evidence to support such statements is lacking. Clozapine is expensive and has a wide range of side effects, some of which may be life-threatening if not monitored correctly.
This question should be answered using a randomised controlled trial in which participants are stratified for the presenting problem. It should report short- and longer-term outcomes (including substance misuse, acceptability of the intervention, and cost effectiveness) of at least 12 months' duration.
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{'Introduction': "This guideline covers the assessment and management of adults and young people (aged 14 years and older) who have a clinical diagnosis of psychosis with coexisting substance misuse.\n\nThe term psychosis is used to describe a group of severe mental health disorders characterised by the presence of delusions and hallucinations that disrupt a person's perception, thoughts, emotions and behaviour. The main forms of psychosis are schizophrenia (including schizoaffective disorder, schizophreniform disorder and delusional disorder), bipolar disorder or other affective psychosis.\n\nSubstance misuse is a broad term encompassing, in this guideline, the harmful use of any psychotropic substance, including alcohol and either legal or illicit drugs. Such use is usually, but not always, regarded as a problem if there is evidence of dependence, characterised by psychological reinforcement of repeated substance-taking behaviour and, in some cases, a withdrawal syndrome. However, substance misuse can be harmful without dependence, especially among people with a coexisting psychosis.\n\nApproximately 40% of people with psychosis misuse substances at some point in their lifetime, at least double the rate seen in the general population. In addition, people with coexisting substance misuse have a higher risk of relapse and hospitalisation, and have higher levels of unmet needs compared with other inpatients with psychosis who do not misuse substances.\n\nSubstance misuse among individuals with psychiatric disorders is associated with significantly poorer outcomes than for individuals with a single disorder. These outcomes include worsening psychiatric symptoms, poorer physical health, increased use of institutional services, poor medication adherence, homelessness, increased risk of HIV infection, greater dropout from services and higher overall treatment costs. Social outcomes are also significantly worse, including greater homelessness and rooflessness, a higher impact on families and carers, and increased contact with the criminal justice system.\n\nRooflessness here refers to living rough or on the streets, whereas homelessness encompasses people who are living in shelters.\n\nPeople with psychosis commonly take various non-prescribed substances as a way of coping with their symptoms, and in a third of people with psychosis, this amounts to harmful or dependent use. The outcome for people with psychosis and coexisting substance misuse is worse than for people without coexisting substance misuse, partly because the substances used may exacerbate the psychosis and partly because substances often interfere with pharmacological or psychological treatment. This guideline aims to help healthcare professionals guide people with psychosis and coexisting substance misuse to stabilise, reduce or stop their substance misuse, to improve treatment adherence and outcomes, and to enhance their lives.\n\nAs well as primary and secondary services, this guideline also applies to services that are delivered by the third sector and commissioned by the NHS.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Definitions of depression and severity\n\nDepression refers to a wide range of mental health problems characterised by the absence of a positive affect (a loss of interest and enjoyment in ordinary things and experiences), low mood and a range of associated emotional, cognitive, physical and behavioural symptoms. For more detail, see the International Classification of Diseases-11 (ICD-11) or the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria for depression.\n\nDepression severity exists along a continuum and is essentially composed of 3 elements:\n\nsymptoms (which may vary in frequency and intensity)\n\nduration of the disorder\n\nthe impact on personal and social functioning.\n\nSeverity of depression is therefore a consequence of the contribution of all of these elements.\n\nTraditionally, depression severity has been grouped under 4 categories (subthreshold, mild, moderate and severe) but in the development of this guideline the committee wanted to develop a way of representing the severity of depression which best represents the available evidence on the classification and would help the uptake of the recommendations in routine clinical practice. This guideline has therefore defined new episodes of depression as less severe or more severe depression.\n\nLess severe depression encompasses subthreshold and mild depression, and more severe depression encompasses moderate and severe depression. Thresholds on validated scales were used in this guideline as an indicator of severity. For example, a score 16 on the PHQ-9 scale was used, with scores less than 16 defined as less severe depression, and scores of 16 or more defined as more severe depression.\n\nThe following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\n# Principles of care\n\n## Working with adults and young people with psychosis and coexisting substance misuse\n\nWhen working with adults and young people with known or suspected psychosis and coexisting substance misuse, take time to engage the person from the start, and build a respectful, trusting, non-judgemental relationship in an atmosphere of hope and optimism. Be direct in your communications, use a flexible and motivational approach, and take into account that:\n\nstigma and discrimination are associated with both psychosis and substance misuse\n\nsome people will try to conceal either one or both of their conditions\n\nmany people with psychosis and coexisting substance misuse fear being detained or imprisoned, being given psychiatric medication forcibly or having their children taken into care, and some fear that they may be 'mad'.\n\nWhen working with adults and young people with known or suspected psychosis and coexisting substance misuse:\n\nensure that discussions take place in settings in which confidentiality, privacy and dignity can be maintained\n\navoid clinical language without adequate explanation\n\nprovide independent interpreters (who are not related to the person) if needed\n\naim to preserve continuity of care and minimise changes of key workers in order to foster a therapeutic relationship.\n\n## Race and culture\n\nHealthcare professionals working with adults and young people with psychosis and coexisting substance misuse should ensure that they are competent to engage, assess, and negotiate with service users from diverse cultural and ethnic backgrounds and their families, carers or significant others.'Significant other' refers not just to a partner but also to friends and any person the service user considers to be important to them.\n\nWork with local black and minority ethnic organisations and groups to help support and engage adults and young people with psychosis and coexisting substance misuse. Offer organisations and groups information and training about how to recognise psychosis with coexisting substance misuse and access treatment and care locally.\n\n## Providing information\n\nOffer written and verbal information to adults and young people appropriate to their level of understanding about the nature and treatment of both their psychosis and substance misuse. Written information should:\n\ninclude the information for the public (available in English and Welsh), which contains a list of organisations that can provide more information\n\nbe available in the appropriate language or, for those who cannot use written text, in an alternative format (audio or video).\n\nAll healthcare professionals in primary, secondary or specialist substance misuse services working with adults and young people with psychosis should offer information and advice about the risks associated with substance misuse and the negative impact that it can have on the experience and management of psychosis.\n\n## Working with and supporting families, carers and significant others\n\nEncourage families, carers or significant others to be involved in the treatment of adults and young people with psychosis and coexisting substance misuse to help support treatment and care and promote recovery.\n\nWhen families, carers or significant others live or are in close contact with the person with psychosis and coexisting substance misuse, offer family intervention as recommended in NICE guideline on psychosis and schizophrenia in adults.\n\nWhen families, carers or significant others are involved in supporting the person with psychosis and coexisting substance misuse, discuss with them any concerns about the impact of these conditions on them and on other family members.\n\nOffer families, carers or significant others a carer's assessment of their caring, physical, social, and mental health needs. Where needs are identified, develop a care plan for the family member or carer.\n\nOffer written and verbal information to families, carers or significant others appropriate to their level of understanding about the nature and treatment of psychosis and substance misuse, including how they can help to support the person. Written information should be available in the appropriate language or, for those who cannot use written text, in an accessible format (audio or video).\n\nOffer information to families, carers or significant others about local family or carer support groups and voluntary organisations, including those for psychosis and for substance misuse, and help families, carers or significant others to access these.\n\nNegotiate confidentiality and sharing of information between the person with psychosis and coexisting substance misuse and their family, carer or a significant other.'Significant other' refers not just to a partner but also to friends and any person the service user considers to be important to them.\n\nEnsure the needs of young carers or dependent adults of the person with psychosis and coexisting substance misuse are assessed. Initiate safeguarding procedures where appropriate (see recommendations 1.1.16 to 1.1.20 on safeguarding issues).\n\n## Support for healthcare professionals\n\nWorking with people with psychosis and coexisting substance misuse can be challenging and healthcare professionals should seek effective support – for example, through professional supervision or staff support groups.\n\n## Safeguarding issues\n\nIf people with psychosis and coexisting substance misuse are parents or carers of children or young people, ensure that the child's or young person's needs are assessed according to local safeguarding procedures. See also, safeguarding children on the Gov.uk website.\n\nIf children or young people being cared for by people with psychosis and coexisting substance misuse are referred to CAMHS under local safeguarding procedures:\n\nuse a multi-agency approach, including social care and education, to ensure that various perspectives on the child's life are considered\n\nconsider using the Common Assessment Framework (CAF); advice on this can be sought from the local named lead for safeguarding.\n\nIf serious concerns are identified, health or social care professionals working with the child or young person (see recommendation 1.1.17) should develop a child protection plan.\n\nWhen working with people with psychosis and coexisting substance misuse who are responsible for vulnerable adults, ensure that the home situation is risk assessed and that safeguarding procedures are in place for the vulnerable adult. Advice on safeguarding vulnerable adults can be sought from the local named lead for safeguarding.\n\nConsider adults with psychosis and coexisting substance misuse for assessment according to local safeguarding procedures for vulnerable adults if there are concerns regarding exploitation or self-care, or if they have been in contact with the criminal justice system.\n\n## Consent, capacity and treatment decisions\n\nBefore undertaking any investigations for substance misuse, and before each treatment decision is taken:\n\nprovide service users with full information appropriate to their needs about psychosis and substance misuse and the management of both conditions, to ensure informed consent\n\nunderstand and apply the principles underpinning the Mental Capacity Act (2005), and be aware that mental capacity is decision-specific (that is, if there is doubt about mental capacity, assessment of mental capacity should be made in relation to each decision)\n\nbe able to assess mental capacity using the test set out in the Mental Capacity Act (2005).These principles should apply whether or not people are being detained or treated under the Mental Health Act (1983; amended 1995 and 2007).\n\n## Advance decisions and statements\n\nDevelop advance decisions and advance statements in collaboration with adults with psychosis and coexisting substance misuse, especially if their condition is severe and they have been treated under the Mental Health Act (1983; amended 1995 and 2007). Record the decisions and statements and include copies in the care plan in primary and secondary care. Give copies to the person, their care coordinator, and their family, carer or a significant other if the person agrees.'Significant other' refers not just to a partner but also to friends and any person the service user considers to be important to them.\n\nTake advance decisions and advance statements into account in accordance with the Mental Capacity Act (2005). Although advance decisions and advance statements can be overridden using the Mental Health Act (1983; amended 1995 and 2007), try to honour them wherever possible.\n\n## Working with the voluntary sector\n\nHealthcare professionals in primary care and secondary care mental health services, and in specialist substance misuse services, should work collaboratively with voluntary sector organisations that provide help and support for adults and young people with psychosis and coexisting substance misuse. Ensure that advocates from such organisations are included in the care planning and care programming process wherever this is possible and agreed by the person with psychosis and coexisting substance misuse.\n\nHealthcare professionals in primary care and secondary care mental health services, and in specialist substance misuse services, should work collaboratively with voluntary sector organisations providing services for adults and young people with psychosis and coexisting substance misuse to develop agreed protocols for routine and crisis care.\n\n# Recognition of psychosis with coexisting substance misuse\n\nHealthcare professionals in all settings, including primary care, secondary care mental health services, CAMHS and accident and emergency departments, and those in prisons and criminal justice mental health liaison schemes, should routinely ask adults and young people with known or suspected psychosis about their use of alcohol and/or prescribed and non-prescribed (including illicit) drugs. If the person has used substances ask them about all of the following:\n\nparticular substance(s) used\n\nquantity, frequency and pattern of use\n\nroute of administration\n\nduration of current level of use.In addition, conduct an assessment of dependency (see NICE guidelines on drug misuse in over 16s: opioid detoxification and alcohol-use disorders: diagnosis, assessment and management of harmful drinking (high-risk drinking) and alcohol dependence) and also seek corroborative evidence from families, carers or significant others, where this is possible and permission is given.\n\nHealthcare professionals in all settings, including primary care, secondary care mental health services, CAMHS and accident and emergency departments, and those in prisons and criminal justice mental health liaison schemes, should routinely assess adults and young people with known or suspected substance misuse for possible psychosis. Seek corroborative evidence from families, carers or significant others, where this is possible and permission is given.'Significant other' refers not just to a partner but also to friends and any person the service user considers to be important to them.\n\n# Primary care\n\n## Referral from primary care\n\nRefer all adults and young people with psychosis or suspected psychosis, including those who are suspected of coexisting substance misuse, to either secondary care mental health services or CAMHS for assessment and further management.\n\nRefer all adults and young people with substance misuse or suspected substance misuse who are suspected of having coexisting psychosis to secondary care mental health services or CAMHS for assessment and further management.\n\n## Physical healthcare\n\nMonitor the physical health of adults and young people with psychosis and coexisting substance misuse, as described in the NICE guideline on psychosis and schizophrenia in adults. Pay particular attention to the impact of alcohol and drugs (prescribed and non-prescribed) on physical health. Monitoring should be conducted at least once a year or more frequently if the person has a significant physical illness or there is a risk of physical illness because of substance misuse.\n\n# Secondary care mental health services\n\n## Competence\n\nHealthcare professionals working within secondary care mental health services should ensure they are competent in the recognition, treatment and care of adults and young people with psychosis and coexisting substance misuse.\n\nHealthcare professionals working within secondary care mental health services with adults and young people with psychosis and coexisting substance misuse should consider having supervision, advice, consultation and/or training from specialists in substance misuse services. This is to aid in the development and implementation of treatment plans for substance misuse within CAMHS or adult community mental health services.\n\n## Pathways into care\n\nDo not exclude adults and young people with psychosis and coexisting substance misuse from age-appropriate mental healthcare because of their substance misuse.\n\nDo not exclude adults and young people with psychosis and coexisting substance misuse from age-appropriate substance misuse services because of a diagnosis of psychosis.\n\nFor most adults with psychosis and coexisting substance misuse, treatment for both conditions should be provided by healthcare professionals in secondary care mental health services such as community-based mental health teams.\n\n## Coordinating care\n\nConsider seeking specialist advice and initiating joint working arrangements with specialist substance misuse services for adults and young people with psychosis being treated by community mental health teams, and known to be:\n\nseverely dependent on alcohol or\n\ndependent on both alcohol and benzodiazepines or\n\ndependent on opioids and/or cocaine or crack cocaine.Adult community mental health services or CAMHS should continue to provide care coordination and treatment for the psychosis within joint working arrangements.\n\nConsider seeking specialist advice and initiate joint working arrangements with specialist substance misuse services if the person's substance misuse:\n\nis difficult to control and/or\n\nleads to significant impairment of functioning, family breakdown or significant social disruption such as homelessness.\n\nIf a person with psychosis and coexisting substance misuse requires planned detoxification from either drugs or alcohol, this should take place in an inpatient setting (see section 1.6).\n\nDelivery of care and transfer between services for adults and young people with psychosis and coexisting substance misuse should include a care coordinator and use the Care Programme Approach.\n\n## Assessment\n\nAdults and young people with psychosis and coexisting substance misuse attending secondary care mental health services should be offered a comprehensive, multidisciplinary assessment, including assessment of all of the following:\n\npersonal history\n\nmental, physical and sexual health\n\nsocial, family and economic situation\n\naccommodation, including history of homelessness and stability of current living arrangements\n\ncurrent and past substance misuse and its impact upon their life, health and response to treatment\n\ncriminal justice history and current status\n\npersonal strengths and weaknesses and readiness to change their substance use and\xa0other aspects of their lives. The assessment may need to take place over several meetings to gain a full understanding of the person and the range of problems they experience, and to promote engagement.\n\nWhen assessing adults and young people with psychosis and coexisting substance misuse, seek corroborative evidence from families, carers or significant others where this is possible and permission is given. Summarise the findings, share this with the person and record it in their care plan.'Significant other' refers not just to a partner but also to friends and any person the service user considers to be important to them.\n\nReview any changes in the person's use of substances. This should include changes in:\n\nthe way the use of substances affects the person over time\n\npatterns of use\n\nmental and physical state\n\ncircumstances and treatment. Share the summary with the person and record it in their care plan.\n\nWhen assessing adults and young people with psychosis and coexisting substance misuse, be aware that low levels of substance use that would not usually be considered harmful or problematic in people without psychosis, can have a significant impact on the mental health of people with psychosis.\n\nRegularly assess and monitor risk of harm to self and/or others and develop and implement a risk management plan to be reviewed when the service users' circumstances or levels of risk change. Specifically consider additional risks associated with substance misuse, including:\n\nphysical health risks (for example, withdrawal seizures, delirium tremens, blood-borne viruses, accidental overdose, and interactions with prescribed medication) and\n\nthe impact that substance use may have on other risks such as self-harm, suicide, self-neglect, violence, abuse of or by others, exploitation, accidental injury and offending behaviour.\n\n## Biological/physical testing\n\nBiological or physical tests for substance use (such as blood and urine tests or hair analysis) may be useful in the assessment, treatment and management of substance misuse for adults and young people with psychosis. However, this should be agreed with the person first as part of their care plan. Do not use biological or physical tests in routine screening for substance misuse in adults and young people with psychosis.\n\n## Treatment\n\nBefore starting treatment for adults and young people with psychosis and coexisting substance misuse, review:\n\nthe diagnosis of psychosis and of the coexisting substance misuse, especially if either diagnosis has been made during a crisis or emergency presentation and\n\nthe effectiveness of previous and current treatments and their acceptability to the person; discontinue ineffective treatments.\n\nWhen developing a care plan for an adult or young person with psychosis and coexisting substance misuse, take account of the complex and individual relationships between substance misuse, psychotic symptoms, emotional state, behaviour and the person's social context.\n\nEnsure that adults and young people with psychosis and coexisting substance misuse are offered evidence-based treatments for both conditions (see recommendations 1.4.19 and 1.4.20).\n\nFor the treatment of psychosis, see NICE guideline on bipolar disorder or the guideline on NICE guideline on psychosis and schizophrenia in adults.\n\nFor the treatment of substance misuse, see:\n\nNICE guidelines on alcohol-use disorders: diagnosis and clinical management of alcohol-related physical complications and alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence and/or\n\nNICE guidelines on drug misuse in over 16s: psychosocial interventions and opioid detoxification.\n\nWhen developing a treatment plan for a person with psychosis and coexisting substance misuse, tailor the plan and the sequencing of treatments to the person and take account of:\n\nthe relative severity of both the psychosis and the substance misuse at different times and\n\nthe person's social and treatment context and\n\nthe person's readiness for change.\n\nDo not exclude adults and young people with psychosis and coexisting substance misuse from contingency management programmes because of their psychosis.\n\nUse antipsychotics according to the guideline on NICE guidelines on psychosis and schizophrenia in adults or bipolar disorder because there is no evidence for any differential benefit for one antipsychotic over another for people with psychosis and coexisting substance misuse.\n\nUse depot/long-acting injectable antipsychotics according to the NICE guideline on psychosis and schizophrenia in managing covert non-adherence with treatment for psychosis and not as a specific\xa0treatment for\xa0psychosis and coexisting substance misuse.\n\nWhen prescribing medication for adults and young people with psychosis and coexisting substance misuse:\n\ntake into account the level and type of substance misuse, especially of alcohol, as this may alter the metabolism of prescribed medication, decrease its effectiveness and/or increase the risk of side effects\n\nwarn the person about potential interactions between substances of misuse and prescribed medication\n\ndiscuss the problems and potential dangers of using non-prescribed substances and alcohol to counteract the effects or side effects of prescribed medication.\n\n# Substance misuse services\n\n## Competence\n\nHealthcare professionals in substance misuse services should be competent to:\n\nrecognise the signs and symptoms of psychosis\n\nundertake a mental health needs and risk assessment sufficient to know how and when to refer to secondary care mental health services.\n\n## Assessment\n\nAdults and young people with psychosis and coexisting substance misuse attending substance misuse services should be offered a comprehensive, multidisciplinary mental health assessment in addition to an assessment of their substance misuse.\n\n## Joint working\n\nHealthcare professionals in substance misuse services should be present at Care Programme Approach meetings for adults and young people with psychosis and coexisting substance misuse within their service who are also receiving treatment and support in other health services.\n\nSpecialist substance misuse services should provide advice, consultation, and training for healthcare professionals in adult mental health services and CAMHS regarding the assessment and treatment of substance misuse, and of substance misuse with coexisting psychosis.\n\nSpecialist substance misuse services should work closely with secondary care mental health services to develop local protocols derived from this guideline for adults and young people with psychosis and coexisting substance misuse. The agreed local protocols should set out responsibilities and processes for assessment, referral, treatment and shared care across the whole care pathway.\n\n# Inpatient mental health services\n\n## Substance misuse\n\nAll inpatient mental health services should ensure that they have policies and procedures for promoting a therapeutic environment free from drugs and alcohol that have been developed together with service users and their families, carers or significant others. These should include: search procedures, visiting arrangements, planning and reviewing leave, drug and alcohol testing, disposal of legal and illicit substances, and other security measures. Soon after admission, provide all service users, and their families, carers or significant others, with information about the policies and procedures.'Significant other' refers not just to a partner but also to friends and any person the service user considers to be important to them.\n\nWhen carrying out a comprehensive assessment for all adults and young people admitted to inpatient mental health services, ensure that they are assessed for current substance misuse and evidence of withdrawal symptoms at the point of admission.\n\nBiological or physical tests for substance use should only be considered in inpatient services as part of the assessment and treatment planning for adults and young people with psychosis and coexisting substance misuse. Obtain consent for these tests and inform the person of the results as part of an agreed treatment plan. Where mental capacity is lacking, refer to the Mental Capacity Act (2005).\n\nEnsure that planned detoxification from either drugs or alcohol is undertaken only:\n\nwith the involvement and advice of substance misuse services\n\nin an inpatient setting, preferably in specialist detoxification units, or designated detoxification beds within inpatient mental health services and\n\nas part of an overall treatment plan. For the further management of opioid detoxification see the NICE guideline on drug misuse in over 16s: opioid detoxification. For the further management of assisted alcohol withdrawal see the NICE guideline on alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence.\n\n## Discharge\n\nDo not discharge adults and young people with psychosis and coexisting substance misuse from an inpatient mental health service solely because of their substance misuse.\n\nWhen adults and young people with psychosis and coexisting substance misuse are discharged from an inpatient mental health service, ensure that they have:\n\nan identified care coordinator and\n\na care plan that includes a consideration of needs associated with both their psychosis and their substance misuse and\n\nbeen informed of the risks of overdose if they start reusing substances, especially opioids, that have been reduced or discontinued during the inpatient stay.\n\n# Staffed accommodation\n\n## Exclusion from services\n\nDo not exclude people with psychosis and coexisting substance misuse from staffed accommodation (such as supported or residential care) solely because of their substance misuse\n\nDo not exclude people with psychosis and coexisting substance misuse from staffed accommodation aimed at addressing substance misuse solely because of their diagnosis of psychosis.\n\n## Aims of treatment\n\nEnsure that people with psychosis and coexisting substance misuse who live in staffed accommodation receive treatment for both their psychosis and their substance misuse with the explicit aim of helping the person remain in stable accommodation.\n\n# Specific issues for young people with psychosis and coexisting substance misuse\n\n## Competence\n\nProfessionals in Tier 1 (primary care and educational settings) should be competent to recognise early signs of psychosis and substance misuse in young people.\n\nHealthcare professionals in Tier 3 (community mental health teams) and Tier 4 (specialist inpatient and regional services) CAMHS, and in early intervention in psychosis services, should be competent in the management of psychosis and substance misuse in young people.\n\n## Identification and referral\n\nProfessionals in Tier 1 (primary care and educational settings) should seek advice or consultation from Tier 2 CAMHS (primary care) when signs of psychosis are detected in young people. If healthcare professionals in Tier 2 CAMHS detect signs of psychosis in young people, a referral to Tier 3 CAMHS or early intervention in psychosis services for young people should be made according to local protocols.\n\nAsk all young people seen in Tier 3 and Tier 4 CAMHS and in early intervention in psychosis services who have psychosis or suspected psychosis about substance misuse (see recommendation 1.2.1).\n\nChildren and young people who, after comprehensive assessment, are considered to be at high risk of harm to themselves or others, should be referred directly to Tier 4 CAMHS including inpatient services where necessary.\n\n## Assessment and treatment\n\nHealthcare professionals working with young people with psychosis and coexisting substance misuse should ensure they are familiar with the legal framework that applies to young people including the Mental Health Act (1983; amended 1995 and 2007), the Mental Capacity Act (2005), and the Children Act (2004).\n\nFor psychological, psychosocial, family and medical interventions for young people, follow the recommendations for adults in this guideline; they may need to be adapted according to the young person's circumstances and age. In addition, other agencies, including children's services, should be involved to ensure that the young person's educational, employment, family and housing needs are met.\n\nWhen prescribing medication, take into account the young person's age and weight when determining the dose. If it is appropriate to prescribe unlicensed medication, explain to the young person and/or their parents or carers the reasons for doing this.\n\nThose providing and commissioning services should ensure that:\n\nage-appropriate mental health services are available for young people with psychosis and coexisting substance misuse and\n\ntransition arrangements to adult mental health services are in place where appropriate.", 'Recommendations for research': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline.\n\n# Determining prevalence, risk and protective factors, and course of illness\n\nWhat are the prevalence, risk and protective factors, and course of illness for different combinations of psychosis and coexisting substance misuse (for example, schizophrenia and cannabis misuse or bipolar disorder and alcohol misuse)?\n\n## Why this is important\n\nStudies vary in terms of the definitions and diagnosis of psychosis and substance misuse, and how they are conducted. This makes it difficult to draw conclusions about prevalence and patterns in patient groups differentiated by diagnosis, ethnicity and other demographics. Additionally, most studies are cross-sectional, so little is known about how both conditions change over time. Moreover, there is little guidance about which levels and patterns of substance misuse in which patient groups are associated with the worst clinical and social outcomes. Such information is necessary to target resources at groups most at risk of very poor outcomes.\n\nThis question should be answered using a longitudinal study design with a representative sample large enough to establish the prevalence, pattern, and epidemiology of different combinations of psychosis and coexisting substance misuse, associated social determinants, treatment and outcome. The study should also collect information that could inform the development of new interventions or the modification of existing interventions to improve prognosis.\n\n# Predicting the onset of substance misuse in young people with psychosis\n\nWhat risk factors predict the onset of substance misuse in young people with psychosis?\n\n## Why this is important\n\nPeople with psychosis and coexisting substance misuse are more likely to be non-adherent to prescribed medication, and have poor engagement with treatment programmes, increased risk of suicide, more and longer inpatient stays, increased risk of violence and time spent in the criminal justice system, and poorer overall prognosis. Because the onset of psychosis at a younger age is also an indicator of poor prognosis, people with a combination of younger age of onset and coexisting substance misuse may have a particularly poor prognosis. A clearer understanding of the risk and protective factors for substance misuse in young people with psychosis, and the interrelationship of the two conditions over time, may facilitate the development of treatment approaches for the coexisting conditions in this group. This may then improve the longer term outcome for a group of people who tend to have a poor prognosis.\n\nThis question should be answered using a prospective cohort study design.\n\n# Psychosocial interventions versus standard care\n\nAre psychosocial interventions clinically and cost effective when compared with standard care for people with psychosis and coexisting substance misuse?\n\n## Why this is important\n\nPsychosocial interventions are recommended for the treatment of substance misuse, with contingency management showing particular promise. However, they have not been adequately tested in people who also have psychosis.\n\nThis question should be answered using a randomised controlled trial that examines short- and medium-term outcomes over at least 18\xa0months. Studies should focus on people whose misuse of substances is most often encountered in clinical practice and has the greatest impact on mental health (such as cannabis and polysubstance misuse) and on those interventions – such as contingency management, cognitive therapy and relapse prevention – that show most promise in people with substance misuse without psychosis. Those providing the intervention should be trained and supervised to ensure that the results are robust and generalisable. Outcomes should reflect both observer and service user-rated assessments of improvement (including mental health and social functioning) and the intervention's acceptability. Studies need to be large enough to determine the intervention's costs and cost effectiveness.\n\n# Environmental interventions versus standard care\n\nAre environmental interventions clinically and cost effective when compared with standard care for people with psychosis and coexisting substance misuse?\n\n## Why this is important\n\nSocial and other environmental factors can play a role in triggering and maintaining substance misuse in people with psychosis, and in reducing the likelihood of progress and recovery. Evidence suggests that when the primary focus of management involves improving the environment, both conditions may improve.\n\nThis question should be answered using a randomised controlled trial that examines short- and medium-term outcomes over at least 12\xa0months. Studies should focus on people with psychosis whose misuse of substances is most often encountered in clinical practice and has the greatest impact on mental health (such as cannabis and polysubstance misuse), and on interventions that take a collaborative approach to identifying and modifying social and environmental factors that may trigger substance misuse. Those providing the intervention should be trained and supervised to ensure that the results are robust and generalisable. Outcomes should reflect both observer and service user-rated assessments of improvement (including mental health and social functioning) and the intervention's acceptability. Studies need to be large enough to determine the intervention's costs and cost effectiveness.\n\n# Clozapine versus other pharmacological interventions\n\nIs clozapine clinically and cost effective when compared with other pharmacological interventions for people with psychosis and coexisting substance misuse?\n\n## Why this is important\n\nThe NICE guideline on psychosis and schizophrenia states that clozapine should be offered to people with schizophrenia whose illness has not responded adequately to treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs. However, there is insufficient evidence to guide healthcare professionals about the use of clozapine in people with psychosis and coexisting substance misuse. Expert opinion often advocates clozapine as having a particular role in this population, but the evidence to support such statements is lacking. Clozapine is expensive and has a wide range of side effects, some of which may be life-threatening if not monitored correctly.\n\nThis question should be answered using a randomised controlled trial in which participants are stratified for the presenting problem. It should report short- and longer-term outcomes (including substance misuse, acceptability of the intervention, and cost effectiveness) of at least 12 months' duration."}
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https://www.nice.org.uk/guidance/cg120
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This guideline covers assessing and managing people aged 14 years and over with coexisting severe mental illness (psychosis) and substance misuse. It aims to help healthcare professionals guide people with psychosis with coexisting substance misuse to stabilise, reduce or stop their substance misuse, to improve treatment adherence and outcomes, and to enhance their lives.
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6b55b9d9dff3384a38d23779ab6bea0e026ae3dd
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nice
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Deep brain stimulation for refractory chronic pain syndromes (excluding headache)
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Deep brain stimulation for refractory chronic pain syndromes (excluding headache)
The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Deep brain stimulation for refractory chronic pain syndromes (excluding headache).
# Guidance
Current evidence on the safety of deep brain stimulation (DBS) for refractory chronic pain syndromes (excluding headache) shows that there are serious but well-known risks. There is evidence that the procedure is efficacious in some patients who are refractory to other forms of pain control. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.
During the consent process patients should be informed that DBS may not control their chronic pain symptoms. They should be fully informed about the possible risks associated with this procedure including the small risk of death.
DBS should only be used in patients with refractory chronic pain syndromes that other treatments have failed to control. Patient selection should be carried out by a multidisciplinary team specialising in pain management.# The procedure
# Indications and current treatments
Chronic refractory pain syndromes often have a complex natural history and unclear aetiology. Pain may be nociceptive, neuropathic or deafferentation or in some cases, of uncertain origin.
Treatment of chronic refractory pain usually includes physical, psychological and/or pharmacological treatments. Neurostimulation of the motor cortex, spinal or peripheral nerves have been introduced as treatment options for patients whose condition is unresponsive to other forms of treatment.
# Outline of the procedure
DBS involves stereotactic targeting of specific anatomical sites within the brain (such as the sensory thalamus or periaqueductal grey matter) to modulate the central processing of pain signals.
With the patient under local anaesthesia and/or intravenous sedation, or general anaesthesia, electrodes are inserted into the brain using magnetic resonance imaging and/or computed tomography. A test stimulation (or macrostimulation) is used to check for side effects. Postoperative scans may be used to assess the position of the electrodes and to identify complications such as local haemorrhage.
Following satisfactory electrode testing, a pulse generator is implanted under the chest wall and connected by tunnelled wires to the electrodes. The generator usually remains switched 'on'.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A non-randomised comparative study of 43 patients with post-stroke pain treated by DBS or motor cortex stimulation reported pain reduction greater than 60% in 25% (3/12) and 48% (15/31) of patients respectively (measured on a visual analogue scale ; follow-up not stated).
A case series of 112 patients with chronic intractable deafferentation pain reported that 47% (42/89) of patients were pain-free and 32% (28/89) of patients were 'improved' at follow-ups ranging from 6 months to 6 years. The procedure was considered to have failed in the remaining patients (21% ).
A case series of 122 patients reported treatment success (defined as the patient being able to control their pain using the device with or without medication) in 77% (50/65) of patients with severe intractable pain of peripheral origin (follow-up not stated).
The Specialist Advisers listed key efficacy outcomes as a reduction in frequency and severity of pain, improvement in physical and mental function, improvement in quality of life, and reduction in medication requirements.
# Safety
Intracranial haemorrhage was reported in 4% (5/141) of patients (timing of events not stated) in a case series of 141 patients with nociceptive or deafferentation pain; 1 patient died and 4 patients had neurological deficits, of whom 2 recovered completely and 2 were left with significant deficits.
The case series of 122 patients reported 2 deaths: 1 due to massive cerebral oedema and haematoma in the basal ganglia and the other to coronary occlusion occurring 9 weeks after ventricular haemorrhage (a complication of the procedure).
The case series of 141 patients reported infection in 12% (17/141) of patients (23 cases). Of these, 12 cases occurred within 30 days of the procedure and 10 cases were reported after 30 days (1 case not described). One patient was successfully treated with antibiotics alone, 2 with antibiotics and debridement, and 11 with antibiotics and electrode removal (3 patients not described).
The case series of 122 patients reported ventriculitis in 1 patient, subgaleal infection in 4 patients and subdural empyema in 1 patient. The patient with ventriculitis and 3 of those with subgaleal infection were successfully treated with antibiotics, but the remaining 2 patients required removal of the DBS system.
The case series of 141 patients reported erosion of hardware in 7% (10/141) of patients. Of these, 5 patients had the DBS system removed and 5 had successful re-implantation without the need for antibiotics. Electrode migration occurred only with early versions of the electrodes.
The Specialist Advisers listed anecdotal adverse events as suspected development of a new neuropathic pain condition after migration of the lead, mood change from aberrant stimulation, stimulation-induced reversible side effects such as dysarthria, and seizures. The Specialist Advisers considered theoretical adverse events to include cerebral infarction.
# Other comments
The Committee noted that the available studies described heterogeneous treatment protocols and patient groups. In addition, most were published some years ago and DBS techniques have evolved. These factors made interpretation of the evidence difficult. The Committee considered that there was insufficient evidence to assess efficacy in different patient groups.
The Committee noted strongly positive commentaries from patients who had been treated by DBS; some described how even partial relief of their pain had resulted in significantly improved quality of life.# Further information
For related NICE guidance see our website.
Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.
Changes since publication
January 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
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{'Guidance': 'Current evidence on the safety of deep brain stimulation (DBS) for refractory chronic pain syndromes (excluding headache) shows that there are serious but well-known risks. There is evidence that the procedure is efficacious in some patients who are refractory to other forms of pain control. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.\n\nDuring the consent process patients should be informed that DBS may not control their chronic pain symptoms. They should be fully informed about the possible risks associated with this procedure including the small risk of death.\n\nDBS should only be used in patients with refractory chronic pain syndromes that other treatments have failed to control. Patient selection should be carried out by a multidisciplinary team specialising in pain management.', 'The procedure': "# Indications and current treatments\n\nChronic refractory pain syndromes often have a complex natural history and unclear aetiology. Pain may be nociceptive, neuropathic or deafferentation or in some cases, of uncertain origin.\n\nTreatment of chronic refractory pain usually includes physical, psychological and/or pharmacological treatments. Neurostimulation of the motor cortex, spinal or peripheral nerves have been introduced as treatment options for patients whose condition is unresponsive to other forms of treatment.\n\n# Outline of the procedure\n\nDBS involves stereotactic targeting of specific anatomical sites within the brain (such as the sensory thalamus or periaqueductal grey matter) to modulate the central processing of pain signals.\n\nWith the patient under local anaesthesia and/or intravenous sedation, or general anaesthesia, electrodes are inserted into the brain using magnetic resonance imaging and/or computed tomography. A test stimulation (or macrostimulation) is used to check for side effects. Postoperative scans may be used to assess the position of the electrodes and to identify complications such as local haemorrhage.\n\nFollowing satisfactory electrode testing, a pulse generator is implanted under the chest wall and connected by tunnelled wires to the electrodes. The generator usually remains switched 'on'.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA non-randomised comparative study of 43 patients with post-stroke pain treated by DBS or motor cortex stimulation reported pain reduction greater than 60% in 25% (3/12) and 48% (15/31) of patients respectively (measured on a visual analogue scale [not described]; follow-up not stated).\n\nA case series of 112 patients with chronic intractable deafferentation pain reported that 47% (42/89) of patients were pain-free and 32% (28/89) of patients were 'improved' at follow-ups ranging from 6\xa0months to 6\xa0years. The procedure was considered to have failed in the remaining patients (21% [19/89]).\n\nA case series of 122 patients reported treatment success (defined as the patient being able to control their pain using the device with or without medication) in 77% (50/65) of patients with severe intractable pain of peripheral origin (follow-up not stated).\n\nThe Specialist Advisers listed key efficacy outcomes as a reduction in frequency and severity of pain, improvement in physical and mental function, improvement in quality of life, and reduction in medication requirements.\n\n# Safety\n\nIntracranial haemorrhage was reported in 4% (5/141) of patients (timing of events not stated) in a case series of 141 patients with nociceptive or deafferentation pain; 1 patient died and 4 patients had neurological deficits, of whom 2 recovered completely and 2 were left with significant deficits.\n\nThe case series of 122 patients reported 2 deaths: 1 due to massive cerebral oedema and haematoma in the basal ganglia and the other to coronary occlusion occurring 9\xa0weeks after ventricular haemorrhage (a complication of the procedure).\n\nThe case series of 141 patients reported infection in 12% (17/141) of patients (23 cases). Of these, 12 cases occurred within 30 days of the procedure and 10 cases were reported after 30 days (1 case not described). One patient was successfully treated with antibiotics alone, 2 with antibiotics and debridement, and 11 with antibiotics and electrode removal (3 patients not described).\n\nThe case series of 122 patients reported ventriculitis in 1 patient, subgaleal infection in 4 patients and subdural empyema in 1 patient. The patient with ventriculitis and 3 of those with subgaleal infection were successfully treated with antibiotics, but the remaining 2 patients required removal of the DBS system.\n\nThe case series of 141 patients reported erosion of hardware in 7% (10/141) of patients. Of these, 5 patients had the DBS system removed and 5 had successful re-implantation without the need for antibiotics. Electrode migration occurred only with early versions of the electrodes.\n\nThe Specialist Advisers listed anecdotal adverse events as suspected development of a new neuropathic pain condition after migration of the lead, mood change from aberrant stimulation, stimulation-induced reversible side effects such as dysarthria, and seizures. The Specialist Advisers considered theoretical adverse events to include cerebral infarction.\n\n# Other comments\n\nThe Committee noted that the available studies described heterogeneous treatment protocols and patient groups. In addition, most were published some years ago and DBS techniques have evolved. These factors made interpretation of the evidence difficult. The Committee considered that there was insufficient evidence to assess efficacy in different patient groups.\n\nThe Committee noted strongly positive commentaries from patients who had been treated by DBS; some described how even partial relief of their pain had resulted in significantly improved quality of life.", 'Further information': "For related NICE guidance see our website.\n\nInformation for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg382
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The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Deep brain stimulation for refractory chronic pain syndromes (excluding headache).
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e11054a9a54576260464f1fdad70c4c8dfcb2757
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nice
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Hand allotransplantation
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Hand allotransplantation
Evidence-based recommendations on hand transplant surgery (allotransplantation). Individuals whose hands have been severely damaged by injury or disease may undergo amputation
# Guidance
Current evidence on the efficacy and safety of hand allotransplantation is inadequate in quantity. In addition, there are risks from the prolonged immunosuppression required after the procedure. Therefore this procedure should only be used with special arrangements for clinical governance, consent and research.
Clinicians wishing to undertake hand allotransplantation should take the following actions.
Inform the clinical governance leads in their Trusts.
Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy, in particular the need for and risks of long-term immunosuppression, and the fact that functioning of the transplant may be both delayed and limited. Patients should also be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.
Hand allotransplantation should be carried out only in units with surgical teams experienced in limb reimplantation and with experts in transplantation medicine. Patients' suitability for hand allotransplantation should be carefully assessed in line with practice recommended by NHS Blood and Transplant. Alternative methods of management should be discussed, as well as appropriate rehabilitation. Units carrying out the procedure should work within the provisions of the Human Tissue Act 2004.
Clinicians should submit data to the International Registry on Hand and Composite Tissue Transplantation and Transplant UK.
Further research into hand allotransplantation should include data on long-term functional outcomes, and any occurrence of malignancy associated with long-term immunosuppression should be published. NICE may review this procedure on publication of further evidence.# The procedure
# Indications and current treatments
Amputation of an extremity may result from trauma, surgery carried out to control pain or a disease process in the affected limb. The usual way to restore some hand function after amputation of the arm is to fit a prosthesis. It may be possible to reimplant the hand after traumatic amputation.
# Outline of the procedure
Hand allotransplantation aims to provide a hand that looks more natural than a mechanical prosthesis, and which restores some sensation and movement.
Before the procedure, psychological assessment is required of a patient's motivation and likely compliance with postoperative rehabilitation and immunosuppressive medication.
A cadaveric limb removed surgically from a donor, below the elbow, is used for the transplant. Its suitability for the recipient is assessed by basic matching for sex, size, appearance, and sometimes genetic matching.
Hand allotransplantation is carried out with the patient under general anaesthesia, which may be supplemented by a regional nerve block. A tourniquet may be used for haemostasis. The radius and ulna from the donor limb are fixed to those of the recipient using intramedullary pins or plates. Arteries and veins are anastomosed using standard techniques. The major nerves are repaired and others are joined if possible. Tendons are repaired either individually or in groups.
Following the procedure the limb may be immobilised in a plaster splint for a number of weeks. The patient should undergo intensive rehabilitation, including physiotherapy, occupational therapy and possibly electrostimulation for best restoration of function. Long-term immunosuppression is needed to reduce the possibility of rejection.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A case series of 30 patients (38 hands) reported that more than 70% of patients had improved quality of life following hand allotransplantation and that 'most' patients returned to work (absolute figures and follow-up not stated).
The case series of 30 patients reported 100% (37/37) graft survival at 1- and 2-year follow-up; however, graft failure occurred later in 10 hands because of non-compliance with the immunosuppression regimen (timing not stated). Acute rejection episodes occurred in 85% of patients within the first year; all episodes were reversed when promptly reported and treated.
A case report of 1 patient (1 hand) described re-amputation of the transplanted hand after 12 hours because of thrombosis of the radial artery distal to the entry site of a cannula in the donor arm. A case report of 5 patients (5 hands) reported re-amputation of 1 hand at 9-month follow-up because of intractable ischaemia.
The case series of 30 patients reported that 90% of patients achieved tactile sensibility and 72% developed discriminative sensibility at follow-ups ranging from 6 months to 9 years (absolute figures not stated).
The case report of 5 patients reported an 'excellent' functional outcome in 1 patient, intrinsic muscle recovery in another patient, good function but no intrinsic muscle recovery in 2 patients, and good early progress in the remaining patient (2-month to 10‑year follow-up).
The Specialist Advisers listed key efficacy outcomes as hand function, rejection-free survival of the transplant and patient satisfaction.
# Safety
Arterial thrombosis and venous thrombosis each occurred in 1 of 37 procedures in the case series of 30 patients; both patients required additional surgery (timing of events not stated).
Multiple arteriovenous fistulae requiring additional surgery were reported in 1 of 37 procedures in the case series of 30 patients (timing of events not stated).
Indolent (marginal zone) lymphoma was reported in 1 patient in the case report of 5 patients (follow-up ranged from 2 months to 10 years).
The case series of 30 patients reported opportunistic infections in 65% of the 29 patients receiving immunosuppression at follow-ups ranging from 6 months to 9 years. These included cytomegalovirus reactivation, cutaneous mycosis, herpes virus and Clostridium difficile. Most infections resolved with treatment.
The case series of 30 patients reported that metabolic complications related to immunosuppression therapy occurred in 52% (15/29) of patients at follow-ups ranging from 6 months to 9 years.
The Specialist Advisers listed adverse events reported in the literature as acute and chronic rejection (when immunosuppression was stopped), poor neurological function of the hand and immunosuppression-induced diabetes. They considered theoretical adverse events to include malignant changes or tumour development and graft–versus–host disease.# Further information
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.
Changes since publication
January 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': "Current evidence on the efficacy and safety of hand allotransplantation is inadequate in quantity. In addition, there are risks from the prolonged immunosuppression required after the procedure. Therefore this procedure should only be used with special arrangements for clinical governance, consent and research.\n\nClinicians wishing to undertake hand allotransplantation should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy, in particular the need for and risks of long-term immunosuppression, and the fact that functioning of the transplant may be both delayed and limited. Patients should also be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nHand allotransplantation should be carried out only in units with surgical teams experienced in limb reimplantation and with experts in transplantation medicine. Patients' suitability for hand allotransplantation should be carefully assessed in line with practice recommended by NHS Blood and Transplant. Alternative methods of management should be discussed, as well as appropriate rehabilitation. Units carrying out the procedure should work within the provisions of the Human Tissue Act 2004.\n\nClinicians should submit data to the International Registry on Hand and Composite Tissue Transplantation and Transplant UK.\n\nFurther research into hand allotransplantation should include data on long-term functional outcomes, and any occurrence of malignancy associated with long-term immunosuppression should be published. NICE may review this procedure on publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nAmputation of an extremity may result from trauma, surgery carried out to control pain or a disease process in the affected limb. The usual way to restore some hand function after amputation of the arm is to fit a prosthesis. It may be possible to reimplant the hand after traumatic amputation.\n\n# Outline of the procedure\n\nHand allotransplantation aims to provide a hand that looks more natural than a mechanical prosthesis, and which restores some sensation and movement.\n\nBefore the procedure, psychological assessment is required of a patient's motivation and likely compliance with postoperative rehabilitation and immunosuppressive medication.\n\nA cadaveric limb removed surgically from a donor, below the elbow, is used for the transplant. Its suitability for the recipient is assessed by basic matching for sex, size, appearance, and sometimes genetic matching.\n\nHand allotransplantation is carried out with the patient under general anaesthesia, which may be supplemented by a regional nerve block. A tourniquet may be used for haemostasis. The radius and ulna from the donor limb are fixed to those of the recipient using intramedullary pins or plates. Arteries and veins are anastomosed using standard techniques. The major nerves are repaired and others are joined if possible. Tendons are repaired either individually or in groups.\n\nFollowing the procedure the limb may be immobilised in a plaster splint for a number of weeks. The patient should undergo intensive rehabilitation, including physiotherapy, occupational therapy and possibly electrostimulation for best restoration of function. Long-term immunosuppression is needed to reduce the possibility of rejection.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 30 patients (38 hands) reported that more than 70% of patients had improved quality of life following hand allotransplantation and that 'most' patients returned to work (absolute figures and follow-up not stated).\n\nThe case series of 30 patients reported 100% (37/37) graft survival at 1- and 2-year follow-up; however, graft failure occurred later in 10\xa0hands because of non-compliance with the immunosuppression regimen (timing not stated). Acute rejection episodes occurred in 85% of patients within the first year; all episodes were reversed when promptly reported and treated.\n\nA case report of 1 patient (1 hand) described re-amputation of the transplanted hand after 12\xa0hours because of thrombosis of the radial artery distal to the entry site of a cannula in the donor arm. A case report of 5\xa0patients (5 hands) reported re-amputation of 1 hand at 9-month follow-up because of intractable ischaemia.\n\nThe case series of 30 patients reported that 90% of patients achieved tactile sensibility and 72% developed discriminative sensibility at follow-ups ranging from 6\xa0months to 9\xa0years (absolute figures not stated).\n\nThe case report of 5 patients reported an 'excellent' functional outcome in 1 patient, intrinsic muscle recovery in another patient, good function but no intrinsic muscle recovery in 2 patients, and good early progress in the remaining patient (2-month to 10‑year follow-up).\n\nThe Specialist Advisers listed key efficacy outcomes as hand function, rejection-free survival of the transplant and patient satisfaction.\n\n# Safety\n\nArterial thrombosis and venous thrombosis each occurred in 1 of 37\xa0procedures in the case series of 30 patients; both patients required additional surgery (timing of events not stated).\n\nMultiple arteriovenous fistulae requiring additional surgery were reported in 1 of 37 procedures in the case series of 30 patients (timing of events not stated).\n\nIndolent (marginal zone) lymphoma was reported in 1 patient in the case report of 5 patients (follow-up ranged from 2\xa0months to 10\xa0years).\n\nThe case series of 30 patients reported opportunistic infections in 65% of the 29 patients receiving immunosuppression at follow-ups ranging from 6\xa0months to 9\xa0years. These included cytomegalovirus reactivation, cutaneous mycosis, herpes virus and Clostridium difficile. Most infections resolved with treatment.\n\nThe case series of 30 patients reported that metabolic complications related to immunosuppression therapy occurred in 52% (15/29) of patients at follow-ups ranging from 6\xa0months to 9\xa0years.\n\nThe Specialist Advisers listed adverse events reported in the literature as acute and chronic rejection (when immunosuppression was stopped), poor neurological function of the hand and immunosuppression-induced diabetes. They considered theoretical adverse events to include malignant changes or tumour development and graft–versus–host disease.", 'Further information': "# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg383
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Evidence-based recommendations on hand transplant surgery (allotransplantation). Individuals whose hands have been severely damaged by injury or disease may undergo amputation
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cb31622648f8dec07e23cf4325b1141cb4264eb7
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nice
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Percutaneous retroperitoneal endoscopic necrosectomy
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Percutaneous retroperitoneal endoscopic necrosectomy
The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Percutaneous retroperitoneal endoscopic necrosectomy.
# Guidance
This document replaces previous guidance on percutaneous pancreatic necrosectomy (interventional procedure guidance 33).
Current evidence on the safety and efficacy of percutaneous retroperitoneal endoscopic necrosectomy is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.
The procedure should only be carried out by a team experienced in the management of complex pancreatic disease.# The procedure
# Indications and current treatments
Pancreatic necrosis (also called necrotising pancreatitis) is a serious complication of acute pancreatitis that can occur in some patients. It is associated with significant morbidity, requiring prolonged hospitalisation, and high mortality.
Traditionally pancreatic necrosis has been treated by open necrosectomy via laparotomy, but image-guided drainage or laparoscopic drainage may also be used.
# Outline of the procedure
Percutaneous retroperitoneal endoscopic necrosectomy aims to remove necrotic tissue under direct vision. The procedure is less invasive and may improve prognosis compared with traditional open surgery. Percutaneous drainage may be attempted as part of the management prior to the procedure.
With the patient under general anaesthesia, an endoscope (which may be rigid or flexible) is inserted via a posterolateral approach into the retroperitoneal space to visualise the area of necrosis. Dead tissue is removed, for example using suction, lavage or forceps, and debrided where necessary using forceps. Drains may be placed for irrigation in the postoperative period. The procedure may be repeated if required.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A randomised controlled trial (RCT) of 88 patients treated by a step-up protocol involving drainage followed-up as required by percutaneous retroperitoneal endoscopic necrosectomy versus primary open necrosectomy, reported mortality rates of 19% (8/43) and 16% (7/45) respectively (p = 0.70) (patients in this study were followed-up for up to 6 months from hospital discharge). In the group randomised to drainage followed as required by percutanenous retroperitoneal endoscopic necrosectomy 60% (26/43) of patients underwent the procedure, 35% (15/43) of patients required drainage alone and 5% (2/43) of patients with multiple organ failure were too unstable for the procedure and underwent endoscopic transgastric drainage.
A non-randomised controlled study of 189 patients treated by the procedure or open pancreatic necrosectomy reported mortality rates of 19% (26/137) and 38% (20/52) respectively (p = 0.009) (follow-up not stated).
A non-randomised controlled study of 30 patients treated by the procedure or open necrosectomy reported in-hospital mortality rates of 7% (1/15) and 40% (6/15) respectively (p = 0.08).
The non-randomised controlled study of 30 patients treated by the procedure or open necrosectomy reported postoperative multiple organ failure in 13% (2/15) and 67% (10/15) of patients respectively (p = 0.008).
The RCT of 88 patients comparing drainage followed as required by percutanenous retroperitoneal endoscopic necrosectomy with primary open necrosectomy, reported a composite rate of major complication or death in 40% (17/43) and 69% (31/45) of patients in either group respectively (p = 0.006) (follow-up of up to 3 months from hospital discharge).
The Specialist Advisers listed key efficacy outcomes as a reduction in mortality and morbidity, reduction of requirement for postoperative critical care, number of interventions required and length of hospital stay.
# Safety
The RCT of 88 patients comparing percutanenous retroperitoneal endoscopic necrosectomy with primary open necrosectomy, reported fistula formation or perforation requiring intervention in 33% (14/43) and 22% (10/45) of patients respectively (p = 0.32) (patients in this study were followed-up for up to 6 months from hospital discharge).
Bowel perforation occurred in 7% (1/15) of patients treated by the procedure and in 13% (2/15) of patients treated by open necrosectomy in the non-randomised controlled trial of 30 patients (p = not significant). In the same study, pancreatic fistula developed in 13% (2/15) of patients and 0% (0/15) of patients respectively (p = not significant; follow-up not stated).
The RCT of 88 patients reported that bleeding requiring intervention occurred in 16% (7/43) of patients treated in the percutanenous retroperitoneal endoscopic necrosectomy group and in 22% (10/45) of patients treated by open necrosectomy (p = 0.48).
The Specialist Advisers stated that adverse events reported in the literature include incomplete drainage and/or sepsis control, iatrogenic injury to the kidney or spleen, colonic necrosis, pseudocyst formation, venous thrombosis and death.# Further information
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
It updates and replaces NICE interventional procedure guidance 33.
We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.
Changes since publication
January 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': 'This document replaces previous guidance on percutaneous pancreatic necrosectomy (interventional procedure guidance 33).\n\nCurrent evidence on the safety and efficacy of percutaneous retroperitoneal endoscopic necrosectomy is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nThe procedure should only be carried out by a team experienced in the management of complex pancreatic disease.', 'The procedure': '# Indications and current treatments\n\nPancreatic necrosis (also called necrotising pancreatitis) is a serious complication of acute pancreatitis that can occur in some patients. It is associated with significant morbidity, requiring prolonged hospitalisation, and high mortality.\n\nTraditionally pancreatic necrosis has been treated by open necrosectomy via laparotomy, but image-guided drainage or laparoscopic drainage may also be used.\n\n# Outline of the procedure\n\nPercutaneous retroperitoneal endoscopic necrosectomy aims to remove necrotic tissue under direct vision. The procedure is less invasive and may improve prognosis compared with traditional open surgery. Percutaneous drainage may be attempted as part of the management prior to the procedure.\n\nWith the patient under general anaesthesia, an endoscope (which may be rigid or flexible) is inserted via a posterolateral approach into the retroperitoneal space to visualise the area of necrosis. Dead tissue is removed, for example using suction, lavage or forceps, and debrided where necessary using forceps. Drains may be placed for irrigation in the postoperative period. The procedure may be repeated if required.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 88 patients treated by a step-up protocol involving drainage followed-up as required by percutaneous retroperitoneal endoscopic necrosectomy versus primary open necrosectomy, reported mortality rates of 19% (8/43) and 16% (7/45) respectively (p = 0.70) (patients in this study were followed-up for up to 6 months from hospital discharge). In the group randomised to drainage followed as required by percutanenous retroperitoneal endoscopic necrosectomy 60% (26/43) of patients underwent the procedure, 35% (15/43) of patients required drainage alone and 5% (2/43) of patients with multiple organ failure were too unstable for the procedure and underwent endoscopic transgastric drainage.\n\nA non-randomised controlled study of 189 patients treated by the procedure or open pancreatic necrosectomy reported mortality rates of 19% (26/137) and 38% (20/52) respectively (p = 0.009) (follow-up not stated).\n\nA non-randomised controlled study of 30 patients treated by the procedure or open necrosectomy reported in-hospital mortality rates of 7% (1/15) and 40% (6/15) respectively (p\xa0=\xa00.08).\n\nThe non-randomised controlled study of 30 patients treated by the procedure or open necrosectomy reported postoperative multiple organ failure in 13% (2/15) and 67% (10/15) of patients respectively (p\xa0=\xa00.008).\n\nThe RCT of 88 patients comparing drainage followed as required by percutanenous retroperitoneal endoscopic necrosectomy with primary open necrosectomy, reported a composite rate of major complication or death in 40% (17/43) and 69% (31/45) of patients in either group respectively (p\xa0=\xa00.006) (follow-up of up to 3 months from hospital discharge).\n\nThe Specialist Advisers listed key efficacy outcomes as a reduction in mortality and morbidity, reduction of requirement for postoperative critical care, number of interventions required and length of hospital stay.\n\n# Safety\n\nThe RCT of 88 patients comparing percutanenous retroperitoneal endoscopic necrosectomy with primary open necrosectomy, reported fistula formation or perforation requiring intervention in 33% (14/43) and 22% (10/45) of patients respectively (p\xa0=\xa00.32) (patients in this study were followed-up for up to 6 months from hospital discharge).\n\nBowel perforation occurred in 7% (1/15) of patients treated by the procedure and in 13% (2/15) of patients treated by open necrosectomy in the non-randomised controlled trial of 30\xa0patients (p = not significant). In the same study, pancreatic fistula developed in 13% (2/15) of patients and 0% (0/15) of patients respectively (p = not significant; follow-up not stated).\n\nThe RCT of 88 patients reported that bleeding requiring intervention occurred in 16% (7/43) of patients treated in the percutanenous retroperitoneal endoscopic necrosectomy group and in 22% (10/45) of patients treated by open necrosectomy (p\xa0=\xa00.48).\n\nThe Specialist Advisers stated that adverse events reported in the literature include incomplete drainage and/or sepsis control, iatrogenic injury to the kidney or spleen, colonic necrosis, pseudocyst formation, venous thrombosis and death.', 'Further information': "# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 33.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg384
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The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Percutaneous retroperitoneal endoscopic necrosectomy.
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b8d34ea0970381cc398be26d626732a10004ff6c
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nice
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Laser correction of refractive error following non-refractive ophthalmic surgery
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Laser correction of refractive error following non-refractive ophthalmic surgery
# Guidance
Current evidence on the safety and efficacy of laser correction of refractive error following non-refractive ophthalmic surgery is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.
Patient selection and treatment should be carried out only by ophthalmologists who specialise in corneal surgery.# The procedure
# Indications and current treatments
Refractive errors (myopia, hyperopia or astigmatism) can result from non-refractive ophthalmic surgery such as cataract surgery or corneal transplantation.
Refractive errors are usually managed by wearing spectacles or contact lenses. In patients for whom spectacles and contact lenses do not adequately correct the refractive error, other options include corneal relieving incisions, intraocular surgery such as cataract extraction with standard or toric intraocular lenses and laser corrective procedures.
# Outline of the procedure
Three types of laser correction are considered in this guidance: photorefractive keratectomy (PRK), laser epithelial keratomileusis (LASEK) and laser in situ keratomileusis (LASIK), all performed with the patient under local anaesthesia. If required, they can be performed on both eyes during the same treatment session.
PRK involves removal of the corneal epithelium by surgical dissection followed by excimer laser ablation of a calculated amount of the stromal bed of the cornea. LASEK is a modification of PRK in which dilute alcohol is used to loosen the corneal epithelium before it is lifted from the treatment zone as a hinged sheet, and then replaced at the end of the procedure. In LASIK, a flap is created with a microkeratome, lifted before laser ablation and then repositioned. Patients may be given pre- or postoperative antibiotics as prophylaxis against infection.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A case series of 62 patients (87 eyes) who had LASIK after non-refractive ophthalmic surgery or refractive surgery reported that mean spherical equivalent refraction (MSER; a negative reading indicates myopia, a positive reading indicates hyperopia) improved from −5.25 D preoperatively to −0.70 D at 1-year follow-up.
A case series of 59 patients (85 eyes) who had LASIK after multifocal intraocular lens implantation reported that MSER improved from −0.34 D preoperatively to −0.07 D at 6-month follow-up (p = 0.004).
A case series of 48 patients (57 eyes) who had LASIK after penetrating keratoplasty (PK) reported that MSER improved from −3.94 D preoperatively to −0.61 D at 2-year follow-up.
A case series of 38 patients (46 eyes) who had LASIK after PK reported improvement in preoperative mean spherical refraction in myopic eyes (n = 40) and hyperopic eyes (n = 3) from −5.16 D to −0.44 D and 5.75 D to 1.67 D respectively, and improvement in mean preoperative cylindrical refraction in eyes with mixed astigmatism (n = 3) from −5.50 D to −2.42 D at 5-year follow-up. Overall, at 5-year follow-up, 63% (29/46) had a refractive error within 1.00 D of emmetropia.
The case series of 62 patients reported that the proportion of patients' eyes with uncorrected visual acuity of 0.5 or better increased from 5% (4/87) preoperatively to 70% (61/87) at 1-year follow-up.
Case series of 62, 59 and 48 patients who had LASIK after non-refractive ophthalmic surgery reported LASIK re-operation in 22% (19/87), 6% (5/85) and 9% (5/57) of eyes because of residual refractive errors, at follow-ups of 12, 6 and 24 months respectively.
The Specialist Advisers listed key efficacy outcomes as uncorrected visual acuity, reduced refractive error, maintained best‑corrected spectacle vision and improved quality of life.
# Safety
The case series of 48 patients reported that 15% (8/52) of eyes had lost ≥ 2 Snellen lines of best-corrected visual acuity at 1-year.
A case series of 41 patients (44 eyes) who had PRK after PK reported 3 eyes with grade 2 haze all requiring retreatment.
The case series of 59 patients reported 4 eyes with moderate or marked dry eye developing between 3 and 6 months follow-up. All eyes were treated frequently with lubricant. The case series of 48 patients treated with LASIK after PK reported persistent dry eye in 3 eyes at a mean follow-up of 21 months.
The case series of 48 patients reported: 4 eyes with epithelial ingrowth (requiring removal) between 1 week and 12 months; 2 eyes that required repeat graft for persistent astigmatism between 1 and 3 years; 3 eyes needing repeat graft for oedema between 8 months and 3 years; and 5 eyes with flap dislocation between 1 day and 1 week (2 required sutures, 1 flap was removed and 1 was repositioned without sutures).
A case series of 57 eyes reported: 2% (1/57) of eyes with macular haemorrhages 7 days after LASIK; 7% (4/57) of eyes with epithelial ingrowth; 4% (2/57) of eyes with induced astigmatism; 4% (2/57) of eyes with a free cap; and 25% (14/57) of eyes with night vision problems at a mean follow-up of 9 months.
The case series of 38 patients who had LASIK after PK reported endothelial rejection, which was successfully treated in 1 eye.
The Specialist Advisers considered theoretical adverse events to include ectasia, recurrent epithelial erosion syndrome, epithelial defects, bleeding from the flap edge, interface haemorrhage, interface debris, flap striae, diffuse lamellar keratitis, corneal scarring, glare, infection and pain after treatment.
# Other comments
These procedures can make it more difficult to measure accurately the intraocular pressure used to detect glaucoma, and the intraocular lens power required for cataract surgery. Techniques are available to address these difficulties, provided it is known that photorefractive surgery has previously been done.# Further information
For related NICE guidance see our website.
Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.
Changes since publication
January 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': 'Current evidence on the safety and efficacy of laser correction of refractive error following non-refractive ophthalmic surgery is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatient selection and treatment should be carried out only by ophthalmologists who specialise in corneal surgery.', 'The procedure': "# Indications and current treatments\n\nRefractive errors (myopia, hyperopia or astigmatism) can result from non-refractive ophthalmic surgery such as cataract surgery or corneal transplantation.\n\nRefractive errors are usually managed by wearing spectacles or contact lenses. In patients for whom spectacles and contact lenses do not adequately correct the refractive error, other options include corneal relieving incisions, intraocular surgery such as cataract extraction with standard or toric intraocular lenses and laser corrective procedures.\n\n# Outline of the procedure\n\nThree types of laser correction are considered in this guidance: photorefractive keratectomy (PRK), laser epithelial keratomileusis (LASEK) and laser in situ keratomileusis (LASIK), all performed with the patient under local anaesthesia. If required, they can be performed on both eyes during the same treatment session.\n\nPRK involves removal of the corneal epithelium by surgical dissection followed by excimer laser ablation of a calculated amount of the stromal bed of the cornea. LASEK is a modification of PRK in which dilute alcohol is used to loosen the corneal epithelium before it is lifted from the treatment zone as a hinged sheet, and then replaced at the end of the procedure. In LASIK, a flap is created with a microkeratome, lifted before laser ablation and then repositioned. Patients may be given pre- or postoperative antibiotics as prophylaxis against infection.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 62\xa0patients (87\xa0eyes) who had LASIK after non-refractive ophthalmic surgery or refractive surgery reported that mean spherical equivalent refraction (MSER; a negative reading indicates myopia, a positive reading indicates hyperopia) improved from −5.25\xa0D preoperatively to −0.70\xa0D at 1-year follow-up.\n\nA case series of 59\xa0patients (85\xa0eyes) who had LASIK after multifocal intraocular lens implantation reported that MSER improved from −0.34\xa0D preoperatively to −0.07 D at 6-month follow-up (p\xa0=\xa00.004).\n\nA case series of 48\xa0patients (57\xa0eyes) who had LASIK after penetrating keratoplasty (PK) reported that MSER improved from −3.94\xa0D preoperatively to −0.61\xa0D at 2-year follow-up.\n\nA case series of 38\xa0patients (46\xa0eyes) who had LASIK after PK reported improvement in preoperative mean spherical refraction in myopic eyes (n\xa0=\xa040) and hyperopic eyes (n\xa0=\xa03) from −5.16\xa0D to −0.44\xa0D and 5.75\xa0D to 1.67\xa0D respectively, and improvement in mean preoperative cylindrical refraction in eyes with mixed astigmatism (n\xa0=\xa03) from −5.50\xa0D to −2.42\xa0D at 5-year follow-up. Overall, at 5-year follow-up, 63% (29/46) had a refractive error within 1.00\xa0D of emmetropia.\n\nThe case series of 62\xa0patients reported that the proportion of patients' eyes with uncorrected visual acuity of 0.5 or better increased from 5% (4/87) preoperatively to 70% (61/87) at 1-year follow-up.\n\nCase series of 62, 59 and 48 patients who had LASIK after non-refractive ophthalmic surgery reported LASIK re-operation in 22% (19/87), 6% (5/85) and 9% (5/57) of eyes because of residual refractive errors, at follow-ups of 12, 6 and 24 months respectively.\n\nThe Specialist Advisers listed key efficacy outcomes as uncorrected visual acuity, reduced refractive error, maintained best‑corrected spectacle vision and improved quality of life.\n\n# Safety\n\nThe case series of 48\xa0patients reported that 15% (8/52) of eyes had lost ≥\xa02\xa0Snellen lines of best-corrected visual acuity at 1-year.\n\nA case series of 41\xa0patients (44 eyes) who had PRK after PK reported 3\xa0eyes with grade 2 haze all requiring retreatment.\n\nThe case series of 59\xa0patients reported 4\xa0eyes with moderate or marked dry eye developing between 3 and 6\xa0months follow-up. All eyes were treated frequently with lubricant. The case series of 48\xa0patients treated with LASIK after PK reported persistent dry eye in 3\xa0eyes at a mean follow-up of 21\xa0months.\n\nThe case series of 48\xa0patients reported: 4\xa0eyes with epithelial ingrowth (requiring removal) between 1\xa0week and 12\xa0months; 2\xa0eyes that required repeat graft for persistent astigmatism between 1 and 3\xa0years; 3\xa0eyes needing repeat graft for oedema between 8\xa0months and 3\xa0years; and 5\xa0eyes with flap dislocation between 1\xa0day and 1\xa0week (2 required sutures, 1 flap was removed and 1 was repositioned without sutures).\n\nA case series of 57\xa0eyes reported: 2% (1/57) of\xa0eyes with macular haemorrhages 7\xa0days after LASIK; 7% (4/57) of\xa0eyes with epithelial ingrowth; 4% (2/57) of\xa0eyes with induced astigmatism; 4% (2/57) of\xa0eyes with a free cap; and 25% (14/57) of eyes with night vision problems at a mean follow-up of 9\xa0months.\n\nThe case series of 38\xa0patients who had LASIK after PK reported endothelial rejection, which was successfully treated in 1\xa0eye.\n\nThe Specialist Advisers considered theoretical adverse events to include ectasia, recurrent epithelial erosion syndrome, epithelial defects, bleeding from the flap edge, interface haemorrhage, interface debris, flap striae, diffuse lamellar keratitis, corneal scarring, glare, infection and pain after treatment.\n\n# Other comments\n\nThese procedures can make it more difficult to measure accurately the intraocular pressure used to detect glaucoma, and the intraocular lens power required for cataract surgery. Techniques are available to address these difficulties, provided it is known that photorefractive surgery has previously been done.", 'Further information': "For related NICE guidance see our website.\n\nInformation for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg385
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b3ae7d05b041e3097b89f467159722570c6b8dca
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nice
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Therapeutic hypothermia following cardiac arrest
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Therapeutic hypothermia following cardiac arrest
# Guidance
Current evidence on the safety and efficacy of therapeutic hypothermia following cardiac arrest is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, audit and consent.# The procedure
# Indications and current treatments
Cardiac arrest leads to loss of consciousness and death unless emergency resuscitation is given and the heart can be restarted. The abnormal cardiac rhythms most commonly associated with cardiac arrest are asystole, pulseless electrical activity, ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT).
Brain injury following cardiac arrest may be prevented by early cardiopulmonary resuscitation, including defibrillation to treat VF and pulseless VT rhythms. Drugs such as adrenaline are also commonly required.
# Outline of the procedure
After cardiac arrest, comatose patients who have a return of spontaneous circulation (ROSC) can be cooled to a core temperature of 32–34°C with the aim of reducing brain injury and improving neurological outcome. The exact mechanism by which cooling confers cerebral protection is unknown.
As soon as possible after the cardiac arrest, mild hypothermia is induced by using surface techniques (for example heat exchange cooling pads, cooling blankets, ice packs), internal techniques (for example an endovascular cooling device) or a combination of cooling methods. Core body temperature is maintained at 32–34°C for 12–24 hours from the start of cooling and is monitored using a bladder temperature probe. Controlled re-warming is usually done over a number of hours. In addition to cooling, patients generally receive standard critical care measures, together with intravenous sedation and muscle relaxants (to prevent shivering).
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A systematic review of 481 patients reported that a significantly higher proportion of patients who had therapeutic hypothermia survived to hospital discharge compared with patients in the standard care group (risk ratio 1.35, 95% confidence interval 1.10 to 1.65, 3 studies).
The systematic review of 481 patients reported that a significantly higher proportion of patients in the hypothermia group had a good neurological outcome at hospital discharge compared with patients in the standard care group (RR 1.55, 95% CI 1.24 to 1.94, 5 studies).
A randomised controlled trial (RCT) of 275 patients (137 hypothermia vs 138 normothermia) reported a significantly higher proportion of patients in the hypothermia group with a favourable neurological outcome at 6 months compared with patients in the normothermia group, after adjusting for baseline variables (RR 1.47, 95% CI 1.09 to 1.82).
An RCT of 54 patients (36 hypothermia vs 18 normothermia) reported that a significantly higher proportion of patients in the hypothermia group had a good neurological outcome at 1 month compared with patients in the normothermia group (50% vs 11%, p < 0.05).
The Specialist Advisers listed key efficacy outcomes as survival, reduced long-term neurological disability, independent living, quality of life (SF-36, Health Utility Index 3), and reductions in length of critical care and hospital stay.
# Safety
A case series of 986 patients reported sepsis and pneumonia rates of 4% (35/986) and 41% (407/986) respectively. The systematic review of 481 patients reported higher rates of pneumonia and sepsis in the hypothermia group compared with patients in the standard care group but the differences were not significant (pneumonia: RR 1.27, 95% CI 0.90 to 1.78, 1 study; sepsis: RR 1.93, 95% CI 0.89 to 1.78, 1 study).
The systematic review of 481 patients reported numerically higher rates of hypophosphataemia (abnormally low level of phosphate in the blood which can cause muscle weakness, respiratory problems and changes in mental state) in the hypothermia group compared with standard care but the differences were not significant (RR 1.12, 95% CI 0.65 to 2.25, 1 study).
An RCT of 61 patients (20 haemofiltration only vs 22 hypothermia plus haemofiltration vs 19 controls) reported similar 6-month hypokalaemia rates of 25% (5/20) in the haemofiltration only group and 23% (5/22) in the hypothermia plus haemofiltration group. The same study reported similar 6-month hypophosphataemia rates of 45% (9/20) in the haemofiltration only group and 55% (12/22) in the hypothermia plus haemofiltration group.
The systematic review of 481 patients reported a numerically higher rate of bleeding requiring platelet transfusion in the hypothermia group compared with standard care but the difference was not significant (RR 5.11, 95% CI 0.25 to 5.47, 1 study).
An RCT of 64 patients (34 hypothermia using gel pads with feedback control vs 30 hypothermia using blankets and ice) reported heparin-induced thrombocytopenia within 90 days in 1 patient in the gel pads with feedback control group and no patients in the blankets and ice group. The same study reported 2 patients with a gastrointestinal bleed within 90 days in the blankets and ice group and no patients in the gel pads group.
A case series of 986 patients reported bleeding requiring transfusion in 5% (44/986) of patients.
The RCT of 64 patients reported similar 90-day seizure and/or status epilepticus rates in both groups (19% vs 17% ).
The systematic review of 481 patients reported a higher rate of lethal or long lasting arrhythmias in the hypothermia group compared with standard care but the differences were not significant (RR 1.21, 95% CI 0.88 to 1.67, 1 study).
The Specialist Advisers listed anecdotal adverse events as coagulation and immune modulation due to overcooling, thermal injury to skin from cooling devices, arrhythmias, secondary infections, shivering, electrolyte imbalance, pancreatitis, peripheral vasoconstriction and thrombosis related to endovascular devices. They considered theoretical adverse events to include ileus, hepatic failure and renal failure.
# Other comments
The Committee noted that the majority of evidence was on patients with ventricular fibrillation arrest and continuing loss of consciousness. Evidence on other patients is limited.
The Committee also noted that while this procedure is efficacious in some patients, the outcomes are variable and unpredictable.# Further information
For related NICE guidance see our website.
Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.
Changes since publication
January 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': 'Current evidence on the safety and efficacy of therapeutic hypothermia following cardiac arrest is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, audit and consent.', 'The procedure': '# Indications and current treatments\n\nCardiac arrest leads to loss of consciousness and death unless emergency resuscitation is given and the heart can be restarted. The abnormal cardiac rhythms most commonly associated with cardiac arrest are asystole, pulseless electrical activity, ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT).\n\nBrain injury following cardiac arrest may be prevented by early cardiopulmonary resuscitation, including defibrillation to treat VF and pulseless VT rhythms. Drugs such as adrenaline are also commonly required.\n\n# Outline of the procedure\n\nAfter cardiac arrest, comatose patients who have a return of spontaneous circulation (ROSC) can be cooled to a core temperature of 32–34°C with the aim of reducing brain injury and improving neurological outcome. The exact mechanism by which cooling confers cerebral protection is unknown.\n\nAs soon as possible after the cardiac arrest, mild hypothermia is induced by using surface techniques (for example heat exchange cooling pads, cooling blankets, ice packs), internal techniques (for example an endovascular cooling device) or a combination of cooling methods. Core body temperature is maintained at 32–34°C for 12–24 hours from the start of cooling and is monitored using a bladder temperature probe. Controlled re-warming is usually done over a number of hours. In addition to cooling, patients generally receive standard critical care measures, together with intravenous sedation and muscle relaxants (to prevent shivering).\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA systematic review of 481 patients reported that a significantly higher proportion of patients who had therapeutic hypothermia survived to hospital discharge compared with patients in the standard care group (risk ratio [RR] 1.35, 95% confidence interval [CI]1.10 to 1.65, 3 studies).\n\nThe systematic review of 481 patients reported that a significantly higher proportion of patients in the hypothermia group had a good neurological outcome at hospital discharge compared with patients in the standard care group (RR 1.55, 95% CI\xa01.24 to 1.94, 5 studies).\n\nA randomised controlled trial (RCT) of 275 patients (137 hypothermia vs 138 normothermia) reported a significantly higher proportion of patients in the hypothermia group with a favourable neurological outcome at 6 months compared with patients in the normothermia group, after adjusting for baseline variables (RR\xa01.47, 95% CI 1.09 to 1.82).\n\nAn RCT of 54 patients (36 hypothermia vs 18 normothermia) reported that a significantly higher proportion of patients in the hypothermia group had a good neurological outcome at 1 month compared with patients in the normothermia group (50% vs 11%, p\xa0<\xa00.05).\n\nThe Specialist Advisers listed key efficacy outcomes as survival, reduced long-term neurological disability, independent living, quality of life (SF-36, Health Utility Index 3), and reductions in length of critical care and hospital stay.\n\n# Safety\n\nA case series of 986 patients reported sepsis and pneumonia rates of 4% (35/986) and 41% (407/986) respectively. The systematic review of 481 patients reported higher rates of pneumonia and sepsis in the hypothermia group compared with patients in the standard care group but the differences were not significant (pneumonia: RR 1.27, 95% CI\xa00.90 to 1.78, 1\xa0 study; sepsis: RR 1.93, 95% CI\xa00.89 to 1.78, 1 study).\n\nThe systematic review of 481 patients reported numerically higher rates of hypophosphataemia (abnormally low level of phosphate in the blood which can cause muscle weakness, respiratory problems and changes in mental state) in the hypothermia group compared with standard care but the differences were not significant (RR 1.12, 95%\xa0CI\xa00.65 to 2.25, 1\xa0study).\n\nAn RCT of 61 patients (20 haemofiltration only vs 22 hypothermia plus haemofiltration vs 19 controls) reported similar 6-month hypokalaemia rates of 25% (5/20) in the haemofiltration only group and 23% (5/22) in the hypothermia plus haemofiltration group. The same study reported similar 6-month hypophosphataemia rates of 45% (9/20) in the haemofiltration only group and 55% (12/22) in the hypothermia plus haemofiltration group.\n\nThe systematic review of 481 patients reported a numerically higher rate of bleeding requiring platelet transfusion in the hypothermia group compared with standard care but the difference was not significant (RR 5.11, 95% CI\xa00.25 to 5.47, 1\xa0study).\n\nAn RCT of 64 patients (34 hypothermia using gel pads with feedback control vs 30 hypothermia using blankets and ice) reported heparin-induced thrombocytopenia within 90 days in 1\xa0patient in the gel pads with feedback control group and no patients in the blankets and ice group. The same study reported 2\xa0patients with a gastrointestinal bleed within 90 days in the blankets and ice group and no patients in the gel pads group.\n\nA case series of 986 patients reported bleeding requiring transfusion in 5% (44/986) of patients.\n\nThe RCT of 64 patients reported similar 90-day seizure and/or status epilepticus rates in both groups (19% [6/32] vs 17% [5/29]).\n\nThe systematic review of 481 patients reported a higher rate of lethal or long lasting arrhythmias in the hypothermia group compared with standard care but the differences were not significant (RR 1.21, 95% CI\xa00.88 to 1.67, 1 study).\n\nThe Specialist Advisers listed anecdotal adverse events as coagulation and immune modulation due to overcooling, thermal injury to skin from cooling devices, arrhythmias, secondary infections, shivering, electrolyte imbalance, pancreatitis, peripheral vasoconstriction and thrombosis related to endovascular devices. They considered theoretical adverse events to include ileus, hepatic failure and renal failure.\n\n# Other comments\n\nThe Committee noted that the majority of evidence was on patients with ventricular fibrillation arrest and continuing loss of consciousness. Evidence on other patients is limited.\n\nThe Committee also noted that while this procedure is efficacious in some patients, the outcomes are variable and unpredictable.', 'Further information': "For related NICE guidance see our website.\n\nInformation for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n \n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg386
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0070c6438369af2230a3b8dda48954e2fea79101
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nice
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Deep brain stimulation for intractable trigeminal autonomic cephalalgias
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Deep brain stimulation for intractable trigeminal autonomic cephalalgias
The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Deep brain stimulation for intractable trigeminal autonomic cephalalgias.
# Guidance
Current evidence on the efficacy of deep brain stimulation (DBS) for intractable trigeminal autonomic cephalalgias (TACs) is limited and inconsistent, and the evidence on safety shows that there are serious but well-known side effects. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake DBS for intractable TACs should take the following actions:
Inform the clinical governance leads in their Trusts.
Ensure that patients and their carers understand the uncertainty about the procedure's efficacy. They should be specifically informed that DBS may not control their headache symptoms and they should be fully informed about the possible risks associated with the procedure, including the small risk of death. Clinicians should provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.
Audit and review clinical outcomes of all patients having DBS for intractable TACs (see section 3.1).
Patient selection for DBS for intractable TACs should be carried out by a multidisciplinary team specialising in pain management.
Further research studies should clearly define patient selection and report the intensity and duration of stimulation, medication use and quality of life, in addition to documenting the effects on headache symptoms as clearly as possible.# The procedure
# Indications and current treatments
TACs (for example cluster headaches) are characterised by relatively short-lasting but severe pain attacks associated with autonomic manifestations such as sweating, flushing, and ipsilateral rhinorrhea.
The first-line treatment for TACs is usually medical therapy, carried out with the aim of either preventing or limiting the duration of episodes. Surgery to interrupt the trigeminal sensory or autonomic pathways is sometimes used, but this has a risk of serious complications including diplopia and corneal ulcers.
# Outline of the procedure
DBS involves stereotactic targeting of specific anatomical sites within the brain (such as the sensory thalamus or periaqueductal grey matter) to modulate the central processing of the pain signals.
DBS for intractable TACs is usually carried out with the patient under local anaesthesia and/or intravenous sedation. Electrodes are inserted into the brain using magnetic resonance imaging and/or computed tomography. A test stimulation (or macrostimulation) is used to check for side effects. Postoperative scans may be used to assess the position of the electrodes and to identify complications such as local haemorrhage.
Following satisfactory electrode testing, a pulse generator is implanted under the chest wall and connected by tunnelled wires to the electrodes. The generator usually remains switched 'on'.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A crossover randomised controlled trial (RCT) of 12 patients with refractory chronic cluster headache (CH) reported that there was no significant difference between the 'on' and 'off' periods in either the 'on–off' group or the 'off–on' group for a number of outcomes including frequency of attacks, pain intensity and patient satisfaction.
During a 10-month open phase of the RCT of 12 patients, when all patients received DBS, the mean weekly attack frequency decreased by 48% from baseline (from a median of 14 to 8 attacks per week; p = 0.08).
A case series of 20 patients reported that all 16 patients treated for refractory chronic CH had relief from pain at a mean follow-up of 23 months. Time to response occurred at a mean of 42 days (range 1 to 86 days) with mean 71% of pain-free days.
The RCT of 12 patients reported reduced Hospital Anxiety and Depression Scale scores (7 anxiety items and 7 depression items with scores greater than 7 indicating anxiety and depression, respectively) in the open phase only. Median anxiety scores decreased from 13 to 7.5 (p = 0.008) and median depression scores decreased from 10 to 4.5 (p = 0.052).
The Specialist Advisers listed key efficacy outcomes as improvement in the number of headaches, severity and duration of attacks, and quality of life, measured by headache scoring systems.
# Safety
In a case series of 6 patients with unilateral refractory chronic CH, 1 patient died 3 days after the procedure from an intracerebral haemorrhage which developed along the lead tract a few hours after the procedure.
The RCT of 12 patients reported subcutaneous infection 3 weeks after surgery in 1 patient, and the case series of 21 patients reported 1 occurrence of deep infection. Both resolved after hardware removal and antibiotic treatment.
In the RCT of 12 patients, 1 patient developed transient loss of consciousness with hemiparesis shortly after test stimulation and subsequent severe micturition syncopes associated with a decrease in blood pressure in the standing position (not otherwise described).
The case series of 6 patients reported that all patients had diplopia and dizziness if high levels of electrical stimulation were used (above 1.5 V). One patient became tachypnoeic and tachycardic but symptoms resolved after the recording electrode was removed.
The Specialist Advisers listed anecdotal adverse events as stroke, seizures and lead migration.
# Other comments
The Committee found interpretation of the evidence difficult: the single RCT dealt only with a subgroup of patients.
The Committee noted patient commentary, which reported improvements in quality of life, even if pain was relieved only partially, and noted that some patients were no longer suicidal after treatment.# Further information
This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
For related NICE guidance see our website.
Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Changes since publication
January 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
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{'Guidance': "Current evidence on the efficacy of deep brain stimulation (DBS) for intractable trigeminal autonomic cephalalgias (TACs) is limited and inconsistent, and the evidence on safety shows that there are serious but well-known side effects. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake DBS for intractable TACs should take the following actions:\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's efficacy. They should be specifically informed that DBS may not control their headache symptoms and they should be fully informed about the possible risks associated with the procedure, including the small risk of death. Clinicians should provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having DBS for intractable TACs (see section 3.1).\n\nPatient selection for DBS for intractable TACs should be carried out by a multidisciplinary team specialising in pain management.\n\nFurther research studies should clearly define patient selection and report the intensity and duration of stimulation, medication use and quality of life, in addition to documenting the effects on headache symptoms as clearly as possible.", 'The procedure': "# Indications and current treatments\n\nTACs (for example cluster headaches) are characterised by relatively short-lasting but severe pain attacks associated with autonomic manifestations such as sweating, flushing, and ipsilateral rhinorrhea.\n\nThe first-line treatment for TACs is usually medical therapy, carried out with the aim of either preventing or limiting the duration of episodes. Surgery to interrupt the trigeminal sensory or autonomic pathways is sometimes used, but this has a risk of serious complications including diplopia and corneal ulcers.\n\n# Outline of the procedure\n\nDBS involves stereotactic targeting of specific anatomical sites within the brain (such as the sensory thalamus or periaqueductal grey matter) to modulate the central processing of the pain signals.\n\nDBS for intractable TACs is usually carried out with the patient under local anaesthesia and/or intravenous sedation. Electrodes are inserted into the brain using magnetic resonance imaging and/or computed tomography. A test stimulation (or macrostimulation) is used to check for side effects. Postoperative scans may be used to assess the position of the electrodes and to identify complications such as local haemorrhage.\n\nFollowing satisfactory electrode testing, a pulse generator is implanted under the chest wall and connected by tunnelled wires to the electrodes. The generator usually remains switched 'on'.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA crossover randomised controlled trial (RCT) of 12 patients with refractory chronic cluster headache (CH) reported that there was no significant difference between the 'on' and 'off' periods in either the 'on–off' group or the 'off–on' group for a number of outcomes including frequency of attacks, pain intensity and patient satisfaction.\n\nDuring a 10-month open phase of the RCT of 12 patients, when all patients received DBS, the mean weekly attack frequency decreased by 48% from baseline (from a median of 14 to 8 attacks per week; p\xa0=\xa00.08).\n\nA case series of 20 patients reported that all 16 patients treated for refractory chronic CH had relief from pain at a mean follow-up of 23 months. Time to response occurred at a mean of\xa042 days (range 1 to 86\xa0days) with mean 71% of pain-free days.\n\nThe RCT of 12 patients reported reduced Hospital Anxiety and Depression Scale scores (7\xa0anxiety items and 7\xa0depression items with scores greater than 7 indicating anxiety and depression, respectively) in the open phase only. Median anxiety scores decreased from 13 to 7.5 (p = 0.008) and median depression scores decreased from 10 to 4.5 (p\xa0=\xa00.052).\n\nThe Specialist Advisers listed key efficacy outcomes as improvement in the number of headaches, severity and duration of attacks, and quality of life, measured by headache scoring systems.\n\n# Safety\n\nIn a case series of 6 patients with unilateral refractory chronic CH, 1 patient died 3 days after the procedure from an intracerebral haemorrhage which developed along the lead tract a few hours after the procedure.\n\nThe RCT of 12 patients reported subcutaneous infection 3 weeks after surgery in 1 patient, and the case series of 21 patients reported 1 occurrence of deep infection. Both resolved after hardware removal and antibiotic treatment.\n\nIn the RCT of 12 patients, 1 patient developed transient loss of consciousness with hemiparesis shortly after test stimulation and subsequent severe micturition syncopes associated with a decrease in blood pressure in the standing position (not otherwise described).\n\nThe case series of 6 patients reported that all patients had diplopia and dizziness if high levels of electrical stimulation were used (above 1.5\xa0V). One patient became tachypnoeic and tachycardic but symptoms resolved after the recording electrode was removed.\n\nThe Specialist Advisers listed anecdotal adverse events as stroke, seizures and lead migration.\n\n# Other comments\n\nThe Committee found interpretation of the evidence difficult: the single RCT dealt only with a subgroup of patients.\n\nThe Committee noted patient commentary, which reported improvements in quality of life, even if pain was relieved only partially, and noted that some patients were no longer suicidal after treatment.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\nInformation for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg381
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The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Deep brain stimulation for intractable trigeminal autonomic cephalalgias.
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21d9b03888ca7f454bfdef1291bdcc2cf2a841ce
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nice
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Bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer
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Bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer
Evidence-based recommendations on bevacizumab (Avastin), with a taxane, for treating metastatic breast cancer in adults.
# Guidance
During the course of this appraisal the European Medicines Agency conducted a review of the use of bevacizumab in combination with taxanes for the treatment of metastatic breast cancer. Following that review, the EMA's Committee for Medicinal Products for Human Use (CHMP) recommended that bevacizumab, when used to treat metastatic breast cancer, should be used only in combination with the taxane paclitaxel.
This guidance updates and replaces terminated technology appraisal 147, Bevacizumab in combination with paclitaxel for the first-line treatment of metastatic breast cancer, issued June 2008.
Bevacizumab in combination with a taxane is not recommended for the first-line treatment of metastatic breast cancer.
Patients currently receiving bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer should have the option to continue therapy until they and their clinicians consider it appropriate to stop.# The technology
Bevacizumab (Avastin, Roche) is a humanised anti-vascular endothelial growth factor (VEGF) monoclonal antibody that inhibits VEGF-induced signalling and inhibits VEGF-driven angiogenesis. This reduces vascularisation of tumours, thereby inhibiting tumour growth. Bevacizumab is administered by intravenous infusion. The recommended dose is 10 mg/kg body weight given once every 2 weeks or 15 mg/kg body weight given once every 3 weeks. Bevacizumab in combination with paclitaxel or docetaxel has a marketing authorisation for 'first-line treatment of patients with metastatic breast cancer'.
The summary of product characteristics (SPC) lists the following adverse effects that may be associated with bevacizumab treatment: gastrointestinal perforations, fistulae, wound healing complications, hypertension, proteinuria, arterial and venous thromboembolism, haemorrhage, pulmonary haemorrhage/haemoptysis, congestive heart failure, reversible posterior leucoencephalopathy syndrome and neutropenia. For full details of side effects and contraindications, see the SPC.
Bevacizumab is available in 100-mg and 400-mg vials at net prices of £242.66 and £924.40, respectively (excluding VAT; 'British national formulary' edition 59). The acquisition cost of bevacizumab (excluding VAT and assuming wastage) for a patient weighing 70 kg is £1652.38 at a dosage of 10 mg/kg every 2 weeks and £2576.78 at a dosage of 15 mg/kg every 3 weeks. This amounts to an average monthly cost of £3304.76 at a dosage of 10 mg/kg every 2 weeks and £3435.70 at a dosage of 15 mg/kg every 3 weeks. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of bevacizumab and a review of its submission by the Evidence Review Group (ERG; appendix B). This appraisal will replace the terminated technology appraisal number 147, June 2008, 'Bevacizumab in combination with paclitaxel for the first-line treatment of metastatic breast cancer'.
The manufacturer's original submission focused on the combination of bevacizumab plus paclitaxel. The manufacturer did not submit evidence on the clinical or cost effectiveness of bevacizumab plus docetaxel in its original submission. The evidence from this submission is outlined from paragraphs 3.1 to 3.12. Following consultation on the appraisal consultation document, the manufacturer provided additional subgroup data on prior taxane-treated groups and groups with triple negative disease, as well as additional data from the AVADO and RIBBON-1 studies. The evidence from this additional submission is outlined from sections 3.21 to 3.33.
# Clinical effectiveness
The manufacturer's original submission presented clinical-effectiveness data from one randomised, open-label, controlled trial (E2100). A total of 722 patients were randomised to either bevacizumab plus weekly paclitaxel (n = 368) or weekly paclitaxel alone (n = 354). The randomisation was stratified by disease-free interval (less than or equal to 24 months; greater than 24 months), number of metastatic sites (less than 3; greater than or equal to 3), prior receipt of adjuvant chemotherapy (yes; no) and oestrogen receptor status (positive; negative; and unknown). All patients were given intravenous weekly paclitaxel (90 mg/m2 over 1 hour) once a week for 3 weeks, with no treatment given at week 4. Patients in the bevacizumab plus weekly paclitaxel arm also received intravenous bevacizumab (10 mg/kg) every 2 weeks, until progression of disease or unacceptable toxicity occurred. There was no limit to the number of cycles of therapy allowed. The patients in the trial had locally recurrent or metastatic breast cancer and over 90% had HER2-negative breast cancer. The primary endpoint of the trial was duration of progression-free survival. Secondary endpoints were overall survival, objective response (complete response and partial response) rate, duration of response and health-related quality of life. Health-related quality of life was measured by the Functional Assessment of Cancer Therapy (FACT-B) questionnaire, which is a scale for measuring quality of life among breast cancer patients.
At the time of the manufacturer's interim analysis most patients had discontinued randomised therapy; for 360 patients (50%) this was because of disease progression, and 131 patients (18%) withdrew from the study because of unacceptable toxicity. The interim analyses consisted of a stratified log rank test where the stratification factors were disease-free interval and prior adjuvant chemotherapy. There was a statistically significant increase in median progression-free survival of 5.5 months, from 5.8 months in the paclitaxel alone arm to 11.3 months in the bevacizumab plus paclitaxel arm. The stratified hazard ratio for progression was 0.48 (95% confidence interval 0.39 to 0.61; p < 0.0001). The stratified hazard ratio for death was 0.87 (95% CI 0.72 to 1.05; p = 0.14), indicating a non-statistically significant improvement in median overall survival of 1.7 months, from 24.8 months with paclitaxel alone to 26.5 months with bevacizumab plus paclitaxel.
At baseline, 302 (87.3%) patients in the paclitaxel alone arm and 317 (88.8%) patients in the bevacizumab plus paclitaxel arm completed the FACT-B questionnaire. At week 33, 163 patients in the paclitaxel arm and 205 patients in the bevacizumab plus paclitaxel arm completed the questionnaire. If scores were missing at week 17 or week 33, the patient was not included in the analysis for that respective time point – except when disease progression or death was recorded earlier. For those patients who died or had disease progression, a value of zero (that is, the worst score) for each of the five subscales in the FACT-B questionnaire was imputed (rather than the patient being excluded from the analysis). When imputed values were used, the difference in total FACT-B score between the two treatment arms was statistically significant (p = 0.0046) in favour of the bevacizumab plus paclitaxel arm at week 33. There were no statistically significant differences between treatment arms at week 17, or at week 33 if imputed values were not used. The manufacturer stated that, taken together, these results demonstrated that the addition of bevacizumab to paclitaxel led to a relative improvement in health-related quality of life.
The safety analyses from the E2100 trial reported that the addition of bevacizumab to paclitaxel resulted in a 20% overall increase in the incidence of grade 3–5 adverse events. These included neuropathy (25.3%), hypertension (16%), arterial thromboembolic events (3.6%), proteinuria (3%), bleeding (2.2%) and congestive heart failure (2.2%). In addition, adverse event data from a non-randomised single-arm, open-label study (ATHENA, n = 2251) were presented. The most frequent serious adverse events (grade 3–5) were febrile neutropenia (5.1%), neutropenia (3.6%) and pyrexia (1.5%).
The manufacturer carried out indirect comparisons for bevacizumab plus weekly paclitaxel compared with docetaxel alone and gemcitabine plus 3-weekly paclitaxel. The comparisons were carried out by an indirect method using two comparators to link three trials. The manufacturer noted that studies conducted only in patients having first-line treatment for metastatic breast cancer were not always available, so the exclusion criteria specified that trials in which more than 60% of patients were receiving second or later lines of treatment would be excluded. The manufacturer noted that one study used a higher docetaxel dosage (100 mg/m2 3-weekly) and a longer duration of treatment (maximum 32 cycles) compared with standard UK practice (considered by the manufacturer to be 75 mg/m2 3-weekly; maximum 6–8 cycles). However, based on the similar populations, baseline characteristics and exclusion/inclusion criteria, the manufacturer assumed that heterogeneity would not be significant.
The hazard ratio for progression with bevacizumab plus weekly paclitaxel compared with docetaxel alone was estimated to be 0.56 (95% CI 0.39 to 0.78) and 0.46 (95% CI 0.34 to 0.64) compared with gemcitabine plus 3-weekly paclitaxel. For weekly paclitaxel compared with 3-weekly docetaxel the hazard ratio for progression was 1.15 (95% CI 0.89 to 1.48) and for weekly paclitaxel compared with gemcitabine plus 3-weekly paclitaxel the hazard ratio for progression was 0.96 (95% CI 0.76 to 1.21).
# Cost effectiveness
The manufacturer's model was a 3-state Markov model with a cycle length of 1 month. Patients in the model received treatment with either bevacizumab plus weekly paclitaxel or the comparator treatment, that is:
weekly paclitaxel or
docetaxel or
gemcitabine plus 3-weekly paclitaxel.Although bevacizumab plus docetaxel was included in the scope it was not formally evaluated in the manufacturer's economic analysis.
Patients were assumed to be in one of three possible discrete health states at any given time: 'progression-free survival', 'progressed' or 'death'. It was assumed that patients would have the same risk of dying after disease progression regardless of the first-line treatment they had received. In addition, the model assumed that patients would have the same sequence of further treatment and resource use after disease progression, regardless of their initial treatment. The number of patients who died while in the 'progression-free survival' state was determined either by the maximum of background mortality or the monthly rate at which patients died (from any cause) while progression-free in the E2100 trial. In the base-case model, the progression-free mortality rates for weekly paclitaxel alone were used as a proxy for the mortality rates for docetaxel and gemcitabine plus paclitaxel.
The manufacturer provided two base-case analyses, both incorporating a 10-year time horizon:
The first used the list prices in accordance with the NICE reference case. The prices for bevacizumab (total average cost per patient, £25,929) and paclitaxel (total average cost per patient, £7720) were taken from the BNF, edition 58. Drug costs were calculated according to the recommended adult dose and duration of treatment was estimated from the E2100 trial. Dose reductions were not modelled.
The second used an average NHS cost for paclitaxel (total average cost per patient, £649) based on the average price paid by NHS trusts over a 4-month period, and a patient access scheme for bevacizumab whereby the NHS covers the cost of the first 10 g bevacizumab needed for each patient. Sensitivity analyses were only provided for this case. The patient access scheme (10-g cap) for bevacizumab was not approved by the Department of Health and was not considered by the Committee.
The base-case utility values were taken from one study that derived proxy utility values from oncology nurses, using the standard gamble technique. The values were 0.73 for progression-free survival (this was an average of values of 0.81 for response and 0.65 for stable disease), 0.45 for progressive disease, and −0.21 for disutility from febrile neutropenia and peripheral sensory neuropathy (both applied only in month 1 of experiencing the event). It was assumed that the remaining adverse events (hypersensitivity, infection and hypertension) would not have a notable impact on health-related quality of life.
The results based on the NHS list prices indicated incremental costs of £30,469, £31,416 and £27,358 and incremental quality-adjusted life years (QALYs) of 0.259, 0.273 and 0.259 for bevacizumab plus weekly paclitaxel therapy relative to weekly paclitaxel, docetaxel and gemcitabine plus paclitaxel therapy respectively. The cost per QALY was £117,803, £115,059 and £105,777 for bevacizumab plus weekly paclitaxel therapy relative to weekly paclitaxel, docetaxel and gemcitabine plus paclitaxel therapy respectively. The results based on average prices paid by NHS trusts over a 4-month period for paclitaxel and the patient access scheme (not approved by the Department of Health) for bevacizumab were provided and indicated a lower cost per QALY for bevacizumab plus weekly paclitaxel therapy relative to weekly paclitaxel, docetaxel and gemcitabine plus paclitaxel therapy respectively, though remaining above £57,000 per QALY gained. The manufacturer stated that it can be inferred from the high incremental cost-effectiveness ratios (ICERs) in the model that bevacizumab plus docetaxel (the more expensive taxane) is unlikely to provide a more cost-effective outcome than the analysis presented in the submission and, hence, a full economic analysis of bevacizumab plus docetaxel was not presented. The manufacturer carried out sensitivity analyses only on the second base-case scenario, in which the average price of paclitaxel paid by NHS trusts over a 4-month period and the patient access scheme for bevacizumab were used, and it was observed that using different parametric functions for time to progression and alternative assumptions on treatment duration had the largest impact on the ICERs.
The manufacturer conducted further analyses in response to points of clarification requested by the ERG, incorporating into the model a comparison of bevacizumab plus weekly paclitaxel with 3-weekly paclitaxel alone. The ICER for bevacizumab plus weekly paclitaxel compared with 3-weekly paclitaxel was £59,339 per QALY gained using average prices paid by NHS trusts for paclitaxel and incorporating the patient access scheme for bevacizumab. The manufacturer also incorporated the results of the evidence synthesis into the economic model as opposed to assuming that all comparators were equally effective. This was also based on the average price of paclitaxel paid by NHS trusts and the patient access scheme for bevacizumab. This resulted in an ICER for bevacizumab plus weekly paclitaxel compared with docetaxel and gemcitabine plus 3-weekly paclitaxel of £59,310 and £51,795 per QALY gained respectively.
# ERG comments on the original manufacturer's submission
The ERG had several concerns about the selection and quality of the evidence presented in the manufacturer's original submission. The evaluation of the clinical effectiveness of bevacizumab was based primarily on a single trial comparing bevacizumab plus weekly paclitaxel with weekly paclitaxel alone. The ERG highlighted limitations in the methodological quality of the study: for example, lack of blinding and lack of data collection about treatments given after disease progression. The ERG noted concerns that, as the conclusions about health-related quality of life were based primarily on the analyses using extreme imputed values for patients who had died or whose disease had progressed, the significant improvement in the FACT-B score stated by the manufacturer may not be reliable. The ERG noted that the results reported in the manufacturer's submission were derived from interim analyses and suggested that more recent follow-up data would be valuable, particularly for survival outcomes. The ERG also noted that the E2100 trial suggested that overall survival was not statistically significantly different between the treatment arms. However, the ERG was unable to establish whether or not the lack of difference in overall survival was due to crossover between treatment groups or any other post-progression events, because these data were not collected in the trial.
The ERG noted that the manufacturer had not presented any data on the clinical effectiveness of bevacizumab plus docetaxel in its submission. The ERG noted that a trial of bevacizumab plus docetaxel compared with docetaxel plus placebo (the AVADO trial) had been excluded. In addition, the ERG also considered that data from the RIBBON-1 trial could potentially have been included. The RIBBON-1 trial was excluded by the manufacturer because of insufficient statistical power for the relevant docetaxel comparison. Data from both these studies were provided by the manufacturer in response to consultation on the appraisal consultation document (see sections 3.23 and 3.24).
The ERG also highlighted a number of concerns about the indirect comparison conducted by the manufacturer. The ERG noted that an additional study (the Will Weekly Win study comparing weekly paclitaxel with 3-weekly paclitaxel, for which there were some data reported in an abstract) had not been included by the manufacturer. The ERG noted that the inclusion criteria specified that studies could be included as long as fewer than 60% (rather than a strict majority of 50%) of patients were receiving second-line treatments for metastatic breast cancer. The ERG highlighted that the validity of the studies included in the indirect comparison had not been adequately assessed. The ERG also reported concerns about the methods of the indirect comparison, noting differences between patient populations and potentially important methodological limitations among the trials included in this comparison. Given these methodological limitations, the ERG did not consider the findings of the indirect comparison to be reliable.
The ERG had a number of concerns about the economic model submitted by the manufacturer. The ERG considered that the series of pair wise comparisons for bevacizumab plus paclitaxel relative to each separate comparator regimen were inappropriate. It stated that, to establish the correct estimate of the ICER for bevacizumab plus paclitaxel, a fully incremental analysis should have been conducted, comparing all the regimens simultaneously. In addition, the ERG noted that the model assumed that mortality after disease progression was independent of initial treatment. It assumed that the rate of death after progression was constant over time and the same for all initial treatments. This meant that the differences in mean progression-free survival between treatments were maintained in the estimates of mean overall survival. The ERG stated that this was likely to have led to overestimates of overall survival for bevacizumab plus paclitaxel versus paclitaxel alone compared with the results of the E2100 trial.
The ERG highlighted that the base-case model did not include the results from the indirect comparison and that the model made the assumption that all included comparators (docetaxel alone, paclitaxel alone and gemcitabine plus paclitaxel) were equally effective in terms of progression-free survival and overall survival. Additionally, in the second base case, the cost of bevacizumab was based on the NHS paying for a maximum dose of 10 g per patient, and this patient access scheme had not been agreed with the Department of Health. The cost of paclitaxel used in the second base case was based on the average price paid by NHS trusts over a 4-month period, whereas other proprietary prices were taken from the BNF 58. The ERG also reported that the utility values were taken from a non-systematic review of the literature. In addition, the ERG noted that the manufacturer had not attempted to map health-related quality of life data from the E2100 study (measured by the FACT-B instrument) to a preference-based measure or collate alternative values.
The ERG conducted two sets of exploratory incremental analyses, both including 3-weekly paclitaxel as a comparator. One was based on the revised results, that incorporated the indirect comparison undertaken by the manufacturer rather than assuming that all comparators were equally effective. The second analysis was based on the original approach employed by the manufacturer where all comparators were assumed to be equally effective. These analyses used the following drug acquisition costs:
Case 1 (ERG re-analysis) – NHS list prices from BNF 58 excluding the patient access scheme for bevacizumab.
Case 2 (manufacturer re-analysis) – average prices paid by NHS trusts over a 4-month period for paclitaxel including the patient access scheme for bevacizumab.
Case 3 (ERG re-analysis) – average prices paid by NHS trusts for paclitaxel over a 4-month period excluding the patient access scheme for bevacizumab.In both analyses, for Case 1 and Case 3 (excluding the patient access scheme), the ICER for bevacizumab plus paclitaxel versus the next best treatment exceeded £100,000 per QALY gained. .
The ERG agreed with the manufacturer's conclusion that bevacizumab plus paclitaxel and bevacizumab plus docetaxel would be expected to be of similar effectiveness. Therefore, the inclusion and exclusion of studies in the indirect comparison would not have a major effect. The analyses by the ERG found that the acquisition cost of docetaxel had very little effect on the ICER of bevacizumab plus paclitaxel compared with docetaxel.
The ERG conducted further exploratory analyses and calibrated the model to the E2100 trial results for overall survival. This was considered important to test the internal validity of the model by comparing the median progression-free survival and overall survival found by the E2100 trial with the model predictions. The pair wise ICER of bevacizumab plus paclitaxel versus weekly paclitaxel was £259,267 per QALY gained (incremental cost of £29,675 and incremental QALY of 0.114) in the exploratory analyses.
# Extra analyses provided by the manufacturer
After consultation on the appraisal consultation document, the manufacturer provided summaries of the results from the AVADO and RIBBON-1 trials. In addition, new evidence for two subgroups was provided:
Patients who had previously received treatment with a taxane, and
Patients with disease that was triple negative (that is, oestrogen and progesterone receptor negative, and HER2 negative).
## Clinical effectiveness
The manufacturer stated that these groups are likely to have poorer prognosis and may gain greater benefit from bevacizumab therapy than the full licensed population. In addition to the data from the E2100 trial the manufacturer also included data from the AVADO and RIBBON-1 trials as evidence to support the subgroups identified.
The AVADO trial (n = 736) was a randomised double blind trial that investigated the combination of bevacizumab with docetaxel in women with HER2 negative disease who had not previously received chemotherapy for metastatic disease. Patients were assigned to receive either docetaxel plus bevacizumab at 7.5mg/kg every 3 weeks, docetaxel plus bevacizumab at 15 mg/kg every 3 weeks or docetaxel plus placebo. Docetaxel was given at 100 mg/m2 on day 1 of each 3 week cycle for a maximum of 9 cycles. The primary endpoint was progression-free survival. The manufacturer presented results for the licensed dose of bevacizumab at 15 mg/kg every 3 weeks. Median progression-free survival for the intention-to-treat population was 8.2 months in the docetaxel plus placebo arm and 10.1 months in the docetaxel plus bevacizumab arm (unstratified HR 0.77, 95% CI 0.64 to 0.93). Median overall survival was 31.9 months in the placebo arm and 30.2 months in the bevacizumab arm (HR 1.03, 95% CI: 0.70, 1.33).
The RIBBON-1 trial (n = 1237) was a randomised double-blind placebo controlled trial of standard chemotherapy with or without bevacizumab. Three hundred and seven patients received taxane chemotherapy with or without bevacizumab. Results for progression-free survival were provided for the group of patients receiving either anthracycline or taxane chemotherapy (n = 622). Median progression-free survival increased from 8 months in the chemotherapy arm to 9.2 months in the bevacizumab plus chemotherapy arm (HR 0.66, 95% CI 0.54 to 0.81).
For the triple negative subgroup, results from the E2100 study (n = 232) indicated a statistically significant increase in median progression-free survival of 5.3 months, from 5.3 months in the paclitaxel alone arm to 10.6 months in the bevacizumab plus paclitaxel arm. The unstratified hazard ratio for progression was 0.49 (95% CI 0.34 to 0.70). The hazard ratio for death was 0.89 (95% CI 0.66 to 1.19), indicating a non-statistically significant improvement in median overall survival of 4.2 months, from 16.3 months in the paclitaxel alone arm to 20.5 months in the bevacizumab plus paclitaxel arm. Results from the AVADO study (n = 111) indicated that the unstratified hazard ratio for progression with bevacizumab plus docetaxel compared with docetaxel alone was estimated to be 0.68 (95% CI 0.46 to 0.99). The hazard ratio for death with bevacizumab plus docetaxel compared with docetaxel alone was estimated to be 0.82 (95% CI 0.51 to 1.32).
For the prior taxane-treated subgroup, results from the E2100 study (n = 140) indicated a statistically significant increase in median progression-free survival of 7.3 months, from 5.8 months in the paclitaxel alone arm to 13.1 months in the bevacizumab plus paclitaxel arm. The unstratified hazard ratio for progression was 0.33 (95% CI 0.20 to 0.54). There was a statistically significant increase in median overall survival of 8.7 months, from 17.6 months in the paclitaxel alone arm to 26.3 months in the bevacizumab plus paclitaxel arm. The hazard ratio for death was 0.67 (95% CI 0.45 to 0.99). Results from the AVADO study (n = 78) indicated a statistically significant increase in median progression-free survival of 3.6 months, from 6.7 months in the docetaxel alone arm to 10.3 months in the bevacizumab plus docetaxel arm. The unstratified hazard ratio for progression with bevacizumab plus docetaxel compared with docetaxel alone was estimated to be 0.53 (95% CI 0.33 to 0.85). There was a 9.3-month increase in median overall survival, from 22.3 months in the docetaxel alone arm to 31.6 months in the bevacizumab plus docetaxel arm. The hazard ratio for death was 0.58 (95% CI 0.31 to 1.08).
The manufacturer also provided meta-analyses based on individual patient data. One was a meta-analysis of progression-free survival and overall survival in 2447 patients from the E2100, AVADO and RIBBON-1 trials. In this pooled intention-to-treat analysis, there was a statistically significant increase in median progression-free survival of 2.5 months, from 6.7 months in the chemotherapy alone arm to 9.2 months in the bevacizumab plus chemotherapy arm. The hazard ratio for progression with bevacizumab plus chemotherapy compared with chemotherapy alone was estimated to be 0.64 (95% CI 0.58 to 0.71). The hazard ratio for death was 0.97 (95% CI 0.86 to 1.08), indicating a non-statistically significant difference in median overall survival of 0.3 months from 26.4 months in the chemotherapy alone arm to 26.7 months in the bevacizumab plus chemotherapy arm. The pooled dataset also included 621 patients with triple negative disease who were meta-analysed separately. Results were similar in this triple negative subgroup to the results from the overall population, with a hazard ratio for progression with bevacizumab plus chemotherapy compared with chemotherapy alone estimated to be 0.63 (95% CI 0.52 to 0.76). The hazard ratio for death with bevacizumab plus chemotherapy compared with chemotherapy alone was estimated to be 0.96 (95% CI 0.79 to 1.16). Median length of progression-free and overall survival for the triple negative subgroup were not provided. No data were provided for the group (n = 1826) that did not have triple negative disease.
Another meta-analysis was described as exploratory and focused on the prior taxane-treated subgroup. This analysis was restricted to the 1765 patients treated with taxanes, with or without bevacizumab, in the E2100, AVADO and RIBBON-1 trials. No data for the entire group of 1765 patients were provided. For the prior taxane-treated subgroup (n = 311), results indicated a statistically significant increase in median progression-free survival of 4.5 months, from 6.2 months in the taxane alone arm to 10.7 months in the bevacizumab plus taxane arm. The hazard ratio for progression was 0.47 (95% CI 0.35 to 0.62). There was a statistically significant increase in median overall survival of 5.6 months, from 21.3 months in the taxane alone arm to 26.9 months in the bevacizumab plus taxane arm. The hazard ratio for death was 0.73 (95% CI 0.55 to 0.97). No data were provided for the group (n = 1454) that had not received prior taxanes.
## Cost-effectiveness
The manufacturer provided cost-effectiveness estimates for the two subgroups. The model that was used in the original submission was adapted to reflect the progression-free survival, overall survival, time to stopping treatment and adverse event rates of the subgroups. Overall survival curves for the relevant subgroups from the E2100 study were fitted with parametric functions. The analysis focused on the cost effectiveness of bevacizumab plus paclitaxel and did not consider the comparator of gemcitabine plus paclitaxel. The analysis assumed equal efficacy for weekly paclitaxel and 3-weekly docetaxel.
For both subgroups, a log-logistic model was selected as the best fit for progression-free survival and overall survival and the Weibull function was used for both treatments to reflect time to stopping treatment for each treatment arm. The base-case results were presented using both the average price of paclitaxel paid by NHS trusts and the list price. The patient access scheme for bevacizumab was excluded from the base case, although it was included in sensitivity analysis.
For the triple negative subgroup, the cost per QALY for bevacizumab plus paclitaxel compared with paclitaxel alone was £87,865 (with an incremental cost of £27,387 and an incremental QALY of 0.312) based on list prices for paclitaxel and £82,469 (with an incremental cost of £25,705 and an incremental QALY of 0.312) based on the average price paid by NHS trusts for paclitaxel. The cost per QALY for bevacizumab plus paclitaxel compared with docetaxel alone was £84,740 (with an incremental cost of £26,540 and an incremental QALY of 0.313) based on list prices for paclitaxel and £64,092 (with an incremental cost of £20,073 and an incremental QALY of 0.313) based on the average price paid by NHS trusts for paclitaxel.
For the prior taxane-treated subgroup, the cost per QALY for bevacizumab plus paclitaxel compared with paclitaxel alone was £74,640 (with an incremental cost of £37,358 and an incremental QALY of 0.501) based on list prices for paclitaxel and £67,714 (with an incremental cost of £33,892 and an incremental QALY of 0.501) based on the average price paid by NHS trusts for paclitaxel. The cost per QALY for bevacizumab plus paclitaxel compared with docetaxel alone was £73,605 (with an incremental cost of £36,951 and an incremental QALY of 0.502) based on list prices for paclitaxel and £57,416 (with an incremental cost of £28,824 and an incremental QALY of 0.502) based on the average price paid by NHS trusts for paclitaxel.
Sensitivity analysis was conducted on the prior taxane-treated subgroup assuming that variations in ICERs would be similarly reflected in the triple negative subgroup. The analysis indicated that there was considerable variation in the estimate of cost effectiveness depending on the function adopted. Probabilistic sensitivity analyses produced similar estimates of cost effectiveness, and the probability of bevacizumab being cost effective at £30,000 per QALY gained was 0% against both weekly paclitaxel and 3-weekly docetaxel.
# ERG comments on the extra subgroup analysis
The ERG noted that 25% (615/2447) of all patients included in the intention-to-treat meta-analysis that was used to address the triple negative subgroup received bevacizumab plus capecitabine, a combination that is outside the scope of this appraisal. The ERG highlighted that the progression-free survival and overall survival hazard ratios for the intention-to-treat population and the triple negative subgroup were almost identical. Furthermore, the median progression-free survival, overall survival and 1-year survival data were not reported for this subgroup. It was noted that these data were not provided for the RIBBON-1 study.
The ERG noted that the meta-analysis addressing the prior taxane-treated subgroup was described as an exploratory meta-analysis. It stated that it included only a small number of patients from trials that individually were insufficiently powered to detect a difference in overall survival. Only one trial (AVADO) appeared to stratify for taxane pre-treatment and no interaction tests were conducted. Therefore, although the hazard ratios did show a trend towards being more favourable towards bevacizumab than in the intention-to-treat meta-analysis for both progression-free survival and overall survival, the ERG stated that the analysis cannot be considered as convincing evidence of a subgroup effect.
The ERG had a number of concerns about the economic modelling. The ERG highlighted that rather than using estimates from these subgroup meta-analyses in the subsequent economic model, only the subgroup data from the E2100 trial were used. The ERG noted that this approach may have yielded more favourable ICER estimates because the progression-free survival and overall survival values for E2100 were more favourable than those from the meta-analyses.
The ERG commented that, although the manufacturer selected the log-logistic model as the best fit, the difference in goodness of fit statistics was small, suggesting that the choice between different functions was marginal. However, there was subsequent variation in the ICER estimates based on the different survival functions. At the extreme ends, for the prior taxane-treated subgroup, the ICER using the log-logistic function (the manufacturer's base case), and incorporating the average price for paclitaxel paid by NHS trusts, was £67,714 per QALY gained, whereas if the Weibull function had been used this figure would have risen to £86,854 per QALY gained. When the NHS list prices for paclitaxel were incorporated, the ICERs ranged from £74,640 per QALY gained with the log-logistic function to £95,807 per QALY gained with the Weibull function. The ERG concluded that there was considerable uncertainty surrounding the choice of statistical function used in the cost-effectiveness analysis for the prior taxane-treated subgroup. Equivalent goodness of fit statistics were not reported for the triple negative subgroup so the ERG could not undertake a similar assessment for this subgroup.
The ERG undertook an exploratory analysis in the prior taxane-treated subgroup using the hazard ratio estimated from the individual patient data meta-analysis of the prior taxane-treated group presented by the manufacturer (HR = 0.738) and the Weibull function. The results demonstrated an increase in the ICER from £95,807 to £109,242 per QALY gained using the list prices for paclitaxel and from £86,854 to £98,834 per QALY gained using the average price for paclitaxel paid by NHS trusts.
The ERG noted that all the parametric functions investigated by the manufacturer assumed long-term sustained treatment effects for overall survival with bevacizumab plus paclitaxel. Consequently, the ERG undertook an exploratory analysis for both subgroups using the manufacturer's model. This analysis used the Kaplan-Meier survival estimates from the E2100 study up to about 3.2 years, assuming no difference in survival after that point, since the curves suggested that the difference in overall survival may not be sustained over a longer time horizon. For the prior taxane-treated subgroup, the ICERs increased from £74,640 per QALY gained when using the log-logistic function to £129,794 per QALY gained when using the Kaplan-Meier function, both incorporating the list prices for paclitaxel, and from £67,714 per QALY gained when using the log-logistic function to £117,587 per QALY gained when using the Kaplan-Meier function, both incorporating the average price for paclitaxel paid by NHS trusts. For the triple negative subgroup, the ICERs increased from £87,865 per QALY gained when using the log-logistic function to £187,339 per QALY gained when using the Kaplan-Meier function, incorporating the list prices for paclitaxel, and from £82,469 per QALY gained when using the log-logistic function to £175,575 per QALY gained when using the Kaplan-Meier function, incorporating the average price for paclitaxel paid by NHS trusts.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab in combination with a taxane, having considered evidence on the nature of metastatic breast cancer and the value placed on the benefits of bevacizumab in combination with a taxane by people with metastatic breast cancer, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
# Clinical effectiveness
The Committee considered current clinical practice for the treatment of metastatic breast cancer. The Committee noted the manufacturer's clarification response, which stated that approximately 30% of patients receive a taxane in the adjuvant setting, particularly in node positive disease at diagnosis. The clinical specialist stated that in current practice, if metastatic disease subsequently develops, taxanes (that is, weekly paclitaxel or 3-weekly docetaxel) are then offered as first-line treatment for the majority of people in England and Wales. The Committee also heard from the clinical specialist that 3-weekly paclitaxel is no longer routinely used in clinical practice, having been largely replaced by weekly dosing schedules. The Committee heard that the choice between the two taxanes is made locally and that weekly paclitaxel and 3-weekly docetaxel are considered to have comparable efficacy. The Committee concluded that the relevant comparators for bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer are weekly paclitaxel and 3-weekly docetaxel.
The Committee discussed the clinical effectiveness of bevacizumab in combination with a taxane. It heard that bevacizumab is the first VEGF-targeted therapy for this indication. The Committee discussed the E2100 trial which compared bevacizumab plus paclitaxel with weekly paclitaxel. The Committee heard from the ERG that the trial had several limitations, such as the lack of blinding. The trial demonstrated a statistically significant increase in median progression-free survival of 5.5 months, from 5.8 months in the paclitaxel alone arm to 11.3 months in the bevacizumab plus paclitaxel arm. The Committee explored the value of an increase in progression-free survival with the clinical specialist and patient expert. It heard about the importance and significance of progression-free survival for patients in terms of being able to carry out normal daily activities, as well as being a therapeutic aim of treatment for clinicians.
The Committee then discussed the overall survival results of the E2100 trial and noted a non-statistically significant increase in median survival of 1.7 months, from 24.8 months with paclitaxel alone to 26.5 months with bevacizumab plus paclitaxel. The Committee discussed the possible reasons for the increase in progression-free survival not being reflected in overall survival in the trial. It acknowledged that although it was possible that the relative treatment effect may have been confounded by crossover or other treatments received after disease progression, no data on this had been collected. The Committee heard from the clinical specialist that the response in E2100 to paclitaxel alone was lower than demonstrated in previous studies. The Committee concluded that it was likely that bevacizumab plus paclitaxel improved progression-free survival relative to weekly paclitaxel, but that there was no robust evidence that bevacizumab plus paclitaxel improved overall survival compared with weekly paclitaxel alone.
The Committee discussed the health-related quality of life data for bevacizumab plus paclitaxel compared with weekly paclitaxel. The Committee heard from the primary care trust expert that robust data on the magnitude of quality of life improvements were important. The Committee noted concerns about the data presented by the manufacturer. It was aware that a statistically significant improvement in health-related quality of life at 33 weeks was only demonstrated when extreme values were imputed. The Committee also heard from the clinical specialist that the scores for psychological and emotional wellbeing were not explicitly addressed by the manufacturer. The Committee concluded that the magnitude of health-related quality of life benefits with bevacizumab plus paclitaxel compared with paclitaxel alone was uncertain.
The Committee noted the adverse events and the side-effect profile from the E2100 trial as well as from a large uncontrolled study (ATHENA). The Committee noted that the frequency of grade 3–5 adverse events was slightly higher with the addition of bevacizumab to paclitaxel. However, the Committee heard from the clinical specialist that many of the adverse events were those expected in cytotoxic regimens, and could be attributed to the taxane. Increased treatment duration would also lead to an increase in the incidence of adverse events. The Committee understood that most adverse events could be satisfactorily managed (for example with dose reductions). Specific adverse events associated with bevacizumab, notably hypertension, were also readily treatable. The Committee concluded that the addition of bevacizumab did not lead to unacceptable toxicity compared with paclitaxel alone, and that adverse effects were manageable.
The Committee noted that evidence from the AVADO study for the clinical effectiveness of bevacizumab plus docetaxel had been provided by the manufacturer after consultation on the appraisal consultation document. The Committee noted the manufacturer's comment that the AVADO dosing regimen of 9 cycles of 100 mg/m2 docetaxel was not routine UK clinical practice as 3-weekly docetaxel was usually given for 6 cycles.The Committee heard from the clinical specialist that 100 mg/m2 was the standard dose used in the absence of contraindications, and that therefore he considered that the trial data were relevant to UK clinical practice. The clinical specialist also highlighted the high methodological quality of the AVADO trial and its placebo-controlled design. The Committee noted that the results from this study demonstrated an approximate 2-month, statistically significant improvement in progression-free survival for bevacizumab at a dose of 15 mg/m2 plus docetaxel. However, the Committee also noted the hazard ratio for death which was 1.03 (95% CI 0.70 to 1.33), indicating a non-statistically significant reduction in median overall survival of 1.7 months from 31.9 months in the docetaxel alone arm to 30.2 months in the bevacizumab plus docetaxel arm. The Committee concluded that bevacizumab plus docetaxel was modestly clinically effective compared with docetaxel alone in terms of progression-free survival. However, its effect on overall survival was uncertain.
The Committee discussed the indirect treatment comparison presented by the manufacturer for bevacizumab plus weekly paclitaxel compared with docetaxel alone and gemcitabine plus 3-weekly paclitaxel. The Committee noted the ERG's comments related to the reliability of the indirect treatment comparison. The quality of the included studies was variable, and the trials included variable numbers of patients receiving second-line treatment, where the prognosis may be worse than for first-line chemotherapy. Also, it was not clear that the selection criteria for included studies had been consistently applied, with the AVADO trial being excluded on the grounds of the docetaxel dose used, while another study using the same dose of docetaxel was included. The Committee concluded that the indirect treatment comparison was not robust and that the results were not considered reliable.
The Committee discussed the additional data presented by the manufacturer for the triple negative subgroup in response to consultation on the appraisal consultation document. The Committee explored whether bevacizumab might be more clinically effective in this subgroup. The Committee heard from the clinical specialist that for the subgroup of women with triple negative cancers (that is, cancers that do not have receptors for oestrogen, progesterone or HER2) there may be worse outcomes. The Committee noted, however, that while it was plausible that bevacizumab could be more effective in some tumour types than others, there was no proposal of a biologically plausible specific mechanism of effect for bevacizumab having an increased benefit for this subgroup. The Committee discussed the results of the manufacturer's meta-analysis that demonstrated that the progression-free survival and overall survival hazard ratios for the triple negative subgroup (0.63 and 0.96) were indistinguishable from those of the intention-to-treat population (0.64 and 0.97). Moreover, the results for the overall survival difference were not statistically significant (95% CI 0.79 to 1.16). The Committee concluded that there was no evidence of any greater clinical benefit in the triple negative subgroup than in the intention-to-treat population.
The Committee then discussed the additional data provided by the manufacturer for the prior taxane-treated subgroup. It heard from the clinical specialist that this was an area of clinical need as 30% to 40% of patients, usually those with lymph node involvement, would have received taxanes in the adjuvant setting. These patients would generally have a worse prognosis and might need different treatment options if the disease progressed after treatment. The Committee noted that although there could be taxane resistance in this subgroup, there were no specific biological markers or other hypotheses to suggest why VEGF agents would work more effectively in this subgroup compared with the intention-to-treat population. The Committee discussed the results provided for this subgroup, noting that these were based on post hoc analyses. The Committee noted that the hazard ratio for death in the E2100 trial for the prior taxane-treated subgroup was 0.67 (95% CI 0.45 to 0.99), indicating a statistically significant increase from 17.6 months in the paclitaxel alone arm to 26.3 months in the bevacizumab plus paclitaxel arm, and that the hazard ratio for death in the meta-analysis for the prior taxane-treated subgroup was 0.73 (95% CI 0.55 to 0.97), indicating a statistically significant increase from 21.3 in the taxane only arm to 26.9 months in the bevacizumab plus taxane arm. However, the Committee identified a number of concerns that questioned the robustness of the data. It noted that the E2100 trial was unblinded and did not stratify for prior taxane-treated patients, and the AVADO study, though stratified, had a very small number of patients (n = 78). Further, although the results for this subgroup were statistically significant for both progression-free survival and overall survival, there was no indication of the hazard ratios for the group who did not receive prior taxane treatment in the adjuvant setting and there were no statistical tests for interaction. The clinical specialist, while expressing interest in the findings, agreed on their exploratory nature. The Committee also noted the manufacturer's comment in its submission that although in the meta-analysis these differences appear to be statistically significant, it should be noted that this analysis is exploratory only.
Consequently, the Committee considered that although the results of the prior taxane-treated subgroup analyses were interesting in terms of possible clinical benefit, they were not sufficiently robust to use for the development of guidance. The Committee concluded that the results needed to be confirmed in larger, well designed studies, and that the estimates of effectiveness could not be considered suitable as the basis of a cost-effectiveness analysis. The Committee discussed whether there were any subgroups other than those presented by the manufacturer that may have an increased benefit from bevacizumab treatment. It heard from the clinical specialist that the groups identified by the manufacturer were key subgroups. The Committee noted the clinical specialist's comment that further research into whether there are any clinical or biological subgroups (such as subgroups by biological markers) for whom bevacizumab is particularly beneficial would be useful. The Committee concluded that no robust evidence on subgroups was currently available and that the data that were available were not reliable and could not be carried forward as the basis for a cost-effectiveness analysis.
# Cost effectiveness
The Committee discussed the pair wise cost-effectiveness estimates of bevacizumab plus paclitaxel as presented by the manufacturer. The Committee noted that the manufacturer had provided two base cases, one of which was based on average prices paid by NHS trusts for paclitaxel over a 4-month period and a patient access scheme for bevacizumab. The Committee was aware that no patient access scheme had been approved by the Department of Health and that therefore the scheme could not be taken into account in the consideration of cost effectiveness. The Committee was also aware that it was not in accordance with the NICE methods guide for the manufacturer to use average prices paid by NHS trusts for paclitaxel over a 4-month period rather than a nationally agreed discounted price that is consistently available to the NHS. However, the Committee noted the confirmation from the Department of Health Commercial Medicines Unit that discounts for paclitaxel are in a range greater than 95% from the BNF list price of the branded presentation and that prices within these ranges are available to all NHS hospital trusts in England. The Committee concluded that it would consider the range of the ICERs based both on the list prices and the average prices paid by NHS trusts for paclitaxel.
The Committee was aware that the manufacturer's analysis used a series of pair wise comparisons for bevacizumab plus paclitaxel relative to each separate comparator regimen. The Committee accepted comments from the ERG that the correct methodological approach would have been a fully incremental analysis. The Committee noted that the incremental analysis carried out by the ERG resulted in ICERs that were similar to the pair wise ICERs. The Committee therefore concluded that, taking this into account, together with the fact that the ERG's exploratory analyses had been conducted using the pair wise ICERs, these were appropriate for consideration in this instance.
The Committee noted that the manufacturer's base case assumed that the clinical effectiveness of all the comparators (that is, 3-weekly docetaxel, gemcitabine plus paclitaxel and 3-weekly paclitaxel) were the same as weekly paclitaxel. The manufacturer subsequently conducted revised analyses substituting the clinical effectiveness results from the indirect comparison. The Committee noted its earlier conclusions that the results of the indirect comparison were not reliable and that there were only two relevant comparators. In addition, the Committee heard from the clinical specialist that weekly paclitaxel and 3-weekly docetaxel were not considered to demonstrate clinically meaningful differences in effectiveness. The Committee concluded that the cost-effectiveness estimates derived from assuming comparators had equivalent effectiveness to weekly paclitaxel were acceptable.
The Committee discussed the way in which the manufacturer had modelled overall survival in the economic model provided in the original submission. It noted that a key assumption made by the manufacturer was that patients would have the same risk of dying per unit time once disease progressed, regardless of the first-line treatment they had received. This resulted in improvements in observed progression-free survival being carried over to projected improvements in overall survival. The Committee was aware that there are various ways of modelling that would result in different estimates of overall survival. The Committee noted that the manufacturer's model (whereby overall survival was independent of previous treatments received) resulted in mean life years of 2.68 years in the bevacizumab plus paclitaxel arm and 2.33 years in the paclitaxel alone arm (an incremental benefit of 0.35 years) and a pair wise ICER of £118,000 per QALY gained, using the list price for paclitaxel. The manufacturer indicated that this represented an optimistic scenario compared with the trial data. The manufacturer did not provide results for a scenario including the average price for paclitaxel paid by NHS trusts without the patient access scheme; however, an analysis of this by the ERG indicated an ICER of £110,500 per QALY gained. The Committee also examined the exploratory analyses carried out by the ERG that attempted to calibrate overall survival in the model with that directly observed in the E2100 trial by using an area under the curve method. These analyses resulted in mean life years of 2.16 years in the bevacizumab plus paclitaxel arm and 2.13 years in the paclitaxel alone arm (an incremental benefit of 0.03 years) and a pair wise ICER of £259,000 per QALY gained, based on the list price for paclitaxel. Using the average price for paclitaxel paid by NHS trusts, the ERG reported that the ICER remained over £200,000 per QALY gained. The ERG acknowledged that this represented a pessimistic scenario. The Committee therefore concluded that the true ICER for bevacizumab plus paclitaxel compared with weekly paclitaxel probably lay between £110,000 and £259,000 per QALY gained.
The Committee noted that the ICER for bevacizumab plus paclitaxel versus docetaxel alone presented by the manufacturer was £115,000 per QALY gained, based on list prices for paclitaxel. Although the ERG did not conduct a further exploratory analysis for this comparison, the Committee considered that it would also have resulted in a substantially higher ICER. The Committee concluded that the true pair wise ICER for bevacizumab plus paclitaxel compared with 3-weekly docetaxel was over £115,000 per QALY gained.
The Committee noted that the manufacturer did not provide any clinical or cost-effectiveness data related to bevacizumab plus docetaxel, even though it was specified in the scope. The Committee considered the manufacturer's statement that it can be inferred from the high ICERs in the model that bevacizumab plus docetaxel (the more expensive taxane) is unlikely to provide a more cost-effective outcome than the analysis presented in the submission and, hence, a full economic analysis of bevacizumab plus docetaxel was not warranted. The Committee agreed that the ICER for bevacizumab plus docetaxel would be higher than the ICER for bevacizumab plus paclitaxel compared with weekly paclitaxel and 3-weekly docetaxel.
The Committee discussed the estimates of the ICERs given by the manufacturer using subgroup data from the E2100 study. For the triple negative subgroup, the cost per QALY for bevacizumab plus paclitaxel ranged from £64,100 to £87,900 per QALY gained depending on the comparator and whether the list price for paclitaxel was used or the average price for paclitaxel paid by NHS trusts was used. For the prior taxane-treated subgroup, the corresponding range was £57,400 to £74,600 per QALY gained. The Committee noted that these estimates remained above the conventional levels normally considered cost effective, and would be further increased if alternative techniques were used to model overall survival. The Committee considered that because of the uncertainty around the subgroup clinical effectiveness estimates, those estimates could not be carried forward to form the basis of a cost-effectiveness analysis and guidance to the NHS. The Committee concluded that the estimates of cost effectiveness for the intention-to-treat population represented the most plausible estimate of cost effectiveness for bevacizumab.
The Committee discussed whether there were any equality issues relating to population groups protected by equality legislation. It noted information from the manufacturer's submission relating to the potential for worse outcomes in lower socioeconomic groups or by ethnicity. The Committee heard from the clinical specialist that there may be differences in overall treatment outcomes between these groups, but that they are likely to result from factors such as lower uptake of screening or later presentation of disease rather than differences in treatment. The Committee noted that the triple negative subgroup may be over-represented in some ethnic groups. The Committee concluded that there was no evidence of differences in access to treatment or response to treatment by socioeconomic status or ethnicity in patients with disease at the metastatic stage.
The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of people with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust.
The Committee discussed whether bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer fulfilled the criteria for a life-extending, end-of-life treatment. The Committee noted that the E2100 trial data indicated that median overall survival in the paclitaxel alone arm was 24.8 months. The Committee considered the fact that this was just above the defined limit of life expectancy of less than 24 months in the end-of-life criteria. The Committee also noted that the change in median overall survival was an increase of 1.7 months with bevacizumab plus paclitaxel compared with paclitaxel alone. The Committee accepted that, although it was possible that this increase had been underestimated (because of the possibility of crossover or additional treatments), there was no robust evidence that bevacizumab plus paclitaxel offers an extension to life of an additional 3 months, compared with paclitaxel alone. The Committee agreed that the robustness of evidence for the subgroups was not convincing; therefore, the Committee did not discuss whether the subgroups presented fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee also noted that bevacizumab is licensed for a relatively large population across a range of indications, such as colorectal cancer, non-small-cell lung cancer and renal cell carcinoma, and hence does not meet the third criterion that the treatment should be licensed for small populations. The Committee concluded that bevacizumab in combination with a taxane did not fulfil the criteria for special consideration as a life-extending, end-of-life treatment.
In summary, the Committee concluded that the most plausible ICER for bevacizumab plus paclitaxel versus weekly paclitaxel was between £110,000 and £259,000 per QALY gained and that the ICER for bevacizumab plus paclitaxel versus docetaxel would be greater than £115,000 per QALY gained. The Committee accepted the manufacturer's statement that the ICER for bevacizumab plus docetaxel would be higher than that for bevacizumab plus paclitaxel since docetaxel is the more expensive taxane. The Committee considered that although the subgroup results were promising in terms of potential clinical benefit, they were not sufficiently robust to develop guidance and could not be carried forward as the basis for a cost-effectiveness analysis. The Committee concluded that bevacizumab in combination with a taxane as a first-line treatment for metastatic breast cancer was not a cost-effective use of NHS resources.
# Summary of Appraisal Committee's key conclusions
TA214 (STA)
Appraisal title: Bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer
FAD section
Key conclusion
Bevacizumab in combination with a taxane is not recommended for the first-line treatment of metastatic breast cancer. Patients currently receiving bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer should have the option to continue therapy until they and their clinicians consider it appropriate to stop. The Committee concluded that bevacizumab in combination with a taxane as a first-line treatment for metastatic breast cancer was not a cost-effective use of NHS resources.
Current practice
Clinical need of patients including the availability of alternative treatments
The clinical specialist stated that in current practice, taxanes (that is, weekly paclitaxel or 3-weekly docetaxel) are offered as first-line treatment for the majority of people with metastatic breast cancer in England and Wales.
The Committee heard from the clinical specialist that for women with triple negative cancers (that is, cancers that do not have receptors for oestrogen, progesterone or HER2) there may be worse outcomes.
The Committee heard from the clinical specialist that there was an area of clinical need associated with prior taxane use as 30% to 40% of patients would have received taxanes in the adjuvant setting. These patients would generally have a worse prognosis and might need different treatment options if their disease returned following adjuvant treatment.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee heard that bevacizumab is the first VEGF-targeted therapy for this indication.
The Committee heard about the importance and significance of progression-free survival for patients in terms of being able to carry out normal daily activities, as well as being a therapeutic aim of treatment for clinicians. The Committee concluded that it was likely that bevacizumab plus paclitaxel improved progression-free survival, but that there was no robust evidence that bevacizumab plus paclitaxel improved overall survival compared with weekly paclitaxel alone. The Committee concluded that the magnitude of health-related quality of life benefits with bevacizumab plus paclitaxel compared with paclitaxel alone was uncertain.
What is the position of the treatment in the pathway of care for the condition?
Bevacizumab in combination with paclitaxel or docetaxel has a marketing authorisation for 'first-line treatment of patients with metastatic breast cancer'.
Adverse events
The Committee understood that most adverse events could be satisfactorily managed (for example with dose reductions). Specific adverse events associated with bevacizumab, notably hypertension, were also readily treatable. The Committee concluded that the addition of bevacizumab did not lead to any unacceptable toxicity compared with paclitaxel alone, and that adverse effects were manageable.
Evidence for clinical effectiveness
Quality, availability and nature of evidence
The Committee noted that the original submission was based on one trial (E2100) which compared bevacizumab plus paclitaxel with weekly paclitaxel.
The Committee heard from the ERG that the E2100 trial had several limitations, such as the lack of blinding. The Committee heard from the clinical specialist that the response in E2100 to paclitaxel alone was lower than demonstrated in previous studies.
The Committee noted that evidence from the AVADO study for the clinical effectiveness of bevacizumab plus docetaxel had been provided by the manufacturer after consultation on the appraisal consultation document.
The Committee noted the ERG's comments related to the reliability of the indirect treatment comparison included in the manufacturer's submission and concluded that the indirect treatment comparison was not robust and that the results were not considered reliable.
Relevance to general clinical practice in the NHS
The Committee concluded that the relevant comparators for bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer are weekly paclitaxel and 3-weekly docetaxel.
The Committee understood that the manufacturer had not considered the AVADO trial in its submission because the dose of docetaxel (100 mg/m2) was considered to be higher than that used in clinical practice. The Committee heard from the clinical specialist that the dose used in the trial was standard for 3-weekly docetaxel in the absence of contraindications and therefore the trial data were relevant to UK clinical practice. The Committee noted the manufacturer's comment in the appraisal consultation document that the AVADO dosing regimen of 9 cycles of 100mg/m2 docetaxel was not routine UK clinical practice as 3-weekly docetaxel was usually given for 6 cycles.
Uncertainties generated by the evidence
The Committee concluded that it was likely that bevacizumab plus paclitaxel improved progression-free survival relative to weekly paclitaxel, but that there was no robust evidence that bevacizumab plus paclitaxel improved overall survival compared with weekly paclitaxel alone.
The Committee was aware that a statistically significant improvement in health-related quality of life at 33 weeks was only demonstrated when extreme values were imputed. The Committee also heard from the clinical specialist that the measures of psychological elements and emotional wellbeing were not provided by the manufacturer. The Committee concluded that the magnitude of health-related quality of life benefits with bevacizumab plus paclitaxel compared with paclitaxel alone was uncertain.
The Committee considered that although the results of the subgroup analyses were promising in terms of possible clinical benefit, they were not sufficiently robust to use for the development of guidance.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
For the subgroup of women with triple negative cancers, the Committee noted that while it was plausible that bevacizumab could be more effective in some tumour types than others, there was no proposal of a biologically plausible specific mechanism of effect for bevacizumab having an increased benefit for this subgroup.
For the prior taxane-treated subgroup, the Committee noted that although there could be taxane resistance in this subgroup, there were no specific biological markers or other hypotheses to suggest why VEGF agents would work more effectively in this subgroup compared with the intention-to-treat population.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee discussed the E2100 trial which compared bevacizumab plus paclitaxel with weekly paclitaxel. The trial demonstrated a statistically significant increase in median progression-free survival of 5.5 months, from 5.8 months in the paclitaxel alone arm to 11.3 months in the bevacizumab plus paclitaxel arm. However, the Committee noted that the trial did not produce similar results for overall survival, with a non-statistically significant increase in median survival of 1.7 months, from 24.8 months with paclitaxel alone to 26.5 months with bevacizumab plus paclitaxel.
The Committee noted that the results from the AVADO study demonstrated an approximate 2-month, statistically significant improvement in progression-free survival for bevacizumab at a dose of 15 mg/m2 plus docetaxel. Overall survival results indicated a non-statistically significant reduction in median overall survival from 31.9 months with docetaxel alone to 30.2 months with the addition of bevacizumab (95% CI 0.7 to 1.33). The Committee concluded that bevacizumab plus docetaxel was modestly clinically effective compared with docetaxel alone in terms of progression-free survival.
The Committee discussed the results of the manufacturer's meta-analysis that demonstrated that the progression-free survival and overall survival hazard ratios for the triple negative subgroup (0.63 and 0.96) were indistinguishable from those of the intention-to-treat population (0.64 and 0.97). Moreover, the results for the overall survival difference were not statistically significant (95% CI 0.79 to 1.16). The Committee concluded that there was no evidence of any greater clinical benefit in the triple negative subgroup than in the intention-to-treat population.
For the prior taxane-treated subgroup, the Committee recognised that there was a statistically significant result in overall survival estimates from the E2100 trial, from 17.6 to 26.3 months with the addition of bevacizumab (95% CI 0.45 to 0.99), and in the meta-analysis for the prior taxane-treated subgroup, from 21.3 to 26.9 months with the addition of bevacizumab (95% CI 0.55 to 0.97). However, the Committee identified a number of concerns that questioned the robustness of the data. The Committee considered that although the results of the prior taxane-treated subgroup analyses were promising in terms of possible clinical benefit, they were not sufficiently robust to use for the development of guidance.
Evidence for cost effectiveness
Availability and nature of evidence
The manufacturer used a Markov model to evaluate the cost effectiveness of bevacizumab plus paclitaxel compared with weekly paclitaxel, 3-weekly docetaxel and gemcitabine plus paclitaxel, using pair wise comparison for bevacizumab plus paclitaxel with each separate comparator regimen. As an additional analysis, the manufacturer presented a comparison with 3-weekly paclitaxel.
Bevacizumab plus docetaxel was not formally evaluated.
The Committee considered that because of the uncertainty around the subgroup clinical effectiveness estimates those estimates could not be carried forward to form the basis of a cost-effectiveness analysis and guidance to the NHS. The Committee concluded that the estimates of cost effectiveness for the intention-to-treat population represented the most plausible estimate of cost effectiveness for bevacizumab.
Uncertainties around and plausibility of assumptions and inputs in the economic model
A key assumption made by the manufacturer in its base-case analysis was that patients would have the same risk of dying per unit time once disease progressed, regardless of the first-line treatment they had received. This resulted in improvements in observed progression-free survival being carried over to projected improvements in overall survival, resulting in an incremental benefit of 0.35 years for the bevacizumab plus paclitaxel arm compared with the paclitaxel alone arm and a pair wise ICER of £118,000 per QALY gained, using the list price for paclitaxel. The manufacturer indicated that this represented an optimistic scenario compared with the trial data. Including the average price for paclitaxel paid by NHS trusts, without the patient access scheme, indicated an ICER of £110,500 per QALY gained.
The Committee also examined the exploratory analyses carried out by the ERG that attempted to calibrate overall survival in the model with that directly observed in the E2100 trial by using an area under the curve method. These analyses resulted in mean life years of 2.16 years in the bevacizumab plus paclitaxel arm and 2.13 years in the paclitaxel alone arm (an incremental benefit of 0.03 years) and a pair wise ICER of £259,000 per QALY gained, based on the list price for paclitaxel. Using the average price for paclitaxel paid by NHS trusts, the ERG reported that the ICER remained over £200,000 per QALY gained. The ERG acknowledged that this represented a pessimistic scenario.
Incorporation of health-related quality of life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
No health-related benefits were identified that were not included in the economic models
NA
Most likely cost-effectiveness estimate (given as an ICER)
The Committee concluded that the most plausible ICER for bevacizumab plus paclitaxel versus weekly paclitaxel was between £110,000 and £259,000 per QALY gained and that the ICER for bevacizumab plus paclitaxel versus docetaxel would be greater than £115,000 per QALY gained. The Committee accepted the manufacturer's statement that the ICER for bevacizumab plus docetaxel would be higher than that for bevacizumab plus paclitaxel since docetaxel is the more expensive taxane.
Additional factors taken into account
Patient access scheme
The Committee noted that the manufacturer had provided two base cases, one of which was based on average prices for paclitaxel paid by NHS trusts over a 4-month period and included a patient access scheme for bevacizumab. The Committee was aware that no patient access scheme had been approved by the Department of Health and therefore the scheme could not be taken into account in the consideration of cost effectiveness.
End-of-life considerations
The Committee concluded that bevacizumab in combination with a taxane did not fulfil the criteria for being a life-extending, end-of-life treatment.
Equalities considerations, Social value judgements
The Committee concluded that there was no evidence of differences in access to treatment or response to treatment by socioeconomic status or ethnicity in patients with disease at the metastatic stage.
# Recommendations for further research
Further research designed to investigate differences in health-related quality of life and the clinical effectiveness of bevacizumab in subgroups, such as those with prior taxane exposure, would be particularly useful.# Related NICE guidance
Advanced breast cancer: diagnosis and treatment. NICE clinical guideline 81 (2009).
Bevacizumab for the first-line treatment of metastatic breast cancer (terminated appraisal).NICE technology appraisal 147 (2008).
Gemcitabine for the treatment of metastatic breast cancer. NICE technology appraisal guidance 116 (2007).# Review of guidance
The guidance on this technology will be considered for review in July 2013.
Andrew DillonChief ExecutiveFebruary 2011# Changes after publication
February 2014:
minor maintenance
March 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
It updates and replaces terminated technology appraisal 147, Bevacizumab in combination with paclitaxel for the first-line treatment of metastatic breast cancer, issued June 2008.
The recommendations from this guideline have been incorporated into a NICE Pathway. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': "During the course of this appraisal the European Medicines Agency conducted a review of the use of bevacizumab in combination with taxanes for the treatment of metastatic breast cancer. Following that review, the EMA's Committee for Medicinal Products for Human Use (CHMP) recommended that bevacizumab, when used to treat metastatic breast cancer, should be used only in combination with the taxane paclitaxel.\n\nThis guidance updates and replaces terminated technology appraisal 147, Bevacizumab in combination with paclitaxel for the first-line treatment of metastatic breast cancer, issued June 2008.\n\nBevacizumab in combination with a taxane is not recommended for the first-line treatment of metastatic breast cancer.\n\nPatients currently receiving bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer should have the option to continue therapy until they and their clinicians consider it appropriate to stop.", 'The technology ': "Bevacizumab (Avastin, Roche) is a humanised anti-vascular endothelial growth factor (VEGF) monoclonal antibody that inhibits VEGF-induced signalling and inhibits VEGF-driven angiogenesis. This reduces vascularisation of tumours, thereby inhibiting tumour growth. Bevacizumab is administered by intravenous infusion. The recommended dose is 10\xa0mg/kg body weight given once every 2\xa0weeks or 15\xa0mg/kg body weight given once every 3\xa0weeks. Bevacizumab in combination with paclitaxel or docetaxel has a marketing authorisation for 'first-line treatment of patients with metastatic breast cancer'.\n\nThe summary of product characteristics (SPC) lists the following adverse effects that may be associated with bevacizumab treatment: gastrointestinal perforations, fistulae, wound healing complications, hypertension, proteinuria, arterial and venous thromboembolism, haemorrhage, pulmonary haemorrhage/haemoptysis, congestive heart failure, reversible posterior leucoencephalopathy syndrome and neutropenia. For full details of side effects and contraindications, see the SPC.\n\nBevacizumab is available in 100-mg and 400-mg vials at net prices of £242.66 and £924.40, respectively (excluding VAT; 'British national formulary' [BNF] edition 59). The acquisition cost of bevacizumab (excluding VAT and assuming wastage) for a patient weighing 70\xa0kg is £1652.38 at a dosage of 10\xa0mg/kg every 2\xa0weeks and £2576.78 at a dosage of 15\xa0mg/kg every 3\xa0weeks. This amounts to an average monthly cost of £3304.76 at a dosage of 10\xa0mg/kg every 2\xa0weeks and £3435.70 at a dosage of 15\xa0mg/kg every 3\xa0weeks. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of bevacizumab and a review of its submission by the Evidence Review Group (ERG; appendix B). This appraisal will replace the terminated technology appraisal number 147, June 2008, 'Bevacizumab in combination with paclitaxel for the first-line treatment of metastatic breast cancer'.\n\nThe manufacturer's original submission focused on the combination of bevacizumab plus paclitaxel. The manufacturer did not submit evidence on the clinical or cost effectiveness of bevacizumab plus docetaxel in its original submission. The evidence from this submission is outlined from paragraphs 3.1 to 3.12. Following consultation on the appraisal consultation document, the manufacturer provided additional subgroup data on prior taxane-treated groups and groups with triple negative disease, as well as additional data from the AVADO and RIBBON-1 studies. The evidence from this additional submission is outlined from sections 3.21 to 3.33.\n\n# Clinical effectiveness\n\nThe manufacturer's original submission presented clinical-effectiveness data from one randomised, open-label, controlled trial (E2100). A total of 722 patients were randomised to either bevacizumab plus weekly paclitaxel (n\xa0=\xa0368) or weekly paclitaxel alone (n\xa0=\xa0354). The randomisation was stratified by disease-free interval (less than or equal to 24 months; greater than 24 months), number of metastatic sites (less than 3; greater than or equal to 3), prior receipt of adjuvant chemotherapy (yes; no) and oestrogen receptor status (positive; negative; and unknown). All patients were given intravenous weekly paclitaxel (90\xa0mg/m2 over 1\xa0hour) once a week for 3\xa0weeks, with no treatment given at week\xa04. Patients in the bevacizumab plus weekly paclitaxel arm also received intravenous bevacizumab (10\xa0mg/kg) every 2\xa0weeks, until progression of disease or unacceptable toxicity occurred. There was no limit to the number of cycles of therapy allowed. The patients in the trial had locally recurrent or metastatic breast cancer and over 90% had HER2-negative breast cancer. The primary endpoint of the trial was duration of progression-free survival. Secondary endpoints were overall survival, objective response (complete response and partial response) rate, duration of response and health-related quality of life. Health-related quality of life was measured by the Functional Assessment of Cancer Therapy (FACT-B) questionnaire, which is a scale for measuring quality of life among breast cancer patients.\n\nAt the time of the manufacturer's interim analysis most patients had discontinued randomised therapy; for 360 patients (50%) this was because of disease progression, and 131 patients (18%) withdrew from the study because of unacceptable toxicity. The interim analyses consisted of a stratified log rank test where the stratification factors were disease-free interval and prior adjuvant chemotherapy. There was a statistically significant increase in median progression-free survival of 5.5\xa0months, from 5.8\xa0months in the paclitaxel alone arm to 11.3\xa0months in the bevacizumab plus paclitaxel arm. The stratified hazard ratio for progression was 0.48 (95% confidence interval [CI] 0.39 to 0.61; p\xa0<\xa00.0001). The stratified hazard ratio for death was 0.87 (95% CI 0.72 to 1.05; p\xa0=\xa00.14), indicating a non-statistically significant improvement in median overall survival of 1.7 months, from 24.8 months with paclitaxel alone to 26.5 months with bevacizumab plus paclitaxel.\n\nAt baseline, 302 (87.3%) patients in the paclitaxel alone arm and 317 (88.8%) patients in the bevacizumab plus paclitaxel arm completed the FACT-B questionnaire. At week\xa033, 163 patients in the paclitaxel arm and 205 patients in the bevacizumab plus paclitaxel arm completed the questionnaire. If scores were missing at week\xa017 or week\xa033, the patient was not included in the analysis for that respective time point – except when disease progression or death was recorded earlier. For those patients who died or had disease progression, a value of zero (that is, the worst score) for each of the five subscales in the FACT-B questionnaire was imputed (rather than the patient being excluded from the analysis). When imputed values were used, the difference in total FACT-B score between the two treatment arms was statistically significant (p\xa0=\xa00.0046) in favour of the bevacizumab plus paclitaxel arm at week\xa033. There were no statistically significant differences between treatment arms at week\xa017, or at week\xa033 if imputed values were not used. The manufacturer stated that, taken together, these results demonstrated that the addition of bevacizumab to paclitaxel led to a relative improvement in health-related quality of life.\n\nThe safety analyses from the E2100 trial reported that the addition of bevacizumab to paclitaxel resulted in a 20% overall increase in the incidence of grade 3–5 adverse events. These included neuropathy (25.3%), hypertension (16%), arterial thromboembolic events (3.6%), proteinuria (3%), bleeding (2.2%) and congestive heart failure (2.2%). In addition, adverse event data from a non-randomised single-arm, open-label study (ATHENA, n\xa0=\xa02251) were presented. The most frequent serious adverse events (grade 3–5) were febrile neutropenia (5.1%), neutropenia (3.6%) and pyrexia (1.5%).\n\nThe manufacturer carried out indirect comparisons for bevacizumab plus weekly paclitaxel compared with docetaxel alone and gemcitabine plus 3-weekly paclitaxel. The comparisons were carried out by an indirect method using two comparators to link three trials. The manufacturer noted that studies conducted only in patients having first-line treatment for metastatic breast cancer were not always available, so the exclusion criteria specified that trials in which more than 60% of patients were receiving second or later lines of treatment would be excluded. The manufacturer noted that one study used a higher docetaxel dosage (100\xa0mg/m2 3-weekly) and a longer duration of treatment (maximum 32\xa0cycles) compared with standard UK practice (considered by the manufacturer to be 75\xa0mg/m2 3-weekly; maximum 6–8\xa0cycles). However, based on the similar populations, baseline characteristics and exclusion/inclusion criteria, the manufacturer assumed that heterogeneity would not be significant.\n\nThe hazard ratio for progression with bevacizumab plus weekly paclitaxel compared with docetaxel alone was estimated to be 0.56 (95% CI 0.39 to 0.78) and 0.46 (95% CI 0.34 to 0.64) compared with gemcitabine plus 3-weekly paclitaxel. For weekly paclitaxel compared with 3-weekly docetaxel the hazard ratio for progression was 1.15 (95% CI 0.89 to 1.48) and for weekly paclitaxel compared with gemcitabine plus 3-weekly paclitaxel the hazard ratio for progression was 0.96 (95% CI 0.76 to 1.21).\n\n# Cost effectiveness\n\nThe manufacturer's model was a 3-state Markov model with a cycle length of 1\xa0month. Patients in the model received treatment with either bevacizumab plus weekly paclitaxel or the comparator treatment, that is:\n\nweekly paclitaxel or\n\ndocetaxel or\n\ngemcitabine plus 3-weekly paclitaxel.Although bevacizumab plus docetaxel was included in the scope it was not formally evaluated in the manufacturer's economic analysis.\n\nPatients were assumed to be in one of three possible discrete health states at any given time: 'progression-free survival', 'progressed' or 'death'. It was assumed that patients would have the same risk of dying after disease progression regardless of the first-line treatment they had received. In addition, the model assumed that patients would have the same sequence of further treatment and resource use after disease progression, regardless of their initial treatment. The number of patients who died while in the 'progression-free survival' state was determined either by the maximum of background mortality or the monthly rate at which patients died (from any cause) while progression-free in the E2100 trial. In the base-case model, the progression-free mortality rates for weekly paclitaxel alone were used as a proxy for the mortality rates for docetaxel and gemcitabine plus paclitaxel.\n\nThe manufacturer provided two base-case analyses, both incorporating a 10-year time horizon:\n\nThe first used the list prices in accordance with the NICE reference case. The prices for bevacizumab (total average cost per patient, £25,929) and paclitaxel (total average cost per patient, £7720) were taken from the BNF, edition 58. Drug costs were calculated according to the recommended adult dose and duration of treatment was estimated from the E2100 trial. Dose reductions were not modelled.\n\nThe second used an average NHS cost for paclitaxel (total average cost per patient, £649) based on the average price paid by NHS trusts over a 4-month period, and a patient access scheme for bevacizumab whereby the NHS covers the cost of the first 10\xa0g bevacizumab needed for each patient. Sensitivity analyses were only provided for this case. The patient access scheme (10-g cap) for bevacizumab was not approved by the Department of Health and was not considered by the Committee.\n\nThe base-case utility values were taken from one study that derived proxy utility values from oncology nurses, using the standard gamble technique. The values were 0.73 for progression-free survival (this was an average of values of 0.81 for response and 0.65 for stable disease), 0.45 for progressive disease, and −0.21 for disutility from febrile neutropenia and peripheral sensory neuropathy (both applied only in month\xa01 of experiencing the event). It was assumed that the remaining adverse events (hypersensitivity, infection and hypertension) would not have a notable impact on health-related quality of life.\n\nThe results based on the NHS list prices indicated incremental costs of £30,469, £31,416 and £27,358 and incremental quality-adjusted life years (QALYs) of 0.259, 0.273 and 0.259 for bevacizumab plus weekly paclitaxel therapy relative to weekly paclitaxel, docetaxel and gemcitabine plus paclitaxel therapy respectively. The cost per QALY was £117,803, £115,059 and £105,777 for bevacizumab plus weekly paclitaxel therapy relative to weekly paclitaxel, docetaxel and gemcitabine plus paclitaxel therapy respectively. The results based on average prices paid by NHS trusts over a 4-month period for paclitaxel and the patient access scheme (not approved by the Department of Health) for bevacizumab were provided and indicated a lower cost per QALY for bevacizumab plus weekly paclitaxel therapy relative to weekly paclitaxel, docetaxel and gemcitabine plus paclitaxel therapy respectively, though remaining above £57,000 per QALY gained. The manufacturer stated that it can be inferred from the high incremental cost-effectiveness ratios (ICERs) in the model that bevacizumab plus docetaxel (the more expensive taxane) is unlikely to provide a more cost-effective outcome than the analysis presented in the submission and, hence, a full economic analysis of bevacizumab plus docetaxel was not presented. The manufacturer carried out sensitivity analyses only on the second base-case scenario, in which the average price of paclitaxel paid by NHS trusts over a 4-month period and the patient access scheme for bevacizumab were used, and it was observed that using different parametric functions for time to progression and alternative assumptions on treatment duration had the largest impact on the ICERs.\n\nThe manufacturer conducted further analyses in response to points of clarification requested by the ERG, incorporating into the model a comparison of bevacizumab plus weekly paclitaxel with 3-weekly paclitaxel alone. The ICER for bevacizumab plus weekly paclitaxel compared with 3-weekly paclitaxel was £59,339 per QALY gained using average prices paid by NHS trusts for paclitaxel and incorporating the patient access scheme for bevacizumab. The manufacturer also incorporated the results of the evidence synthesis into the economic model as opposed to assuming that all comparators were equally effective. This was also based on the average price of paclitaxel paid by NHS trusts and the patient access scheme for bevacizumab. This resulted in an ICER for bevacizumab plus weekly paclitaxel compared with docetaxel and gemcitabine plus 3-weekly paclitaxel of £59,310 and £51,795 per QALY gained respectively.\n\n# ERG comments on the original manufacturer's submission\n\nThe ERG had several concerns about the selection and quality of the evidence presented in the manufacturer's original submission. The evaluation of the clinical effectiveness of bevacizumab was based primarily on a single trial comparing bevacizumab plus weekly paclitaxel with weekly paclitaxel alone. The ERG highlighted limitations in the methodological quality of the study: for example, lack of blinding and lack of data collection about treatments given after disease progression. The ERG noted concerns that, as the conclusions about health-related quality of life were based primarily on the analyses using extreme imputed values for patients who had died or whose disease had progressed, the significant improvement in the FACT-B score stated by the manufacturer may not be reliable. The ERG noted that the results reported in the manufacturer's submission were derived from interim analyses and suggested that more recent follow-up data would be valuable, particularly for survival outcomes. The ERG also noted that the E2100 trial suggested that overall survival was not statistically significantly different between the treatment arms. However, the ERG was unable to establish whether or not the lack of difference in overall survival was due to crossover between treatment groups or any other post-progression events, because these data were not collected in the trial.\n\nThe ERG noted that the manufacturer had not presented any data on the clinical effectiveness of bevacizumab plus docetaxel in its submission. The ERG noted that a trial of bevacizumab plus docetaxel compared with docetaxel plus placebo (the AVADO trial) had been excluded. In addition, the ERG also considered that data from the RIBBON-1 trial could potentially have been included. The RIBBON-1 trial was excluded by the manufacturer because of insufficient statistical power for the relevant docetaxel comparison. Data from both these studies were provided by the manufacturer in response to consultation on the appraisal consultation document (see sections 3.23 and 3.24).\n\nThe ERG also highlighted a number of concerns about the indirect comparison conducted by the manufacturer. The ERG noted that an additional study (the Will Weekly Win study comparing weekly paclitaxel with 3-weekly paclitaxel, for which there were some data reported in an abstract) had not been included by the manufacturer. The ERG noted that the inclusion criteria specified that studies could be included as long as fewer than 60% (rather than a strict majority of 50%) of patients were receiving second-line treatments for metastatic breast cancer. The ERG highlighted that the validity of the studies included in the indirect comparison had not been adequately assessed. The ERG also reported concerns about the methods of the indirect comparison, noting differences between patient populations and potentially important methodological limitations among the trials included in this comparison. Given these methodological limitations, the ERG did not consider the findings of the indirect comparison to be reliable.\n\nThe ERG had a number of concerns about the economic model submitted by the manufacturer. The ERG considered that the series of pair wise comparisons for bevacizumab plus paclitaxel relative to each separate comparator regimen were inappropriate. It stated that, to establish the correct estimate of the ICER for bevacizumab plus paclitaxel, a fully incremental analysis should have been conducted, comparing all the regimens simultaneously. In addition, the ERG noted that the model assumed that mortality after disease progression was independent of initial treatment. It assumed that the rate of death after progression was constant over time and the same for all initial treatments. This meant that the differences in mean progression-free survival between treatments were maintained in the estimates of mean overall survival. The ERG stated that this was likely to have led to overestimates of overall survival for bevacizumab plus paclitaxel versus paclitaxel alone compared with the results of the E2100 trial.\n\nThe ERG highlighted that the base-case model did not include the results from the indirect comparison and that the model made the assumption that all included comparators (docetaxel alone, paclitaxel alone and gemcitabine plus paclitaxel) were equally effective in terms of progression-free survival and overall survival. Additionally, in the second base case, the cost of bevacizumab was based on the NHS paying for a maximum dose of 10 g per patient, and this patient access scheme had not been agreed with the Department of Health. The cost of paclitaxel used in the second base case was based on the average price paid by NHS trusts over a 4-month period, whereas other proprietary prices were taken from the BNF 58. The ERG also reported that the utility values were taken from a non-systematic review of the literature. In addition, the ERG noted that the manufacturer had not attempted to map health-related quality of life data from the E2100 study (measured by the FACT-B instrument) to a preference-based measure or collate alternative values.\n\nThe ERG conducted two sets of exploratory incremental analyses, both including 3-weekly paclitaxel as a comparator. One was based on the revised results, that incorporated the indirect comparison undertaken by the manufacturer rather than assuming that all comparators were equally effective. The second analysis was based on the original approach employed by the manufacturer where all comparators were assumed to be equally effective. These analyses used the following drug acquisition costs:\n\nCase 1 (ERG re-analysis) – NHS list prices from BNF 58 excluding the patient access scheme for bevacizumab.\n\nCase 2 (manufacturer re-analysis) – average prices paid by NHS trusts over a 4-month period for paclitaxel including the patient access scheme for bevacizumab.\n\nCase 3 (ERG re-analysis) – average prices paid by NHS trusts for paclitaxel over a 4-month period excluding the patient access scheme for bevacizumab.In both analyses, for Case 1 and Case 3 (excluding the patient access scheme), the ICER for bevacizumab plus paclitaxel versus the next best treatment exceeded £100,000 per QALY gained. .\n\nThe ERG agreed with the manufacturer's conclusion that bevacizumab plus paclitaxel and bevacizumab plus docetaxel would be expected to be of similar effectiveness. Therefore, the inclusion and exclusion of studies in the indirect comparison would not have a major effect. The analyses by the ERG found that the acquisition cost of docetaxel had very little effect on the ICER of bevacizumab plus paclitaxel compared with docetaxel.\n\nThe ERG conducted further exploratory analyses and calibrated the model to the E2100 trial results for overall survival. This was considered important to test the internal validity of the model by comparing the median progression-free survival and overall survival found by the E2100 trial with the model predictions. The pair wise ICER of bevacizumab plus paclitaxel versus weekly paclitaxel was £259,267 per QALY gained (incremental cost of £29,675 and incremental QALY of 0.114) in the exploratory analyses.\n\n# Extra analyses provided by the manufacturer\n\nAfter consultation on the appraisal consultation document, the manufacturer provided summaries of the results from the AVADO and RIBBON-1 trials. In addition, new evidence for two subgroups was provided:\n\nPatients who had previously received treatment with a taxane, and\n\nPatients with disease that was triple negative (that is, oestrogen and progesterone receptor negative, and HER2 negative).\n\n## Clinical effectiveness\n\nThe manufacturer stated that these groups are likely to have poorer prognosis and may gain greater benefit from bevacizumab therapy than the full licensed population. In addition to the data from the E2100 trial the manufacturer also included data from the AVADO and RIBBON-1 trials as evidence to support the subgroups identified.\n\nThe AVADO trial (n\xa0=\xa0736) was a randomised double blind trial that investigated the combination of bevacizumab with docetaxel in women with HER2 negative disease who had not previously received chemotherapy for metastatic disease. Patients were assigned to receive either docetaxel plus bevacizumab at 7.5mg/kg every 3 weeks, docetaxel plus bevacizumab at 15\xa0mg/kg every 3 weeks or docetaxel plus placebo. Docetaxel was given at 100\xa0mg/m2 on day 1 of each 3 week cycle for a maximum of 9 cycles. The primary endpoint was progression-free survival. The manufacturer presented results for the licensed dose of bevacizumab at 15\xa0mg/kg every 3 weeks. Median progression-free survival for the intention-to-treat population was 8.2 months in the docetaxel plus placebo arm and 10.1 months in the docetaxel plus bevacizumab arm (unstratified HR 0.77, 95% CI 0.64 to 0.93). Median overall survival was 31.9 months in the placebo arm and 30.2 months in the bevacizumab arm (HR 1.03, 95% CI: 0.70, 1.33).\n\nThe RIBBON-1 trial (n\xa0=\xa01237) was a randomised double-blind placebo controlled trial of standard chemotherapy with or without bevacizumab. Three hundred and seven patients received taxane chemotherapy with or without bevacizumab. Results for progression-free survival were provided for the group of patients receiving either anthracycline or taxane chemotherapy (n\xa0=\xa0622). Median progression-free survival increased from 8 months in the chemotherapy arm to 9.2 months in the bevacizumab plus chemotherapy arm (HR 0.66, 95% CI 0.54 to 0.81).\n\nFor the triple negative subgroup, results from the E2100 study (n\xa0=\xa0232) indicated a statistically significant increase in median progression-free survival of 5.3 months, from 5.3 months in the paclitaxel alone arm to 10.6 months in the bevacizumab plus paclitaxel arm. The unstratified hazard ratio for progression was 0.49 (95% CI 0.34 to 0.70). The hazard ratio for death was 0.89 (95% CI 0.66 to 1.19), indicating a non-statistically significant improvement in median overall survival of 4.2 months, from 16.3 months in the paclitaxel alone arm to 20.5 months in the bevacizumab plus paclitaxel arm. Results from the AVADO study (n\xa0=\xa0111) indicated that the unstratified hazard ratio for progression with bevacizumab plus docetaxel compared with docetaxel alone was estimated to be 0.68 (95% CI 0.46 to 0.99). The hazard ratio for death with bevacizumab plus docetaxel compared with docetaxel alone was estimated to be 0.82 (95% CI 0.51 to 1.32).\n\nFor the prior taxane-treated subgroup, results from the E2100 study (n\xa0=\xa0140) indicated a statistically significant increase in median progression-free survival of 7.3 months, from 5.8 months in the paclitaxel alone arm to 13.1 months in the bevacizumab plus paclitaxel arm. The unstratified hazard ratio for progression was 0.33 (95% CI 0.20 to 0.54). There was a statistically significant increase in median overall survival of 8.7 months, from 17.6 months in the paclitaxel alone arm to 26.3 months in the bevacizumab plus paclitaxel arm. The hazard ratio for death was 0.67 (95% CI 0.45 to 0.99). Results from the AVADO study (n\xa0=\xa078) indicated a statistically significant increase in median progression-free survival of 3.6 months, from 6.7 months in the docetaxel alone arm to 10.3 months in the bevacizumab plus docetaxel arm. The unstratified hazard ratio for progression with bevacizumab plus docetaxel compared with docetaxel alone was estimated to be 0.53 (95% CI 0.33 to 0.85). There was a 9.3-month increase in median overall survival, from 22.3 months in the docetaxel alone arm to 31.6 months in the bevacizumab plus docetaxel arm. The hazard ratio for death was 0.58 (95% CI 0.31 to 1.08).\n\nThe manufacturer also provided meta-analyses based on individual patient data. One was a meta-analysis of progression-free survival and overall survival in 2447 patients from the E2100, AVADO and RIBBON-1 trials. In this pooled intention-to-treat analysis, there was a statistically significant increase in median progression-free survival of 2.5 months, from 6.7 months in the chemotherapy alone arm to 9.2 months in the bevacizumab plus chemotherapy arm. The hazard ratio for progression with bevacizumab plus chemotherapy compared with chemotherapy alone was estimated to be 0.64 (95% CI 0.58 to 0.71). The hazard ratio for death was 0.97 (95% CI 0.86 to 1.08), indicating a non-statistically significant difference in median overall survival of 0.3 months from 26.4 months in the chemotherapy alone arm to 26.7 months in the bevacizumab plus chemotherapy arm. The pooled dataset also included 621 patients with triple negative disease who were meta-analysed separately. Results were similar in this triple negative subgroup to the results from the overall population, with a hazard ratio for progression with bevacizumab plus chemotherapy compared with chemotherapy alone estimated to be 0.63 (95% CI 0.52 to 0.76). The hazard ratio for death with bevacizumab plus chemotherapy compared with chemotherapy alone was estimated to be 0.96 (95% CI 0.79 to 1.16). Median length of progression-free and overall survival for the triple negative subgroup were not provided. No data were provided for the group (n\xa0=\xa01826) that did not have triple negative disease.\n\nAnother meta-analysis was described as exploratory and focused on the prior taxane-treated subgroup. This analysis was restricted to the 1765 patients treated with taxanes, with or without bevacizumab, in the E2100, AVADO and RIBBON-1 trials. No data for the entire group of 1765 patients were provided. For the prior taxane-treated subgroup (n\xa0=\xa0311), results indicated a statistically significant increase in median progression-free survival of 4.5 months, from 6.2 months in the taxane alone arm to 10.7 months in the bevacizumab plus taxane arm. The hazard ratio for progression was 0.47 (95% CI 0.35 to 0.62). There was a statistically significant increase in median overall survival of 5.6 months, from 21.3 months in the taxane alone arm to 26.9 months in the bevacizumab plus taxane arm. The hazard ratio for death was 0.73 (95% CI 0.55 to 0.97). No data were provided for the group (n\xa0=\xa01454) that had not received prior taxanes.\n\n## Cost-effectiveness\n\nThe manufacturer provided cost-effectiveness estimates for the two subgroups. The model that was used in the original submission was adapted to reflect the progression-free survival, overall survival, time to stopping treatment and adverse event rates of the subgroups. Overall survival curves for the relevant subgroups from the E2100 study were fitted with parametric functions. The analysis focused on the cost effectiveness of bevacizumab plus paclitaxel and did not consider the comparator of gemcitabine plus paclitaxel. The analysis assumed equal efficacy for weekly paclitaxel and 3-weekly docetaxel.\n\nFor both subgroups, a log-logistic model was selected as the best fit for progression-free survival and overall survival and the Weibull function was used for both treatments to reflect time to stopping treatment for each treatment arm. The base-case results were presented using both the average price of paclitaxel paid by NHS trusts and the list price. The patient access scheme for bevacizumab was excluded from the base case, although it was included in sensitivity analysis.\n\nFor the triple negative subgroup, the cost per QALY for bevacizumab plus paclitaxel compared with paclitaxel alone was £87,865 (with an incremental cost of £27,387 and an incremental QALY of 0.312) based on list prices for paclitaxel and £82,469 (with an incremental cost of £25,705 and an incremental QALY of 0.312) based on the average price paid by NHS trusts for paclitaxel. The cost per QALY for bevacizumab plus paclitaxel compared with docetaxel alone was £84,740 (with an incremental cost of £26,540 and an incremental QALY of 0.313) based on list prices for paclitaxel and £64,092 (with an incremental cost of £20,073 and an incremental QALY of 0.313) based on the average price paid by NHS trusts for paclitaxel.\n\nFor the prior taxane-treated subgroup, the cost per QALY for bevacizumab plus paclitaxel compared with paclitaxel alone was £74,640 (with an incremental cost of £37,358 and an incremental QALY of 0.501) based on list prices for paclitaxel and £67,714 (with an incremental cost of £33,892 and an incremental QALY of 0.501) based on the average price paid by NHS trusts for paclitaxel. The cost per QALY for bevacizumab plus paclitaxel compared with docetaxel alone was £73,605 (with an incremental cost of £36,951 and an incremental QALY of 0.502) based on list prices for paclitaxel and £57,416 (with an incremental cost of £28,824 and an incremental QALY of 0.502) based on the average price paid by NHS trusts for paclitaxel.\n\nSensitivity analysis was conducted on the prior taxane-treated subgroup assuming that variations in ICERs would be similarly reflected in the triple negative subgroup. The analysis indicated that there was considerable variation in the estimate of cost effectiveness depending on the function adopted. Probabilistic sensitivity analyses produced similar estimates of cost effectiveness, and the probability of bevacizumab being cost effective at £30,000 per QALY gained was 0% against both weekly paclitaxel and 3-weekly docetaxel.\n\n# ERG comments on the extra subgroup analysis\n\nThe ERG noted that 25% (615/2447) of all patients included in the intention-to-treat meta-analysis that was used to address the triple negative subgroup received bevacizumab plus capecitabine, a combination that is outside the scope of this appraisal. The ERG highlighted that the progression-free survival and overall survival hazard ratios for the intention-to-treat population and the triple negative subgroup were almost identical. Furthermore, the median progression-free survival, overall survival and 1-year survival data were not reported for this subgroup. It was noted that these data were not provided for the RIBBON-1 study.\n\nThe ERG noted that the meta-analysis addressing the prior taxane-treated subgroup was described as an exploratory meta-analysis. It stated that it included only a small number of patients from trials that individually were insufficiently powered to detect a difference in overall survival. Only one trial (AVADO) appeared to stratify for taxane pre-treatment and no interaction tests were conducted. Therefore, although the hazard ratios did show a trend towards being more favourable towards bevacizumab than in the intention-to-treat meta-analysis for both progression-free survival and overall survival, the ERG stated that the analysis cannot be considered as convincing evidence of a subgroup effect.\n\nThe ERG had a number of concerns about the economic modelling. The ERG highlighted that rather than using estimates from these subgroup meta-analyses in the subsequent economic model, only the subgroup data from the E2100 trial were used. The ERG noted that this approach may have yielded more favourable ICER estimates because the progression-free survival and overall survival values for E2100 were more favourable than those from the meta-analyses.\n\nThe ERG commented that, although the manufacturer selected the log-logistic model as the best fit, the difference in goodness of fit statistics was small, suggesting that the choice between different functions was marginal. However, there was subsequent variation in the ICER estimates based on the different survival functions. At the extreme ends, for the prior taxane-treated subgroup, the ICER using the log-logistic function (the manufacturer's base case), and incorporating the average price for paclitaxel paid by NHS trusts, was £67,714 per QALY gained, whereas if the Weibull function had been used this figure would have risen to £86,854 per QALY gained. When the NHS list prices for paclitaxel were incorporated, the ICERs ranged from £74,640 per QALY gained with the log-logistic function to £95,807 per QALY gained with the Weibull function. The ERG concluded that there was considerable uncertainty surrounding the choice of statistical function used in the cost-effectiveness analysis for the prior taxane-treated subgroup. Equivalent goodness of fit statistics were not reported for the triple negative subgroup so the ERG could not undertake a similar assessment for this subgroup.\n\nThe ERG undertook an exploratory analysis in the prior taxane-treated subgroup using the hazard ratio estimated from the individual patient data meta-analysis of the prior taxane-treated group presented by the manufacturer (HR\xa0=\xa00.738) and the Weibull function. The results demonstrated an increase in the ICER from £95,807 to £109,242 per QALY gained using the list prices for paclitaxel and from £86,854 to £98,834 per QALY gained using the average price for paclitaxel paid by NHS trusts.\n\nThe ERG noted that all the parametric functions investigated by the manufacturer assumed long-term sustained treatment effects for overall survival with bevacizumab plus paclitaxel. Consequently, the ERG undertook an exploratory analysis for both subgroups using the manufacturer's model. This analysis used the Kaplan-Meier survival estimates from the E2100 study up to about 3.2 years, assuming no difference in survival after that point, since the curves suggested that the difference in overall survival may not be sustained over a longer time horizon. For the prior taxane-treated subgroup, the ICERs increased from £74,640 per QALY gained when using the log-logistic function to £129,794 per QALY gained when using the Kaplan-Meier function, both incorporating the list prices for paclitaxel, and from £67,714 per QALY gained when using the log-logistic function to £117,587 per QALY gained when using the Kaplan-Meier function, both incorporating the average price for paclitaxel paid by NHS trusts. For the triple negative subgroup, the ICERs increased from £87,865 per QALY gained when using the log-logistic function to £187,339 per QALY gained when using the Kaplan-Meier function, incorporating the list prices for paclitaxel, and from £82,469 per QALY gained when using the log-logistic function to £175,575 per QALY gained when using the Kaplan-Meier function, incorporating the average price for paclitaxel paid by NHS trusts.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab in combination with a taxane, having considered evidence on the nature of metastatic breast cancer and the value placed on the benefits of bevacizumab in combination with a taxane by people with metastatic breast cancer, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee considered current clinical practice for the treatment of metastatic breast cancer. The Committee noted the manufacturer's clarification response, which stated that approximately 30% of patients receive a taxane in the adjuvant setting, particularly in node positive disease at diagnosis. The clinical specialist stated that in current practice, if metastatic disease subsequently develops, taxanes (that is, weekly paclitaxel or 3-weekly docetaxel) are then offered as first-line treatment for the majority of people in England and Wales. The Committee also heard from the clinical specialist that 3-weekly paclitaxel is no longer routinely used in clinical practice, having been largely replaced by weekly dosing schedules. The Committee heard that the choice between the two taxanes is made locally and that weekly paclitaxel and 3-weekly docetaxel are considered to have comparable efficacy. The Committee concluded that the relevant comparators for bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer are weekly paclitaxel and 3-weekly docetaxel.\n\nThe Committee discussed the clinical effectiveness of bevacizumab in combination with a taxane. It heard that bevacizumab is the first VEGF-targeted therapy for this indication. The Committee discussed the E2100 trial which compared bevacizumab plus paclitaxel with weekly paclitaxel. The Committee heard from the ERG that the trial had several limitations, such as the lack of blinding. The trial demonstrated a statistically significant increase in median progression-free survival of 5.5\xa0months, from 5.8\xa0months in the paclitaxel alone arm to 11.3\xa0months in the bevacizumab plus paclitaxel arm. The Committee explored the value of an increase in progression-free survival with the clinical specialist and patient expert. It heard about the importance and significance of progression-free survival for patients in terms of being able to carry out normal daily activities, as well as being a therapeutic aim of treatment for clinicians.\n\nThe Committee then discussed the overall survival results of the E2100 trial and noted a non-statistically significant increase in median survival of 1.7\xa0months, from 24.8\xa0months with paclitaxel alone to 26.5\xa0months with bevacizumab plus paclitaxel. The Committee discussed the possible reasons for the increase in progression-free survival not being reflected in overall survival in the trial. It acknowledged that although it was possible that the relative treatment effect may have been confounded by crossover or other treatments received after disease progression, no data on this had been collected. The Committee heard from the clinical specialist that the response in E2100 to paclitaxel alone was lower than demonstrated in previous studies. The Committee concluded that it was likely that bevacizumab plus paclitaxel improved progression-free survival relative to weekly paclitaxel, but that there was no robust evidence that bevacizumab plus paclitaxel improved overall survival compared with weekly paclitaxel alone.\n\nThe Committee discussed the health-related quality of life data for bevacizumab plus paclitaxel compared with weekly paclitaxel. The Committee heard from the primary care trust expert that robust data on the magnitude of quality of life improvements were important. The Committee noted concerns about the data presented by the manufacturer. It was aware that a statistically significant improvement in health-related quality of life at 33\xa0weeks was only demonstrated when extreme values were imputed. The Committee also heard from the clinical specialist that the scores for psychological and emotional wellbeing were not explicitly addressed by the manufacturer. The Committee concluded that the magnitude of health-related quality of life benefits with bevacizumab plus paclitaxel compared with paclitaxel alone was uncertain.\n\nThe Committee noted the adverse events and the side-effect profile from the E2100 trial as well as from a large uncontrolled study (ATHENA). The Committee noted that the frequency of grade 3–5 adverse events was slightly higher with the addition of bevacizumab to paclitaxel. However, the Committee heard from the clinical specialist that many of the adverse events were those expected in cytotoxic regimens, and could be attributed to the taxane. Increased treatment duration would also lead to an increase in the incidence of adverse events. The Committee understood that most adverse events could be satisfactorily managed (for example with dose reductions). Specific adverse events associated with bevacizumab, notably hypertension, were also readily treatable. The Committee concluded that the addition of bevacizumab did not lead to unacceptable toxicity compared with paclitaxel alone, and that adverse effects were manageable.\n\nThe Committee noted that evidence from the AVADO study for the clinical effectiveness of bevacizumab plus docetaxel had been provided by the manufacturer after consultation on the appraisal consultation document. The Committee noted the manufacturer's comment that the AVADO dosing regimen of 9 cycles of 100\xa0mg/m2 docetaxel was not routine UK clinical practice as 3-weekly docetaxel was usually given for 6 cycles.The Committee heard from the clinical specialist that 100\xa0mg/m2 was the standard dose used in the absence of contraindications, and that therefore he considered that the trial data were relevant to UK clinical practice. The clinical specialist also highlighted the high methodological quality of the AVADO trial and its placebo-controlled design. The Committee noted that the results from this study demonstrated an approximate 2-month, statistically significant improvement in progression-free survival for bevacizumab at a dose of 15\xa0mg/m2 plus docetaxel. However, the Committee also noted the hazard ratio for death which was 1.03 (95% CI 0.70 to 1.33), indicating a non-statistically significant reduction in median overall survival of 1.7 months from 31.9 months in the docetaxel alone arm to 30.2 months in the bevacizumab plus docetaxel arm. The Committee concluded that bevacizumab plus docetaxel was modestly clinically effective compared with docetaxel alone in terms of progression-free survival. However, its effect on overall survival was uncertain.\n\nThe Committee discussed the indirect treatment comparison presented by the manufacturer for bevacizumab plus weekly paclitaxel compared with docetaxel alone and gemcitabine plus 3-weekly paclitaxel. The Committee noted the ERG's comments related to the reliability of the indirect treatment comparison. The quality of the included studies was variable, and the trials included variable numbers of patients receiving second-line treatment, where the prognosis may be worse than for first-line chemotherapy. Also, it was not clear that the selection criteria for included studies had been consistently applied, with the AVADO trial being excluded on the grounds of the docetaxel dose used, while another study using the same dose of docetaxel was included. The Committee concluded that the indirect treatment comparison was not robust and that the results were not considered reliable.\n\nThe Committee discussed the additional data presented by the manufacturer for the triple negative subgroup in response to consultation on the appraisal consultation document. The Committee explored whether bevacizumab might be more clinically effective in this subgroup. The Committee heard from the clinical specialist that for the subgroup of women with triple negative cancers (that is, cancers that do not have receptors for oestrogen, progesterone or HER2) there may be worse outcomes. The Committee noted, however, that while it was plausible that bevacizumab could be more effective in some tumour types than others, there was no proposal of a biologically plausible specific mechanism of effect for bevacizumab having an increased benefit for this subgroup. The Committee discussed the results of the manufacturer's meta-analysis that demonstrated that the progression-free survival and overall survival hazard ratios for the triple negative subgroup (0.63 and 0.96) were indistinguishable from those of the intention-to-treat population (0.64 and 0.97). Moreover, the results for the overall survival difference were not statistically significant (95% CI 0.79 to 1.16). The Committee concluded that there was no evidence of any greater clinical benefit in the triple negative subgroup than in the intention-to-treat population.\n\nThe Committee then discussed the additional data provided by the manufacturer for the prior taxane-treated subgroup. It heard from the clinical specialist that this was an area of clinical need as 30% to 40% of patients, usually those with lymph node involvement, would have received taxanes in the adjuvant setting. These patients would generally have a worse prognosis and might need different treatment options if the disease progressed after treatment. The Committee noted that although there could be taxane resistance in this subgroup, there were no specific biological markers or other hypotheses to suggest why VEGF agents would work more effectively in this subgroup compared with the intention-to-treat population. The Committee discussed the results provided for this subgroup, noting that these were based on post hoc analyses. The Committee noted that the hazard ratio for death in the E2100 trial for the prior taxane-treated subgroup was 0.67 (95% CI 0.45 to 0.99), indicating a statistically significant increase from 17.6 months in the paclitaxel alone arm to 26.3 months in the bevacizumab plus paclitaxel arm, and that the hazard ratio for death in the meta-analysis for the prior taxane-treated subgroup was 0.73 (95% CI 0.55 to 0.97), indicating a statistically significant increase from 21.3 in the taxane only arm to 26.9 months in the bevacizumab plus taxane arm. However, the Committee identified a number of concerns that questioned the robustness of the data. It noted that the E2100 trial was unblinded and did not stratify for prior taxane-treated patients, and the AVADO study, though stratified, had a very small number of patients (n\xa0=\xa078). Further, although the results for this subgroup were statistically significant for both progression-free survival and overall survival, there was no indication of the hazard ratios for the group who did not receive prior taxane treatment in the adjuvant setting and there were no statistical tests for interaction. The clinical specialist, while expressing interest in the findings, agreed on their exploratory nature. The Committee also noted the manufacturer's comment in its submission that although in the meta-analysis these differences appear to be statistically significant, it should be noted that this analysis is exploratory only.\n\nConsequently, the Committee considered that although the results of the prior taxane-treated subgroup analyses were interesting in terms of possible clinical benefit, they were not sufficiently robust to use for the development of guidance. The Committee concluded that the results needed to be confirmed in larger, well designed studies, and that the estimates of effectiveness could not be considered suitable as the basis of a cost-effectiveness analysis. The Committee discussed whether there were any subgroups other than those presented by the manufacturer that may have an increased benefit from bevacizumab treatment. It heard from the clinical specialist that the groups identified by the manufacturer were key subgroups. The Committee noted the clinical specialist's comment that further research into whether there are any clinical or biological subgroups (such as subgroups by biological markers) for whom bevacizumab is particularly beneficial would be useful. The Committee concluded that no robust evidence on subgroups was currently available and that the data that were available were not reliable and could not be carried forward as the basis for a cost-effectiveness analysis.\n\n# Cost effectiveness\n\nThe Committee discussed the pair wise cost-effectiveness estimates of bevacizumab plus paclitaxel as presented by the manufacturer. The Committee noted that the manufacturer had provided two base cases, one of which was based on average prices paid by NHS trusts for paclitaxel over a 4-month period and a patient access scheme for bevacizumab. The Committee was aware that no patient access scheme had been approved by the Department of Health and that therefore the scheme could not be taken into account in the consideration of cost effectiveness. The Committee was also aware that it was not in accordance with the NICE methods guide for the manufacturer to use average prices paid by NHS trusts for paclitaxel over a 4-month period rather than a nationally agreed discounted price that is consistently available to the NHS. However, the Committee noted the confirmation from the Department of Health Commercial Medicines Unit that discounts for paclitaxel are in a range greater than 95% from the BNF list price of the branded presentation and that prices within these ranges are available to all NHS hospital trusts in England. The Committee concluded that it would consider the range of the ICERs based both on the list prices and the average prices paid by NHS trusts for paclitaxel.\n\nThe Committee was aware that the manufacturer's analysis used a series of pair wise comparisons for bevacizumab plus paclitaxel relative to each separate comparator regimen. The Committee accepted comments from the ERG that the correct methodological approach would have been a fully incremental analysis. The Committee noted that the incremental analysis carried out by the ERG resulted in ICERs that were similar to the pair wise ICERs. The Committee therefore concluded that, taking this into account, together with the fact that the ERG's exploratory analyses had been conducted using the pair wise ICERs, these were appropriate for consideration in this instance.\n\nThe Committee noted that the manufacturer's base case assumed that the clinical effectiveness of all the comparators (that is, 3-weekly docetaxel, gemcitabine plus paclitaxel and 3-weekly paclitaxel) were the same as weekly paclitaxel. The manufacturer subsequently conducted revised analyses substituting the clinical effectiveness results from the indirect comparison. The Committee noted its earlier conclusions that the results of the indirect comparison were not reliable and that there were only two relevant comparators. In addition, the Committee heard from the clinical specialist that weekly paclitaxel and 3-weekly docetaxel were not considered to demonstrate clinically meaningful differences in effectiveness. The Committee concluded that the cost-effectiveness estimates derived from assuming comparators had equivalent effectiveness to weekly paclitaxel were acceptable.\n\nThe Committee discussed the way in which the manufacturer had modelled overall survival in the economic model provided in the original submission. It noted that a key assumption made by the manufacturer was that patients would have the same risk of dying per unit time once disease progressed, regardless of the first-line treatment they had received. This resulted in improvements in observed progression-free survival being carried over to projected improvements in overall survival. The Committee was aware that there are various ways of modelling that would result in different estimates of overall survival. The Committee noted that the manufacturer's model (whereby overall survival was independent of previous treatments received) resulted in mean life years of 2.68\xa0years in the bevacizumab plus paclitaxel arm and 2.33\xa0years in the paclitaxel alone arm (an incremental benefit of 0.35\xa0years) and a pair wise ICER of £118,000 per QALY gained, using the list price for paclitaxel. The manufacturer indicated that this represented an optimistic scenario compared with the trial data. The manufacturer did not provide results for a scenario including the average price for paclitaxel paid by NHS trusts without the patient access scheme; however, an analysis of this by the ERG indicated an ICER of £110,500 per QALY gained. The Committee also examined the exploratory analyses carried out by the ERG that attempted to calibrate overall survival in the model with that directly observed in the E2100 trial by using an area under the curve method. These analyses resulted in mean life years of 2.16\xa0years in the bevacizumab plus paclitaxel arm and 2.13\xa0years in the paclitaxel alone arm (an incremental benefit of 0.03\xa0years) and a pair wise ICER of £259,000 per QALY gained, based on the list price for paclitaxel. Using the average price for paclitaxel paid by NHS trusts, the ERG reported that the ICER remained over £200,000 per QALY gained. The ERG acknowledged that this represented a pessimistic scenario. The Committee therefore concluded that the true ICER for bevacizumab plus paclitaxel compared with weekly paclitaxel probably lay between £110,000 and £259,000 per QALY gained.\n\nThe Committee noted that the ICER for bevacizumab plus paclitaxel versus docetaxel alone presented by the manufacturer was £115,000 per QALY gained, based on list prices for paclitaxel. Although the ERG did not conduct a further exploratory analysis for this comparison, the Committee considered that it would also have resulted in a substantially higher ICER. The Committee concluded that the true pair wise ICER for bevacizumab plus paclitaxel compared with 3-weekly docetaxel was over £115,000 per QALY gained.\n\nThe Committee noted that the manufacturer did not provide any clinical or cost-effectiveness data related to bevacizumab plus docetaxel, even though it was specified in the scope. The Committee considered the manufacturer's statement that it can be inferred from the high ICERs in the model that bevacizumab plus docetaxel (the more expensive taxane) is unlikely to provide a more cost-effective outcome than the analysis presented in the submission and, hence, a full economic analysis of bevacizumab plus docetaxel was not warranted. The Committee agreed that the ICER for bevacizumab plus docetaxel would be higher than the ICER for bevacizumab plus paclitaxel compared with weekly paclitaxel and 3-weekly docetaxel.\n\nThe Committee discussed the estimates of the ICERs given by the manufacturer using subgroup data from the E2100 study. For the triple negative subgroup, the cost per QALY for bevacizumab plus paclitaxel ranged from £64,100 to £87,900 per QALY gained depending on the comparator and whether the list price for paclitaxel was used or the average price for paclitaxel paid by NHS trusts was used. For the prior taxane-treated subgroup, the corresponding range was £57,400 to £74,600 per QALY gained. The Committee noted that these estimates remained above the conventional levels normally considered cost effective, and would be further increased if alternative techniques were used to model overall survival. The Committee considered that because of the uncertainty around the subgroup clinical effectiveness estimates, those estimates could not be carried forward to form the basis of a cost-effectiveness analysis and guidance to the NHS. The Committee concluded that the estimates of cost effectiveness for the intention-to-treat population represented the most plausible estimate of cost effectiveness for bevacizumab.\n\nThe Committee discussed whether there were any equality issues relating to population groups protected by equality legislation. It noted information from the manufacturer's submission relating to the potential for worse outcomes in lower socioeconomic groups or by ethnicity. The Committee heard from the clinical specialist that there may be differences in overall treatment outcomes between these groups, but that they are likely to result from factors such as lower uptake of screening or later presentation of disease rather than differences in treatment. The Committee noted that the triple negative subgroup may be over-represented in some ethnic groups. The Committee concluded that there was no evidence of differences in access to treatment or response to treatment by socioeconomic status or ethnicity in patients with disease at the metastatic stage.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of people with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust.\n\nThe Committee discussed whether bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer fulfilled the criteria for a life-extending, end-of-life treatment. The Committee noted that the E2100 trial data indicated that median overall survival in the paclitaxel alone arm was 24.8\xa0months. The Committee considered the fact that this was just above the defined limit of life expectancy of less than 24\xa0months in the end-of-life criteria. The Committee also noted that the change in median overall survival was an increase of 1.7 months with bevacizumab plus paclitaxel compared with paclitaxel alone. The Committee accepted that, although it was possible that this increase had been underestimated (because of the possibility of crossover or additional treatments), there was no robust evidence that bevacizumab plus paclitaxel offers an extension to life of an additional 3\xa0months, compared with paclitaxel alone. The Committee agreed that the robustness of evidence for the subgroups was not convincing; therefore, the Committee did not discuss whether the subgroups presented fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee also noted that bevacizumab is licensed for a relatively large population across a range of indications, such as colorectal cancer, non-small-cell lung cancer and renal cell carcinoma, and hence does not meet the third criterion that the treatment should be licensed for small populations. The Committee concluded that bevacizumab in combination with a taxane did not fulfil the criteria for special consideration as a life-extending, end-of-life treatment.\n\nIn summary, the Committee concluded that the most plausible ICER for bevacizumab plus paclitaxel versus weekly paclitaxel was between £110,000 and £259,000 per QALY gained and that the ICER for bevacizumab plus paclitaxel versus docetaxel would be greater than £115,000 per QALY gained. The Committee accepted the manufacturer's statement that the ICER for bevacizumab plus docetaxel would be higher than that for bevacizumab plus paclitaxel since docetaxel is the more expensive taxane. The Committee considered that although the subgroup results were promising in terms of potential clinical benefit, they were not sufficiently robust to develop guidance and could not be carried forward as the basis for a cost-effectiveness analysis. The Committee concluded that bevacizumab in combination with a taxane as a first-line treatment for metastatic breast cancer was not a cost-effective use of NHS resources.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA214 (STA)\n\n\n\nAppraisal title: Bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer\n\nFAD section\n\nKey conclusion\n\nBevacizumab in combination with a taxane is not recommended for the first-line treatment of metastatic breast cancer. Patients currently receiving bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer should have the option to continue therapy until they and their clinicians consider it appropriate to stop. The Committee concluded that bevacizumab in combination with a taxane as a first-line treatment for metastatic breast cancer was not a cost-effective use of NHS resources.\n\n, 1.2\n\n\n\nCurrent practice\n\nClinical need of patients including the availability of alternative treatments\n\nThe clinical specialist stated that in current practice, taxanes (that is, weekly paclitaxel or 3-weekly docetaxel) are offered as first-line treatment for the majority of people with metastatic breast cancer in England and Wales.\n\nThe Committee heard from the clinical specialist that for women with triple negative cancers (that is, cancers that do not have receptors for oestrogen, progesterone or HER2) there may be worse outcomes.\n\nThe Committee heard from the clinical specialist that there was an area of clinical need associated with prior taxane use as 30% to 40% of patients would have received taxanes in the adjuvant setting. These patients would generally have a worse prognosis and might need different treatment options if their disease returned following adjuvant treatment.\n\n\n\n, 4.9, 4.10\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee heard that bevacizumab is the first VEGF-targeted therapy for this indication.\n\n\n\nThe Committee heard about the importance and significance of progression-free survival for patients in terms of being able to carry out normal daily activities, as well as being a therapeutic aim of treatment for clinicians. The Committee concluded that it was likely that bevacizumab plus paclitaxel improved progression-free survival, but that there was no robust evidence that bevacizumab plus paclitaxel improved overall survival compared with weekly paclitaxel alone. The Committee concluded that the magnitude of health-related quality of life benefits with bevacizumab plus paclitaxel compared with paclitaxel alone was uncertain.\n\n\n\n, 4.4, 4.5\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nBevacizumab in combination with paclitaxel or docetaxel has a marketing authorisation for 'first-line treatment of patients with metastatic breast cancer'.\n\n\n\n\n\nAdverse events\n\n\n\nThe Committee understood that most adverse events could be satisfactorily managed (for example with dose reductions). Specific adverse events associated with bevacizumab, notably hypertension, were also readily treatable. The Committee concluded that the addition of bevacizumab did not lead to any unacceptable toxicity compared with paclitaxel alone, and that adverse effects were manageable.\n\n\n\n\n\nEvidence for clinical effectiveness\n\nQuality, availability and nature of evidence\n\n\n\nThe Committee noted that the original submission was based on one trial (E2100) which compared bevacizumab plus paclitaxel with weekly paclitaxel.\n\nThe Committee heard from the ERG that the E2100 trial had several limitations, such as the lack of blinding. The Committee heard from the clinical specialist that the response in E2100 to paclitaxel alone was lower than demonstrated in previous studies.\n\n\n\nThe Committee noted that evidence from the AVADO study for the clinical effectiveness of bevacizumab plus docetaxel had been provided by the manufacturer after consultation on the appraisal consultation document.\n\n\n\nThe Committee noted the ERG's comments related to the reliability of the indirect treatment comparison included in the manufacturer's submission and concluded that the indirect treatment comparison was not robust and that the results were not considered reliable.\n\n\n\n, 4.4, 4.7, 4.8\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\n\n\nThe Committee concluded that the relevant comparators for bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer are weekly paclitaxel and 3-weekly docetaxel.\n\n\n\nThe Committee understood that the manufacturer had not considered the AVADO trial in its submission because the dose of docetaxel (100\xa0mg/m2) was considered to be higher than that used in clinical practice. The Committee heard from the clinical specialist that the dose used in the trial was standard for 3-weekly docetaxel in the absence of contraindications and therefore the trial data were relevant to UK clinical practice. The Committee noted the manufacturer's comment in the appraisal consultation document that the AVADO dosing regimen of 9 cycles of 100mg/m2 docetaxel was not routine UK clinical practice as 3-weekly docetaxel was usually given for 6 cycles.\n\n\n\n\n\n,\n\n\n\nUncertainties generated by the evidence\n\n\n\nThe Committee concluded that it was likely that bevacizumab plus paclitaxel improved progression-free survival relative to weekly paclitaxel, but that there was no robust evidence that bevacizumab plus paclitaxel improved overall survival compared with weekly paclitaxel alone.\n\n\n\nThe Committee was aware that a statistically significant improvement in health-related quality of life at 33 weeks was only demonstrated when extreme values were imputed. The Committee also heard from the clinical specialist that the measures of psychological elements and emotional wellbeing were not provided by the manufacturer. The Committee concluded that the magnitude of health-related quality of life benefits with bevacizumab plus paclitaxel compared with paclitaxel alone was uncertain.\n\n\n\nThe Committee considered that although the results of the subgroup analyses were promising in terms of possible clinical benefit, they were not sufficiently robust to use for the development of guidance.\n\n\n\n, 4.5, 4.11\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nFor the subgroup of women with triple negative cancers, the Committee noted that while it was plausible that bevacizumab could be more effective in some tumour types than others, there was no proposal of a biologically plausible specific mechanism of effect for bevacizumab having an increased benefit for this subgroup.\n\n\n\nFor the prior taxane-treated subgroup, the Committee noted that although there could be taxane resistance in this subgroup, there were no specific biological markers or other hypotheses to suggest why VEGF agents would work more effectively in this subgroup compared with the intention-to-treat population.\n\n, 4.10\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee discussed the E2100 trial which compared bevacizumab plus paclitaxel with weekly paclitaxel. The trial demonstrated a statistically significant increase in median progression-free survival of 5.5 months, from 5.8 months in the paclitaxel alone arm to 11.3 months in the bevacizumab plus paclitaxel arm. However, the Committee noted that the trial did not produce similar results for overall survival, with a non-statistically significant increase in median survival of 1.7 months, from 24.8 months with paclitaxel alone to 26.5 months with bevacizumab plus paclitaxel.\n\n\n\nThe Committee noted that the results from the AVADO study demonstrated an approximate 2-month, statistically significant improvement in progression-free survival for bevacizumab at a dose of 15 mg/m2 plus docetaxel. Overall survival results indicated a non-statistically significant reduction in median overall survival from 31.9 months with docetaxel alone to 30.2 months with the addition of bevacizumab (95% CI 0.7 to 1.33). The Committee concluded that bevacizumab plus docetaxel was modestly clinically effective compared with docetaxel alone in terms of progression-free survival.\n\n\n\nThe Committee discussed the results of the manufacturer's meta-analysis that demonstrated that the progression-free survival and overall survival hazard ratios for the triple negative subgroup (0.63 and 0.96) were indistinguishable from those of the intention-to-treat population (0.64 and 0.97). Moreover, the results for the overall survival difference were not statistically significant (95% CI 0.79 to 1.16). The Committee concluded that there was no evidence of any greater clinical benefit in the triple negative subgroup than in the intention-to-treat population.\n\n\n\nFor the prior taxane-treated subgroup, the Committee recognised that there was a statistically significant result in overall survival estimates from the E2100 trial, from 17.6 to 26.3 months with the addition of bevacizumab (95% CI 0.45 to 0.99), and in the meta-analysis for the prior taxane-treated subgroup, from 21.3 to 26.9 months with the addition of bevacizumab (95% CI 0.55 to 0.97). However, the Committee identified a number of concerns that questioned the robustness of the data. The Committee considered that although the results of the prior taxane-treated subgroup analyses were promising in terms of possible clinical benefit, they were not sufficiently robust to use for the development of guidance.\n\n\n\n, 4.4, 4.7, 4.9, 4.10, 4.11\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nThe manufacturer used a Markov model to evaluate the cost effectiveness of bevacizumab plus paclitaxel compared with weekly paclitaxel, 3-weekly docetaxel and gemcitabine plus paclitaxel, using pair wise comparison for bevacizumab plus paclitaxel with each separate comparator regimen. As an additional analysis, the manufacturer presented a comparison with 3-weekly paclitaxel.\n\n\n\nBevacizumab plus docetaxel was not formally evaluated.\n\n\n\nThe Committee considered that because of the uncertainty around the subgroup clinical effectiveness estimates those estimates could not be carried forward to form the basis of a cost-effectiveness analysis and guidance to the NHS. The Committee concluded that the estimates of cost effectiveness for the intention-to-treat population represented the most plausible estimate of cost effectiveness for bevacizumab.\n\n, 4.18\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nA key assumption made by the manufacturer in its base-case analysis was that patients would have the same risk of dying per unit time once disease progressed, regardless of the first-line treatment they had received. This resulted in improvements in observed progression-free survival being carried over to projected improvements in overall survival, resulting in an incremental benefit of 0.35\xa0years for the bevacizumab plus paclitaxel arm compared with the paclitaxel alone arm and a pair wise ICER of £118,000 per QALY gained, using the list price for paclitaxel. The manufacturer indicated that this represented an optimistic scenario compared with the trial data. Including the average price for paclitaxel paid by NHS trusts, without the patient access scheme, indicated an ICER of £110,500 per QALY gained.\n\n\n\nThe Committee also examined the exploratory analyses carried out by the ERG that attempted to calibrate overall survival in the model with that directly observed in the E2100 trial by using an area under the curve method. These analyses resulted in mean life years of 2.16 years in the bevacizumab plus paclitaxel arm and 2.13 years in the paclitaxel alone arm (an incremental benefit of 0.03 years) and a pair wise ICER of £259,000 per QALY gained, based on the list price for paclitaxel. Using the average price for paclitaxel paid by NHS trusts, the ERG reported that the ICER remained over £200,000 per QALY gained. The ERG acknowledged that this represented a pessimistic scenario.\n\n\n\n\n\nIncorporation of health-related quality of life benefits and utility values\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\n\n\nNo health-related benefits were identified that were not included in the economic models\n\n\n\n\n\n\n\nNA\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nThe Committee concluded that the most plausible ICER for bevacizumab plus paclitaxel versus weekly paclitaxel was between £110,000 and £259,000 per QALY gained and that the ICER for bevacizumab plus paclitaxel versus docetaxel would be greater than £115,000 per QALY gained. The Committee accepted the manufacturer's statement that the ICER for bevacizumab plus docetaxel would be higher than that for bevacizumab plus paclitaxel since docetaxel is the more expensive taxane.\n\n\n\nAdditional factors taken into account\n\nPatient access scheme\n\n\n\nThe Committee noted that the manufacturer had provided two base cases, one of which was based on average prices for paclitaxel paid by NHS trusts over a 4-month period and included a patient access scheme for bevacizumab. The Committee was aware that no patient access scheme had been approved by the Department of Health and therefore the scheme could not be taken into account in the consideration of cost effectiveness.\n\n\n\nEnd-of-life considerations\n\n\n\nThe Committee concluded that bevacizumab in combination with a taxane did not fulfil the criteria for being a life-extending, end-of-life treatment.\n\n\n\nEqualities considerations, Social value judgements\n\n\n\nThe Committee concluded that there was no evidence of differences in access to treatment or response to treatment by socioeconomic status or ethnicity in patients with disease at the metastatic stage.\n\n", 'Recommendations for further research': 'Further research designed to investigate differences in health-related quality of life and the clinical effectiveness of bevacizumab in subgroups, such as those with prior taxane exposure, would be particularly useful.', 'Related NICE guidance': 'Advanced breast cancer: diagnosis and treatment. NICE clinical guideline 81 (2009).\n\nBevacizumab for the first-line treatment of metastatic breast cancer (terminated appraisal).NICE technology appraisal 147 (2008).\n\nGemcitabine for the treatment of metastatic breast cancer. NICE technology appraisal guidance 116 (2007).', 'Review of guidance': 'The guidance on this technology will be considered for review in July 2013.\n\nAndrew DillonChief ExecutiveFebruary 2011', 'Changes after publication': 'February 2014:\n minor maintenance\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nIt updates and replaces terminated technology appraisal 147, Bevacizumab in combination with paclitaxel for the first-line treatment of metastatic breast cancer, issued June 2008.\n\nThe recommendations from this guideline have been incorporated into a NICE Pathway. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta214
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Evidence-based recommendations on bevacizumab (Avastin), with a taxane, for treating metastatic breast cancer in adults.
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3c4259edd87df7bf5186b0ec2bbfa70b5cbea3a3
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nice
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Bendamustine for the first-line treatment of chronic lymphocytic leukaemia
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Bendamustine for the first-line treatment of chronic lymphocytic leukaemia
Evidence-based recommendations on bendamustine for treating chronic lymphocytic leukaemia in adults.
# Guidance
Bendamustine is recommended as an option for the first-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate.# The technology
Bendamustine (Levact, Napp Pharmaceuticals) is an alkylating anti-tumour agent. It has a UK marketing authorisation for the 'first-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate'.
The most common adverse reactions with bendamustine hydrochloride are haematological adverse reactions (leukopenia, thrombocytopenia), dermatological toxicities (allergic reactions), constitutional symptoms (fever) and gastrointestinal symptoms (nausea, vomiting). For full details of side effects and contraindications, see the summary of product characteristics.
Bendamustine is administered by intravenous infusion, over 30–60 minutes on days 1 and 2, every 4 weeks. Dose depends on body surface area (100 mg/m²). Bendamustine is available as 25-mg vials in packs of 5 and 20 for £347.26 and £1379.04 respectively, and 100-mg vials in packs of 5 for £1379.04 (excluding VAT; 'Monthly index of medical specialities' , November 2010). The mean cost of bendamustine per person taken from the manufacturer's submission is £4741.54, assuming a body surface area of 1.72 m2 and an average treatment course of 4.9 cycles (including product wastage). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of bendamustine and a review of this submission by the Evidence Review Group (ERG; appendix B).
# Clinical effectiveness
One trial was identified by the manufacturer for inclusion in its submission to NICE. Trial 02CLLIII compared bendamustine with chlorambucil in 319 people with previously untreated chronic lymphocytic leukaemia, for whom fludarabine-based therapy was not considered appropriate. It was a phase III, open-label (because of the method of administration), multicentre parallel group international study comparing initial treatment of patients with Binet stage B or C chronic lymphocytic leukaemia. This study was carried out at 45 sites across Europe, including one centre in the UK. Recruitment started in November 2002 and follow-up was completed in June 2008, 1 year after the last enrolled patient completed treatment.
The manufacturer considered that patients in trial 02CLLIII were representative of the group of patients in the UK who would usually be treated with chlorambucil, that is, people for whom fludarabine-based therapy was not considered appropriate. The manufacturer stated that the group of patients currently treated with chlorambucil in the UK is heterogeneous with respect to performance status, age and comorbidities. In study 02CLLIII, 51% of patients were aged below 65 years and 49% were aged 65 years or above. Patients also had a range of World Health Organization (WHO) performance status scores: 67% with WHO 0, 28% with WHO 1 and 3% with WHO 2. The manufacturer also highlighted that a study of fludarabine combination therapy (trial CLL8) was recruiting at the same time as trial 02CLLIII. Therefore, clinicians nominating their patients for a clinical trial would have judged the suitability of fludarabine-based therapy for them and put them forward for the most appropriate treatment.
Patients in trial 02CLLIII were randomised 1:1 to receive either intravenous bendamustine or oral chlorambucil (stratified by centre and Binet stage). In the bendamustine group, participants received 100 mg/m²/day intravenously over 30 minutes on days 1 and 2 of a 28-day treatment cycle. The next cycle started on day 29. In the chlorambucil group, patients were administered 0.8 mg/kg (Broca's normalised weight in kg = height in cm minus 100) orally on days 1 and 15 or, if necessary, given as divided doses on days 1-2 and days 15-16 of a 28-day treatment cycle. The next cycle started on day 29. Patients were followed up every 3 months. Patients' response to treatment was assessed after three treatment cycles and at the end of treatment. The median number of treatment cycles per patient was six in both groups. The mean number of treatment cycles per patient was 4.9 (standard deviation = 1.7) in both groups. Following first-line treatment with chlorambucil, patients who remained progression-free for at least 12 months could be re-treated with chlorambucil. 63.1% received one or more re-treatment cycles. The mean number of cycles for those patients who were re-treated was 1.13.
There were two primary outcomes: overall response rate, which included complete response, nodular partial response and partial response; and progression-free survival (the time from randomisation to first progressive disease, or relapse after intercurrent remission or death owing to any cause, whichever occurred first). There were five secondary outcomes: time to progression of disease, or relapse, or death; duration of response or remission; overall survival; quality of life (assessed using European Organisation for Research and Treatment of Cancer criteria); and adverse events (toxicities).
## Response rates
Bendamustine was associated with a significantly higher overall response rate compared with chlorambucil (68% of participants compared with 31% respectively, relative risk = 2.22, 95% confidence interval 1.76 to 2.81), a higher likelihood of achieving a complete response (31% of participants compared with 2% respectively, RR = 16.15, 95% CI 7.36 to 35.46) and a higher likelihood of achieving a nodular partial response (11% of participants compared with 3% respectively, RR = 4.12, 95% CI 1.56 to 10.88). There was no statistically significant difference between treatments for partial response.
Regardless of Binet stage, there was a higher likelihood of overall response and of complete response with bendamustine compared with chlorambucil. The manufacturer highlighted that the differences in response rates between the treatment groups were maintained regardless of age, but that variation by age group was greater in the results for the bendamustine group: the overall response rate for the bendamustine arm was 72% for people aged below 65 years and 64% for those aged 65 years or older (p > 0.3). This compared with 28% and 33% respectively within the chlorambucil arm (p > 0.6).
## Survival
Median progression-free survival was 21.6 months in the bendamustine arm compared with 8.3 months in the chlorambucil arm (hazard ratio = 4.37, 95% CI 3.14 to 6.07, p < 0.0001). This difference between the treatment groups was evident in patients with Binet stage B disease (21.4 months versus 9.0 months) and for stage C disease (25.4 months versus 6.3 months).
In terms of overall survival after 35 months of follow-up, 72 of the trial patients had died: 31 in the bendamustine group and 41 in the chlorambucil group (hazard ratio = 1.45, 95% CI 0.91 to 2.31, p = 0.1623). Death due to chronic lymphocytic leukaemia was reported for 13 patients in the bendamustine group and 21 patients in the chlorambucil group. The manufacturer stated that an estimation of median overall survival was possible only for patients in the chlorambucil group (65.4 months).
The manufacturer presented a breakdown of overall survival according to response rate. The manufacturer suggested that the numbers of patients in whom complete response and nodular partial response was seen, drove the overall survival advantage. The manufacturer also suggested that this was in line with the published literature, which contains increasing evidence that a meaningful remission is needed, particularly a complete remission, to gain an improvement in overall survival from therapy.
The manufacturer reported on an unpublished abstract that described results from study 02CLLIII after a median observation time of 54 months. The results from this study showed that bendamustine offered significantly greater response rates and progression-free survival and a much longer time to next treatment than chlorambucil. The manufacturer commented that this confirmed the overall survival benefit for bendamustine compared with chlorambucil, but that the result was not statistically significant (hazard ratio = 1.3 in favour of bendamustine, p = 0.24).
## Quality of life
During the treatment period, patients' quality of life was assessed using the EORTC quality-of-life questionnaires. Patients' overall quality of life was modestly improved in both groups during treatment with no significant differences between the groups. The manufacturer explained in its submission that the quality-of-life data collected during the trial showed that patients receiving the more effective therapy (bendamustine) experienced a greater number of adverse events during the treatment period, leading to a quality-of-life detriment in some health dimensions.
## Adverse events
The manufacturer's submission reported that most adverse events in study 02CLLIII were haematological, that these were generally higher in number in the bendamustine group than in the chlorambucil group, and that they were usually manageable and of short duration. Overall, adverse events were reported in 89% (n = 143) of the bendamustine group and 81% (n = 122) of the chlorambucil group. Fifty patients had serious adverse events: 31 (19%) in the bendamustine group and 19 (13%) in the chlorambucil group. The most common serious adverse events in the bendamustine group were hypersensitivity, pneumonia, anaemia, vomiting, pyrexia and tumour-lysis syndrome. The most common serious adverse event in the chlorambucil group was herpes zoster.
Overall, 54 (34%) of patients in the bendamustine group and 46 (31%) in the chlorambucil group needed at least one dose reduction. The most common reasons for dose reduction in both groups were neutropenia and thrombocytopenia. Of the trial population, 23 were withdrawn from the study due to unacceptable toxicity or because the risk/benefit assessment was no longer considered acceptable by the investigator (18 in the bendamustine group and five in the chlorambucil group). The most frequent adverse events leading to withdrawal from the study were hypersensitivity reactions including skin and subcutaneous tissue reactions (nine patients treated with bendamustine and two treated with chlorambucil).
# Cost effectiveness
The manufacturer developed a de novo economic model using a Markov framework to estimate the cost effectiveness of bendamustine compared with chlorambucil for the first-line treatment of chronic lymphocytic leukaemia in patients for whom fludarabine-based therapies were considered inappropriate. The model used a lifetime time horizon, which was assumed to be 35 years, and a cycle length of 3 months. The model started with the patient entering a course of first-line treatment with either bendamustine or chlorambucil. Patients who remained progression free on chlorambucil for at least 12 months were re-treated with chlorambucil, whereas the base-case analysis assumed that patients could be treated with bendamustine only once. All patients began treatment in the stable disease health state. In the next model cycle they moved to the state representing their best overall response: stable disease, partial response, complete response, progressive disease or death. The patient moved around the model according to transition probabilities, derived from study 02CLLIII, until death. Alternatively if the patient entered the progressive state they could move to a second stage of the model, in which they had an equal chance of being offered treatment with fludarabine plus cyclophosphamide, or best supportive care.
If the patient entered the fludarabine plus cyclophosphamide treatment option, they were modelled as receiving treatment, starting in the stable disease state, then moving around the model in the same way as for first-line treatment. In this part of the model, if the patient moved into the progressive disease stage they may have moved into supportive care, or entered the death state. At the supportive care stage, the patient received best supportive care until death. In total, 39 health states were modelled.
The costs used were from the perspective of the NHS and Personal Social Services (PSS) and were for drug acquisition, drug administration, disease management (such as visits to the haematologist, blood tests and blood transfusions), and for adverse events. The manufacturer commissioned an advisory board of five UK haematologists to investigate treatment pathways and estimate resource use for other costs of chronic lymphocytic leukaemia while on treatment. Resource use when not on drug treatment (first or second line), including for adverse events, was informed by clinical experts, and was assumed to be independent of treatment arm.
The mean cost of bendamustine per person assumed in the manufacturer's model was £4741.54 assuming a body surface area of 1.72 m2, and an average treatment course of 4.9 cycles (including product wastage). Drug costs for chlorambucil and fludarabine plus cyclophosphamide were taken from the 'British national formulary' (edition 59). The mean cost of chlorambucil was £91.76 based on a Broca's weight of 68.73 kg for 4.9 treatment cycles. The mean cost of second-line treatment with fludarabine plus cyclophosphamide was £1250.54. Total costs of treatment (including cost of therapy and other costs – the costs of infusion, haematologist outpatient visits, blood count, biochemistry and antiemetic cost per cycle) were: £7673.00, £1136.60 and £2232.51 for treatment with bendamustine, chlorambucil, and fludarabine plus cyclophosphamide respectively.
Utilities in the manufacturer's model were derived using two different methods. One method of deriving utilities for the model was to estimate utility using vignettes. The vignettes described various disease-specific health states, and participants from the UK general population were asked to value these health states using the standard gamble method (Beusterien et al, 2010). With the exception of the treatment period (see below), utility values were assigned to health states based on Beusterien et al (2010).
In the second method, utilities in the treatment period were based on the quality-of-life data collected in study 02CLLIII (EORTC-C30) and obtained by using a mapping equation to derive EQ-5D utility estimates from the EORTC-C30. The mapping equation was developed using a dataset of 199 patients with inoperable oesophageal cancer, in which the EORTC-C30 and the EQ-5D were both collected. For the bendamustine and chlorambucil treatment period (about 4.9 months), utility was set to 0.70 in both groups.
The results of the manufacturer's model gave a total cost (including cost of therapy and other costs ) per cycle of £49,000 for bendamustine and £33,821 for chlorambucil. Bendamustine was associated with more quality-adjusted life years (QALYs) than chlorambucil: 4.82 QALYs compared with 3.55 QALYs, resulting in a cost per QALY gained of £11,960 for bendustamine. Treatment with bendamustine was predicted to yield a mean of 1.27 extra QALYs compared with chlorambucil, of which 0.98 were gained in progression-free survival and 0.29 in progressive disease. Treatment with bendamustine was expected to cost £15,179 more per person than chlorambucil. This difference is largely explained by the greater costs associated with bendamustine in the following: per person acquisition cost compared with chlorambucil (+£4576), first-line drug administration (+£1216), blood transfusion (+£6299), and haematologist visits in progressive disease (+£2379).
The manufacturer presented estimates of cost effectiveness for three subgroups: people aged 65 years or older; people with a WHO physical status of 1 or higher; and people aged 65 years or older who also had a WHO physical status of 1 or higher. The data suggested that the treatment effect of bendamustine was maintained across these subgroups, although uncertainty around the treatment effects was high due to the smaller sample sizes. Incremental cost-effectiveness ratios (ICERs) were lower than £15,000 regardless of subgroup.
The manufacturer conducted univariate sensitivity analyses around inputs into the model including treatment effects, survival distributions, treatment pathway after first-line therapy, data sources for subsequent line therapies, utilities, discount rate, time horizon, patient's body surface area, time to retreatment, response rates and costs. The one-way sensitivity analyses had little effect on the cost effectiveness of bendamustine relative to chlorambucil, with results of the cost per QALY gained ranging from £4886 to £13,387.
The manufacturer estimated the probability of the two treatments being cost effective at given thresholds. The probabilities of bendamustine being cost effective were 90% at a threshold of £20,000 per QALY gained, 96% at £25,000 and 98% at £30,000.
# ERG comments
## Clinical effectiveness
The ERG commented that the manufacturer conducted appropriate searches, that the submission contained all the relevant studies and the relevant data within those studies, and that the submitted evidence in the manufacturer's submission adequately reflected the decision problem.
The ERG noted that the evidence base for this appraisal comprised only one randomised controlled trial (RCT). Nevertheless, the ERG found that study 02CLLIII was of good quality and reflected UK clinical practice. The ERG noted that study 02CLLIII was an open-label study and, therefore, lacked blinding for both participants and investigators, which introduced the potential for bias. However, outcomes were reviewed by an independent review team according to criteria defined by the National Cancer Institute Working Group on chronic lymphocytic leukaemia. The ERG noted that study 02CLLIII was an international study, employing 45 centres across Europe, one of which was in the UK, but that no further details were reported about the other sites involved or the number of patients recruited in the UK, and that no analysis by country was performed. The ERG commented that since any multicentre trial may have inherent variations in disease management, knowing the proportion of trial participants based in the UK may improve confidence about applicability of trial results in this country.
The ERG highlighted that patients for whom fludarabine was unsuitable were noted in the manufacturer's submission (section 2.1, page 21) to be 'more elderly...with comorbidities and lower performance status'. Therefore the ERG questioned whether the 65–70% of patients in study 02CLLIII with a WHO performance status of 0, coupled with a relatively young mean age of 63–64 years, were representative of the target population.
The ERG pointed out that maximum follow-up was approximately 5 years and that median survival was 2–7 years in the population of interest. As such, a longer follow-up would increase validity.
The ERG noted that because the quality-of-life data were collected only during the treatment period, it was inadequate to capture the long-term effects of bendamustine or chlorambucil. Also, patients who stopped therapy were not followed up, introducing the possibility of attrition bias.
The ERG noted that the dosage regimen used for bendamustine was the same as that proposed in the summary of product characteristics, but that the dosage regimen for chlorambucil varies in clinical practice. However, the ERG considered that the course of therapy used in study 02CLLIII was broadly consistent with UK clinical practice and so this should be considered a relatively minor issue.
## Cost effectiveness
Overall, the ERG considered that the manufacturer's economic model was of high quality and contained no logical errors. The ERG found the structure of the model to be typical of models for haematological malignancies in that the progression-free survival and progressive disease health states were modelled. The ERG considered the model to be more sophisticated than some models for the following two reasons. First, progression-free survival was split according to response: complete response, partial response or stable disease. The depth of response influenced the utilities (better responses having higher utility) and the disease-management costs (better responses carrying lower costs). Second, re-treatment with first-line therapy and subsequent second-line fludarabine combination therapy was modelled. This reflects the reality of management, in which a patient's improvement on initial therapy may permit subsequent use of fludarabine combination therapy.
The ERG commented that the utility data to inform the cost-effectiveness modelling were sparse, however it considered that this was an issue for all economic evaluations in this condition. The ERG believed that it was appropriate to use the baseline utility of 0.70 estimated from the data collected during the main RCT. Although this approach was based on mapping between EORTC and EQ-5D, rather than on EQ-5D data collected in the trial, the ERG stated that this method is supported within the NICE reference case. The ERG noted that the manufacturer based the utilities for patients after treatment on data from Beusterien et al (2010), a study commissioned by the manufacturer. The ERG was generally satisfied with the use of these data for the cost-effectiveness model, given the absence of clearly superior alternative data. Furthermore, the ERG found the cost effectiveness of bendamustine to be relatively insensitive to the source of the utilities.
The ERG was broadly satisfied with the costs used in the model. The ERG found that the modelled dosing schedules of bendamustine and chlorambucil and that the assumption of a mean of 4.9 treatment cycles per patient (as experienced in the RCT), were appropriate. It considered that there was no consensus on the appropriate dosing of chlorambucil, but that any differences between the dosing of chlorambucil in the model and in clinical practice would have a negligible effect on the cost effectiveness of bendamustine, because chlorambucil has a low acquisition cost. The ERG was satisfied with the assumptions about the costs of administration of bendamustine. The ERG considered that the cost for an outpatient visit to a haematologist (per cycle) for a patient taking bendamustine should be £270 not £131. However, the effect of this on the ICER was marginal.
The manufacturer extrapolated survival over many years within the model. The ERG cautioned that although the extrapolation in the model was considered to be reasonable, the extrapolation introduced uncertainty to the modelled overall survival, and hence to the cost effectiveness of bendamustine.
The manufacturer's base-case ICER for bendamustine versus chlorambucil was £12,000 per QALY gained (rounded up in the ERG report from £11,960 in the manufacturer's submission). The ERG disagreed with the assumptions used in the manufacturer's model on three main points (see sections 3.35 to 3.37). However when the ERG used revised figures in the manufacturer's model, the resulting ICERs were lower than the base-case ICER estimated by the manufacturer in all instances.
The ERG disagreed with the assumption in the manufacturer's economic evaluation that patients with progressive disease had a blood transfusion every 3 weeks. Instead, the ERG believed a more appropriate assumption was that patients received a blood transfusion every 4 weeks for the last 6 months of life, in both treatment arms. Under this revised assumption, the base-case ICER fell from £12,000 to £7000 per QALY gained.
The ERG believed that the treatment effect modelled by the manufacturer in terms of the hazard ratio for overall survival was too high, biasing the cost effectiveness in favour of bendamustine. When the ERG applied the hazard ratio for overall survival from the most mature data provided by the manufacturer (1.30 instead of 1.66 as assumed in the manufacturer's model), the manufacturer's base-case ICER decreased from £12,000 to £11,700 per QALY gained. When the ERG applied the hazard ratio of 1.30 for overall survival together with the revised assumptions for blood transfusion costs (see section 3.35), the ICER increased from £7000 to £9700 per QALY. The ERG explained this paradox as follows: when the hazard ratio was reduced, the incremental discounted QALYs fell substantially from 1.27 to 0.70. However, the base-case incremental blood transfusion costs also decreased substantially, from £6300 to £1400. The net effect was to leave the base-case ICER virtually unchanged. On the other hand, starting with the assumption of no incremental blood transfusion costs, although incremental QALYs again fell substantially, the incremental blood transfusion costs remained at zero when the hazard ratio reduced. Therefore, the ICER increased substantially, from £7000 to £9700 per QALY gained.
The ERG disagreed with the manufacturer's assumptions about dose intensities for bendamustine and chlorambucil and frequency of visits to a haematologist when not treated. Changing the assumption for dose intensities (from 100% to the intensities seen in the RCT: 90% for bendamustine and 95% for chlorambucil) the manufacturer's base-case ICER decreased from £12,000 to £11,600 per QALY gained. Changing the assumption for the frequency of visits to a haematologist when not treated, the ICER decreased from £12,000 to £11,500 per QALY gained.
When the ERG updated the manufacturer's model with the revised assumptions for blood transfusions, the hazard ratio for overall survival, dose intensities and frequency of visits to a haematologist, as outlined in sections 3.35 to 3.37, the ICER decreased from £12,000 to £9,400 per QALY gained.
The ERG stated that it was not possible to confirm the ICERs in the subgroups (patient's age ≥ 65 years; WHO status ≥ 1; and patient's age ≥ 65 years plus WHO status ≥ 1) because there was no independent source with which to check the subgroup-specific response data and survival curves. Additionally, the ERG stated that it did not explore alternative ICERs for the subgroups because it did not have updated estimates for the hazard ratios by subgroup for overall survival.
The ERG highlighted that a higher proportion of patients in the chlorambucil arm of the RCT were given second-line drugs compared with patients in the bendamustine arm. The ERG was broadly satisfied with the manufacturer's approach to incorporating second-line drug costs, but explored two alternative methods. In the first method, the ERG costed all second-line drugs received in each treatment arm in the RCT and modelled the actual, unadjusted overall survival from the RCT. The result of this was that the manufacturer's base-case ICER fell from £12,000 to less than £10,900 per QALY gained, and the ERG's revised base-case ICER of £9,400 fell to less than £8,700 per QALY gained. In the second method, the ERG did not cost the second-line drugs received in the RCT, but estimated overall survival for each treatment arm assuming no second-line drug treatment. The ICERs fell in the same way.
Although the manufacturer identified no cost-effectiveness studies, the ERG identified a recent poster reporting a cost-effectiveness study of bendamustine versus alemtuzumab and chlorambucil for chronic lymphocytic leukaemia, presented at the 15th International Society for Pharmacoeconomics and Outcomes Research meeting in 2010. Using a discrete event simulation, taking a US payer perspective, the ICER for bendamustine versus chlorambucil was $50,800 per QALY gained, or about £33,000 per QALY gained. The ERG highlighted that the submission base-case ICER of £12,000 per QALY is substantially lower than this US study. The ERG explained this by the fact that the US study predicted a far lower life expectancy for people taking bendamustine, compared with those taking bendamustine in study 02CLLIII (predicted median overall survival of 6.1 years for the US study versus 8.3 years for study 02CLLIII) and highlighted the influence of overall survival gains in determining the cost effectiveness of bendamustine.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bendamustine, having considered evidence on the nature of chronic lymphocytic leukaemia in patients for whom fludarabine combination chemotherapy is not appropriate and the value placed on the benefits of bendamustine by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
# Clinical effectiveness
The Committee discussed the place of bendamustine in the clinical pathway for chronic lymphocytic leukaemia. The Committee heard from the clinical specialists that bendamustine is used as a first-line treatment in UK clinical practice when fludarabine combination chemotherapy is not considered an appropriate treatment, that a second round of bendamustine may be offered, and that bendamustine is sometimes used as a second-line treatment. The Committee noted that second-line treatment is currently outside of bendamustine's UK marketing authorisation.
The Committee heard from the clinical specialists that bendamustine is less toxic than fludarabine combination therapy and is a useful addition to the available treatments for patients with chronic lymphocytic leukaemia in whom fludarabine combination therapy is unsuitable. The only available treatment for these patients is chlorambucil. The Committee heard that although bendamustine is slightly more toxic than chlorambucil and is associated with more adverse events, the clinical specialists considered bendamustine to be the more effective treatment. The Committee also noted the views of the patient groups in their submissions to NICE that because of its improved efficacy compared with chlorambucil, people with the condition would be willing to accept the side effects associated with bendamustine. The Committee was satisfied from the testimonies of the clinical specialists and patient experts that bendamustine represents an important treatment for patients with chronic lymphocytic leukaemia for whom fludarabine combination therapy is not appropriate.
The Committee heard from the clinical specialists that there are no definitively agreed criteria for deciding when fludarabine combination therapy is unsuitable as a first-line treatment for patients with chronic lymphocytic leukaemia. They commented that there is a growing consensus that patients should be offered the most effective treatment that they can tolerate first. Therefore fludarabine combination therapy (that is, fludarabine, cyclophosphamide and rituximab) is first choice unless there are important factors related to age, physical fitness and the presence of comorbidities to suggest that fludarabine combination therapy should not be used. The Committee accepted, therefore, that any future NICE-recommended use of bendamustine would be determined by clinical judgement based on the factors listed above.
The Committee discussed the clinical trial data from study 02CLLIII and agreed with the ERG's comments that it was a well-conducted RCT. It noted the higher response rates and longer progression-free survival (21.6 months versus 8.3 months) in patients treated with bendamustine compared with patients treated with chlorambucil. The Committee was concerned, however, about two issues related to the clinical trial evidence. The Committee's first concern was that the trial population may not have been representative of the population that would be treated with bendamustine in clinical practice. The Committee noted the exclusion from trial 02CLLIII of patients with comorbidities including abnormal liver, renal or cardiac function. It was also aware of the high performance status of the majority of participants and the relatively low mean age (63–64 years). However the Committee was reassured by the subgroup analysis conducted by the manufacturer, which demonstrated the clinical effectiveness of bendamustine relative to chlorambucil in the trial participants who had a lower performance status and in patients aged 65 years and over. It also accepted that the exclusion criteria were standard and that there was no reason to suppose that the results would not hold in people with a lower performance status, or people with comorbidities, in particular renal impairment (which is a contraindication of fludarabine). The Committee agreed that inferences could be made about the clinical effectiveness of bendamustine for the population specified in the marketing authorisation, using the available trial data.
The Committee's second concern about the evidence from study 02CLLIII was that it may have underestimated the clinical effectiveness of chlorambucil. The Committee heard from the clinical specialists how patients treated with chlorambucil in another trial, CLL4 (which compared chlorambucil with fludarabine and fludarabine plus cyclophosphamide), experienced higher response rates and longer progression-free survival compared with the patients treated with chlorambucil in trial 02CLLIII. The Committee discussed the possible reasons for the differences in the results between the two trials. It noted the views of the clinical specialists that the variation in the results may have been because of differences in the patient populations and differences in the doses of chlorambucil used.
The Committee explored the differences in the patient populations between the two trials. It heard from the manufacturer that one way in which the patient populations of the two trials differed was that the 02CLLIII study did not include people with Binet stage A chronic lymphocytic leukaemia. It also heard from the clinical specialists that the patient population in the CLL4 trial may have been healthier than the patient population in trial 02CLLIII. The Committee was satisfied that the differences between the patient populations in the two trials may have contributed to the differences in the results for chlorambucil.
The Committee discussed the different doses of chlorambucil used in the 02CLLIII study compared with the CLL4 trial. The clinical specialists explained that the dose used in trial 02CLLIII was consistent with the dose used for other chronic lymphocytic leukaemia studies, and that the dose used in the CLL4 study was unique at the time the study was set up. The clinical specialists also explained that the cumulative dose for chlorambucil in the 02CLLIII study was approximately 85% of the dose used in the CLL4 trial, which might explain the difference in progression-free survival in the chlorambucil arms of the two trials. The Committee heard from the clinical specialists that many different doses of chlorambucil were used in UK clinical practice, but that there was an increasing shift towards the dose used in the CLL4 study, following on from the results of that trial. Furthermore, new chronic lymphocytic leukaemia trials with chlorambucil as a comparator were increasingly using the same dose as was used in the CLL4 study. The Committee accepted that the doses of chlorambucil used in the two trials may have contributed to the differences in the results but that the precise impact of this was unknown, and that this represented an important area for future research. The Committee concluded that there was sufficient evidence to demonstrate that bendamustine was more clinically effective than chlorambucil, leading to higher response rates and longer progression-free survival.
# Cost effectiveness
The Committee discussed the manufacturer's economic model. It agreed with the ERG that the manufacturer's model was of high quality and was more sophisticated than other models in the disease area. The Committee discussed that because of the added complexity of the model, the data to inform some of the model parameters, such as transition probabilities (particularly for second-line treatment) were sparse. On balance, the Committee considered that the model was appropriate and fit for purpose.
The Committee noted that the cost per QALY gained of treatment with bendamustine compared with chlorambucil was £12,000 in the manufacturer's base-case analysis. The Committee discussed the robustness of the ICER to the subgroup and sensitivity analyses conducted by the manufacturer. The Committee was satisfied with the effect of the subgroup and sensitivity analyses, noting that the ICER remained lower than £15,000 in all of the analyses.
The Committee was aware that the ERG had made some adjustments to the assumptions used in the manufacturer's economic model about the frequency of blood transfusions, the hazard ratio for overall survival, the dose intensity of bendamustine and chlorambucil and the frequency of visits to a haematologist. The Committee heard from the clinical specialists that the ERG's changes to the assumptions reflected clinical practice. The Committee noted that the effect of these adjustments caused the ICER to fall from £12,000 to £9400, thus becoming more favourable to bendamustine than the base-case ICER presented by the manufacturer. The Committee agreed that the adjustments made by the ERG were reasonable and was satisfied with the resulting effect on the ICER.
The Committee discussed the potential effect on the ICER of comparing bendamustine with the higher dose of chlorambucil given in the CLL4 study. The Committee considered that an increased dose of chlorambucil would push up the cost of chlorambucil as well as increase the number of QALYs gained. The Committee accepted that since the influence of a higher chlorambucil dose on the clinical effectiveness of the treatment had not been determined, any resulting effect on the ICER could not be quantified with any precision. The Committee agreed, however, that the ICER of bendamustine would be unlikely to increase above the level generally considered to be a cost-effective use of NHS resources. It therefore concluded that bendamustine should be recommended as a first-line treatment option for patients with chronic lymphocytic leukaemia for whom fludarabine combination chemotherapy is not appropriate.
# Summary of Appraisal Committee's key conclusions
TA216
Appraisal title: bendamustine for the first-line treatment of chronic lymphocytic leukaemia
Section
Key conclusion
Bendamustine is recommended as an option for the first-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate.
Current practice
Clinical need of patients, including the availability of alternative treatments
Bendamustine is less toxic than fludarabine combination therapy and is a useful addition to the available treatments for patients with chronic lymphocytic leukaemia in whom fludarabine combination therapy is unsuitable. The only available treatment for this group of patients is chlorambucil.
The technology
Proposed benefits of the technology
Bendamustine is considered to be a more effective treatment than chlorambucil.
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
People treated with bendamustine had, on average, higher response rates and longer progression-free survival than people treated with chlorambucil.
What is the position of the treatment in the pathway of care for the condition?
Bendamustine is used as a first-line treatment in UK clinical practice when fludarabine combination chemotherapy is not considered an appropriate treatment.
Adverse effects
Bendamustine is associated with more adverse events compared with chlorambucil. However, because of its improved efficacy in comparison with chlorambucil, the patient groups considered that people with the condition would be willing to accept the side effects associated with bendamustine.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee agreed with the ERG's comments that study 02CLLIII was a well conducted randomised controlled trial.
The Committee was concerned that the evidence from study 02CLLIII may have underestimated the clinical effectiveness of chlorambucil. The Committee was satisfied that the differences between the patient populations in the 02CLLIII study and the CLL4 study may have contributed to the differences in the results for chlorambucil. The Committee accepted that the doses of chlorambucil used in the two trials may also have contributed to the differences in the results, but that the precise impact of this was unknown. The Committee concluded that there was sufficient evidence to demonstrate that bendamustine is more clinically effective than chlorambucil.
Relevance to general clinical practice in the NHS
The Committee was concerned that the trial population in study 02CLLIII may not have been representative of the population that would be treated with bendamustine in clinical practice. The Committee agreed that inferences could be made about the clinical effectiveness of bendamustine for the population specified in the marketing authorisation, using the available trial data.
Uncertainties generated by the evidence
There are no definitively agreed criteria for deciding when fludarabine combination therapy is unsuitable as a first-line treatment for patients with chronic lymphocytic leukaemia. Fludarabine combination therapy (that is, fludarabine, cyclophosphamide and rituximab) is generally first choice unless there are important factors related to age, physical fitness and the presence of comorbidities to suggest that fludarabine combination therapy should not be used.
The influence of a higher chlorambucil dose on the relative clinical effectiveness of bendamustine has not been determined, and this represents an important area for future research.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The subgroup analyses conducted by the manufacturer demonstrated clinical effectiveness of bendamustine relative to chlorambucil in the trial participants who had a lower performance status and in patients aged 65 years and over.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
Clinical trial data from study 02CLLIII showed higher response rates and longer progression-free survival (21.6 months versus 8.3 months) in patients treated with bendamustine compared with patients treated with chlorambucil.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee agreed with the ERG that the manufacturer's model was of high quality and was more sophisticated than other models in the disease area.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee discussed that because of the added complexity of the model, the data to inform some of the model parameters, such as transition probabilities (particularly for second-line treatment) were sparse. On balance, the Committee considered that the model was appropriate and fit for purpose.
The ERG had made some adjustments to the assumptions used in the manufacturer's economic model about the frequency of blood transfusions, the hazard ratio for overall survival, the dose intensity of bendamustine and chlorambucil and the frequency of visits to a haematologist. The Committee agreed that the adjustments made by the ERG were reasonable and was satisfied with the resulting effect on the ICER (a change from £12,000 to £9400).
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
There were no issues raised about health-related quality-of-life values that were thought to be relevant. No health-related benefits were identified that were not included in the economic model.
n/a
Are there specific groups of people for whom the technology is particularly cost effective?
The base-case ICER was found to be robust to subgroup analysis. The ICER remained lower than £15,000 in all of the analyses.
What are the key drivers of cost effectiveness?
Higher response rates and longer progression-free survival.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee agreed that the adjustments made by the ERG to the manufacturer's model were reasonable and it was satisfied with the resulting change in the ICER from £12,000 to £9400. The Committee accepted that because the influence of a higher chlorambucil dose on the clinical effectiveness of the treatment had not been determined, any resulting effect on the ICER could not be quantified with any precision. The Committee agreed, however, that the ICER of bendamustine would be unlikely to increase above the level generally considered to be a cost-effective use of NHS resources.
Additional factors taken into account
Patient access schemes (PPRS)
No patient access schemes were submitted.
n/a
End-of-life considerations
The Committee did not discuss end-of-life considerations because bendamustine was considered to be cost-effective.
n/a
Equalities considerations and social value judgements
No equalities issues raised were thought to be relevant.
n/a# Recommendations for further research
Research should be carried out to compare the clinical effectiveness of bendamustine with chlorambucil at the higher dose used in the CLL4 trial.# Related NICE guidance
Ofatumumab for the treatment of chronic lymphocytic leukaemia refractory to fludarabine and alemtuzumab. NICE technology appraisal guidance 202 (2010).
Rituximab for the treatment of relapsed or refractory chronic lymphocytic leukaemia. NICE technology appraisal guidance 193 (2010).
Rituximab for the first-line treatment of chronic lymphocytic leukaemia. NICE technology appraisal guidance 174 (2009).
Fludarabine monotherapy for the first-line treatment of chronic lymphocytic leukemia. NICE technology appraisal guidance 119 (2007).
Improving outcomes in haematological cancers. NICE cancer service guidance (2003).# Review of guidance
The guidance on this technology will be considered for review in December 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveFebruary 2011# Changes after publication
February 2014: implementation section updated to clarify that bendamustine is recommended as an option for treating chronic lymphocytic leukaemia. Additional minor maintenance update also carried out.
March 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Bendamustine is recommended as an option for the first-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate.', 'The technology ': "Bendamustine (Levact, Napp Pharmaceuticals) is an alkylating anti-tumour agent. It has a UK marketing authorisation for the 'first-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate'.\n\nThe most common adverse reactions with bendamustine hydrochloride are haematological adverse reactions (leukopenia, thrombocytopenia), dermatological toxicities (allergic reactions), constitutional symptoms (fever) and gastrointestinal symptoms (nausea, vomiting). For full details of side effects and contraindications, see the summary of product characteristics.\n\nBendamustine is administered by intravenous infusion, over 30–60 minutes on days 1 and 2, every 4 weeks. Dose depends on body surface area (100 mg/m²). Bendamustine is available as 25-mg vials in packs of 5 and 20 for £347.26 and £1379.04 respectively, and 100-mg vials in packs of 5 for £1379.04 (excluding VAT; 'Monthly index of medical specialities' [MIMS], November 2010). The mean cost of bendamustine per person taken from the manufacturer's submission is £4741.54, assuming a body surface area of 1.72\xa0m2 and an average treatment course of 4.9\xa0cycles (including product wastage). Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of bendamustine and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\n# Clinical effectiveness\n\nOne trial was identified by the manufacturer for inclusion in its submission to NICE. Trial 02CLLIII compared bendamustine with chlorambucil in 319 people with previously untreated chronic lymphocytic leukaemia, for whom fludarabine-based therapy was not considered appropriate. It was a phase III, open-label (because of the method of administration), multicentre parallel group international study comparing initial treatment of patients with Binet stage B or C chronic lymphocytic leukaemia. This study was carried out at 45 sites across Europe, including one centre in the UK. Recruitment started in November 2002 and follow-up was completed in June\xa02008, 1 year after the last enrolled patient completed treatment.\n\nThe manufacturer considered that patients in trial 02CLLIII were representative of the group of patients in the UK who would usually be treated with chlorambucil, that is, people for whom fludarabine-based therapy was not considered appropriate. The manufacturer stated that the group of patients currently treated with chlorambucil in the UK is heterogeneous with respect to performance status, age and comorbidities. In study 02CLLIII, 51% of patients were aged below 65 years and 49% were aged 65 years or above. Patients also had a range of World Health Organization (WHO) performance status scores: 67% with WHO 0, 28% with WHO 1 and 3% with WHO 2. The manufacturer also highlighted that a study of fludarabine combination therapy (trial CLL8) was recruiting at the same time as trial 02CLLIII. Therefore, clinicians nominating their patients for a clinical trial would have judged the suitability of fludarabine-based therapy for them and put them forward for the most appropriate treatment.\n\nPatients in trial 02CLLIII were randomised 1:1 to receive either intravenous bendamustine or oral chlorambucil (stratified by centre and Binet stage). In the bendamustine group, participants received 100 mg/m²/day intravenously over 30 minutes on days 1 and 2 of a 28-day treatment cycle. The next cycle started on day 29. In the chlorambucil group, patients were administered 0.8 mg/kg (Broca's normalised weight in kg = height in cm minus 100) orally on days 1 and 15 or, if necessary, given as divided doses on days 1-2 and days 15-16 of a 28-day treatment cycle. The next cycle started on day 29. Patients were followed up every 3 months. Patients' response to treatment was assessed after three treatment cycles and at the end of treatment. The median number of treatment cycles per patient was six in both groups. The mean number of treatment cycles per patient was 4.9 (standard deviation = 1.7) in both groups. Following first-line treatment with chlorambucil, patients who remained progression-free for at least 12 months could be re-treated with chlorambucil. 63.1% received one or more re-treatment cycles. The mean number of cycles for those patients who were re-treated was 1.13.\n\nThere were two primary outcomes: overall response rate, which included complete response, nodular partial response and partial response; and progression-free survival (the time from randomisation to first progressive disease, or relapse after intercurrent remission or death owing to any cause, whichever occurred first). There were five secondary outcomes: time to progression of disease, or relapse, or death; duration of response or remission; overall survival; quality of life (assessed using European Organisation for Research and Treatment of Cancer [EORTC] criteria); and adverse events (toxicities).\n\n## Response rates\n\nBendamustine was associated with a significantly higher overall response rate compared with chlorambucil (68% of participants compared with 31% respectively, relative risk [RR] = 2.22, 95% confidence interval [CI] 1.76 to 2.81), a higher likelihood of achieving a complete response (31% of participants compared with 2% respectively, RR = 16.15, 95% CI 7.36 to 35.46) and a higher likelihood of achieving a nodular partial response (11% of participants compared with 3% respectively, RR = 4.12, 95% CI 1.56 to 10.88). There was no statistically significant difference between treatments for partial response.\n\nRegardless of Binet stage, there was a higher likelihood of overall response and of complete response with bendamustine compared with chlorambucil. The manufacturer highlighted that the differences in response rates between the treatment groups were maintained regardless of age, but that variation by age group was greater in the results for the bendamustine group: the overall response rate for the bendamustine arm was 72% for people aged below 65 years and 64% for those aged 65 years or older (p > 0.3). This compared with 28% and 33% respectively within the chlorambucil arm (p > 0.6).\n\n## Survival\n\nMedian progression-free survival was 21.6 months in the bendamustine arm compared with 8.3 months in the chlorambucil arm (hazard ratio = 4.37, 95% CI 3.14 to 6.07, p < 0.0001). This difference between the treatment groups was evident in patients with Binet stage B disease (21.4 months versus 9.0 months) and for stage C disease (25.4 months versus 6.3 months).\n\nIn terms of overall survival after 35 months of follow-up, 72 of the trial patients had died: 31 in the bendamustine group and 41 in the chlorambucil group (hazard ratio = 1.45, 95% CI 0.91 to 2.31, p\xa0=\xa00.1623). Death due to chronic lymphocytic leukaemia was reported for 13\xa0patients in the bendamustine group and 21 patients in the chlorambucil group. The manufacturer stated that an estimation of median overall survival was possible only for patients in the chlorambucil group (65.4 months).\n\nThe manufacturer presented a breakdown of overall survival according to response rate. The manufacturer suggested that the numbers of patients in whom complete response and nodular partial response was seen, drove the overall survival advantage. The manufacturer also suggested that this was in line with the published literature, which contains increasing evidence that a meaningful remission is needed, particularly a complete remission, to gain an improvement in overall survival from therapy.\n\nThe manufacturer reported on an unpublished abstract that described results from study 02CLLIII after a median observation time of 54 months. The results from this study showed that bendamustine offered significantly greater response rates and progression-free survival and a much longer time to next treatment than chlorambucil. The manufacturer commented that this confirmed the overall survival benefit for bendamustine compared with chlorambucil, but that the result was not statistically significant (hazard ratio = 1.3 in favour of bendamustine, p = 0.24).\n\n## Quality of life\n\nDuring the treatment period, patients' quality of life was assessed using the EORTC quality-of-life questionnaires. Patients' overall quality of life was modestly improved in both groups during treatment with no significant differences between the groups. The manufacturer explained in its submission that the quality-of-life data collected during the trial showed that patients receiving the more effective therapy (bendamustine) experienced a greater number of adverse events during the treatment period, leading to a quality-of-life detriment in some health dimensions.\n\n## Adverse events\n\nThe manufacturer's submission reported that most adverse events in study 02CLLIII were haematological, that these were generally higher in number in the bendamustine group than in the chlorambucil group, and that they were usually manageable and of short duration. Overall, adverse events were reported in 89% (n = 143) of the bendamustine group and 81% (n = 122) of the chlorambucil group. Fifty patients had serious adverse events: 31 (19%) in the bendamustine group and 19 (13%) in the chlorambucil group. The most common serious adverse events in the bendamustine group were hypersensitivity, pneumonia, anaemia, vomiting, pyrexia and tumour-lysis syndrome. The most common serious adverse event in the chlorambucil group was herpes zoster.\n\nOverall, 54 (34%) of patients in the bendamustine group and 46\xa0(31%) in the chlorambucil group needed at least one dose reduction. The most common reasons for dose reduction in both groups were neutropenia and thrombocytopenia. Of the trial population, 23 were withdrawn from the study due to unacceptable toxicity or because the risk/benefit assessment was no longer considered acceptable by the investigator (18 in the bendamustine group and five in the chlorambucil group). The most frequent adverse events leading to withdrawal from the study were hypersensitivity reactions including skin and subcutaneous tissue reactions (nine patients treated with bendamustine and two treated with chlorambucil).\n\n# Cost effectiveness\n\nThe manufacturer developed a de novo economic model using a Markov framework to estimate the cost effectiveness of bendamustine compared with chlorambucil for the first-line treatment of chronic lymphocytic leukaemia in patients for whom fludarabine-based therapies were considered inappropriate. The model used a lifetime time horizon, which was assumed to be 35\xa0years, and a cycle length of 3 months. The model started with the patient entering a course of first-line treatment with either bendamustine or chlorambucil. Patients who remained progression free on chlorambucil for at least 12 months were re-treated with chlorambucil, whereas the base-case analysis assumed that patients could be treated with bendamustine only once. All patients began treatment in the stable disease health state. In the next model cycle they moved to the state representing their best overall response: stable disease, partial response, complete response, progressive disease or death. The patient moved around the model according to transition probabilities, derived from study 02CLLIII, until death. Alternatively if the patient entered the progressive state they could move to a second stage of the model, in which they had an equal chance of being offered treatment with fludarabine plus cyclophosphamide, or best supportive care.\n\nIf the patient entered the fludarabine plus cyclophosphamide treatment option, they were modelled as receiving treatment, starting in the stable disease state, then moving around the model in the same way as for first-line treatment. In this part of the model, if the patient moved into the progressive disease stage they may have moved into supportive care, or entered the death state. At the supportive care stage, the patient received best supportive care until death. In total, 39 health states were modelled.\n\nThe costs used were from the perspective of the NHS and Personal Social Services (PSS) and were for drug acquisition, drug administration, disease management (such as visits to the haematologist, blood tests and blood transfusions), and for adverse events. The manufacturer commissioned an advisory board of five UK haematologists to investigate treatment pathways and estimate resource use for other costs of chronic lymphocytic leukaemia while on treatment. Resource use when not on drug treatment (first or second line), including for adverse events, was informed by clinical experts, and was assumed to be independent of treatment arm.\n\nThe mean cost of bendamustine per person assumed in the manufacturer's model was £4741.54 assuming a body surface area of 1.72\xa0m2, and an average treatment course of 4.9\xa0cycles (including product wastage). Drug costs for chlorambucil and fludarabine plus cyclophosphamide were taken from the 'British national formulary' (edition 59). The mean cost of chlorambucil was £91.76 based on a Broca's weight of 68.73 kg for 4.9 treatment cycles. The mean cost of second-line treatment with fludarabine plus cyclophosphamide was £1250.54. Total costs of treatment (including cost of therapy and other costs – the costs of infusion, haematologist outpatient visits, blood count, biochemistry and antiemetic cost per cycle) were: £7673.00, £1136.60 and £2232.51 for treatment with bendamustine, chlorambucil, and fludarabine plus cyclophosphamide respectively.\n\nUtilities in the manufacturer's model were derived using two different methods. One method of deriving utilities for the model was to estimate utility using vignettes. The vignettes described various disease-specific health states, and participants from the UK general population were asked to value these health states using the standard gamble method (Beusterien et al, 2010). With the exception of the treatment period (see below), utility values were assigned to health states based on Beusterien et al (2010).\n\nIn the second method, utilities in the treatment period were based on the quality-of-life data collected in study 02CLLIII (EORTC-C30) and obtained by using a mapping equation to derive EQ-5D utility estimates from the EORTC-C30. The mapping equation was developed using a dataset of 199 patients with inoperable oesophageal cancer, in which the EORTC-C30 and the EQ-5D were both collected. For the bendamustine and chlorambucil treatment period (about 4.9\xa0months), utility was set to 0.70 in both groups.\n\nThe results of the manufacturer's model gave a total cost (including cost of therapy and other costs [see 3.17]) per cycle of £49,000 for bendamustine and £33,821 for chlorambucil. Bendamustine was associated with more quality-adjusted life years (QALYs) than chlorambucil: 4.82 QALYs compared with 3.55 QALYs, resulting in a cost per QALY gained of £11,960 for bendustamine. Treatment with bendamustine was predicted to yield a mean of 1.27 extra QALYs compared with chlorambucil, of which 0.98 were gained in progression-free survival and 0.29 in progressive disease. Treatment with bendamustine was expected to cost £15,179 more per person than chlorambucil. This difference is largely explained by the greater costs associated with bendamustine in the following: per person acquisition cost compared with chlorambucil (+£4576), first-line drug administration (+£1216), blood transfusion (+£6299), and haematologist visits in progressive disease (+£2379).\n\nThe manufacturer presented estimates of cost effectiveness for three subgroups: people aged 65 years or older; people with a WHO physical status of 1 or higher; and people aged 65 years or older who also had a WHO physical status of 1 or higher. The data suggested that the treatment effect of bendamustine was maintained across these subgroups, although uncertainty around the treatment effects was high due to the smaller sample sizes. Incremental cost-effectiveness ratios (ICERs) were lower than £15,000 regardless of subgroup.\n\nThe manufacturer conducted univariate sensitivity analyses around inputs into the model including treatment effects, survival distributions, treatment pathway after first-line therapy, data sources for subsequent line therapies, utilities, discount rate, time horizon, patient's body surface area, time to retreatment, response rates and costs. The one-way sensitivity analyses had little effect on the cost effectiveness of bendamustine relative to chlorambucil, with results of the cost per QALY gained ranging from £4886 to £13,387.\n\nThe manufacturer estimated the probability of the two treatments being cost effective at given thresholds. The probabilities of bendamustine being cost effective were 90% at a threshold of £20,000 per QALY gained, 96% at £25,000 and 98% at £30,000.\n\n# ERG comments\n\n## Clinical effectiveness\n\nThe ERG commented that the manufacturer conducted appropriate searches, that the submission contained all the relevant studies and the relevant data within those studies, and that the submitted evidence in the manufacturer's submission adequately reflected the decision problem.\n\nThe ERG noted that the evidence base for this appraisal comprised only one randomised controlled trial (RCT). Nevertheless, the ERG found that study 02CLLIII was of good quality and reflected UK clinical practice. The ERG noted that study 02CLLIII was an open-label study and, therefore, lacked blinding for both participants and investigators, which introduced the potential for bias. However, outcomes were reviewed by an independent review team according to criteria defined by the National Cancer Institute Working Group on chronic lymphocytic leukaemia. The ERG noted that study 02CLLIII was an international study, employing 45 centres across Europe, one of which was in the UK, but that no further details were reported about the other sites involved or the number of patients recruited in the UK, and that no analysis by country was performed. The ERG commented that since any multicentre trial may have inherent variations in disease management, knowing the proportion of trial participants based in the UK may improve confidence about applicability of trial results in this country.\n\nThe ERG highlighted that patients for whom fludarabine was unsuitable were noted in the manufacturer's submission (section\xa02.1, page 21) to be 'more elderly...with comorbidities and lower performance status'. Therefore the ERG questioned whether the 65–70% of patients in study 02CLLIII with a WHO performance status of 0, coupled with a relatively young mean age of 63–64 years, were representative of the target population.\n\nThe ERG pointed out that maximum follow-up was approximately 5\xa0years and that median survival was 2–7 years in the population of interest. As such, a longer follow-up would increase validity.\n\nThe ERG noted that because the quality-of-life data were collected only during the treatment period, it was inadequate to capture the long-term effects of bendamustine or chlorambucil. Also, patients who stopped therapy were not followed up, introducing the possibility of attrition bias.\n\nThe ERG noted that the dosage regimen used for bendamustine was the same as that proposed in the summary of product characteristics, but that the dosage regimen for chlorambucil varies in clinical practice. However, the ERG considered that the course of therapy used in study 02CLLIII was broadly consistent with UK clinical practice and so this should be considered a relatively minor issue.\n\n## Cost effectiveness\n\nOverall, the ERG considered that the manufacturer's economic model was of high quality and contained no logical errors. The ERG found the structure of the model to be typical of models for haematological malignancies in that the progression-free survival and progressive disease health states were modelled. The ERG considered the model to be more sophisticated than some models for the following two reasons. First, progression-free survival was split according to response: complete response, partial response or stable disease. The depth of response influenced the utilities (better responses having higher utility) and the disease-management costs (better responses carrying lower costs). Second, re-treatment with first-line therapy and subsequent second-line fludarabine combination therapy was modelled. This reflects the reality of management, in which a patient's improvement on initial therapy may permit subsequent use of fludarabine combination therapy.\n\nThe ERG commented that the utility data to inform the cost-effectiveness modelling were sparse, however it considered that this was an issue for all economic evaluations in this condition. The ERG believed that it was appropriate to use the baseline utility of 0.70 estimated from the data collected during the main RCT. Although this approach was based on mapping between EORTC and EQ-5D, rather than on EQ-5D data collected in the trial, the ERG stated that this method is supported within the NICE reference case. The ERG noted that the manufacturer based the utilities for patients after treatment on data from Beusterien et al (2010), a study commissioned by the manufacturer. The ERG was generally satisfied with the use of these data for the cost-effectiveness model, given the absence of clearly superior alternative data. Furthermore, the ERG found the cost effectiveness of bendamustine to be relatively insensitive to the source of the utilities.\n\nThe ERG was broadly satisfied with the costs used in the model. The ERG found that the modelled dosing schedules of bendamustine and chlorambucil and that the assumption of a mean of 4.9 treatment cycles per patient (as experienced in the RCT), were appropriate. It considered that there was no consensus on the appropriate dosing of chlorambucil, but that any differences between the dosing of chlorambucil in the model and in clinical practice would have a negligible effect on the cost effectiveness of bendamustine, because chlorambucil has a low acquisition cost. The ERG was satisfied with the assumptions about the costs of administration of bendamustine. The ERG considered that the cost for an outpatient visit to a haematologist (per cycle) for a patient taking bendamustine should be £270 not £131. However, the effect of this on the ICER was marginal.\n\nThe manufacturer extrapolated survival over many years within the model. The ERG cautioned that although the extrapolation in the model was considered to be reasonable, the extrapolation introduced uncertainty to the modelled overall survival, and hence to the cost effectiveness of bendamustine.\n\nThe manufacturer's base-case ICER for bendamustine versus chlorambucil was £12,000 per QALY gained (rounded up in the ERG report from £11,960 in the manufacturer's submission). The ERG disagreed with the assumptions used in the manufacturer's model on three main points (see sections 3.35 to 3.37). However when the ERG used revised figures in the manufacturer's model, the resulting ICERs were lower than the base-case ICER estimated by the manufacturer in all instances.\n\nThe ERG disagreed with the assumption in the manufacturer's economic evaluation that patients with progressive disease had a blood transfusion every 3 weeks. Instead, the ERG believed a more appropriate assumption was that patients received a blood transfusion every 4 weeks for the last 6 months of life, in both treatment arms. Under this revised assumption, the base-case ICER fell from £12,000 to £7000 per QALY gained.\n\nThe ERG believed that the treatment effect modelled by the manufacturer in terms of the hazard ratio for overall survival was too high, biasing the cost effectiveness in favour of bendamustine. When the ERG applied the hazard ratio for overall survival from the most mature data provided by the manufacturer (1.30 instead of 1.66 as assumed in the manufacturer's model), the manufacturer's base-case ICER decreased from £12,000 to £11,700 per QALY gained. When the ERG applied the hazard ratio of 1.30 for overall survival together with the revised assumptions for blood transfusion costs (see section 3.35), the ICER increased from £7000 to £9700 per QALY. The ERG explained this paradox as follows: when the hazard ratio was reduced, the incremental discounted QALYs fell substantially from 1.27 to 0.70. However, the base-case incremental blood transfusion costs also decreased substantially, from £6300 to £1400. The net effect was to leave the base-case ICER virtually unchanged. On the other hand, starting with the assumption of no incremental blood transfusion costs, although incremental QALYs again fell substantially, the incremental blood transfusion costs remained at zero when the hazard ratio reduced. Therefore, the ICER increased substantially, from £7000 to £9700 per QALY gained.\n\nThe ERG disagreed with the manufacturer's assumptions about dose intensities for bendamustine and chlorambucil and frequency of visits to a haematologist when not treated. Changing the assumption for dose intensities (from 100% to the intensities seen in the RCT: 90% for bendamustine and 95% for chlorambucil) the manufacturer's base-case ICER decreased from £12,000 to £11,600 per QALY gained. Changing the assumption for the frequency of visits to a haematologist when not treated, the ICER decreased from £12,000 to £11,500 per QALY gained.\n\nWhen the ERG updated the manufacturer's model with the revised assumptions for blood transfusions, the hazard ratio for overall survival, dose intensities and frequency of visits to a haematologist, as outlined in sections 3.35 to 3.37, the ICER decreased from £12,000 to £9,400 per QALY gained.\n\nThe ERG stated that it was not possible to confirm the ICERs in the subgroups (patient's age ≥ 65 years; WHO status ≥ 1; and patient's age ≥ 65 years plus WHO status ≥ 1) because there was no independent source with which to check the subgroup-specific response data and survival curves. Additionally, the ERG stated that it did not explore alternative ICERs for the subgroups because it did not have updated estimates for the hazard ratios by subgroup for overall survival.\n\nThe ERG highlighted that a higher proportion of patients in the chlorambucil arm of the RCT were given second-line drugs compared with patients in the bendamustine arm. The ERG was broadly satisfied with the manufacturer's approach to incorporating second-line drug costs, but explored two alternative methods. In the first method, the ERG costed all second-line drugs received in each treatment arm in the RCT and modelled the actual, unadjusted overall survival from the RCT. The result of this was that the manufacturer's base-case ICER fell from £12,000 to less than £10,900 per QALY gained, and the ERG's revised base-case ICER of £9,400 fell to less than £8,700 per QALY gained. In the second method, the ERG did not cost the second-line drugs received in the RCT, but estimated overall survival for each treatment arm assuming no second-line drug treatment. The ICERs fell in the same way.\n\nAlthough the manufacturer identified no cost-effectiveness studies, the ERG identified a recent poster reporting a cost-effectiveness study of bendamustine versus alemtuzumab and chlorambucil for chronic lymphocytic leukaemia, presented at the 15th International Society for Pharmacoeconomics and Outcomes Research meeting in 2010. Using a discrete event simulation, taking a US payer perspective, the ICER for bendamustine versus chlorambucil was $50,800 per QALY gained, or about £33,000 per QALY gained. The ERG highlighted that the submission base-case ICER of £12,000 per QALY is substantially lower than this US study. The ERG explained this by the fact that the US study predicted a far lower life expectancy for people taking bendamustine, compared with those taking bendamustine in study 02CLLIII (predicted median overall survival of 6.1 years for the US study versus 8.3 years for study 02CLLIII) and highlighted the influence of overall survival gains in determining the cost effectiveness of bendamustine.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bendamustine, having considered evidence on the nature of chronic lymphocytic leukaemia in patients for whom fludarabine combination chemotherapy is not appropriate and the value placed on the benefits of bendamustine by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee discussed the place of bendamustine in the clinical pathway for chronic lymphocytic leukaemia. The Committee heard from the clinical specialists that bendamustine is used as a first-line treatment in UK clinical practice when fludarabine combination chemotherapy is not considered an appropriate treatment, that a second round of bendamustine may be offered, and that bendamustine is sometimes used as a second-line treatment. The Committee noted that second-line treatment is currently outside of bendamustine's UK marketing authorisation.\n\nThe Committee heard from the clinical specialists that bendamustine is less toxic than fludarabine combination therapy and is a useful addition to the available treatments for patients with chronic lymphocytic leukaemia in whom fludarabine combination therapy is unsuitable. The only available treatment for these patients is chlorambucil. The Committee heard that although bendamustine is slightly more toxic than chlorambucil and is associated with more adverse events, the clinical specialists considered bendamustine to be the more effective treatment. The Committee also noted the views of the patient groups in their submissions to NICE that because of its improved efficacy compared with chlorambucil, people with the condition would be willing to accept the side effects associated with bendamustine. The Committee was satisfied from the testimonies of the clinical specialists and patient experts that bendamustine represents an important treatment for patients with chronic lymphocytic leukaemia for whom fludarabine combination therapy is not appropriate.\n\nThe Committee heard from the clinical specialists that there are no definitively agreed criteria for deciding when fludarabine combination therapy is unsuitable as a first-line treatment for patients with chronic lymphocytic leukaemia. They commented that there is a growing consensus that patients should be offered the most effective treatment that they can tolerate first. Therefore fludarabine combination therapy (that is, fludarabine, cyclophosphamide and rituximab) is first choice unless there are important factors related to age, physical fitness and the presence of comorbidities to suggest that fludarabine combination therapy should not be used. The Committee accepted, therefore, that any future NICE-recommended use of bendamustine would be determined by clinical judgement based on the factors listed above.\n\nThe Committee discussed the clinical trial data from study 02CLLIII and agreed with the ERG's comments that it was a well-conducted RCT. It noted the higher response rates and longer progression-free survival (21.6 months versus 8.3 months) in patients treated with bendamustine compared with patients treated with chlorambucil. The Committee was concerned, however, about two issues related to the clinical trial evidence. The Committee's first concern was that the trial population may not have been representative of the population that would be treated with bendamustine in clinical practice. The Committee noted the exclusion from trial 02CLLIII of patients with comorbidities including abnormal liver, renal or cardiac function. It was also aware of the high performance status of the majority of participants and the relatively low mean age (63–64 years). However the Committee was reassured by the subgroup analysis conducted by the manufacturer, which demonstrated the clinical effectiveness of bendamustine relative to chlorambucil in the trial participants who had a lower performance status and in patients aged 65 years and over. It also accepted that the exclusion criteria were standard and that there was no reason to suppose that the results would not hold in people with a lower performance status, or people with comorbidities, in particular renal impairment (which is a contraindication of fludarabine). The Committee agreed that inferences could be made about the clinical effectiveness of bendamustine for the population specified in the marketing authorisation, using the available trial data.\n\nThe Committee's second concern about the evidence from study 02CLLIII was that it may have underestimated the clinical effectiveness of chlorambucil. The Committee heard from the clinical specialists how patients treated with chlorambucil in another trial, CLL4 (which compared chlorambucil with fludarabine and fludarabine plus cyclophosphamide), experienced higher response rates and longer progression-free survival compared with the patients treated with chlorambucil in trial 02CLLIII. The Committee discussed the possible reasons for the differences in the results between the two trials. It noted the views of the clinical specialists that the variation in the results may have been because of differences in the patient populations and differences in the doses of chlorambucil used.\n\nThe Committee explored the differences in the patient populations between the two trials. It heard from the manufacturer that one way in which the patient populations of the two trials differed was that the 02CLLIII study did not include people with Binet stage A chronic lymphocytic leukaemia. It also heard from the clinical specialists that the patient population in the CLL4 trial may have been healthier than the patient population in trial 02CLLIII. The Committee was satisfied that the differences between the patient populations in the two trials may have contributed to the differences in the results for chlorambucil.\n\nThe Committee discussed the different doses of chlorambucil used in the 02CLLIII study compared with the CLL4 trial. The clinical specialists explained that the dose used in trial 02CLLIII was consistent with the dose used for other chronic lymphocytic leukaemia studies, and that the dose used in the CLL4 study was unique at the time the study was set up. The clinical specialists also explained that the cumulative dose for chlorambucil in the 02CLLIII study was approximately 85% of the dose used in the CLL4 trial, which might explain the difference in progression-free survival in the chlorambucil arms of the two trials. The Committee heard from the clinical specialists that many different doses of chlorambucil were used in UK clinical practice, but that there was an increasing shift towards the dose used in the CLL4 study, following on from the results of that trial. Furthermore, new chronic lymphocytic leukaemia trials with chlorambucil as a comparator were increasingly using the same dose as was used in the CLL4 study. The Committee accepted that the doses of chlorambucil used in the two trials may have contributed to the differences in the results but that the precise impact of this was unknown, and that this represented an important area for future research. The Committee concluded that there was sufficient evidence to demonstrate that bendamustine was more clinically effective than chlorambucil, leading to higher response rates and longer progression-free survival.\n\n# Cost effectiveness\n\nThe Committee discussed the manufacturer's economic model. It agreed with the ERG that the manufacturer's model was of high quality and was more sophisticated than other models in the disease area. The Committee discussed that because of the added complexity of the model, the data to inform some of the model parameters, such as transition probabilities (particularly for second-line treatment) were sparse. On balance, the Committee considered that the model was appropriate and fit for purpose.\n\nThe Committee noted that the cost per QALY gained of treatment with bendamustine compared with chlorambucil was £12,000 in the manufacturer's base-case analysis. The Committee discussed the robustness of the ICER to the subgroup and sensitivity analyses conducted by the manufacturer. The Committee was satisfied with the effect of the subgroup and sensitivity analyses, noting that the ICER remained lower than £15,000 in all of the analyses.\n\nThe Committee was aware that the ERG had made some adjustments to the assumptions used in the manufacturer's economic model about the frequency of blood transfusions, the hazard ratio for overall survival, the dose intensity of bendamustine and chlorambucil and the frequency of visits to a haematologist. The Committee heard from the clinical specialists that the ERG's changes to the assumptions reflected clinical practice. The Committee noted that the effect of these adjustments caused the ICER to fall from £12,000 to £9400, thus becoming more favourable to bendamustine than the base-case ICER presented by the manufacturer. The Committee agreed that the adjustments made by the ERG were reasonable and was satisfied with the resulting effect on the ICER.\n\nThe Committee discussed the potential effect on the ICER of comparing bendamustine with the higher dose of chlorambucil given in the CLL4 study. The Committee considered that an increased dose of chlorambucil would push up the cost of chlorambucil as well as increase the number of QALYs gained. The Committee accepted that since the influence of a higher chlorambucil dose on the clinical effectiveness of the treatment had not been determined, any resulting effect on the ICER could not be quantified with any precision. The Committee agreed, however, that the ICER of bendamustine would be unlikely to increase above the level generally considered to be a cost-effective use of NHS resources. It therefore concluded that bendamustine should be recommended as a first-line treatment option for patients with chronic lymphocytic leukaemia for whom fludarabine combination chemotherapy is not appropriate.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA216\n\nAppraisal title: bendamustine for the first-line treatment of chronic lymphocytic leukaemia\n\nSection\n\nKey conclusion\n\nBendamustine is recommended as an option for the first-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nBendamustine is less toxic than fludarabine combination therapy and is a useful addition to the available treatments for patients with chronic lymphocytic leukaemia in whom fludarabine combination therapy is unsuitable. The only available treatment for this group of patients is chlorambucil.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\nBendamustine is considered to be a more effective treatment than chlorambucil.\n\n\n\n, 4.8\n\n\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nPeople treated with bendamustine had, on average, higher response rates and longer progression-free survival than people treated with chlorambucil.\n\n\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nBendamustine is used as a first-line treatment in UK clinical practice when fludarabine combination chemotherapy is not considered an appropriate treatment.\n\n\n\nAdverse effects\n\nBendamustine is associated with more adverse events compared with chlorambucil. However, because of its improved efficacy in comparison with chlorambucil, the patient groups considered that people with the condition would be willing to accept the side effects associated with bendamustine.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee agreed with the ERG's comments that study 02CLLIII was a well conducted randomised controlled trial.\n\n\n\n\n\n\n\n\n\n\n\nThe Committee was concerned that the evidence from study 02CLLIII may have underestimated the clinical effectiveness of chlorambucil. The Committee was satisfied that the differences between the patient populations in the 02CLLIII study and the CLL4 study may have contributed to the differences in the results for chlorambucil. The Committee accepted that the doses of chlorambucil used in the two trials may also have contributed to the differences in the results, but that the precise impact of this was unknown. The Committee concluded that there was sufficient evidence to demonstrate that bendamustine is more clinically effective than chlorambucil.\n\n, 4.7, 4.8\n\nRelevance to general clinical practice in the NHS\n\nThe Committee was concerned that the trial population in study 02CLLIII may not have been representative of the population that would be treated with bendamustine in clinical practice. The Committee agreed that inferences could be made about the clinical effectiveness of bendamustine for the population specified in the marketing authorisation, using the available trial data.\n\n\n\nUncertainties generated by the evidence\n\nThere are no definitively agreed criteria for deciding when fludarabine combination therapy is unsuitable as a first-line treatment for patients with chronic lymphocytic leukaemia. Fludarabine combination therapy (that is, fludarabine, cyclophosphamide and rituximab) is generally first choice unless there are important factors related to age, physical fitness and the presence of comorbidities to suggest that fludarabine combination therapy should not be used.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe influence of a higher chlorambucil dose on the relative clinical effectiveness of bendamustine has not been determined, and this represents an important area for future research.\n\n, 4.12\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe subgroup analyses conducted by the manufacturer demonstrated clinical effectiveness of bendamustine relative to chlorambucil in the trial participants who had a lower performance status and in patients aged 65 years and over.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nClinical trial data from study 02CLLIII showed higher response rates and longer progression-free survival (21.6 months versus 8.3 months) in patients treated with bendamustine compared with patients treated with chlorambucil.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee agreed with the ERG that the manufacturer's model was of high quality and was more sophisticated than other models in the disease area.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee discussed that because of the added complexity of the model, the data to inform some of the model parameters, such as transition probabilities (particularly for second-line treatment) were sparse. On balance, the Committee considered that the model was appropriate and fit for purpose.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe ERG had made some adjustments to the assumptions used in the manufacturer's economic model about the frequency of blood transfusions, the hazard ratio for overall survival, the dose intensity of bendamustine and chlorambucil and the frequency of visits to a haematologist. The Committee agreed that the adjustments made by the ERG were reasonable and was satisfied with the resulting effect on the ICER (a change from £12,000 to £9400).\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThere were no issues raised about health-related quality-of-life values that were thought to be relevant. No health-related benefits were identified that were not included in the economic model.\n\nn/a\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe base-case ICER was found to be robust to subgroup analysis. The ICER remained lower than £15,000 in all of the analyses.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nHigher response rates and longer progression-free survival.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee agreed that the adjustments made by the ERG to the manufacturer's model were reasonable and it was satisfied with the resulting change in the ICER from £12,000 to £9400. The Committee accepted that because the influence of a higher chlorambucil dose on the clinical effectiveness of the treatment had not been determined, any resulting effect on the ICER could not be quantified with any precision. The Committee agreed, however, that the ICER of bendamustine would be unlikely to increase above the level generally considered to be a cost-effective use of NHS resources.\n\n, 4.12\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNo patient access schemes were submitted.\n\nn/a\n\nEnd-of-life considerations\n\nThe Committee did not discuss end-of-life considerations because bendamustine was considered to be cost-effective.\n\nn/a\n\nEqualities considerations and social value judgements\n\nNo equalities issues raised were thought to be relevant.\n\nn/a", 'Recommendations for further research ': 'Research should be carried out to compare the clinical effectiveness of bendamustine with chlorambucil at the higher dose used in the CLL4 trial.', 'Related NICE guidance': 'Ofatumumab for the treatment of chronic lymphocytic leukaemia refractory to fludarabine and alemtuzumab. NICE technology appraisal guidance 202 (2010).\n\nRituximab for the treatment of relapsed or refractory chronic lymphocytic leukaemia. NICE technology appraisal guidance 193 (2010).\n\nRituximab for the first-line treatment of chronic lymphocytic leukaemia. NICE technology appraisal guidance 174 (2009).\n\nFludarabine monotherapy for the first-line treatment of chronic lymphocytic leukemia. NICE technology appraisal guidance 119 (2007).\n\nImproving outcomes in haematological cancers. NICE cancer service guidance (2003).', 'Review of guidance': 'The guidance on this technology will be considered for review in December 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveFebruary 2011', 'Changes after publication': 'February 2014: implementation section updated to clarify that bendamustine is recommended as an option for treating chronic lymphocytic leukaemia. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta216
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Evidence-based recommendations on bendamustine for treating chronic lymphocytic leukaemia in adults.
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6db5735f009e1d7238fa32aa3a09937e67f76377
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nice
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Alcohol-use disorders: diagnosis, assessment and management of harmful drinking (high-risk drinking) and alcohol dependence
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Alcohol-use disorders: diagnosis, assessment and management of harmful drinking (high-risk drinking) and alcohol dependence
This guideline covers identifying, assessing and managing alcohol-use disorders (harmful drinking and alcohol dependence) in adults and young people aged 10 to 17 years. It aims to reduce harms (such as liver disease, heart problems, depression and anxiety) from alcohol by improving assessment and setting goals for reducing alcohol consumption.
# Introduction
This guideline makes recommendations on the diagnosis, assessment and management of harmful drinking (high-risk drinking) and alcohol dependence in adults and in young people aged 10 to 17 years.
This is one of three pieces of NICE guidance addressing alcohol-related problems and should be read in conjunction with:
NICE's guideline on alcohol-use disorders: prevention (2010). Public health guidance on the price, advertising and availability of alcohol, how best to detect alcohol misuse in and outside primary care, and brief interventions to manage it in these settings.
NICE's guideline on alcohol-use disorders: diagnosis and management of physical complications (2010). A clinical guideline covering acute unplanned alcohol withdrawal including delirium tremens, alcohol-related liver damage, alcohol-related pancreatitis and management of Wernicke's encephalopathy.
Harmful drinking (high-risk drinking) is defined as a pattern of alcohol consumption causing health problems directly related to alcohol. This could include psychological problems such as depression, alcohol-related accidents or physical illness such as acute pancreatitis. In the longer term, harmful drinkers may go on to develop high blood pressure, cirrhosis, heart disease and some types of cancer, such as mouth, liver, bowel or breast cancer.
Alcohol dependence is characterised by craving, tolerance, a preoccupation with alcohol and continued drinking in spite of harmful consequences (for example, liver disease or depression caused by drinking). Alcohol dependence is also associated with increased criminal activity and domestic violence, and an increased rate of significant mental and physical disorders. Although alcohol dependence is defined in ICD-10 and DSM-IV in categorical terms for diagnostic and statistical purposes as being either present or absent, in reality dependence exists on a continuum of severity. However, it is helpful from a clinical perspective to subdivide dependence into categories of mild, moderate and severe. People with mild dependence (those scoring 15 or less on the Severity of Alcohol Dependence Questionnaire; SADQ) usually do not need assisted alcohol withdrawal. People with moderate dependence (with a SADQ score of between 15 and 30) usually need assisted alcohol withdrawal, which can typically be managed in a community setting unless there are other risks. People who are severely alcohol dependent (with a SADQ score of more than 30) will need assisted alcohol withdrawal, typically in an inpatient or residential setting. In this guideline these definitions of severity are used to guide selection of appropriate interventions.
For convenience this guideline refers to harmful drinking and alcohol dependence as 'alcohol misuse'. When recommendations apply to both people who are dependent on alcohol and harmful drinkers, the terms 'person who misuses alcohol' or 'service user' are used unless the recommendation is specifically referring to either people who are dependent on alcohol or who are harmful drinkers.
Alcohol dependence affects 4% of people aged between 16 and 65 in England (6% of men and 2% of women), and over 24% of the English population (33% of men and 16% of women) consume alcohol in a way that is potentially or actually harmful to their health or well-being. Alcohol misuse is also an increasing problem in children and young people, with over 24,000 treated in the NHS for alcohol-related problems in 2008 and 2009.
Comorbid mental health disorders commonly include depression, anxiety disorders and drug misuse, some of which may remit with abstinence from alcohol but others may persist and need specific treatment. Physical comorbidities are common, including gastrointestinal disorders (in particular liver disease) and neurological and cardiovascular disease. In some people these comorbidities may remit on stopping or reducing alcohol consumption, but many experience long-term consequences of alcohol misuse that may significantly shorten their life.
Of the 1 million people aged between 16 and 65 who are alcohol dependent in England, only about 6% per year receive treatment. Reasons for this include the often long period between developing alcohol dependence and seeking help, and the limited availability of specialist alcohol treatment services in some parts of England. Additionally, alcohol misuse is under-identified by health and social care professionals, leading to missed opportunities to provide effective interventions.
Diagnosis is made on the basis of the symptoms and consequences of alcohol misuse outlined above. Simple biological measures such as liver function tests are poor indicators of the presence of harmful or dependent drinking. Diagnosis and assessment of the severity of alcohol misuse is important because it points to the treatment interventions required. Acute withdrawal from alcohol in the absence of medical management can be hazardous in people with severe alcohol dependence, as it may lead to seizures, delirium tremens and, in some instances, death.
Current practice across the country is varied and access to a range of assisted withdrawal and treatment services varies as a consequence. Services for assisted alcohol withdrawal vary considerably in intensity and there is a lack of structured intensive community-based assisted withdrawal programmes. Similarly, there is limited access to psychological interventions such as cognitive behavioural therapies specifically focused on alcohol misuse. In addition, when the alcohol misuse has been effectively treated, many people continue to experience problems in accessing services for comorbid mental and physical health problems. Despite the publication of the Models of Care for Alcohol by the Department of Health in 2007 (National Treatment Agency, 2007), alcohol service structures are poorly developed, with care pathways often ill defined. In order to address this last point the three pieces of NICE guidance are integrated into a care pathway.
This guideline will assume that prescribers will use a drug's summary of product characteristics (SPC) to inform their decisions for individual service users.
At the time of publication, no drug recommended in this guideline has a UK marketing authorisation for use in children and young people under the age of 18. However, in 2000, the Royal College of Paediatrics and Child Health issued a policy statement on the use of unlicensed medicines, or the use of licensed medicines for unlicensed applications, in children and young people. This states that such use is necessary in paediatric practice and that doctors are legally allowed to prescribe unlicensed medicines where there are no suitable alternatives and where the use is justified by a responsible body of professional opinion.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Principles of care
## Building a trusting relationship and providing information
When working with people who misuse alcohol:
build a trusting relationship and work in a supportive, empathic and non‑judgmental manner
take into account that stigma and discrimination are often associated with alcohol misuse and that minimising the problem may be part of the service user's presentation
make sure that discussions take place in settings in which confidentiality, privacy and dignity are respected.
When working with people who misuse alcohol:
provide information appropriate to their level of understanding about the nature and treatment of alcohol misuse to support choice from a range of evidence-based treatments
avoid clinical language without explanation
make sure that comprehensive written information is available in an appropriate language or, for those who cannot use written text, in an accessible format
provide independent interpreters (that is, someone who is not known to the service user) if needed.
## Working with and supporting families and carers
Encourage families and carers to be involved in the treatment and care of people who misuse alcohol to help support and maintain positive change.
When families and carers are involved in supporting a person who misuses alcohol, discuss concerns about the impact of alcohol misuse on themselves and other family members, and:
provide written and verbal information on alcohol misuse and its management, including how families and carers can support the service user
-ffer a carer's assessment where necessary (see NICE's guideline on supporting adult carers)
negotiate with the service user and their family or carer about the family or carer's involvement in their care and the sharing of information; make sure the service user's, family's and carer's right to confidentiality is respected.
When the needs of families and carers of people who misuse alcohol have been identified:
-ffer guided self-help, usually consisting of a single session, with the provision of written materials
provide information about, and facilitate contact with, support groups (such as self-help groups specifically focused on addressing the needs of families and carers).
If the families and carers of people who misuse alcohol have not benefited, or are not likely to benefit, from guided self-help and/or support groups and continue to have significant problems, consider offering family meetings. These should:
provide information and education about alcohol misuse
help to identify sources of stress related to alcohol misuse
explore and promote effective coping behaviours
usually consist of at least five weekly sessions.
All staff in contact with parents who misuse alcohol and who have care of or regular contact with their children, should:
take account of the impact of the parent's drinking on the parent–child relationship and the child's development, education, mental and physical health, own alcohol use, safety, and social network
be aware of and comply with the requirements of the Children Act (2004).
# Identification and assessment
## General principles
Make sure that assessment of risk is part of any assessment, that it informs the development of the overall care plan, and that it covers risk to self (including unplanned withdrawal, suicidality and neglect) and risk to others.
Staff working in services provided and funded by the NHS who care for people who potentially misuse alcohol should be competent to identify harmful drinking (high-risk drinking) and alcohol dependence. They should be competent to initially assess the need for an intervention or, if they are not competent, they should refer people who misuse alcohol to a service that can provide an assessment of need.
When conducting an initial assessment, as well as assessing alcohol misuse, the severity of dependence and risk, consider the:
extent of any associated health and social problems
need for assisted alcohol withdrawal.
Use formal assessment tools to assess the nature and severity of alcohol misuse, including the:
AUDIT for identification and as a routine outcome measure
SADQ or LDQ for severity of dependence
Clinical Institute Withdrawal Assessment of Alcohol Scale, revised (CIWA-Ar) for severity of withdrawal
APQ for the nature and extent of the problems arising from alcohol misuse.
When assessing the severity of alcohol dependence and determining the need for assisted withdrawal, adjust the criteria for women, older people, children and young people, and people with established liver disease who may have problems with the metabolism of alcohol.See section 1.3.7 for assessment of children and young people.
Staff responsible for assessing and managing assisted alcohol withdrawal (see section 1.3.4) should be competent in the diagnosis and assessment of alcohol dependence and withdrawal symptoms and the use of drug regimens appropriate to the settings (for example, inpatient or community) in which the withdrawal is managed.
Staff treating people with alcohol dependence presenting with an acute unplanned alcohol withdrawal should refer to the NICE guideline on alcohol-use disorders: diagnosis and management of physical complications.
## Assessment in specialist alcohol services
Treatment goals
In the initial assessment in specialist alcohol services of all people who misuse alcohol, agree the goal of treatment with the service user. Abstinence is the appropriate goal for most people with alcohol dependence, and people who misuse alcohol and have significant psychiatric or physical comorbidity (for example, depression or alcohol-related liver disease). When a service user prefers a goal of moderation but there are considerable risks, advise strongly that abstinence is most appropriate, but do not refuse treatment to service users who do not agree to a goal of abstinence.
For harmful drinking (high-risk drinking) or mild dependence, without significant comorbidity, and if there is adequate social support, consider a moderate level of drinking as the goal of treatment unless the service user prefers abstinence or there are other reasons for advising abstinence.
For people with severe alcohol dependence, or those who misuse alcohol and have significant psychiatric or physical comorbidity, but who are unwilling to consider a goal of abstinence or engage in structured treatment, consider a harm reduction programme of care. However, ultimately the service user should be encouraged to aim for a goal of abstinence.
When developing treatment goals, consider that some people who misuse alcohol may be required to abstain from alcohol as part of a court order or sentence.
Brief triage assessment
All adults who misuse alcohol who are referred to specialist alcohol services should have a brief triage assessment to assess:
the pattern and severity of the alcohol misuse (using AUDIT) and severity of dependence (using SADQ)
the need for urgent treatment including assisted withdrawal
any associated risks to self or others
the presence of any comorbidities or other factors that may need further specialist assessment or intervention.Agree the initial treatment plan, taking into account the service user's preferences and outcomes of any previous treatment.
Comprehensive assessment
Consider a comprehensive assessment for all adults referred to specialist alcohol services who score more than 15 on the AUDIT. A comprehensive assessment should assess multiple areas of need, be structured in a clinical interview, use relevant and validated clinical tools (see recommendation 1.2.1.4), and cover the following areas:
alcohol use, including:
consumption: historical and recent patterns of drinking (using, for example, a retrospective drinking diary), and if possible, additional information (for example, from a family member or carer)
dependence (using, for example, SADQ or LDQ)
alcohol-related problems (using, for example, APQ)
-ther drug misuse, including over-the-counter medication
physical health problems
psychological and social problems
cognitive function (using, for example, the Mini-Mental State Examination )
readiness and belief in ability to change.
Assess comorbid mental health problems as part of any comprehensive assessment, and throughout care for the alcohol misuse, because many comorbid problems (though not all) will improve with treatment for alcohol misuse. Use the assessment of comorbid mental health problems to inform the development of the overall care plan.
For service users whose comorbid mental health problems do not significantly improve after abstinence from alcohol (typically after 3 to 4 weeks), consider providing or referring for specific treatment (see the relevant NICE guideline for the particular disorder).
Consider measuring breath alcohol as part of the management of assisted withdrawal. However, breath alcohol should not usually be measured for routine assessment and monitoring in alcohol treatment programmes.
Consider blood tests to help identify physical health needs, but do not use blood tests routinely for the identification and diagnosis of alcohol use disorders.
Consider brief measures of cognitive functioning (for example, MMSE) to help with treatment planning. Formal measures of cognitive functioning should usually only be performed if impairment persists after a period of abstinence or a significant reduction in alcohol intake.
# Interventions for alcohol misuse
## General principles for all interventions
For all people who misuse alcohol, carry out a motivational intervention as part of the initial assessment. The intervention should contain the key elements of motivational interviewing including:
helping people to recognise problems or potential problems related to their drinking
helping to resolve ambivalence and encourage positive change and belief in the ability to change
adopting a persuasive and supportive rather than an argumentative and confrontational position.
For all people who misuse alcohol, offer interventions to promote abstinence or moderate drinking as appropriate (see recommendations 1.2.2.1 to 1.2.2.4) and prevent relapse, in community-based settings.
Consider offering interventions to promote abstinence and prevent relapse as part of an intensive structured community-based intervention for people with moderate and severe alcohol dependence who have:
very limited social support (for example, they are living alone or have very little contact with family or friends) or
complex physical or psychiatric comorbidities or
not responded to initial community-based interventions (see recommendation 1.3.1.2).
For people with alcohol dependence who are homeless, consider offering residential rehabilitation for a maximum of 3 months. Help the service user find stable accommodation before discharge.
All interventions for people who misuse alcohol should be delivered by appropriately trained and competent staff. Pharmacological interventions should be administered by specialist and competent staff. Psychological interventions should be based on a relevant evidence-based treatment manual, which should guide the structure and duration of the intervention. Staff should consider using competence frameworks developed from the relevant treatment manuals and for all interventions should:
receive regular supervision from individuals competent in both the intervention and supervision
routinely use outcome measurements to make sure that the person who misuses alcohol is involved in reviewing the effectiveness of treatment
engage in monitoring and evaluation of treatment adherence and practice competence, for example, by using video and audio tapes and external audit and scrutiny if appropriate.
All interventions for people who misuse alcohol should be the subject of routine outcome monitoring. This should be used to inform decisions about continuation of both psychological and pharmacological treatments. If there are signs of deterioration or no indications of improvement, consider stopping the current treatment and review the care plan.
For all people seeking help for alcohol misuse:
give information on the value and availability of community support networks and self-help groups (for example, Alcoholics Anonymous or SMART Recovery) and
help them to participate in community support networks and self-help groups by encouraging them to go to meetings and arranging support so that they can attend.
## Care coordination and case management
Care coordination is the routine coordination by any staff involved in the care and treatment of a person who misuses alcohol. Case management is a more intensive process concerned with delivering all aspects of care, including assessment, treatment, monitoring and follow-up.
Care coordination should be part of the routine care of all service users in specialist alcohol services and should:
be provided throughout the whole period of care, including aftercare
be delivered by appropriately trained and competent staff working in specialist alcohol services
include the coordination of assessment, interventions and monitoring of progress, and coordination with other agencies.
Consider case management to increase engagement in treatment for people who have moderate to severe alcohol dependence and who are considered at risk of dropping out of treatment or who have a previous history of poor engagement. If case management is provided it should be throughout the whole period of care, including aftercare.
Case management should be delivered in the context of Tier 3 interventions by staff who take responsibility for the overall coordination of care and should include:
a comprehensive assessment of needs
development of an individualised care plan in collaboration with the service user and relevant others (including families and carers and other staff involved in the service user's care)
coordination of the care plan to deliver a seamless multiagency and integrated care pathway and maximisation of engagement, including the use of motivational interviewing approaches
monitoring of the impact of interventions and revision of the care plan when necessary.
## Interventions for harmful drinking (high-risk drinking) and mild alcohol dependence
For harmful drinkers (high-risk drinkers) and people with mild alcohol dependence, offer a psychological intervention (such as cognitive behavioural therapies, behavioural therapies or social network and environment-based therapies) focused specifically on alcohol-related cognitions, behaviour, problems and social networks.
Offer behavioural couples therapy for harmful drinkers and people with mild alcohol dependence who have a regular partner who is willing to participate in treatment, unless there are indicators that the person is currently experiencing, or is a current perpetrator of, domestic abuse. For advice on the use of nalmefene for alcohol dependence, see NICE's technology appraisal guidance on nalmefene for reducing alcohol consumption in people with alcohol dependence.
For harmful drinkers and people with mild alcohol dependence who have not responded to psychological interventions alone, or who have specifically requested a pharmacological intervention, consider offering acamprosate or oral naltrexone in combination with an individual psychological intervention (cognitive behavioural therapies, behavioural therapies or social network and environment-based therapies) or behavioural couples therapy (see section 1.3.6 for pharmacological interventions).Note that the evidence for acamprosate in the treatment of harmful drinkers (high-risk drinkers) and people who are mildly alcohol dependent is less robust than that for naltrexone. In February 2011, this was an off-label use of acamprosate. See NICE's information on prescribing medicines.
Delivering psychological interventions
Cognitive behavioural therapies focused on alcohol-related problems should usually consist of one 60-minute session per week for 12 weeks.
Behavioural therapies focused on alcohol-related problems should usually consist of one 60-minute session per week for 12 weeks.
Social network and environment-based therapies focused on alcohol-related problems should usually consist of eight 50-minute sessions over 12 weeks.
Behavioural couples therapy should be focused on alcohol-related problems and their impact on relationships. It should aim for abstinence, or a level of drinking predetermined and agreed by the therapist and the service user to be reasonable and safe. It should usually consist of one 60-minute session per week for 12 weeks.
## Assessment and interventions for assisted alcohol withdrawal
See section 1.3.7 for assessment for assisted withdrawal in children and young people.
For service users who typically drink over 15 units of alcohol per day and/or who score 20 or more on the AUDIT, consider offering:
an assessment for and delivery of a community-based assisted withdrawal or
assessment and management in specialist alcohol services if there are safety concerns (see recommendation 1.3.4.5) about a community-based assisted withdrawal.
Service users who need assisted withdrawal should usually be offered a community-based programme, which should vary in intensity according to the severity of the dependence, available social support and the presence of comorbidities.
For people with mild to moderate dependence, offer an outpatient-based assisted withdrawal programme in which contact between staff and the service user averages 2 to 4 meetings per week over the first week.
For people with mild to moderate dependence and complex needs, or severe dependence, offer an intensive community programme following assisted withdrawal in which the service user may attend a day programme lasting between 4 and 7 days per week over a 3-week period. Examples of complex needs include psychiatric comorbidity, poor social support or homelessness.
Outpatient-based community assisted withdrawal programmes should consist of a drug regimen (see section 1.3.5) and psychosocial support including motivational interviewing (see recommendation 1.3.1.1).
Intensive community programmes following assisted withdrawal should consist of a drug regimen (see section 1.3.6) supported by psychological interventions including individual treatments (see section 1.3.6), group treatments, psychoeducational interventions, help to attend self-help groups, family and carer support and involvement, and case management (see recommendation 1.3.2.2).
Consider inpatient or residential assisted withdrawal if a service user meets one or more of the following criteria. They:
drink over 30 units of alcohol per day
have a score of more than 30 on the SADQ
have a history of epilepsy, or experience of withdrawal-related seizures or delirium tremens during previous assisted withdrawal programmes
need concurrent withdrawal from alcohol and benzodiazepines
regularly drink between 15 and 30 units of alcohol per day and have:
significant psychiatric or physical comorbidities (for example, chronic severe depression, psychosis, malnutrition, congestive cardiac failure, unstable angina, chronic liver disease) or
a significant learning disability or cognitive impairment.
Consider a lower threshold for inpatient or residential assisted withdrawal in vulnerable groups, for example, homeless and older people.
## Drug regimens for assisted withdrawal
When conducting community-based assisted withdrawal programmes, use fixed-dose medication regimens. A fixed-dose regimen involves starting treatment with a standard dose, not defined by the level of alcohol withdrawal, and reducing the dose to zero over 7 to 10 days according to a standard protocol.
Fixed-dose or symptom-triggered medication regimens can be used in assisted withdrawal programmes in inpatient or residential settings. If a symptom-triggered regimen is used, all staff should be competent in monitoring symptoms effectively and the unit should have sufficient resources to allow them to do so frequently and safely.A symptom-triggered approach involves tailoring the drug regimen according to the severity of withdrawal and any complications. The service user is monitored on a regular basis and pharmacotherapy only continues as long as the service user is showing withdrawal symptoms.
Prescribe and administer medication for assisted withdrawal within a standard clinical protocol. The preferred medication for assisted withdrawal is a benzodiazepine (chlordiazepoxide or diazepam). Prescribers should be aware of the legislation on controlled drugs and driving: blood concentration limits and advise patients accordingly.
In a fixed-dose regimen, titrate the initial dose of medication to the severity of alcohol dependence and/or regular daily level of alcohol consumption. In severe alcohol dependence higher doses will be required to adequately control withdrawal and should be prescribed according to the SPC. Make sure there is adequate supervision if high doses are administered. Gradually reduce the dose of the benzodiazepine over 7 to 10 days to avoid alcohol withdrawal recurring.
When managing alcohol withdrawal in the community, avoid giving people who misuse alcohol large quantities of medication to take home to prevent overdose or diversion (the drug being taken by someone other than the person it was prescribed for). Prescribe for installment dispensing, with no more than 2 days' medication supplied at any time.
In a community-based assisted withdrawal programme, monitor the service user every other day during assisted withdrawal. A family member or carer should preferably oversee the administration of medication. Adjust the dose if severe withdrawal symptoms or over-sedation occur.
Do not offer clomethiazole for community-based assisted withdrawal because of the risk of overdose and misuse.
For service users having assisted withdrawal, particularly those who are more severely alcohol dependent or those undergoing a symptom-triggered regimen, consider using a formal measure of withdrawal symptoms such as the CIWA-Ar.
Be aware that benzodiazepine doses may need to be reduced for children and young people, older people, and people with liver impairment (see recommendation 1.3.5.10).In February 2011 this was an off-label use of benzodiazepines in children and young people under 18. See NICE's information on prescribing medicines. Prescribers should also see the MHRA's advice on addiction to benzodiazepines and codeine.
If benzodiazepines are used for people with liver impairment, consider one requiring limited liver metabolism (for example, lorazepam); start with a reduced dose and monitor liver function carefully. Avoid using benzodiazepines for people with severe liver impairment.
When managing withdrawal from co-existing benzodiazepine and alcohol dependence increase the dose of benzodiazepine medication used for withdrawal. Calculate the initial daily dose based on the requirements for alcohol withdrawal plus the equivalent regularly used daily dose of benzodiazepine. This is best managed with one benzodiazepine (chlordiazepoxide or diazepam) rather than multiple benzodiazepines. Inpatient withdrawal regimens should last for 2 to 3 weeks or longer, depending on the severity of co-existing benzodiazepine dependence. When withdrawal is managed in the community, and/or where there is a high level of benzodiazepine dependence, the regimen should last for longer than 3 weeks, tailored to the service user's symptoms and discomfort.In February 2011, this was an off-label use of benzodiazepines. See NICE's information on prescribing medicines. Prescribers should also see the MHRA's advice on addiction to benzodiazepines and codeine.
For managing unplanned acute alcohol withdrawal and complications including delirium tremens and withdrawal-related seizures, refer to the NICE guideline on alcohol-use disorders: diagnosis and management of physical complications.
## Interventions for moderate and severe alcohol dependence after successful withdrawal
After a successful withdrawal for people with moderate and severe alcohol dependence, consider offering acamprosate or oral naltrexone in combination with an individual psychological intervention (cognitive behavioural therapies, behavioural therapies or social network and environment-based therapies) focused specifically on alcohol misuse (see section 1.3.3).
After a successful withdrawal for people with moderate and severe alcohol dependence, consider offering acamprosate or oral naltrexone in combination with behavioural couples therapy to service users who have a regular partner and whose partner is willing to participate in treatment (see section 1.3.3).Oral naltrexone is licensed for alcohol dependence. See the summary of product characteristics.
After a successful withdrawal for people with moderate and severe alcohol dependence, consider offering disulfiram in combination with a psychological intervention to service users who:
have a goal of abstinence but for whom acamprosate and oral naltrexone are not suitable, or
prefer disulfiram and understand the relative risks of taking the drug (see recommendation 1.3.6.12).All prescribers should consult the SPC for a full description of the contraindications and the special considerations of the use of disulfiram.
Delivering pharmacological interventions
Before starting treatment with acamprosate, oral naltrexone or disulfiram, conduct a comprehensive medical assessment (baseline urea and electrolytes and liver function tests including gamma glutamyl transferase ). In particular, consider any contraindications or cautions (see the SPC), and discuss these with the service user.In February 2011, this was an off-label use of benzodiazepines. See NICE's information on prescribing medicines. Informed consent should be obtained and documented in line with normal standards of care for patients who may lack capacity (or see NHS Wales) or in line with normal standards in emergency care.
Acamprosate
If using acamprosate, start treatment as soon as possible after assisted withdrawal. Usually prescribe at a dose of 1998 mg (666 mg three times a day) unless the service user weighs less than 60 kg, and then a maximum of 1332 mg should be prescribed per day. Acamprosate should:
usually be prescribed for up to 6 months, or longer for those benefiting from the drug who want to continue with it
be stopped if drinking persists 4 to 6 weeks after starting the drug.In February 2011, use for longer than 12 months was an off-label use of acamprosate. See NICE's information on prescribing medicines.
Service users taking acamprosate should stay under supervision, at least monthly, for 6 months, and at reduced but regular intervals if the drug is continued after 6 months. Do not use blood tests routinely, but consider them to monitor for recovery of liver function and as a motivational aid for service users to show improvement.
Naltrexone
If using oral naltrexone, start treatment after assisted withdrawal. Start prescribing at a dose of 25 mg per day and aim for a maintenance dose of 50 mg per day. Draw the service user's attention to the information card that is issued with oral naltrexone about its impact on opioid-based analgesics. Oral naltrexone should:
usually be prescribed for up to 6 months, or longer for those benefiting from the drug who want to continue with it
be stopped if drinking persists 4 to 6 weeks after starting the drug.
Service users taking oral naltrexone should stay under supervision, at least monthly, for 6 months, and at reduced but regular intervals if the drug is continued after 6 months. Do not use blood tests routinely, but consider them for older people, for people with obesity, for monitoring recovery of liver function and as a motivational aid for service users to show improvement. If the service user feels unwell advise them to stop the oral naltrexone immediately.In February 2011, this was an off-label use of benzodiazepines. See NICE's information on prescribing medicines. Informed consent should be obtained and documented in line with normal standards of care for patients who may lack capacity (or see NHS Wales) or in line with normal standards in emergency care.
Disulfiram
If using disulfiram, start treatment at least 24 hours after the last alcoholic drink consumed. Usually prescribe at a dose of 200 mg per day. For service users who continue to drink, if a dose of 200 mg (taken regularly for at least 1 week) does not cause a sufficiently unpleasant reaction to deter drinking, consider increasing the dose in consultation with the service user.
Before starting treatment with disulfiram, test liver function, urea and electrolytes to assess for liver or renal impairment. Check the SPC for warnings and contraindications in pregnancy and in the following conditions: a history of severe mental illness, stroke, heart disease or hypertension.
Make sure that service users taking disulfiram:
stay under supervision, at least every 2 weeks for the first 2 months, then monthly for the following 4 months
if possible, have a family member or carer, who is properly informed about the use of disulfiram, oversee the administration of the drug
are medically monitored at least every 6 months after the initial 6 months of treatment and monitoring.
Warn service users taking disulfiram, and their families and carers, about:
the interaction between disulfiram and alcohol (which may also be found in food, perfume, aerosol sprays and so on), the symptoms of which may include flushing, nausea, palpitations and, more seriously, arrhythmias, hypotension and collapse
the rapid and unpredictable onset of the rare complication of hepatotoxicity; advise service users that if they feel unwell or develop a fever or jaundice that they should stop taking disulfiram and seek urgent medical attention.
Drugs not to be routinely used for the treatment of alcohol misuse
Do not use antidepressants (including selective serotonin reuptake inhibitors ) routinely for the treatment of alcohol misuse alone.
Do not use gammahydroxybutyrate (GHB) for the treatment of alcohol misuse.
Benzodiazepines should only be used for managing alcohol withdrawal and not as ongoing treatment for alcohol dependence.
## Special considerations for children and young people who misuse alcohol
Assessment and referral of children and young people
If alcohol misuse is identified as a potential problem, with potential physical, psychological, educational or social consequences, in children and young people aged 10 to 17 years, conduct an initial brief assessment to assess:
the duration and severity of the alcohol misuse (the standard adult threshold on the AUDIT for referral and intervention should be lowered for young people aged 10 to 16 years because of the more harmful effects of a given level of alcohol consumption in this population)
any associated health and social problems
the potential need for assisted withdrawal.
Refer all children and young people aged 10 to 15 years to a specialist child and adolescent mental health service (CAMHS) for a comprehensive assessment of their needs, if their alcohol misuse is associated with physical, psychological, educational and social problems and/or comorbid drug misuse.
When considering referral to CAMHS for young people aged 16 to 17 years who misuse alcohol, use the same referral criteria as for adults (see section 1.2.2).
A comprehensive assessment for children and young people (supported if possible by additional information from a parent or carer) should assess multiple areas of need, be structured around a clinical interview using a validated clinical tool (such as the Adolescent Diagnostic Interview or the Teen Addiction Severity Index ), and cover the following areas:
consumption, dependence features and patterns of drinking
comorbid substance misuse (consumption and dependence features) and associated problems
mental and physical health problems
peer relationships and social and family functioning
developmental and cognitive needs, and educational attainment and attendance
history of abuse and trauma
risk to self and others
readiness to change and belief in the ability to change
-btaining consent to treatment
developing a care plan and risk management plan.
Assisted withdrawal in children and young people
Offer inpatient care to children and young people aged 10 to 17 years who need assisted withdrawal.
Base assisted withdrawal for children and young people aged 10 to 17 years on the recommendations for adults (see section 1.3.5) and in the NICE guideline on alcohol-use disorders: diagnosis and management of physical complications. Consult the SPC and adjust drug regimens to take account of age, height and body mass, and stage of development of the child or young person.
Promoting abstinence and preventing relapse in children and young people
For all children and young people aged 10 to 17 years who misuse alcohol, the goal of treatment should usually be abstinence in the first instance.
For children and young people aged 10 to 17 years who misuse alcohol offer:
individual cognitive behavioural therapy for those with limited comorbidities and good social support
multicomponent programmes (such as multidimensional family therapy, brief strategic family therapy, functional family therapy or multisystemic therapy) for those with significant comorbidities and/or limited social support.
After a careful review of the risks and benefits, specialists may consider offering acamprosate or oral naltrexone in combination with cognitive behavioural therapy to young people aged 16 and 17 years who have not engaged with or benefited from a multicomponent treatment programme.In February 2011, this was an off-label use of oral naltrexone, and use for longer than 12 months was an off-label use of acamprosate. See NICE's information on prescribing medicines.
Delivering psychological and psychosocial interventions for children and young people
Multidimensional family therapy should usually consist of 12 to 15 family-focused structured treatment sessions over 12 weeks. There should be a strong emphasis on care coordination and, if necessary, crisis management. As well as family sessions, individual interventions may be provided for both the child or young person and the parents. The intervention should aim to improve:
alcohol and drug misuse
the child or young person's educational and social behaviour
parental well-being and parenting skills
relationships with the wider social system.
Brief strategic family therapy should usually consist of fortnightly meetings over 3 months. It should focus on:
engaging and supporting the family
using the support of the wider social and educational system
identifying maladaptive family interactions
promoting new and more adaptive family interactions.
Functional family therapy should be conducted over 3 months by health or social care staff. It should focus on improving interactions within the family, including:
engaging and motivating the family in treatment (enhancing perception that change is possible, positive reframing and establishing a positive alliance)
problem solving and behaviour change through parent training and communication training
promoting generalisation of change in specific behaviours to broader contexts, both within the family and the community (such as schools).
Multisystemic therapy should be provided over 3 to 6 months by a dedicated member of staff with a low caseload (typically between three and six cases). It should:
focus specifically on problem-solving approaches with the family
use the resources of peer groups, schools and the wider community.
## Interventions for conditions comorbid with alcohol misuse
For people who misuse alcohol and have comorbid depression or anxiety disorders, treat the alcohol misuse first as this may lead to significant improvement in the depression and anxiety. If depression or anxiety continues after 3 to 4 weeks of abstinence from alcohol, assess the depression or anxiety and consider referral and treatment in line with the relevant NICE guideline for the particular disorder. See the NICE guidelines on depression in adults: treatment and management, generalised anxiety disorder and panic disorder in adults: management and antisocial personality disorder: prevention and management. Also see NICE's guideline on coexisting severe mental illness and substance misuse: community health and social care services.
Refer people who misuse alcohol and have a significant comorbid mental health disorder, and those assessed to be at high risk of suicide, to a psychiatrist to make sure that effective assessment, treatment and risk-management plans are in place.
For the treatment of comorbid mental health disorders refer to the relevant NICE guideline for the particular disorder, and:
for alcohol misuse comorbid with opioid misuse actively treat both conditions; take into account the increased risk of mortality with taking alcohol and opioids together
for alcohol misuse comorbid with stimulant, cannabis or benzodiazepine misuse actively treat both conditions. Service users who have been dependent on alcohol will need to be abstinent, or have very significantly reduced their drinking, to benefit from psychological interventions for comorbid mental health disorders. See the NICE guidelines on drug misuse in over 16s: opioid detoxification and drug misuse in over 16s: psychosocial interventions.
For comorbid alcohol and nicotine dependence, encourage service users to stop smoking and refer to the NICE guideline on tobacco.
Wernicke-Korsakoff syndrome
Follow the recommendations in the NICE guideline on alcohol-use disorders: diagnosis and management of physical complications on thiamine for people at high risk of developing, or with suspected, Wernicke's encephalopathy. In addition, offer parenteral thiamine followed by oral thiamine to prevent Wernicke-Korsakoff syndrome in people who are entering planned assisted alcohol withdrawal in specialist inpatient alcohol services or prison settings and who are malnourished or at risk of malnourishment (for example, people who are homeless) or have decompensated liver disease.
For people with Wernicke-Korsakoff syndrome, offer long-term placement in:
supported independent living for those with mild cognitive impairment
supported 24-hour care for those with moderate or severe cognitive impairment.In both settings the environment should be adapted for people with cognitive impairment and support should be provided to help service users maintain abstinence from alcohol.# Research recommendations
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.
# Is contingency management effective in reducing alcohol consumption in people who misuse alcohol compared with standard care?
This question should be answered using a randomised controlled design that reports short-and medium-term outcomes (including cost-effectiveness outcomes) of at least 18 months' duration. Particular attention should be paid to the reproducibility of the treatment model and training and supervision of those providing the intervention to ensure that the results are robust and generalisable. The outcomes chosen should reflect both observer and service user-rated assessments of improvement and the acceptability of the intervention. The study needs to be large enough to determine the presence or absence of clinically important effects, and mediators and moderators of response should be investigated.
## Why this is important
Psychological interventions are an important therapeutic option for people with alcohol-related problems. However, even with the most effective current treatment (for example, cognitive behavioural therapies and social network and environment-based therapies), the effects are modest at best and the treatments are not effective for everyone. Contingency management has a considerable and compelling evidence base in the treatment of substance misuse (for example, opioid misuse) but there is only a limited, if promising, evidence base for contingency management in the treatment of alcohol-related problems. The results of this research will have important implications for the provision of psychological treatment for alcohol misuse in the NHS.
# What methods are most effective for assessing and diagnosing the presence and severity of alcohol misuse in children and young people?
This question should be answered in a programme of research that uses a cross-sectional cohort design testing:
the sensitivity and specificity of a purpose-designed suite of screening and case identification measures of alcohol misuse against a diagnostic gold standard (DSM-IV or ICD-10)
the reliability and validity of a purpose-designed suite in characterising the nature and the severity of the alcohol misuse in children and young people and their predictive validity in identifying the most effective treatment when compared with current best practice. Particular attention should be paid to the feasibility of the measures in routine care and the training required to obtain satisfactory levels of accuracy and predictive validity. The programme needs to be large enough to encompass the age range (10 to 17 years) and the comorbidity that often accompanies alcohol misuse in children and young people.
## Why this is important
Alcohol misuse is an increasingly common problem in children and young people. However, diagnostic instruments are poorly developed or not available for children and young people. In adults there is a range of diagnostic and assessment tools (with reasonable sensitivity and specificity, and reliability and validity) that are recommended for routine use in the NHS to both assess the severity of the alcohol misuse and to guide treatment decisions. No similar well-developed measures exist for children and young people, with the result that problems are missed and/or inappropriate treatment is offered. The results of this study will have important implications for the identification and the provision of effective treatment in the NHS for children and young people with alcohol-related problems.
# Is acupuncture effective in reducing alcohol consumption compared with standard care?
This question should be answered using a randomised controlled design that reports short-and medium-term outcomes (including cost-effectiveness outcomes) of at least 12 months' duration. Particular attention should be paid to the reproducibility of the treatment model and training and supervision of those providing the intervention to ensure that the results are robust and generalisable. The outcomes chosen should reflect both observer and service user-rated assessments of improvement and the acceptability of the treatment. The study needs to be large enough to determine the presence or absence of clinically important effects, and mediators and moderators of response should be investigated.
## Why this is important
Non-pharmacological treatments are an important therapeutic option for people with alcohol-related problems. There is an evidence base for acupuncture in reducing craving but not alcohol consumption in a number of small trials. The evidence for pharmacological treatments (for example, acamprosate or naltrexone) and psychological treatments (for example, cognitive behavioural therapies and social network and environment-based therapies) is modest at best and the treatments are not effective for everyone. Anecdotal evidence suggests that acupuncture, like psychological treatment, is valued by service users both in alcohol misuse and substance misuse services (although the evidence base for effectiveness is weak). The results of this study will have important implications for increased treatment choice in the NHS for people who misuse alcohol.
# For which service users who are moderately and severely dependent on alcohol is an assertive community treatment model a clinically and cost-effective intervention compared with standard care?
This question should be answered using a randomised controlled design in which participants are stratified for severity and complexity of presenting problems. It should report short- and medium-term outcomes (including cost-effectiveness outcomes) of at least 18 months' duration. Particular attention should be paid to the reproducibility of the treatment model and training and supervision of those providing the intervention to ensure that the results are robust and generalisable. The outcomes chosen should reflect both observer and service user-rated assessments of improvement (including personal and social functioning) and the acceptability of the intervention. The study needs to be large enough to determine the presence or absence of clinically important effects, and mediators and moderators of response should be investigated.
## Why this is important
Many people, in particular those with severe problems and complex comorbidities, do not benefit from treatment and/or lose contact with services. This leads to poor outcomes and wastes resources. Assertive community treatment models have been shown to be effective in retaining people in treatment in those with serious mental illness and who misuse alcohol and drugs but the evidence for an impact on outcomes is not proven. A number of small pilot studies suggest that an assertive community approach can bring benefit in both service retention and clinical outcomes in alcohol misuse. Given the high morbidity and mortality associated with chronic severe alcohol dependence the results of this study will have important implications for the structure and provision of alcohol services in the NHS.
# For people with moderate and severe alcohol dependence who have significant comorbid problems, is an intensive residential rehabilitation programme clinically and cost effective when compared with intensive community-based care?
This question should be answered using a prospective cohort study of all people who have moderate and severe alcohol dependence entering residential and intensive community rehabilitation programmes in a purposive sample of alcohol treatment services in the UK. It should report short- and medium-term outcomes (including cost-effectiveness outcomes) of at least 18 months' duration. Particular attention should be paid to the characterisation of the treatment environment and the nature of the interventions provided to inform the analysis of moderators and mediators of treatment effect. The outcomes chosen should reflect both observer and service user-rated assessments of improvement (including personal and social functioning) and the acceptability of the intervention. The study needs to be large enough to determine the presence or absence of clinically important effects, and mediators and moderators of response should be investigated. A cohort study has been chosen as the most appropriate design as previous studies in this area that have attempted to randomise participants to residential or community care have been unable to recruit clinically representative populations.
## Why this is important
Many people, in particular those with severe problems and complex comorbidities, do not benefit from treatment and/or lose contact with services. One common approach is to offer intensive residential rehabilitation and current policy favours this. However, the research on the effectiveness of residential rehabilitation is uncertain with a suggestion that intensive community services may be as effective. The interpretation of this research is limited by the fact that many of the more severely ill people are not entered into the clinical trials because some clinicians are unsure of the safety of the community setting. However, clinical opinion is divided on the benefits of residential rehabilitation, with some suggesting that those who benefit are a motivated and self-selected group who may do just as well with intensive community treatment, which is currently limited in availability. Given the costs associated with residential treatment and the uncertainty about outcomes, the results of this study will have important implications for the cost effectiveness and provision of alcohol services in the NHS.
# For people with alcohol dependence, which medication is most likely to improve adherence and thereby promote abstinence and prevent relapse?
This question should be answered by: a) an initial development phase in which a series of qualitative and quantitative reasons for non-adherence/discontinuing drugs used in the treatment of alcohol are explored; b) a series of pilot trials of novel interventions developed to address the problems identified in (a) undertaken to support the design of a series of definitive trials; c) a (series of) definitive trial(s) of the interventions that were successfully piloted in (b) using a randomised controlled design that reports short-term (for example, 3 months) and longer-term (for example, 18 months) outcomes. The outcomes chosen should reflect both observer and service user-rated assessments of improvement and the acceptability of the intervention. Each individual study needs to be large enough to determine the presence or absence of clinically important effects, and mediators and moderators of response should be investigated.
## Why this is important
Rates of attrition in trials of drugs to promote abstinence and prevent relapse in alcohol dependence are high (often over 65%), yet despite this the interventions are still clinically and cost effective. Retaining more service users in treatment could further significantly improve outcomes for people who misuse alcohol and ensure increased effectiveness in the use of health service resources. The outcome of these studies may also help improve clinical confidence in the use of effective medications (such as acamprosate and naltrexone), which despite their cost effectiveness are currently offered to only a minority of eligible NHS service users. Overall, the results of these studies will have important implications for the provision of pharmacological treatment in the NHS for alcohol misuse.
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{'Introduction': "This guideline makes recommendations on the diagnosis, assessment and management of harmful drinking (high-risk drinking) and alcohol dependence in adults and in young people aged 10 to 17 years.\n\nThis is one of three pieces of NICE guidance addressing alcohol-related problems and should be read in conjunction with:\n\nNICE's guideline on alcohol-use disorders: prevention (2010). Public health guidance on the price, advertising and availability of alcohol, how best to detect alcohol misuse in and outside primary care, and brief interventions to manage it in these settings.\n\nNICE's guideline on alcohol-use disorders: diagnosis and management of physical complications (2010). A clinical guideline covering acute unplanned alcohol withdrawal including delirium tremens, alcohol-related liver damage, alcohol-related pancreatitis and management of Wernicke's encephalopathy.\n\nHarmful drinking (high-risk drinking) is defined as a pattern of alcohol consumption causing health problems directly related to alcohol. This could include psychological problems such as depression, alcohol-related accidents or physical illness such as acute pancreatitis. In the longer term, harmful drinkers may go on to develop high blood pressure, cirrhosis, heart disease and some types of cancer, such as mouth, liver, bowel or breast cancer.\n\nAlcohol dependence is characterised by craving, tolerance, a preoccupation with alcohol and continued drinking in spite of harmful consequences (for example, liver disease or depression caused by drinking). Alcohol dependence is also associated with increased criminal activity and domestic violence, and an increased rate of significant mental and physical disorders. Although alcohol dependence is defined in ICD-10 and DSM-IV in categorical terms for diagnostic and statistical purposes as being either present or absent, in reality dependence exists on a continuum of severity. However, it is helpful from a clinical perspective to subdivide dependence into categories of mild, moderate and severe. People with mild dependence (those scoring 15 or less on the Severity of Alcohol Dependence Questionnaire; SADQ) usually do not need assisted alcohol withdrawal. People with moderate dependence (with a SADQ score of between 15 and 30) usually need assisted alcohol withdrawal, which can typically be managed in a community setting unless there are other risks. People who are severely alcohol dependent (with a SADQ score of more than 30) will need assisted alcohol withdrawal, typically in an inpatient or residential setting. In this guideline these definitions of severity are used to guide selection of appropriate interventions.\n\nFor convenience this guideline refers to harmful drinking and alcohol dependence as 'alcohol misuse'. When recommendations apply to both people who are dependent on alcohol and harmful drinkers, the terms 'person who misuses alcohol' or 'service user' are used unless the recommendation is specifically referring to either people who are dependent on alcohol or who are harmful drinkers.\n\nAlcohol dependence affects 4% of people aged between 16 and 65 in England (6% of men and 2% of women), and over 24% of the English population (33% of men and 16% of women) consume alcohol in a way that is potentially or actually harmful to their health or well-being. Alcohol misuse is also an increasing problem in children and young people, with over 24,000 treated in the NHS for alcohol-related problems in 2008 and 2009.\n\nComorbid mental health disorders commonly include depression, anxiety disorders and drug misuse, some of which may remit with abstinence from alcohol but others may persist and need specific treatment. Physical comorbidities are common, including gastrointestinal disorders (in particular liver disease) and neurological and cardiovascular disease. In some people these comorbidities may remit on stopping or reducing alcohol consumption, but many experience long-term consequences of alcohol misuse that may significantly shorten their life.\n\nOf the 1 million people aged between 16 and 65 who are alcohol dependent in England, only about 6% per year receive treatment. Reasons for this include the often long period between developing alcohol dependence and seeking help, and the limited availability of specialist alcohol treatment services in some parts of England. Additionally, alcohol misuse is under-identified by health and social care professionals, leading to missed opportunities to provide effective interventions.\n\nDiagnosis is made on the basis of the symptoms and consequences of alcohol misuse outlined above. Simple biological measures such as liver function tests are poor indicators of the presence of harmful or dependent drinking. Diagnosis and assessment of the severity of alcohol misuse is important because it points to the treatment interventions required. Acute withdrawal from alcohol in the absence of medical management can be hazardous in people with severe alcohol dependence, as it may lead to seizures, delirium tremens and, in some instances, death.\n\nCurrent practice across the country is varied and access to a range of assisted withdrawal and treatment services varies as a consequence. Services for assisted alcohol withdrawal vary considerably in intensity and there is a lack of structured intensive community-based assisted withdrawal programmes. Similarly, there is limited access to psychological interventions such as cognitive behavioural therapies specifically focused on alcohol misuse. In addition, when the alcohol misuse has been effectively treated, many people continue to experience problems in accessing services for comorbid mental and physical health problems. Despite the publication of the Models of Care for Alcohol by the Department of Health in 2007 (National Treatment Agency, 2007), alcohol service structures are poorly developed, with care pathways often ill defined. In order to address this last point the three pieces of NICE guidance are integrated into a care pathway.\n\nThis guideline will assume that prescribers will use a drug's summary of product characteristics (SPC) to inform their decisions for individual service users.\n\nAt the time of publication, no drug recommended in this guideline has a UK marketing authorisation for use in children and young people under the age of\xa018. However, in 2000, the Royal College of Paediatrics and Child Health issued a policy statement on the use of unlicensed medicines, or the use of licensed medicines for unlicensed applications, in children and young people. This states that such use is necessary in paediatric practice and that doctors are legally allowed to prescribe unlicensed medicines where there are no suitable alternatives and where the use is justified by a responsible body of professional opinion.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Principles of care\n\n## Building a trusting relationship and providing information\n\nWhen working with people who misuse alcohol:\n\nbuild a trusting relationship and work in a supportive, empathic and non‑judgmental manner\n\ntake into account that stigma and discrimination are often associated with alcohol misuse and that minimising the problem may be part of the service user's presentation\n\nmake sure that discussions take place in settings in which confidentiality, privacy and dignity are respected.\n\nWhen working with people who misuse alcohol:\n\nprovide information appropriate to their level of understanding about the nature and treatment of alcohol misuse to support choice from a range of evidence-based treatments\n\navoid clinical language without explanation\n\nmake sure that comprehensive written information is available in an appropriate language or, for those who cannot use written text, in an accessible format\n\nprovide independent interpreters (that is, someone who is not known to the service user) if needed.\n\n## Working with and supporting families and carers\n\nEncourage families and carers to be involved in the treatment and care of people who misuse alcohol to help support and maintain positive change.\n\nWhen families and carers are involved in supporting a person who misuses alcohol, discuss concerns about the impact of alcohol misuse on themselves and other family members, and:\n\nprovide written and verbal information on alcohol misuse and its management, including how families and carers can support the service user\n\noffer a carer's assessment where necessary (see NICE's guideline on supporting adult carers)\n\nnegotiate with the service user and their family or carer about the family or carer's involvement in their care and the sharing of information; make sure the service user's, family's and carer's right to confidentiality is respected.\n\nWhen the needs of families and carers of people who misuse alcohol have been identified:\n\noffer guided self-help, usually consisting of a single session, with the provision of written materials\n\nprovide information about, and facilitate contact with, support groups (such as self-help groups specifically focused on addressing the needs of families and carers).\n\nIf the families and carers of people who misuse alcohol have not benefited, or are not likely to benefit, from guided self-help and/or support groups and continue to have significant problems, consider offering family meetings. These should:\n\nprovide information and education about alcohol misuse\n\nhelp to identify sources of stress related to alcohol misuse\n\nexplore and promote effective coping behaviours\n\nusually consist of at least five weekly sessions.\n\nAll staff in contact with parents who misuse alcohol and who have care of or regular contact with their children, should:\n\ntake account of the impact of the parent's drinking on the parent–child relationship and the child's development, education, mental and physical health, own alcohol use, safety, and social network\n\nbe aware of and comply with the requirements of the Children Act (2004).\n\n# Identification and assessment\n\n## General principles\n\nMake sure that assessment of risk is part of any assessment, that it informs the development of the overall care plan, and that it covers risk to self (including unplanned withdrawal, suicidality and neglect) and risk to others.\n\nStaff working in services provided and funded by the NHS who care for people who potentially misuse alcohol should be competent to identify harmful drinking (high-risk drinking) and alcohol dependence. They should be competent to initially assess the need for an intervention or, if they are not competent, they should refer people who misuse alcohol to a service that can provide an assessment of need.\n\nWhen conducting an initial assessment, as well as assessing alcohol misuse, the severity of dependence and risk, consider the:\n\nextent of any associated health and social problems\n\nneed for assisted alcohol withdrawal.\n\nUse formal assessment tools to assess the nature and severity of alcohol misuse, including the:\n\nAUDIT for identification and as a routine outcome measure\n\nSADQ or LDQ for severity of dependence\n\nClinical Institute Withdrawal Assessment of Alcohol Scale, revised (CIWA-Ar) for severity of withdrawal\n\nAPQ for the nature and extent of the problems arising from alcohol misuse.\n\nWhen assessing the severity of alcohol dependence and determining the need for assisted withdrawal, adjust the criteria for women, older people, children and young people, and people with established liver disease who may have problems with the metabolism of alcohol.See section 1.3.7 for assessment of children and young people.\n\nStaff responsible for assessing and managing assisted alcohol withdrawal (see section 1.3.4) should be competent in the diagnosis and assessment of alcohol dependence and withdrawal symptoms and the use of drug regimens appropriate to the settings (for example, inpatient or community) in which the withdrawal is managed.\n\nStaff treating people with alcohol dependence presenting with an acute unplanned alcohol withdrawal should refer to the NICE guideline on alcohol-use disorders: diagnosis and management of physical complications.\n\n## Assessment in specialist alcohol services\n\nTreatment goals\n\nIn the initial assessment in specialist alcohol services of all people who misuse alcohol, agree the goal of treatment with the service user. Abstinence is the appropriate goal for most people with alcohol dependence, and people who misuse alcohol and have significant psychiatric or physical comorbidity (for example, depression or alcohol-related liver disease). When a service user prefers a goal of moderation but there are considerable risks, advise strongly that abstinence is most appropriate, but do not refuse treatment to service users who do not agree to a goal of abstinence.\n\nFor harmful drinking (high-risk drinking) or mild dependence, without significant comorbidity, and if there is adequate social support, consider a moderate level of drinking as the goal of treatment unless the service user prefers abstinence or there are other reasons for advising abstinence.\n\nFor people with severe alcohol dependence, or those who misuse alcohol and have significant psychiatric or physical comorbidity, but who are unwilling to consider a goal of abstinence or engage in structured treatment, consider a harm reduction programme of care. However, ultimately the service user should be encouraged to aim for a goal of abstinence.\n\nWhen developing treatment goals, consider that some people who misuse alcohol may be required to abstain from alcohol as part of a court order or sentence.\n\nBrief triage assessment\n\nAll adults who misuse alcohol who are referred to specialist alcohol services should have a brief triage assessment to assess:\n\nthe pattern and severity of the alcohol misuse (using AUDIT) and severity of dependence (using SADQ)\n\nthe need for urgent treatment including assisted withdrawal\n\nany associated risks to self or others\n\nthe presence of any comorbidities or other factors that may need further specialist assessment or intervention.Agree the initial treatment plan, taking into account the service user's preferences and outcomes of any previous treatment.\n\nComprehensive assessment\n\nConsider a comprehensive assessment for all adults referred to specialist alcohol services who score more than 15 on the AUDIT. A comprehensive assessment should assess multiple areas of need, be structured in a clinical interview, use relevant and validated clinical tools (see recommendation 1.2.1.4), and cover the following areas:\n\nalcohol use, including:\n\n\n\nconsumption: historical and recent patterns of drinking (using, for example, a retrospective drinking diary), and if possible, additional information (for example, from a family member or carer)\n\ndependence (using, for example, SADQ or LDQ)\n\nalcohol-related problems (using, for example, APQ)\n\n\n\nother drug misuse, including over-the-counter medication\n\nphysical health problems\n\npsychological and social problems\n\ncognitive function (using, for example, the Mini-Mental State Examination [MMSE])\n\nreadiness and belief in ability to change.\n\nAssess comorbid mental health problems as part of any comprehensive assessment, and throughout care for the alcohol misuse, because many comorbid problems (though not all) will improve with treatment for alcohol misuse. Use the assessment of comorbid mental health problems to inform the development of the overall care plan.\n\nFor service users whose comorbid mental health problems do not significantly improve after abstinence from alcohol (typically after 3 to 4\xa0weeks), consider providing or referring for specific treatment (see the relevant NICE guideline for the particular disorder).\n\nConsider measuring breath alcohol as part of the management of assisted withdrawal. However, breath alcohol should not usually be measured for routine assessment and monitoring in alcohol treatment programmes.\n\nConsider blood tests to help identify physical health needs, but do not use blood tests routinely for the identification and diagnosis of alcohol use disorders.\n\nConsider brief measures of cognitive functioning (for example, MMSE) to help with treatment planning. Formal measures of cognitive functioning should usually only be performed if impairment persists after a period of abstinence or a significant reduction in alcohol intake.\n\n# Interventions for alcohol misuse\n\n## General principles for all interventions\n\nFor all people who misuse alcohol, carry out a motivational intervention as part of the initial assessment. The intervention should contain the key elements of motivational interviewing including:\n\nhelping people to recognise problems or potential problems related to their drinking\n\nhelping to resolve ambivalence and encourage positive change and belief in the ability to change\n\nadopting a persuasive and supportive rather than an argumentative and confrontational position.\n\nFor all people who misuse alcohol, offer interventions to promote abstinence or moderate drinking as appropriate (see recommendations 1.2.2.1 to 1.2.2.4) and prevent relapse, in community-based settings.\n\nConsider offering interventions to promote abstinence and prevent relapse as part of an intensive structured community-based intervention for people with moderate and severe alcohol dependence who have:\n\nvery limited social support (for example, they are living alone or have very little contact with family or friends) or\n\ncomplex physical or psychiatric comorbidities or\n\nnot responded to initial community-based interventions (see recommendation 1.3.1.2).\n\nFor people with alcohol dependence who are homeless, consider offering residential rehabilitation for a maximum of 3 months. Help the service user find stable accommodation before discharge.\n\nAll interventions for people who misuse alcohol should be delivered by appropriately trained and competent staff. Pharmacological interventions should be administered by specialist and competent staff. Psychological interventions should be based on a relevant evidence-based treatment manual, which should guide the structure and duration of the intervention. Staff should consider using competence frameworks developed from the relevant treatment manuals and for all interventions should:\n\nreceive regular supervision from individuals competent in both the intervention and supervision\n\nroutinely use outcome measurements to make sure that the person who misuses alcohol is involved in reviewing the effectiveness of treatment\n\nengage in monitoring and evaluation of treatment adherence and practice competence, for example, by using video and audio tapes and external audit and scrutiny if appropriate.\n\nAll interventions for people who misuse alcohol should be the subject of routine outcome monitoring. This should be used to inform decisions about continuation of both psychological and pharmacological treatments. If there are signs of deterioration or no indications of improvement, consider stopping the current treatment and review the care plan.\n\nFor all people seeking help for alcohol misuse:\n\ngive information on the value and availability of community support networks and self-help groups (for example, Alcoholics Anonymous or SMART Recovery)\xa0and\n\nhelp them to participate in community support networks and self-help groups by encouraging them to go to meetings and arranging support so that they can attend.\n\n## Care coordination and case management\n\nCare coordination is the routine coordination by any staff involved in the care and treatment of a person who misuses alcohol. Case management is a more intensive process concerned with delivering all aspects of care, including assessment, treatment, monitoring and follow-up.\n\nCare coordination should be part of the routine care of all service users in specialist alcohol services and should:\n\nbe provided throughout the whole period of care, including aftercare\n\nbe delivered by appropriately trained and competent staff working in specialist alcohol services\n\ninclude the coordination of assessment, interventions and monitoring of progress, and coordination with other agencies.\n\nConsider case management to increase engagement in treatment for people who have moderate to severe alcohol dependence and who are considered at risk of dropping out of treatment or who have a previous history of poor engagement. If case management is provided it should be throughout the whole period of care, including aftercare.\n\nCase management should be delivered in the context of Tier\xa03 interventions by staff who take responsibility for the overall coordination of care and should include:\n\na comprehensive assessment of needs\n\ndevelopment of an individualised care plan in collaboration with the service user and relevant others (including families and carers and other staff involved in the service user's care)\n\ncoordination of the care plan to deliver a seamless multiagency and integrated care pathway and maximisation of engagement, including the use of motivational interviewing approaches\n\nmonitoring of the impact of interventions and revision of the care plan when necessary.\n\n## Interventions for harmful drinking (high-risk drinking) and mild alcohol dependence\n\nFor harmful drinkers (high-risk drinkers) and people with mild alcohol dependence, offer a psychological intervention (such as cognitive behavioural therapies, behavioural therapies or social network and environment-based therapies) focused specifically on alcohol-related cognitions, behaviour, problems and social networks.\n\nOffer behavioural couples therapy for harmful drinkers and people with mild alcohol dependence who have a regular partner who is willing to participate in treatment, unless there are indicators that the person is currently experiencing, or is a current perpetrator of, domestic abuse. For advice on the use of nalmefene for alcohol dependence, see NICE's technology appraisal guidance on nalmefene for reducing alcohol consumption in people with alcohol dependence.\n\nFor harmful drinkers and people with mild alcohol dependence who have not responded to psychological interventions alone, or who have specifically requested a pharmacological intervention, consider offering acamprosate or oral naltrexone in combination with an individual psychological intervention (cognitive behavioural therapies, behavioural therapies or social network and environment-based therapies) or behavioural couples therapy (see section 1.3.6 for pharmacological interventions).Note that the evidence for acamprosate in the treatment of harmful drinkers (high-risk drinkers) and people who are mildly alcohol dependent is less robust than that for naltrexone. In February 2011, this was an off-label use of acamprosate. See NICE's information on prescribing medicines.\n\nDelivering psychological interventions\n\nCognitive behavioural therapies focused on alcohol-related problems should usually consist of one 60-minute session per week for 12\xa0weeks.\n\nBehavioural therapies focused on alcohol-related problems should usually consist of one 60-minute session per week for 12\xa0weeks.\n\nSocial network and environment-based therapies focused on alcohol-related problems should usually consist of eight 50-minute sessions over 12\xa0weeks.\n\nBehavioural couples therapy should be focused on alcohol-related problems and their impact on relationships. It should aim for abstinence, or a level of drinking predetermined and agreed by the therapist and the service user to be reasonable and safe. It should usually consist of one 60-minute session per week for 12\xa0weeks.\n\n## Assessment and interventions for assisted alcohol withdrawal\n\nSee section 1.3.7 for assessment for assisted withdrawal in children and young people.\n\nFor service users who typically drink over 15\xa0units of alcohol per day and/or who score 20 or more on the AUDIT, consider offering:\n\nan assessment for and delivery of a community-based assisted withdrawal or\n\nassessment and management in specialist alcohol services if there are safety concerns (see recommendation 1.3.4.5) about a community-based assisted withdrawal.\n\nService users who need assisted withdrawal should usually be offered a community-based programme, which should vary in intensity according to the severity of the dependence, available social support and the presence of comorbidities.\n\nFor people with mild to moderate dependence, offer an outpatient-based assisted withdrawal programme in which contact between staff and the service user averages 2 to 4\xa0meetings per week over the first week.\n\nFor people with mild to moderate dependence and complex needs, or severe dependence, offer an intensive community programme following assisted withdrawal in which the service user may attend a day programme lasting between 4 and 7\xa0days per week over a 3-week period. Examples of complex needs include psychiatric comorbidity, poor social support or homelessness.\n\nOutpatient-based community assisted withdrawal programmes should consist of a drug regimen (see section 1.3.5) and psychosocial support including motivational interviewing (see recommendation 1.3.1.1).\n\nIntensive community programmes following assisted withdrawal should consist of a drug regimen (see section 1.3.6) supported by psychological interventions including individual treatments (see section 1.3.6), group treatments, psychoeducational interventions, help to attend self-help groups, family and carer support and involvement, and case management (see recommendation 1.3.2.2).\n\nConsider inpatient or residential assisted withdrawal if a service user meets one or more of the following criteria. They:\n\ndrink over 30\xa0units of alcohol per day\n\nhave a score of more than 30 on the SADQ\n\nhave a history of epilepsy, or experience of withdrawal-related seizures or delirium tremens during previous assisted withdrawal programmes\n\nneed concurrent withdrawal from alcohol and benzodiazepines\n\nregularly drink between 15 and 30\xa0units of alcohol per day and have:\n\n\n\nsignificant psychiatric or physical comorbidities (for example, chronic severe depression, psychosis, malnutrition, congestive cardiac failure, unstable angina, chronic liver disease) or\n\na significant learning disability or cognitive impairment.\n\n\n\nConsider a lower threshold for inpatient or residential assisted withdrawal in vulnerable groups, for example, homeless and older people.\n\n## Drug regimens for assisted withdrawal\n\nWhen conducting community-based assisted withdrawal programmes, use fixed-dose medication regimens. A fixed-dose regimen involves starting treatment with a standard dose, not defined by the level of alcohol withdrawal, and reducing the dose to zero over 7 to 10\xa0days according to a standard protocol.\n\nFixed-dose or symptom-triggered medication regimens can be used in assisted withdrawal programmes in inpatient or residential settings. If a symptom-triggered regimen is used, all staff should be competent in monitoring symptoms effectively and the unit should have sufficient resources to allow them to do so frequently and safely.A symptom-triggered approach involves tailoring the drug regimen according to the severity of withdrawal and any complications. The service user is monitored on a regular basis and pharmacotherapy only continues as long as the service user is showing withdrawal symptoms.\n\nPrescribe and administer medication for assisted withdrawal within a standard clinical protocol. The preferred medication for assisted withdrawal is a benzodiazepine (chlordiazepoxide or diazepam). Prescribers should be aware of the legislation on controlled drugs and driving: blood concentration limits and advise patients accordingly.\n\nIn a fixed-dose regimen, titrate the initial dose of medication to the severity of alcohol dependence and/or regular daily level of alcohol consumption. In severe alcohol dependence higher doses will be required to adequately control withdrawal and should be prescribed according to the SPC. Make sure there is adequate supervision if high doses are administered. Gradually reduce the dose of the benzodiazepine over 7 to 10\xa0days to avoid alcohol withdrawal recurring.\n\nWhen managing alcohol withdrawal in the community, avoid giving people who misuse alcohol large quantities of medication to take home to prevent overdose or diversion (the drug being taken by someone other than the person it was prescribed for). Prescribe for installment dispensing, with no more than 2 days' medication supplied at any time.\n\nIn a community-based assisted withdrawal programme, monitor the service user every other day during assisted withdrawal. A family member or carer should preferably oversee the administration of medication. Adjust the dose if severe withdrawal symptoms or over-sedation occur.\n\nDo not offer clomethiazole for community-based assisted withdrawal because of the risk of overdose and misuse.\n\nFor service users having assisted withdrawal, particularly those who are more severely alcohol dependent or those undergoing a symptom-triggered regimen, consider using a formal measure of withdrawal symptoms such as the CIWA-Ar.\n\nBe aware that benzodiazepine doses may need to be reduced for children and young people, older people, and people with liver impairment (see recommendation 1.3.5.10).In February 2011 this was an off-label use of benzodiazepines in children and young people under 18. See NICE's information on prescribing medicines. Prescribers should also see the MHRA's advice on addiction to benzodiazepines and codeine.\n\nIf benzodiazepines are used for people with liver impairment, consider one requiring limited liver metabolism (for example, lorazepam); start with a reduced dose and monitor liver function carefully. Avoid using benzodiazepines for people with severe liver impairment.\n\nWhen managing withdrawal from co-existing benzodiazepine and alcohol dependence increase the dose of benzodiazepine medication used for withdrawal. Calculate the initial daily dose based on the requirements for alcohol withdrawal plus the equivalent regularly used daily dose of benzodiazepine. This is best managed with one benzodiazepine (chlordiazepoxide or diazepam) rather than multiple benzodiazepines. Inpatient withdrawal regimens should last for 2 to 3\xa0weeks or longer, depending on the severity of co-existing benzodiazepine dependence. When withdrawal is managed in the community, and/or where there is a high level of benzodiazepine dependence, the regimen should last for longer than 3\xa0weeks, tailored to the service user's symptoms and discomfort.In February 2011, this was an off-label use of benzodiazepines. See NICE's information on prescribing medicines. Prescribers should also see the MHRA's advice on addiction to benzodiazepines and codeine.\n\nFor managing unplanned acute alcohol withdrawal and complications including delirium tremens and withdrawal-related seizures, refer to the NICE guideline on alcohol-use disorders: diagnosis and management of physical complications.\n\n## Interventions for moderate and severe alcohol dependence after successful withdrawal\n\nAfter a successful withdrawal for people with moderate and severe alcohol dependence, consider offering acamprosate or oral naltrexone in combination with an individual psychological intervention (cognitive behavioural therapies, behavioural therapies or social network and environment-based therapies) focused specifically on alcohol misuse (see section 1.3.3).\n\nAfter a successful withdrawal for people with moderate and severe alcohol dependence, consider offering acamprosate or oral naltrexone in combination with behavioural couples therapy to service users who have a regular partner and whose partner is willing to participate in treatment (see section 1.3.3).Oral naltrexone is licensed for alcohol dependence. See the summary of product characteristics.\n\nAfter a successful withdrawal for people with moderate and severe alcohol dependence, consider offering disulfiram in combination with a psychological intervention to service users who:\n\nhave a goal of abstinence but for whom acamprosate and oral naltrexone are not suitable, or\n\nprefer disulfiram and understand the relative risks of taking the drug (see recommendation 1.3.6.12).All prescribers should consult the SPC for a full description of the contraindications and the special considerations of the use of disulfiram.\n\nDelivering pharmacological interventions\n\nBefore starting treatment with acamprosate, oral naltrexone or disulfiram, conduct a comprehensive medical assessment (baseline urea and electrolytes and liver function tests including gamma glutamyl transferase [GGT]). In particular, consider any contraindications or cautions (see the SPC), and discuss these with the service user.In February 2011, this was an off-label use of benzodiazepines. See NICE's information on prescribing medicines. Informed consent should be obtained and documented in line with normal standards of care for patients who may lack capacity (or see NHS Wales) or in line with normal standards in emergency care.\n\nAcamprosate\n\nIf using acamprosate, start treatment as soon as possible after assisted withdrawal. Usually prescribe at a dose of 1998\xa0mg (666\xa0mg three times a day) unless the service user weighs less than 60\xa0kg, and then a maximum of 1332\xa0mg should be prescribed per day. Acamprosate should:\n\nusually be prescribed for up to 6\xa0months, or longer for those benefiting from the drug who want to continue with it\n\nbe stopped if drinking persists 4 to 6\xa0weeks after starting the drug.In February 2011, use for longer than 12\xa0months was an off-label use of acamprosate. See NICE's information on prescribing medicines.\n\nService users taking acamprosate should stay under supervision, at least monthly, for 6\xa0months, and at reduced but regular intervals if the drug is continued after 6\xa0months. Do not use blood tests routinely, but consider them to monitor for recovery of liver function and as a motivational aid for service users to show improvement.\n\nNaltrexone\n\nIf using oral naltrexone, start treatment after assisted withdrawal. Start prescribing at a dose of 25\xa0mg per day and aim for a maintenance dose of 50\xa0mg per day. Draw the service user's attention to the information card that is issued with oral naltrexone about its impact on opioid-based analgesics. Oral naltrexone should:\n\nusually be prescribed for up to 6\xa0months, or longer for those benefiting from the drug who want to continue with it\n\nbe stopped if drinking persists 4 to 6\xa0weeks after starting the drug.\n\nService users taking oral naltrexone should stay under supervision, at least monthly, for 6\xa0months, and at reduced but regular intervals if the drug is continued after 6\xa0months. Do not use blood tests routinely, but consider them for older people, for people with obesity, for monitoring recovery of liver function and as a motivational aid for service users to show improvement. If the service user feels unwell advise them to stop the oral naltrexone immediately.In February 2011, this was an off-label use of benzodiazepines. See NICE's information on prescribing medicines. Informed consent should be obtained and documented in line with normal standards of care for patients who may lack capacity (or see NHS Wales) or in line with normal standards in emergency care.\n\nDisulfiram\n\nIf using disulfiram, start treatment at least 24\xa0hours after the last alcoholic drink consumed. Usually prescribe at a dose of 200\xa0mg per day. For service users who continue to drink, if a dose of 200\xa0mg (taken regularly for at least 1\xa0week) does not cause a sufficiently unpleasant reaction to deter drinking, consider increasing the dose in consultation with the service user.\n\nBefore starting treatment with disulfiram, test liver function, urea and electrolytes to assess for liver or renal impairment. Check the SPC for warnings and contraindications in pregnancy and in the following conditions: a history of severe mental illness, stroke, heart disease or hypertension.\n\nMake sure that service users taking disulfiram:\n\nstay under supervision, at least every 2\xa0weeks for the first 2\xa0months, then monthly for the following 4\xa0months\n\nif possible, have a family member or carer, who is properly informed about the use of disulfiram, oversee the administration of the drug\n\nare medically monitored at least every 6\xa0months after the initial 6\xa0months of treatment and monitoring.\n\nWarn service users taking disulfiram, and their families and carers, about:\n\nthe interaction between disulfiram and alcohol (which may also be found in food, perfume, aerosol sprays and so on), the symptoms of which may include flushing, nausea, palpitations and, more seriously, arrhythmias, hypotension and collapse\n\nthe rapid and unpredictable onset of the rare complication of hepatotoxicity; advise service users that if they feel unwell or develop a fever or jaundice that they should stop taking disulfiram and seek urgent medical attention.\n\nDrugs not to be routinely used for the treatment of alcohol misuse\n\nDo not use antidepressants (including selective serotonin reuptake inhibitors [SSRIs]) routinely for the treatment of alcohol misuse alone.\n\nDo not use gammahydroxybutyrate (GHB) for the treatment of alcohol misuse.\n\nBenzodiazepines should only be used for managing alcohol withdrawal and not as ongoing treatment for alcohol dependence.\n\n## Special considerations for children and young people who misuse alcohol\n\nAssessment and referral of children and young people\n\nIf alcohol misuse is identified as a potential problem, with potential physical, psychological, educational or social consequences, in children and young people aged 10 to 17\xa0years, conduct an initial brief assessment to assess:\n\nthe duration and severity of the alcohol misuse (the standard adult threshold on the AUDIT for referral and intervention should be lowered for young people aged 10 to 16\xa0years because of the more harmful effects of a given level of alcohol consumption in this population)\n\nany associated health and social problems\n\nthe potential need for assisted withdrawal.\n\nRefer all children and young people aged 10 to 15 years to a specialist child and adolescent mental health service (CAMHS) for a comprehensive assessment of their needs, if their alcohol misuse is associated with physical, psychological, educational and social problems and/or comorbid drug misuse.\n\nWhen considering referral to CAMHS for young people aged 16 to 17\xa0years who misuse alcohol, use the same referral criteria as for adults (see section 1.2.2).\n\nA comprehensive assessment for children and young people (supported if possible by additional information from a parent or carer) should assess multiple areas of need, be structured around a clinical interview using a validated clinical tool (such as the Adolescent Diagnostic Interview [ADI] or the Teen Addiction Severity Index [T‑ASI]), and cover the following areas:\n\nconsumption, dependence features and patterns of drinking\n\ncomorbid substance misuse (consumption and dependence features) and associated problems\n\nmental and physical health problems\n\npeer relationships and social and family functioning\n\ndevelopmental and cognitive needs, and educational attainment and attendance\n\nhistory of abuse and trauma\n\nrisk to self and others\n\nreadiness to change and belief in the ability to change\n\nobtaining consent to treatment\n\ndeveloping a care plan and risk management plan.\n\nAssisted withdrawal in children and young people\n\nOffer inpatient care to children and young people aged 10 to 17\xa0years who need assisted withdrawal.\n\nBase assisted withdrawal for children and young people aged 10 to 17\xa0years on the recommendations for adults (see section 1.3.5) and in the NICE guideline on alcohol-use disorders: diagnosis and management of physical complications. Consult the SPC and adjust drug regimens to take account of age, height and body mass, and stage of development of the child or young person.\n\nPromoting abstinence and preventing relapse in children and young people\n\nFor all children and young people aged 10 to 17\xa0years who misuse alcohol, the goal of treatment should usually be abstinence in the first instance.\n\nFor children and young people aged 10 to 17\xa0years who misuse alcohol offer:\n\nindividual cognitive behavioural therapy for those with limited comorbidities and good social support\n\nmulticomponent programmes (such as multidimensional family therapy, brief strategic family therapy, functional family therapy or multisystemic therapy) for those with significant comorbidities and/or limited social support.\n\nAfter a careful review of the risks and benefits, specialists may consider offering acamprosate or oral naltrexone in combination with cognitive behavioural therapy to young people aged 16 and 17\xa0years who have not engaged with or benefited from a multicomponent treatment programme.In February 2011, this was an off-label use of oral naltrexone, and use for longer than 12 months was an off-label use of acamprosate. See NICE's information on prescribing medicines.\n\nDelivering psychological and psychosocial interventions for children and young people\n\nMultidimensional family therapy should usually consist of 12 to 15 family-focused structured treatment sessions over 12\xa0weeks. There should be a strong emphasis on care coordination and, if necessary, crisis management. As well as family sessions, individual interventions may be provided for both the child or young person and the parents. The intervention should aim to improve:\n\nalcohol and drug misuse\n\nthe child or young person's educational and social behaviour\n\nparental well-being and parenting skills\n\nrelationships with the wider social system.\n\nBrief strategic family therapy should usually consist of fortnightly meetings over 3\xa0months. It should focus on:\n\nengaging and supporting the family\n\nusing the support of the wider social and educational system\n\nidentifying maladaptive family interactions\n\npromoting new and more adaptive family interactions.\n\nFunctional family therapy should be conducted over 3\xa0months by health or social care staff. It should focus on improving interactions within the family, including:\n\nengaging and motivating the family in treatment (enhancing perception that change is possible, positive reframing and establishing a positive alliance)\n\nproblem solving and behaviour change through parent training and communication training\n\npromoting generalisation of change in specific behaviours to broader contexts, both within the family and the community (such as schools).\n\nMultisystemic therapy should be provided over 3 to 6\xa0months by a dedicated member of staff with a low caseload (typically between three and six cases). It should:\n\nfocus specifically on problem-solving approaches with the family\n\nuse the resources of peer groups, schools and the wider community.\n\n## Interventions for conditions comorbid with alcohol misuse\n\nFor people who misuse alcohol and have comorbid depression or anxiety disorders, treat the alcohol misuse first as this may lead to significant improvement in the depression and anxiety. If depression or anxiety continues after 3 to 4\xa0weeks of abstinence from alcohol, assess the depression or anxiety and consider referral and treatment in line with the relevant NICE guideline for the particular disorder. See the NICE guidelines on depression in adults: treatment and management, generalised anxiety disorder and panic disorder in adults: management and antisocial personality disorder: prevention and management. Also see NICE's guideline on coexisting severe mental illness and substance misuse: community health and social care services.\n\nRefer people who misuse alcohol and have a significant comorbid mental health disorder, and those assessed to be at high risk of suicide, to a psychiatrist to make sure that effective assessment, treatment and risk-management plans are in place.\n\nFor the treatment of comorbid mental health disorders refer to the relevant NICE guideline for the particular disorder, and:\n\nfor alcohol misuse comorbid with opioid misuse actively treat both conditions; take into account the increased risk of mortality with taking alcohol and opioids together\n\nfor alcohol misuse comorbid with stimulant, cannabis or benzodiazepine misuse actively treat both conditions. Service users who have been dependent on alcohol will need to be abstinent, or have very significantly reduced their drinking, to benefit from psychological interventions for comorbid mental health disorders. See the NICE guidelines on drug misuse in over 16s: opioid detoxification and drug misuse in over 16s: psychosocial interventions.\n\nFor comorbid alcohol and nicotine dependence, encourage service users to stop smoking and refer to the NICE guideline on tobacco.\n\nWernicke-Korsakoff syndrome\n\nFollow the recommendations in the NICE guideline on alcohol-use disorders: diagnosis and management of physical complications on thiamine for people at high risk of developing, or with suspected, Wernicke's encephalopathy. In addition, offer parenteral thiamine followed by oral thiamine to prevent Wernicke-Korsakoff syndrome in people who are entering planned assisted alcohol withdrawal in specialist inpatient alcohol services or prison settings and who are malnourished or at risk of malnourishment (for example, people who are homeless) or have decompensated liver disease.\n\nFor people with Wernicke-Korsakoff syndrome, offer long-term placement in:\n\nsupported independent living for those with mild cognitive impairment\n\nsupported 24-hour care for those with moderate or severe cognitive impairment.In both settings the environment should be adapted for people with cognitive impairment and support should be provided to help service users maintain abstinence from alcohol.", 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Is contingency management effective in reducing alcohol consumption in people who misuse alcohol compared with standard care?\n\nThis question should be answered using a randomised controlled design that reports short-and medium-term outcomes (including cost-effectiveness outcomes) of at least 18 months' duration. Particular attention should be paid to the reproducibility of the treatment model and training and supervision of those providing the intervention to ensure that the results are robust and generalisable. The outcomes chosen should reflect both observer and service user-rated assessments of improvement and the acceptability of the intervention. The study needs to be large enough to determine the presence or absence of clinically important effects, and mediators and moderators of response should be investigated.\n\n## Why this is important\n\nPsychological interventions are an important therapeutic option for people with alcohol-related problems. However, even with the most effective current treatment (for example, cognitive behavioural therapies and social network and environment-based therapies), the effects are modest at best and the treatments are not effective for everyone. Contingency management has a considerable and compelling evidence base in the treatment of substance misuse (for example, opioid misuse) but there is only a limited, if promising, evidence base for contingency management in the treatment of alcohol-related problems. The results of this research will have important implications for the provision of psychological treatment for alcohol misuse in the NHS.\n\n# What methods are most effective for assessing and diagnosing the presence and severity of alcohol misuse in children and young people?\n\nThis question should be answered in a programme of research that uses a cross-sectional cohort design testing:\n\nthe sensitivity and specificity of a purpose-designed suite of screening and case identification measures of alcohol misuse against a diagnostic gold standard (DSM-IV or ICD-10)\n\nthe reliability and validity of a purpose-designed suite in characterising the nature and the severity of the alcohol misuse in children and young people and their predictive validity in identifying the most effective treatment when compared with current best practice. Particular attention should be paid to the feasibility of the measures in routine care and the training required to obtain satisfactory levels of accuracy and predictive validity. The programme needs to be large enough to encompass the age range (10 to 17\xa0years) and the comorbidity that often accompanies alcohol misuse in children and young people.\n\n## Why this is important\n\nAlcohol misuse is an increasingly common problem in children and young people. However, diagnostic instruments are poorly developed or not available for children and young people. In adults there is a range of diagnostic and assessment tools (with reasonable sensitivity and specificity, and reliability and validity) that are recommended for routine use in the NHS to both assess the severity of the alcohol misuse and to guide treatment decisions. No similar well-developed measures exist for children and young people, with the result that problems are missed and/or inappropriate treatment is offered. The results of this study will have important implications for the identification and the provision of effective treatment in the NHS for children and young people with alcohol-related problems.\n\n# Is acupuncture effective in reducing alcohol consumption compared with standard care?\n\nThis question should be answered using a randomised controlled design that reports short-and medium-term outcomes (including cost-effectiveness outcomes) of at least 12\xa0months' duration. Particular attention should be paid to the reproducibility of the treatment model and training and supervision of those providing the intervention to ensure that the results are robust and generalisable. The outcomes chosen should reflect both observer and service user-rated assessments of improvement and the acceptability of the treatment. The study needs to be large enough to determine the presence or absence of clinically important effects, and mediators and moderators of response should be investigated.\n\n## Why this is important\n\nNon-pharmacological treatments are an important therapeutic option for people with alcohol-related problems. There is an evidence base for acupuncture in reducing craving but not alcohol consumption in a number of small trials. The evidence for pharmacological treatments (for example, acamprosate or naltrexone) and psychological treatments (for example, cognitive behavioural therapies and social network and environment-based therapies) is modest at best and the treatments are not effective for everyone. Anecdotal evidence suggests that acupuncture, like psychological treatment, is valued by service users both in alcohol misuse and substance misuse services (although the evidence base for effectiveness is weak). The results of this study will have important implications for increased treatment choice in the NHS for people who misuse alcohol.\n\n# For which service users who are moderately and severely dependent on alcohol is an assertive community treatment model a clinically and cost-effective intervention compared with standard care?\n\nThis question should be answered using a randomised controlled design in which participants are stratified for severity and complexity of presenting problems. It should report short- and medium-term outcomes (including cost-effectiveness outcomes) of at least 18\xa0months' duration. Particular attention should be paid to the reproducibility of the treatment model and training and supervision of those providing the intervention to ensure that the results are robust and generalisable. The outcomes chosen should reflect both observer and service user-rated assessments of improvement (including personal and social functioning) and the acceptability of the intervention. The study needs to be large enough to determine the presence or absence of clinically important effects, and mediators and moderators of response should be investigated.\n\n## Why this is important\n\nMany people, in particular those with severe problems and complex comorbidities, do not benefit from treatment and/or lose contact with services. This leads to poor outcomes and wastes resources. Assertive community treatment models have been shown to be effective in retaining people in treatment in those with serious mental illness and who misuse alcohol and drugs but the evidence for an impact on outcomes is not proven. A number of small pilot studies suggest that an assertive community approach can bring benefit in both service retention and clinical outcomes in alcohol misuse. Given the high morbidity and mortality associated with chronic severe alcohol dependence the results of this study will have important implications for the structure and provision of alcohol services in the NHS.\n\n# For people with moderate and severe alcohol dependence who have significant comorbid problems, is an intensive residential rehabilitation programme clinically and cost effective when compared with intensive community-based care?\n\nThis question should be answered using a prospective cohort study of all people who have moderate and severe alcohol dependence entering residential and intensive community rehabilitation programmes in a purposive sample of alcohol treatment services in the UK. It should report short- and medium-term outcomes (including cost-effectiveness outcomes) of at least 18\xa0months' duration. Particular attention should be paid to the characterisation of the treatment environment and the nature of the interventions provided to inform the analysis of moderators and mediators of treatment effect. The outcomes chosen should reflect both observer and service user-rated assessments of improvement (including personal and social functioning) and the acceptability of the intervention. The study needs to be large enough to determine the presence or absence of clinically important effects, and mediators and moderators of response should be investigated. A cohort study has been chosen as the most appropriate design as previous studies in this area that have attempted to randomise participants to residential or community care have been unable to recruit clinically representative populations.\n\n## Why this is important\n\nMany people, in particular those with severe problems and complex comorbidities, do not benefit from treatment and/or lose contact with services. One common approach is to offer intensive residential rehabilitation and current policy favours this. However, the research on the effectiveness of residential rehabilitation is uncertain with a suggestion that intensive community services may be as effective. The interpretation of this research is limited by the fact that many of the more severely ill people are not entered into the clinical trials because some clinicians are unsure of the safety of the community setting. However, clinical opinion is divided on the benefits of residential rehabilitation, with some suggesting that those who benefit are a motivated and self-selected group who may do just as well with intensive community treatment, which is currently limited in availability. Given the costs associated with residential treatment and the uncertainty about outcomes, the results of this study will have important implications for the cost effectiveness and provision of alcohol services in the NHS.\n\n# For people with alcohol dependence, which medication is most likely to improve adherence and thereby promote abstinence and prevent relapse?\n\nThis question should be answered by: a) an initial\xa0development phase in which a series of qualitative and quantitative reasons for non-adherence/discontinuing drugs used in the treatment of alcohol are explored; b) a series of pilot trials of novel interventions developed to address the problems identified in (a) undertaken to support the design of a series of definitive trials; c) a (series of) definitive trial(s) of the interventions that were successfully piloted in (b) using a randomised controlled design that reports short-term (for example, 3\xa0months) and longer-term (for example, 18\xa0months) outcomes. The outcomes chosen should reflect both observer and service user-rated assessments of improvement and the acceptability of the intervention. Each individual study needs to be large enough to determine the presence or absence of clinically important effects, and mediators and moderators of response should be investigated.\n\n## Why this is important\n\nRates of attrition in trials of drugs to promote abstinence and prevent relapse in alcohol dependence are high (often over 65%), yet despite this the interventions are still clinically and cost effective. Retaining more service users in treatment could further significantly improve outcomes for people who misuse alcohol and ensure increased effectiveness in the use of health service resources. The outcome of these studies may also help improve clinical confidence in the use of effective medications (such as acamprosate and naltrexone), which despite their cost effectiveness are currently offered to only a minority of eligible NHS service users. Overall, the results of these studies will have important implications for the provision of pharmacological treatment in the NHS for alcohol misuse."}
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https://www.nice.org.uk/guidance/cg115
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This guideline covers identifying, assessing and managing alcohol-use disorders (harmful drinking and alcohol dependence) in adults and young people aged 10 to 17 years. It aims to reduce harms (such as liver disease, heart problems, depression and anxiety) from alcohol by improving assessment and setting goals for reducing alcohol consumption.
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0eac29d2611f3fbdf9817f2da980a5088fcb9d4c
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nice
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Food allergy in under 19s: assessment and diagnosis
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Food allergy in under 19s: assessment and diagnosis
This guideline covers assessing and managing food allergy in children and young people under 19. It aims to improve symptoms such as faltering growth and eczema by offering advice on how to identify food allergy and when to refer to secondary or specialist care.
# Introduction
Food allergy is an adverse immune response to a food. It can be classified into IgE-mediated and non-IgE-mediated reactions. Many non-IgE reactions, which are poorly defined both clinically and scientifically, are believed to be T-cell-mediated. Some reactions involve a mixture of both IgE and non-IgE responses and are classified as mixed IgE and non-IgE allergic reactions. Food allergy may be confused with food intolerance, which is a non- immunological reaction that can be caused by enzyme deficiencies, pharmacological agents and naturally occurring substances. Food intolerance will not be covered in this guideline. The starting point for the guideline is a suspicion of food allergy, and the use of an allergy-focused clinical history will help to determine whether a food allergy is likely.
In its review of allergy services in 2006, the Department of Health and Social Care concluded that there was considerable variation in current practice for allergy care, with no agreed treatment pathways, referral criteria or service models. Specifically, it was reported that many people with allergies practised self-care, using alternative sources of support rather than NHS services (for example, complementary services with non-validated tests and treatments).
In the NHS, most allergy care takes place in primary care. People with a clear diagnosis, and mild but persistent symptoms, are usually managed in general practice without referral to a specialist service. Some people with allergies, and the parents or carers of children and young people with allergies, also buy over-the-counter medicines from community or high-street pharmacies. However, if there is diagnostic doubt or symptoms of a more severe disease, GPs often consider referral for a specialist opinion.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.
# Assessment and allergy-focused clinical history
Consider the possibility of food allergy in children and young people who have one or more of the signs and symptoms in table 1, below. Pay particular attention to persistent symptoms that involve different organ systems.
IgE-mediated
Non-IgE-mediated
The skin
Pruritus
Pruritus
Erythema
Erythema
Acute urticaria – localised or generalised
Atopic eczema
Acute angioedema – most commonly of the lips, face and around the eyes
The gastrointestinal system
Angioedema of the lips, tongue and palate
Gastro-oesophageal reflux disease
Oral pruritus
Loose or frequent stools
Nausea
Blood and/or mucus in stools
Colicky abdominal pain
Abdominal pain
Vomiting
Infantile colic
Diarrhoea
Food refusal or aversion
Constipation
Perianal redness
Pallor and tiredness
Faltering growth in conjunction with at least one or more gastrointestinal symptoms above (with or without significant atopic eczema)
The respiratory system (usually in combination with one or more of the above symptoms and signs)
Upper respiratory tract symptoms (nasal itching, sneezing, rhinorrhoea or congestion )
Lower respiratory tract symptoms (cough, chest tightness, wheezing or shortness of breath)
Other
Signs or symptoms of anaphylaxis or other systemic allergic reactions
Note: this list is not exhaustive. The absence of these symptoms does not exclude food allergy
Consider the possibility of food allergy in children and young people whose symptoms do not respond adequately to treatment for:
atopic eczema (for information about treatment for atopic eczema, see NICE's guideline on atopic eczema in under 12s)
gastro-oesophageal reflux disease (for information about gastro-oesophageal reflux disease, see NICE's guideline on gastro-oesophageal reflux disease in children and young people)
chronic gastrointestinal symptoms, including chronic constipation.Someone with apparent symptoms of food allergy may be suffering from coeliac disease; for information about coeliac disease, see NICE's guideline on coeliac disease.
If food allergy is suspected (by a healthcare professional or the parent, carer, child or young person), a healthcare professional with the appropriate competencies (either a GP or other healthcare professional) should take an allergy-focused clinical history tailored to the presenting symptoms and age of the child or young person. This should include:
any personal history of atopic disease (asthma, eczema or allergic rhinitis)
any individual and family history of atopic disease (such as asthma, eczema or allergic rhinitis) or food allergy in parents or siblings
details of any foods that are avoided and the reasons why
an assessment of presenting symptoms and other symptoms that may be associated with food allergy (see recommendation 1.1.1), including questions about:
the age of the child or young person when symptoms first started
speed of onset of symptoms following food contact
duration of symptoms
severity of reaction
frequency of occurrence
setting of reaction (for example, at school or home)
reproducibility of symptoms on repeated exposure
what food and how much exposure to it causes a reaction
cultural and religious factors that affect the foods they eat
who has raised the concern and suspects the food allergy
what the suspected allergen is
the child or young person's feeding history, whether they were breastfed or formula-fed and the age of weaning
the mother's diet, if the child is currently being breastfed
details of any previous treatment, including medication, for the presenting symptoms and the response to this
any response to the elimination and reintroduction of foods.
Based on the findings of the allergy-focused clinical history, physically examine the child or young person, paying particular attention to:
growth and physical signs of malnutrition (for information about faltering growth, see NICE's guideline on faltering growth)
signs indicating allergy-related comorbidities (atopic eczema, asthma and allergic rhinitis).
# Diagnosis
Food allergy can be classified into IgE-mediated and non-IgE-mediated allergy. IgE-mediated reactions are often immediate and frequently have a rapid onset. Non-IgE-mediated reactions are generally characterised by delayed reactions.
## IgE-mediated food allergy
Based on the results of the allergy-focused clinical history, if IgE-mediated allergy is suspected, offer the child or young person a skin prick test and/or blood tests for specific IgE antibodies to the suspected foods and likely co-allergens
Tests should only be undertaken by healthcare professionals with the appropriate competencies to select, perform and interpret them.
Skin prick tests should only be undertaken where there are facilities to deal with an anaphylactic reaction.
Choose between a skin prick test and a specific IgE antibody blood test based on:
the results of the allergy-focused clinical history and
whether the test is suitable for, safe for and acceptable to the child or young person (or their parent or carer) and
the available competencies of the healthcare professional to undertake the test and interpret the results.
Do not carry out allergy testing without first taking an allergy-focused clinical history. Interpret the results of tests in the context of information from the allergy-focused clinical history.
Do not use atopy patch testing or oral food challenges to diagnose IgE-mediated food allergy in primary care or community settings.
## Non-IgE-mediated food allergy
Based on the results of the allergy-focused clinical history, if non-IgE-mediated food allergy is suspected, trial elimination of the suspected allergen (normally for between 2–6 weeks) and reintroduce after the trial. Seek advice from a dietitian with appropriate competencies, about nutritional adequacies, timings of elimination and reintroduction, and follow-up. (For people undergoing investigation for coeliac disease, see NICE's guideline on coeliac disease.)
## Providing information and support to the child or young person and their parent or carer
Based on the allergy-focused clinical history, offer the child or young person and their parent or carer, information that is age-appropriate about the:
type of allergy suspected
risk of severe allergic reaction
potential impact of the suspected allergy on other healthcare issues, including vaccination
diagnostic process, which may include:
an elimination diet followed by a possible planned rechallenge or initial food reintroduction procedure
skin prick tests and specific IgE antibody testing, including the safety and limitations of these tests
referral to secondary or specialist care.
Offer the child or young person and their parent or carer, information that is relevant to the type of allergy (IgE-mediated, non-IgE-mediated or mixed).
If a food elimination diet is advised as part of the diagnostic process (see recommendation 1.1.11), offer the child or young person and their parent or carer, taking into account socioeconomic status and cultural and religious issues, information on:
what foods and drinks to avoid
how to interpret food labels
alternative sources of nutrition to ensure adequate nutritional intake
the safety and limitations of an elimination diet
the proposed duration of the elimination diet
when, where and how an oral food challenge or food reintroduction procedure may be undertaken
the safety and limitations of the oral food challenge or food reintroduction procedure.
For babies and young children with suspected allergy to cows' milk protein, offer:
food avoidance advice to breastfeeding mothers
information on the most appropriate hypoallergenic formula or milk substitute to mothers of formula-fed babies. Seek advice from a dietitian with appropriate competencies.
Offer the child or young person, or their parent or carer, information about the support available and details of how to contact support groups. (See the information for the public for examples of organisations that provide information and support.)
## Referral to secondary or specialist care
Based on the allergy-focused clinical history, consider referral to secondary or specialist care in any of the following circumstances.
The child or young person has:
faltering growth in combination with one or more of the gastrointestinal symptoms described in recommendation 1.1.1
not responded to a single-allergen elimination diet
had one or more acute systemic reactions
had one or more severe delayed reactions
confirmed IgE-mediated food allergy and concurrent asthma
significant atopic eczema where multiple or cross-reactive food allergies are suspected by the parent or carer.
There is:
persisting parental suspicion of food allergy (especially in children or young people with difficult or perplexing symptoms) despite a lack of supporting history
strong clinical suspicion of IgE-mediated food allergy but allergy test results are negative
clinical suspicion of multiple food allergies.
## Alternative diagnostic tools
Do not use the following alternative diagnostic tests in the diagnosis of food allergy:
vega test
applied kinesiology
hair analysis.
Do not use serum-specific IgG testing in the diagnosis of food allergy.# Recommendations for research
We have made the following recommendations for research, based on our review of evidence, to improve NICE guidance and patient care in the future.
The focus of this guideline was the diagnosis and assessment of food allergy in children and young people in primary care and community settings. Therefore, the management of food allergy after a confirmed diagnosis was not reviewed. The recommendations for research below focus on assessment and diagnosis.
# Prevalence and natural history of non-IgE-mediated food allergy
How common are non-IgE-mediated food allergies in children and young people in primary care and community settings and when food allergies may be outgrown?
## Why this is important
Food allergy has many presentations. IgE-mediated food allergy manifests itself with a relatively homogenous group of presentations. Along with objective tests, measures of prevalence in the relevant settings and later development of tolerance have yielded useful information on the burden of IgE-mediated food allergy. However, non-IgE-mediated food allergy has a more heterogeneous group of presentations and the lack of validated diagnostic tests make it very difficult to assess prevalence without using formal diagnostic food challenges. Until high-quality prevalence studies in primary care and community settings are carried out, the burden of this food allergy will remain unknown. Studies should also evaluate prevalence rates and the resolution of allergies in subgroups, such as by allergies to particular food groups, or by method of infant feeding (exclusive formula, exclusive breastfeeding or mixed).
# Clinical predictors of non-IgE-mediated food allergy
Which features in the clinical history best predict the presence of non-IgE-mediated food allergy in children and young people in primary care and community settings?
## Why this is important
Non-IgE-mediated food allergy often presents with non-specific problems that are common in children and are often non-allergy related, such as colic, reflux, diarrhoea, eczema and faltering growth. Failure to recognise food allergy causes unnecessary morbidity, whereas appropriate food elimination can result in rapid improvement in symptoms. In the absence of a simple diagnostic test, it remains for the history to provide the best diagnostic clues as to which child may benefit from a trial of an elimination diet. A validated, primary care-focused questionnaire, developed by comparison with proven double-blind placebo-controlled food challenge outcomes, would significantly improve the process of diagnosis.
# Information needs for children and young people during their care pathway to diagnosis of food allergy
What do children and young people with IgE-mediated food allergy and their parents or carers want to know during the process of diagnosis and how is this demand best met?
## Why this is important
The patient journey to diagnosis, through testing, can last for several months. The needs of children and young people and their parents or carers, and the most effective method of information and support provision during this time of uncertainty, need to be established.
# Values of skin prick testing and specific IgE antibody testing and their predictive value
Can skin prick testing and specific IgE antibody testing cut-off points be established to diagnose IgE-mediated food allergy in children and young people, and to predict the severity of reaction?
## Why this is important
It is well described that about 1 in 5 people reporting an adverse reaction to food have a true food allergy. Of these, the majority will have non-IgE-mediated allergies. Food challenges are cumbersome and time-consuming and there are some safety risks involved. The availability of skin prick testing and specific IgE testing cut-off points to diagnose food allergy and to predict the severity of reaction would therefore lead to huge cost savings in the NHS and would reduce patient risk. There are published data available from the US, Australia and Europe, but allergists argue that these cut-off points are population-specific and should not be used in the UK.
# Modes of provision of support to healthcare professionals
What would be the impact of dietetic telephone support to healthcare professionals to aid in the diagnosis and assessment of babies showing non-IgE-mediated food allergy symptoms in primary care and community settings?
## Why this is important
There is currently no evidence to assess the impact of early diagnosis of non-IgE-mediated food allergy on the quality of life for babies and their families. The standard method of written referral is not timely (within the first month of presentation), yet there is no evidence whether providing indirect dietary advice via a healthcare professional is acceptable to the family. This system, however, could result in reduced attendances at GP surgeries and health clinics, reduced need for unnecessary medications and treatment, improved health for the whole family and improved skills for the healthcare professionals being supported in the diagnosis. However, it would need increased dietetic support and skills. A community-based randomised controlled trial is needed to compare the standard written dietetic referral method with indirect advice via a healthcare professional following consultation with a dietitian, for families with babies aged under 1 year who present with symptoms of non-IgE-mediated food allergy. Primary outcomes should be an assessment of the quality of life and acceptability of this service to the family. Secondary outcome measures could be related to attendance at GP surgeries, and medications and other interventions implemented.
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{'Introduction': 'Food allergy is an adverse immune response to a food. It can be classified into IgE-mediated and non-IgE-mediated reactions. Many non-IgE reactions, which are poorly defined both clinically and scientifically, are believed to be T-cell-mediated. Some reactions involve a mixture of both IgE and non-IgE responses and are classified as mixed IgE and non-IgE allergic reactions. Food allergy may be confused with food intolerance, which is a non- immunological reaction that can be caused by enzyme deficiencies, pharmacological agents and naturally occurring substances. Food intolerance will not be covered in this guideline. The starting point for the guideline is a suspicion of food allergy, and the use of an allergy-focused clinical history will help to determine whether a food allergy is likely.\n\nIn its review of allergy services in 2006, the Department of Health and Social Care concluded that there was considerable variation in current practice for allergy care, with no agreed treatment pathways, referral criteria or service models. Specifically, it was reported that many people with allergies practised self-care, using alternative sources of support rather than NHS services (for example, complementary services with non-validated tests and treatments).\n\nIn the NHS, most allergy care takes place in primary care. People with a clear diagnosis, and mild but persistent symptoms, are usually managed in general practice without referral to a specialist service. Some people with allergies, and the parents or carers of children and young people with allergies, also buy over-the-counter medicines from community or high-street pharmacies. However, if there is diagnostic doubt or symptoms of a more severe disease, GPs often consider referral for a specialist opinion.', 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\n# Assessment and allergy-focused clinical history\n\nConsider the possibility of food allergy in children and young people who have one or more of the signs and symptoms in table 1, below. Pay particular attention to persistent symptoms that involve different organ systems.\n\nIgE-mediated\n\nNon-IgE-mediated\n\nThe skin\n\nPruritus\n\nPruritus\n\nErythema\n\nErythema\n\nAcute urticaria – localised or generalised\n\nAtopic eczema\n\nAcute angioedema – most commonly of the lips, face and around the eyes\n\n-\n\nThe gastrointestinal system\n\nAngioedema of the lips, tongue and palate\n\nGastro-oesophageal reflux disease\n\nOral pruritus\n\nLoose or frequent stools\n\nNausea\n\nBlood and/or mucus in stools\n\nColicky abdominal pain\n\nAbdominal pain\n\nVomiting\n\nInfantile colic\n\nDiarrhoea\n\nFood refusal or aversion\n\n-\n\nConstipation\n\n-\n\nPerianal redness\n\n-\n\nPallor and tiredness\n\n-\n\nFaltering growth in conjunction with at least one or more gastrointestinal symptoms above (with or without significant atopic eczema)\n\nThe respiratory system (usually in combination with one or more of the above symptoms and signs)\n\nUpper respiratory tract symptoms (nasal itching, sneezing, rhinorrhoea or congestion [with or without conjunctivitis])\n\n-\n\nLower respiratory tract symptoms (cough, chest tightness, wheezing or shortness of breath)\n\nOther\n\nSigns or symptoms of anaphylaxis or other systemic allergic reactions\n\n-\n\nNote: this list is not exhaustive. The absence of these symptoms does not exclude food allergy\n\nConsider the possibility of food allergy in children and young people whose symptoms do not respond adequately to treatment for:\n\natopic eczema (for information about treatment for atopic eczema, see NICE's guideline on atopic eczema in under 12s)\n\ngastro-oesophageal reflux disease (for information about gastro-oesophageal reflux disease, see NICE's guideline on gastro-oesophageal reflux disease in children and young people)\n\nchronic gastrointestinal symptoms, including chronic constipation.Someone with apparent symptoms of food allergy may be suffering from coeliac disease; for information about coeliac disease, see NICE's guideline on coeliac disease.\n\nIf food allergy is suspected (by a healthcare professional or the parent, carer, child or young person), a healthcare professional with the appropriate competencies (either a GP or other healthcare professional) should take an allergy-focused clinical history tailored to the presenting symptoms and age of the child or young person. This should include:\n\nany personal history of atopic disease (asthma, eczema or allergic rhinitis)\n\nany individual and family history of atopic disease (such as asthma, eczema or allergic rhinitis) or food allergy in parents or siblings\n\ndetails of any foods that are avoided and the reasons why\n\nan assessment of presenting symptoms and other symptoms that may be associated with food allergy (see recommendation 1.1.1), including questions about:\n\n\n\nthe age of the child or young person when symptoms first started\n\nspeed of onset of symptoms following food contact\n\nduration of symptoms\n\nseverity of reaction\n\nfrequency of occurrence\n\nsetting of reaction (for example, at school or home)\n\nreproducibility of symptoms on repeated exposure\n\nwhat food and how much exposure to it causes a reaction\n\n\n\ncultural and religious factors that affect the foods they eat\n\nwho has raised the concern and suspects the food allergy\n\nwhat the suspected allergen is\n\nthe child or young person's feeding history, whether they were breastfed or formula-fed and the age of weaning\n\nthe mother's diet, if the child is currently being breastfed\n\ndetails of any previous treatment, including medication, for the presenting symptoms and the response to this\n\nany response to the elimination and reintroduction of foods.\n\nBased on the findings of the allergy-focused clinical history, physically examine the child or young person, paying particular attention to:\n\ngrowth and physical signs of malnutrition (for information about faltering growth, see NICE's guideline on faltering growth)\n\nsigns indicating allergy-related comorbidities (atopic eczema, asthma and allergic rhinitis).\n\n# Diagnosis\n\nFood allergy can be classified into IgE-mediated and non-IgE-mediated allergy. IgE-mediated reactions are often immediate and frequently have a rapid onset. Non-IgE-mediated reactions are generally characterised by delayed reactions.\n\n## IgE-mediated food allergy\n\nBased on the results of the allergy-focused clinical history, if IgE-mediated allergy is suspected, offer the child or young person a skin prick test and/or blood tests for specific IgE antibodies to the suspected foods and likely co-allergens\n\nTests should only be undertaken by healthcare professionals with the appropriate competencies to select, perform and interpret them.\n\nSkin prick tests should only be undertaken where there are facilities to deal with an anaphylactic reaction.\n\nChoose between a skin prick test and a specific IgE antibody blood test based on:\n\nthe results of the allergy-focused clinical history and\n\nwhether the test is suitable for, safe for and acceptable to the child or young person (or their parent or carer) and\n\nthe available competencies of the healthcare professional to undertake the test and interpret the results.\n\nDo not carry out allergy testing without first taking an allergy-focused clinical history. Interpret the results of tests in the context of information from the allergy-focused clinical history.\n\nDo not use atopy patch testing or oral food challenges to diagnose IgE-mediated food allergy in primary care or community settings.\n\n## Non-IgE-mediated food allergy\n\nBased on the results of the allergy-focused clinical history, if non-IgE-mediated food allergy is suspected, trial elimination of the suspected allergen (normally for between 2–6 weeks) and reintroduce after the trial. Seek advice from a dietitian with appropriate competencies, about nutritional adequacies, timings of elimination and reintroduction, and follow-up. (For people undergoing investigation for coeliac disease, see NICE's guideline on coeliac disease.)\n\n## Providing information and support to the child or young person and their parent or carer\n\nBased on the allergy-focused clinical history, offer the child or young person and their parent or carer, information that is age-appropriate about the:\n\ntype of allergy suspected\n\nrisk of severe allergic reaction\n\npotential impact of the suspected allergy on other healthcare issues, including vaccination\n\ndiagnostic process, which may include:\n\n\n\nan elimination diet followed by a possible planned rechallenge or initial food reintroduction procedure\n\nskin prick tests and specific IgE antibody testing, including the safety and limitations of these tests\n\nreferral to secondary or specialist care.\n\n\n\nOffer the child or young person and their parent or carer, information that is relevant to the type of allergy (IgE-mediated, non-IgE-mediated or mixed).\n\nIf a food elimination diet is advised as part of the diagnostic process (see recommendation 1.1.11), offer the child or young person and their parent or carer, taking into account socioeconomic status and cultural and religious issues, information on:\n\nwhat foods and drinks to avoid\n\nhow to interpret food labels\n\nalternative sources of nutrition to ensure adequate nutritional intake\n\nthe safety and limitations of an elimination diet\n\nthe proposed duration of the elimination diet\n\nwhen, where and how an oral food challenge or food reintroduction procedure may be undertaken\n\nthe safety and limitations of the oral food challenge or food reintroduction procedure.\n\nFor babies and young children with suspected allergy to cows' milk protein, offer:\n\nfood avoidance advice to breastfeeding mothers\n\ninformation on the most appropriate hypoallergenic formula or milk substitute to mothers of formula-fed babies. Seek advice from a dietitian with appropriate competencies.\n\nOffer the child or young person, or their parent or carer, information about the support available and details of how to contact support groups. (See the information for the public for examples of organisations that provide information and support.)\n\n## Referral to secondary or specialist care\n\nBased on the allergy-focused clinical history, consider referral to secondary or specialist care in any of the following circumstances.\n\nThe child or young person has:\n\n\n\nfaltering growth in combination with one or more of the gastrointestinal symptoms described in recommendation 1.1.1\n\nnot responded to a single-allergen elimination diet\n\nhad one or more acute systemic reactions\n\nhad one or more severe delayed reactions\n\nconfirmed IgE-mediated food allergy and concurrent asthma\n\nsignificant atopic eczema where multiple or cross-reactive food allergies are suspected by the parent or carer.\n\n\n\nThere is:\n\n\n\npersisting parental suspicion of food allergy (especially in children or young people with difficult or perplexing symptoms) despite a lack of supporting history\n\nstrong clinical suspicion of IgE-mediated food allergy but allergy test results are negative\n\nclinical suspicion of multiple food allergies.\n\n\n\n## Alternative diagnostic tools\n\nDo not use the following alternative diagnostic tests in the diagnosis of food allergy:\n\nvega test\n\napplied kinesiology\n\nhair analysis.\n\nDo not use serum-specific IgG testing in the diagnosis of food allergy.", 'Recommendations for research': 'We have made the following recommendations for research, based on our review of evidence, to improve NICE guidance and patient care in the future.\n\nThe focus of this guideline was the diagnosis and assessment of food allergy in children and young people in primary care and community settings. Therefore, the management of food allergy after a confirmed diagnosis was not reviewed. The recommendations for research below focus on assessment and diagnosis.\n\n# Prevalence and natural history of non-IgE-mediated food allergy\n\nHow common are non-IgE-mediated food allergies in children and young people in primary care and community settings and when food allergies may be outgrown?\n\n## Why this is important\n\nFood allergy has many presentations. IgE-mediated food allergy manifests itself with a relatively homogenous group of presentations. Along with objective tests, measures of prevalence in the relevant settings and later development of tolerance have yielded useful information on the burden of IgE-mediated food allergy. However, non-IgE-mediated food allergy has a more heterogeneous group of presentations and the lack of validated diagnostic tests make it very difficult to assess prevalence without using formal diagnostic food challenges. Until high-quality prevalence studies in primary care and community settings are carried out, the burden of this food allergy will remain unknown. Studies should also evaluate prevalence rates and the resolution of allergies in subgroups, such as by allergies to particular food groups, or by method of infant feeding (exclusive formula, exclusive breastfeeding or mixed).\n\n# Clinical predictors of non-IgE-mediated food allergy\n\nWhich features in the clinical history best predict the presence of non-IgE-mediated food allergy in children and young people in primary care and community settings?\n\n## Why this is important\n\nNon-IgE-mediated food allergy often presents with non-specific problems that are common in children and are often non-allergy related, such as colic, reflux, diarrhoea, eczema and faltering growth. Failure to recognise food allergy causes unnecessary morbidity, whereas appropriate food elimination can result in rapid improvement in symptoms. In the absence of a simple diagnostic test, it remains for the history to provide the best diagnostic clues as to which child may benefit from a trial of an elimination diet. A validated, primary care-focused questionnaire, developed by comparison with proven double-blind placebo-controlled food challenge outcomes, would significantly improve the process of diagnosis.\n\n# Information needs for children and young people during their care pathway to diagnosis of food allergy\n\nWhat do children and young people with IgE-mediated food allergy and their parents or carers want to know during the process of diagnosis and how is this demand best met?\n\n## Why this is important\n\nThe patient journey to diagnosis, through testing, can last for several months. The needs of children and young people and their parents or carers, and the most effective method of information and support provision during this time of uncertainty, need to be established.\n\n# Values of skin prick testing and specific IgE antibody testing and their predictive value\n\nCan skin prick testing and specific IgE antibody testing cut-off points be established to diagnose IgE-mediated food allergy in children and young people, and to predict the severity of reaction?\n\n## Why this is important\n\nIt is well described that about 1 in 5 people reporting an adverse reaction to food have a true food allergy. Of these, the majority will have non-IgE-mediated allergies. Food challenges are cumbersome and time-consuming and there are some safety risks involved. The availability of skin prick testing and specific IgE testing cut-off points to diagnose food allergy and to predict the severity of reaction would therefore lead to huge cost savings in the NHS and would reduce patient risk. There are published data available from the US, Australia and Europe, but allergists argue that these cut-off points are population-specific and should not be used in the UK.\n\n# Modes of provision of support to healthcare professionals\n\nWhat would be the impact of dietetic telephone support to healthcare professionals to aid in the diagnosis and assessment of babies showing non-IgE-mediated food allergy symptoms in primary care and community settings?\n\n## Why this is important\n\nThere is currently no evidence to assess the impact of early diagnosis of non-IgE-mediated food allergy on the quality of life for babies and their families. The standard method of written referral is not timely (within the first month of presentation), yet there is no evidence whether providing indirect dietary advice via a healthcare professional is acceptable to the family. This system, however, could result in reduced attendances at GP surgeries and health clinics, reduced need for unnecessary medications and treatment, improved health for the whole family and improved skills for the healthcare professionals being supported in the diagnosis. However, it would need increased dietetic support and skills. A community-based randomised controlled trial is needed to compare the standard written dietetic referral method with indirect advice via a healthcare professional following consultation with a dietitian, for families with babies aged under 1 year who present with symptoms of non-IgE-mediated food allergy. Primary outcomes should be an assessment of the quality of life and acceptability of this service to the family. Secondary outcome measures could be related to attendance at GP surgeries, and medications and other interventions implemented.'}
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https://www.nice.org.uk/guidance/cg116
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This guideline covers assessing and managing food allergy in children and young people under 19. It aims to improve symptoms such as faltering growth and eczema by offering advice on how to identify food allergy and when to refer to secondary or specialist care.
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9570485f36ce764df71eaffaece055e762bbf4e3
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nice
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Percutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices
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Percutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices
The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Percutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices.
# Guidance
Current evidence on the efficacy of percutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices is inadequate in quality. Evidence on safety is inadequate, specifically with regard to the risk of distal embolisation. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake percutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices should take the following actions.
Inform the clinical governance leads in their Trusts.
Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.
Audit and review clinical outcomes of all patients having percutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices (see section 3.1).
Further research into percutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices should take the form of well-conducted trials, which should define patient selection, treatment protocols and location and types of arterial lesions treated, and report long-term patency outcomes. NICE may review this procedure on publication of further evidence.# The procedure
# Indications and current treatments
Femoropopliteal arterial lesions are common in patients with symptomatic peripheral arterial disease (PAD) of the lower limbs, usually presenting with intermittent claudication.
Cardiovascular risk factor modification is fundamental to management. For patients with severely impaired walking distance or with critical limb ischaemia, revascularisation procedures such as balloon angioplasty, stenting or bypass grafting can be used.
# Outline of the procedure
Percutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices aims to improve arterial flow by removing atheromatous plaque that is restricting blood flow.
With the patient under local anaesthesia, a guidewire is inserted percutaneously into the femoral artery, and the atherectomy catheter is introduced. Catheters of various diameters are available to suit the arterial diameter at the site of the lesion. After appropriately positioning the device, a high-speed rotating cutting blade excises the plaque. Plaque debris is usually collected in a distal nosecone and removed on device withdrawal. Alternatively, depending on the catheter design, the sheathed cutting blade may be advanced over the guidewire beyond the lesion and then exposed so that excision can be undertaken while the device is being withdrawn. Several passes of the catheter may be required. A distal embolic protection device is sometimes used. Adjunctive balloon angioplasty or stenting of the atherectomised segment may be done before removal of the sheath.
Various devices can be used for this procedure.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A case series of 601 patients reported that procedural success (≤ 50% residual stenosis with no death, myocardial infarction, amputation, revascularisation, or major bleeding) was achieved in 95% (778/822) of lesions at 30-day follow-up.
A case series of 275 patients reported that limb amputation was avoided in 93% of patients at 12-month follow-up and 92% of patients at 18-month follow-up (absolute figures not stated). A case series of 60 patients reported that amputation was required in 7% (4/60) of patients at a mean 5-month follow-up. Of these patients, 2 had a patent atherectomy site but continuing ischaemia.
The case series of 601 patients reported that no further target lesion revascularisation was required in 90% of patients at 6-month follow-up (n = 248), and in 80% of patients at 12-month follow-up (n = 87) (absolute figures not stated).
A case series of 34 patients reported clinical PAD improvement of 1 or more grades (on the Trans-Atlantic Inter‑Society Consensus II grading system) in 75% (27/36) of procedures at 1-month follow-up and 55% (12/22) of procedures at 12-month follow-up. A case series of 16 patients (17 limbs) with TASC grade C lesions reported that 71% (12/17) had improved symptoms at 1-month follow-up, and 41% (7/17) of limbs remained symptom-free at 6-month follow-up.
The case series of 275 patients reported that for all primary percutaneous atherectomy procedures (without adjunctive balloon angioplasty) the primary patency rate (arterial duplex ratio between proximal adjacent artery and the arterial lesion in question greater than 5.0) was 53% at 18-month follow-up (absolute figures not stated).
The Specialist Advisers listed key efficacy outcomes as adequate luminal channel and long-term patency, limb salvage, improvement in claudication, quality of life and ulcer healing.
# Safety
Periprocedural embolism was reported in 1 out of 1258 procedures in the case series of 601 patients (clinical sequelae were not described) and in 7% (5/70) of procedures in the case series of 60 patients (treated with suction embolectomy or tissue plasminogen activator). Embolism (treated by atherectomy) was reported in 5% (1/18) of procedures in a case series of 16 patients.
Intraoperative arterial wall perforation occurred in 1% (10/1258) of procedures in the case series of 601 patients (clinical sequelae not described). No arterial wall perforation was reported in case series of 60 and 131 procedures.
Graft thrombosis (requiring surgery) following atherectomy at the inflow end of a femorofemoral crossover graft was reported in 1 patient in the case series of 34 patients. Pseudoaneurysm formation (requiring surgery) was reported in 1 patient in the same case series.
The Specialist Advisers considered theoretical adverse events to include distal embolisation, limb loss, puncture site bleeding/haematoma and device-related complications.# Further information
This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Changes since publication
January 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': "Current evidence on the efficacy of percutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices is inadequate in quality. Evidence on safety is inadequate, specifically with regard to the risk of distal embolisation. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake percutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having percutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices (see section 3.1).\n\nFurther research into percutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices should take the form of well-conducted trials, which should define patient selection, treatment protocols and location and types of arterial lesions treated, and report long-term patency outcomes. NICE may review this procedure on publication of further evidence.", 'The procedure': '# Indications and current treatments\n\nFemoropopliteal arterial lesions are common in patients with symptomatic peripheral arterial disease (PAD) of the lower limbs, usually presenting with intermittent claudication.\n\nCardiovascular risk factor modification is fundamental to management. For patients with severely impaired walking distance or with critical limb ischaemia, revascularisation procedures such as balloon angioplasty, stenting or bypass grafting can be used.\n\n# Outline of the procedure\n\nPercutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices aims to improve arterial flow by removing atheromatous plaque that is restricting blood flow.\n\nWith the patient under local anaesthesia, a guidewire is inserted percutaneously into the femoral artery, and the atherectomy catheter is introduced. Catheters of various diameters are available to suit the arterial diameter at the site of the lesion. After appropriately positioning the device, a high-speed rotating cutting blade excises the plaque. Plaque debris is usually collected in a distal nosecone and removed on device withdrawal. Alternatively, depending on the catheter design, the sheathed cutting blade may be advanced over the guidewire beyond the lesion and then exposed so that excision can be undertaken while the device is being withdrawn. Several passes of the catheter may be required. A distal embolic protection device is sometimes used. Adjunctive balloon angioplasty or stenting of the atherectomised segment may be done before removal of the sheath.\n\nVarious devices can be used for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 601 patients reported that procedural success (≤\xa050% residual stenosis with no death, myocardial infarction, amputation, revascularisation, or major bleeding) was achieved in 95% (778/822) of lesions at 30-day follow-up.\n\nA case series of 275 patients reported that limb amputation was avoided in 93% of patients at 12-month follow-up and 92% of patients at 18-month follow-up (absolute figures not stated). A case series of 60 patients reported that amputation was required in 7% (4/60) of patients at a mean 5-month follow-up. Of these patients, 2 had a patent atherectomy site but continuing ischaemia.\n\nThe case series of 601 patients reported that no further target lesion revascularisation was required in 90% of patients at 6-month follow-up (n\xa0=\xa0248), and in 80% of patients at 12-month follow-up (n\xa0=\xa087) (absolute figures not stated).\n\nA case series of 34 patients reported clinical PAD improvement of 1 or more grades (on the Trans-Atlantic Inter‑Society Consensus [TASC] II grading system) in 75% (27/36) of procedures at 1-month follow-up and 55% (12/22) of procedures at 12-month follow-up. A case series of 16 patients (17 limbs) with TASC grade C lesions reported that 71% (12/17) had improved symptoms at 1-month follow-up, and 41% (7/17) of limbs remained symptom-free at 6-month follow-up.\n\nThe case series of 275 patients reported that for all primary percutaneous atherectomy procedures (without adjunctive balloon angioplasty) the primary patency rate (arterial duplex ratio between proximal adjacent artery and the arterial lesion in question greater than 5.0) was 53% at 18-month follow-up (absolute figures not stated).\n\nThe Specialist Advisers listed key efficacy outcomes as adequate luminal channel and long-term patency, limb salvage, improvement in claudication, quality of life and ulcer healing.\n\n# Safety\n\nPeriprocedural embolism was reported in 1 out of 1258 procedures in the case series of 601 patients (clinical sequelae were not described) and in 7% (5/70) of procedures in the case series of 60\xa0patients (treated with suction embolectomy or tissue plasminogen activator). Embolism (treated by atherectomy) was reported in 5% (1/18) of procedures in a case series of 16 patients.\n\nIntraoperative arterial wall perforation occurred in 1% (10/1258) of procedures in the case series of 601 patients (clinical sequelae not described). No arterial wall perforation was reported in case series of 60 and 131 procedures.\n\nGraft thrombosis (requiring surgery) following atherectomy at the inflow end of a femorofemoral crossover graft was reported in 1\xa0patient in the case series of 34 patients. Pseudoaneurysm formation (requiring surgery) was reported in 1\xa0patient in the same case series.\n\nThe Specialist Advisers considered theoretical adverse events to include distal embolisation, limb loss, puncture site bleeding/haematoma and device-related complications.', 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nInformation for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg380
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The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Percutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices.
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be447129e43e1e65f9fb7dde3a7ff248f4d659dd
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nice
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Aripiprazole for the treatment of schizophrenia in people aged 15 to 17 years
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Aripiprazole for the treatment of schizophrenia in people aged 15 to 17 years
Evidence-based recommendations on aripiprazole for treating schizophrenia in young people aged 15 to 17.
# Guidance
Aripiprazole is recommended as an option for the treatment of schizophrenia in people aged 15 to 17 years who are intolerant of risperidone, or for whom risperidone is contraindicated, or whose schizophrenia has not been adequately controlled with risperidone.
People aged 15 to 17 years currently receiving aripiprazole for the treatment of schizophrenia who do not meet the criteria specified in 1.1 should have the option to continue treatment until it is considered appropriate to stop. This decision should be made jointly by the clinician and the person with schizophrenia, and if appropriate, their parents or carers.# The technology
Aripiprazole (Abilify, Bristol-Myers Squibb and Otsuka Pharmaceuticals) has a UK marketing authorisation for the treatment of schizophrenia in people aged 15 years and older. The initial marketing authorisation for aripiprazole was for the treatment of schizophrenia in adults. Subsequently an extension was sought to include the treatment of schizophrenia in adolescents aged 13 to 17 years. The Committee for Human Medicinal Products concluded that the proposed extension was approvable provided the population is restricted to people aged 15 years and older.
Aripiprazole is administered orally. The summary of product characteristics (SPC) states that the recommended dosage for aripiprazole is '10 mg/day administered on a once-a-day schedule without regard to meals'. It also states: 'Treatment should be initiated at 2 mg (using aripiprazole oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg'.
The SPC lists the most commonly reported adverse reactions associated with aripiprazole treatment to include akathisia and nausea. For full details of adverse reactions, contraindications, special warnings and precautions for use, see the SPC.
Aripiprazole is available in 5 mg, 10 mg, 15 mg and 30 mg tablets. The acquisition cost of aripiprazole 5 mg, 10 mg and 15 mg is £97.67 for 28 tablets. The acquisition cost of aripiprazole 30 mg is £195.33 for 28 tablets. The acquisition cost of aripiprazole oral solution 1 mg/ml is £104.64 for 150 ml. Costs exclude VAT and are from the British national formulary 59th edition. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submissions
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of aripiprazole and a review of this submission by the Evidence Review Group (ERG; appendix B).
# Clinical effectiveness
## Original submission
The decision problem defined the population as people with schizophrenia aged 15 to 17 years, in line with the marketing authorisation. Consideration of the population with schizophrenia aged 18 years and older was outside the remit of this appraisal. The manufacturer considered only one antipsychotic treatment, olanzapine, as a comparator to aripiprazole, despite the decision problem listing risperidone, quetiapine and amisulpride as other comparators. The manufacturer justified these omissions on the grounds that data for these comparators from randomised controlled trials (RCTs) in adolescents were not available.
The manufacturer performed a systematic review to identify RCTs comparing aripiprazole with antipsychotic drugs (olanzapine, risperidone, quetiapine, haloperidol, and amisulpride) or with placebo. Clozapine was listed as a comparator in the decision problem but was excluded from the systematic review because the manufacturer received clinical advice that clozapine is not routinely prescribed for the first-line treatment of schizophrenia in adolescents.
Six RCTs were identified, none of which compared aripiprazole with another antipsychotic drug. Only one RCT on the use of aripiprazole in adolescents (study 31-03-239) compared with placebo was identified. Study 31-03-239 was a phase III, multicentre, randomised, double-blind, placebo-controlled trial that enrolled 302 people aged between 13 and 17 years with schizophrenia (diagnosed using the 'Diagnostic and statistical manual of mental disorders, 4th edition' and confirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version ). Participants were randomly assigned to one of three study arms: a once-daily fixed dose of either 10 mg or 30 mg of aripiprazole, or matching placebo. Supporting data on adverse events were from two open-label single-arm extension studies.
The primary outcome in study 31-03-239 was mean change from baseline in Positive and Negative Syndrome Scale (PANSS) total score at 6-week follow-up. PANSS scores range from 7 (symptoms absent) to 49 (extreme symptoms), with reductions in score indicating improvements in symptoms. Secondary outcomes included PANSS positive and negative subscale scores, Children's Global Assessment Scale (CGAS), Clinical Global Impression for Severity (CGI-severity) and Improvement (CGI-improvement), and time to discontinuation (for all reasons). The number of hospitalisations was also included. Health-related quality of life was assessed using the Paediatric Quality of Life and Enjoyment and Satisfaction Questionnaire (P-QLES-Q) total and overall scores at baseline and at 6-week follow-up.
The results from study 31-03-239 showed that at 6-week follow-up reductions in PANSS score (that is, improvements in symptoms) occurred in all three groups. Statistically significant differences in the degree of improvement versus placebo were observed in the group who received aripiprazole 10 mg (−5.5; p = 0.05) and the group who received aripiprazole 30 mg (−7.4; p = 0.007). At 6-week follow-up all three groups showed reductions in PANSS positive subscale scores, and these reductions were statistically significant in the two groups who received aripiprazole compared with the group who received placebo. All three groups also showed reductions in PANSS negative subscale scores at 6-week follow-up; compared with placebo these reductions were statistically significant only in the group who received 10 mg aripiprazole.
At 6-week follow-up mean change in CGAS scores showed statistically significant increases (improvements) from baseline in the groups in study 31-03-239 who received 10 mg and 30 mg aripiprazole compared with the group who received placebo. Mean CGI-severity and CGI-improvement scores at 6-week follow-up showed statistically significant decreases (improvements) from baseline in the groups who received 10 mg or 30 mg aripiprazole compared with the group who received placebo. Health-related quality of life as assessed by P-QLES-Q total and overall scores at baseline and at 6-week follow-up showed statistically significant changes in both the group who received 10 mg aripiprazole and the group who received 30 mg aripiprazole compared with the group who received placebo.
The manufacturer presented a post-hoc subgroup analysis of the results in participants aged 15 to 17 years in study 31-03-239 (which included participants as young as 13 years). The manufacturer used a cut-off age of 15 years to separate participants aged 15 to 17 years from those aged 13 to 14 years in the trial. From this analysis the manufacturer concluded that efficacy improvements in the subgroup aged 15 to 17 years were comparable to those in the overall dataset, and that the observed effect was maintained during the trial period. The manufacturer also compared side effects in adolescents aged 15 to 17 years with side effects in adults treated with aripiprazole for schizophrenia and concluded that the tolerability and safety profiles were similar in the two age groups.
Data on adverse events were taken from study 31-03-239 comparing aripiprazole with placebo and from two open-label single-arm extension studies (31-03-241 and 31-05-243). Participants who completed study 31-03-239 were eligible to enter an open-label extension study of aripiprazole for 6 months (31-03-241). The second open-label extension study (31-05-243) included participants who had completed the first extension study (31-03-241).
The most common treatment-related adverse events observed in study 31-03-239 comparing aripiprazole with placebo were extrapyramidal disorder, somnolence and tremor. Overall, a higher percentage of participants in the groups who received aripiprazole experienced treatment-related adverse events (71.0% of those who received 10 mg aripiprazole and 72.5% of those who received 30 mg aripiprazole) compared with the placebo group (57.0%). The majority of treatment-related adverse events were mild or moderate in severity. The rates of serious treatment-emergent adverse events were low for all groups; with an incidence of 3% in the placebo group and 4% in the groups who received 10 mg and 30 mg aripiprazole. Mean weight and body mass index z-scores at each visit were within 0.5 standard deviations of the general population for all three groups. A 'significant' weight gain (defined as a weight gain of 7% or more from baseline) was seen at 6-week follow-up in 4% of the participants who received 10 mg aripiprazole, 5.2% of those who received 30 mg aripiprazole and 1% of participants in the placebo group. A 'significant' weight loss (defined as a weight loss of 7% or more from baseline) was seen at 6-week follow-up in 3% of the participants who received 10 mg aripiprazole, 2.1% of those who received 30 mg aripiprazole and 6.1% of participants in the placebo group.
Changes from baseline in extrapyramidal symptoms as shown by the Simpson–Angus scale showed a statistically significant difference between the aripiprazole groups and the placebo group (0.5 in the group who received aripiprazole 10 mg , 0.3 in the group who received aripiprazole 30 mg and −0.3 in the placebo group). In this study, the Barnes scale and the Abnormal Involuntary Movement scale were also analysed and showed no statistically significant differences (data not reported). Mean serum prolactin levels relative to baseline were −8.45 ng/ml for the group who received placebo, −11.93 ng/ml for the group who received 10 mg aripiprazole and −15.14 ng/ml for the group who received 30 mg aripiprazole. The aripiprazole groups showed significantly greater changes in prolactin levels compared with the placebo groups (10 mg aripiprazole group, p = 0.003; 30 mg aripiprazole group, p < 0.0001). The manufacturer's submission stated that overall, aripiprazole has no impact on cardiac conduction, and the available literature suggests that the impact on metabolic parameters and prolactin levels appears to be less than with other atypical antipsychotics.
The results of the first open-label study (31-03-241) showed that the majority of treatment-related adverse events were mild or moderate in severity. In the subgroup of participants with schizophrenia, 69% had at least one treatment-related adverse event and 5.9% had a serious adverse event. At 6-week follow-up, 24.5% of participants had a weight gain from baseline of 7% or more and 4.6% had a weight loss from baseline of 7% or more. There were no clinically meaningful changes reported in mean QT or QTc intervals or other ECG abnormalities.
The results of the second open-label extension study (31-05-243) showed that the majority of treatment-related adverse events were mild or moderate in severity. Approximately 48% of participants who received long-term treatment with aripiprazole reported at least one treatment-related adverse event. Influenza, vomiting and headache were the only treatment-related adverse events reported by 5% or more of the participants. Serious adverse events occurred in 5.9% of participants. The manufacturer's submission stated that data were insufficient to draw conclusions about the impact of aripiprazole treatment on clinical chemistry parameters such as prolactin levels. At 6-week follow-up 12.7% of participants had a weight gain from baseline of 7% or more and 7.0% had a weight loss from baseline of 7% or more. No clinically meaningful changes in mean QT or QTc intervals or other ECG abnormalities were observed.
The manufacturer's systematic review also attempted to identify studies that could be included in an adjusted indirect comparison to provide data comparing aripiprazole with olanzapine, the chosen comparator in the manufacturer's submission. Of the six trials identified, two were deemed eligible for inclusion in an indirect comparison by the manufacturer: study 31-03-239 that compared aripiprazole with placebo, and an RCT by Kryzhanovskaya et al. (2009) that compared olanzapine with placebo; both studies were in adolescents with schizophrenia aged 13 to 17 years. The other four trials identified were deemed by the manufacturer to be unsuitable for inclusion in the indirect comparison as they either did not include a placebo group or did not contain sufficient data for comparison. The olanzapine RCT was a phase III, multicentre, randomised, double-blind, placebo-controlled trial that enrolled 107 participants aged between 13 and 17 years with schizophrenia (diagnosed using the 'Diagnostic and statistical manual of mental disorders, 4th edition text revision' ). Participants were randomly assigned to either flexible doses of olanzapine (2.5–20 mg/day) or placebo.
Data on clinical efficacy (withdrawals because of adverse events, lack of efficacy or other reasons, weight gain of 7% or more, somnolence and treatment with benzodiazepines ) were extracted from the RCTs and analysed for use in the economic evaluation. Data from the study of olanzapine were compared with data from the study of aripiprazole using the placebo arm of each trial as a common comparator. Data were also extracted from the clinical study reports for aripiprazole. No further details on the methodological approach taken to data extraction for the indirect comparison were provided in the manufacturer's submission.
The results of the adjusted indirect comparison were reported as an odds ratio (OR) and relative risk (RR), each with 95% confidence intervals (CI). The manufacturer's submission did not provide further details on how these results were generated from the ORs and RRs of the individual RCTs. The estimates of the effectiveness of aripiprazole relative to olanzapine were used primarily to inform the economic model. These estimates included the probability of discontinuation of olanzapine compared with aripiprazole 10 mg (due to adverse events OR 1.57, lack of efficacy OR 5.00, and other reasons OR 4.00), the probability of adverse events with olanzapine compared with aripiprazole 10 mg (weight gain OR 0.51 and somnolence OR 5.34) and the probability of relapse with aripiprazole or olanzapine (information provided as commercial in confidence).
The ERG noted that the evidence of clinical effectiveness was based on only one RCT (study 31-03-239), which compared aripiprazole with placebo. The ERG considered that the RCT was relevant to the decision problem and provided evidence that is generalisable to the UK population. However, the trial included adolescents aged 13 to 17 years, which is broader than the population defined in the decision problem and in the UK marketing authorisation for aripiprazole (which is for people aged 15 years and older). The ERG also noted that there were differences in the three treatment arms of the trial, with a greater proportion of white people, people who had previously received antipsychotic treatment and females in the 10 mg aripiprazole group compared with the 30 mg aripiprazole group. The ERG noted that the two open-label extension studies included adolescents and adults with schizophrenia and with bipolar disorder.
The ERG commented on the clinical outcomes presented in the manufacturer's submission. The ERG noted that there are no agreed parameters by which clinically meaningful changes or differences in PANSS, CGI, CGAS, and P-QLES-Q can be pre-defined. The ERG noted that the clinical significance of the differences observed in PANSS score, which was the manufacturer's chosen primary outcome, was not explained by the manufacturer. The ERG commented that no explanation was given by the manufacturer of the apparent placebo effect observed in the trial. The ERG also noted that data from three scales used to assess the clinical effects of aripiprazole were reported in the 31-03-239 study and clinical study report, but were not included in the manufacturer's submission.
The ERG noted that only a subset of the relevant outcomes reported in the RCTs was used in the indirect comparison. The ERG also commented that no formal assessment of heterogeneity was carried out on the indirect comparison by the manufacturer. The ERG further noted that the manufacturer's submission did not provide an interpretation of the results of the adjusted indirect comparison or any critical assessment of the results of the analysis. It noted that a trial reported by Haas and colleagues comparing standard and subtherapeutic (that is, lower doses than the indicated dosage regimen) doses of risperidone in adolescents with schizophrenia was not identified in the systematic review or included in the indirect comparison because it was published after the manufacturer's systematic review of the literature was carried out.
## Additional submission after consultation
In response to the appraisal consultation document issued in July 2010 in which the Committee was minded not to recommend aripiprazole for the treatment of schizophrenia in people aged 15 to 17 years, the manufacturer was asked to submit further clinical data to incorporate into an updated indirect comparison. Data from two additional RCTs were provided, one comparing quetiapine with placebo (Findling et al. 2008) and the other comparing risperidone with placebo (Haas et al. 2009). Both RCTs included people aged 13 to 17 years with schizophrenia, a wider population than that defined in the decision problem (which specified an age range of 15 to 17 years). No studies were identified that compared amisulpride with placebo. Three studies were identified that compared clozapine with placebo. However, the manufacturer did not consider clozapine to be a main comparator and therefore deemed these three studies unsuitable for inclusion in its analysis. No clinical data on the use of aripiprazole in adolescents with learning difficulties were identified.
The manufacturer also reported conclusions from a systematic review of head-to-head and placebo-controlled comparisons of atypical antipsychotics in children and adolescents with psychotic and bipolar spectrum disorders (Fraguas et al. 2010). The systematic review found differences in mean weight gain across second-generation antipsychotics. Olanzapine was associated with the largest mean weight gain (3.8 to 16.2 kg) and aripiprazole was associated with the smallest (0 to 4.4 kg). The systematic review also reported that the greatest increase in prolactin levels occurred in people receiving risperidone (mean change from 8.3 to 49.6 ng/ml) followed by people receiving olanzapine (−1.5 to 13.7 ng/ml). The manufacturer also presented results from a study of children and adolescents aged 4 to 19 years that reported hyperprolactinaemia (> 25.7 ng/ml) in 84.1% of participants who received risperidone, 52.9% of those who received olanzapine, 14.4% of those who received quetiapine and 9.5% of those who received aripiprazole (Correll 2007).
The trials for each comparator all reported significant differences in PANSS total score at 6-week follow-up. The largest differences were reported in the trials with risperidone 1–3 mg per day (−12.7 versus placebo; p = <0.001) and risperidone 4–6 mg per day (−13.4 versus placebo; p = <0.001), followed by the trial with olanzapine 2.5–20 mg per day (−12.5 versus placebo; p = 0.005) and the trial with quetiapine 800 mg per day (−9.29 versus placebo; p = 0.009) and 400 mg per day (−8.16 versus placebo; p = 0.043). The smallest differences were reported in the trials with aripiprazole 10 mg per day (−5.5 versus placebo; p = 0.05) and aripiprazole 30 mg per day (−7.4 versus placebo; p = 0.007).
The trials for each comparator (except quetiapine) reported data on PANSS subscores. Reductions in PANSS positive subscores at 6-week follow-up were reported in each of these trials: olanzapine 2.5–20 mg per day (−3.9 versus placebo), risperidone 1–3 mg per day (−3.3 versus placebo), risperidone 4–6 mg per day (−3.5 versus placebo), aripiprazole 10 mg per day (−2.0 versus placebo) and aripiprazole 30 mg per day (−2.5 versus placebo). Similarly, reductions in PANSS negative subscores at 6-week follow-up were reported in each of these trials: risperidone 1–3 mg per day (−3.5 versus placebo), risperidone 4–6 mg per day (−3.0 versus placebo), olanzapine 2.5–20 mg per day (−2.0 versus placebo), aripiprazole 10 mg per day (−1.5 versus placebo) and aripiprazole 30 mg per day (−1.2 versus placebo). PANSS subscores were not reported in the trial comparing quetiapine with placebo (Findling et al. 2008).
CGI-severity and CGI-improvement scores were reported only in the trials that compared olanzapine and aripiprazole with placebo. The reported mean CGI-severity scores at 6-week follow-up showed a decrease (improvement) in the group who received olanzapine 2.5–20 mg per day (−0.6 versus placebo; p = 0.004), the group who received aripiprazole 10 mg per day (−0.3 versus placebo; p = 0.008) and the group who received aripiprazole 30 mg per day (−0.4 versus placebo; p = 0.002). The reported mean CGI-improvement scores at 6-week follow-up showed a decrease in the group who received olanzapine 2.5–20 mg per day (−1.1 versus placebo; p < 0.001). Reductions in CGI-improvement scores at 6-week follow-up were also reported in the groups who received aripiprazole 10 mg per day (−0.4 versus placebo; p = 0.02) and aripiprazole 30 mg per day (−0.6 versus placebo; p = 0.0004). CGAS scores were reported only in the risperidone and aripiprazole trials. The risperidone trial reported increases (improvements) in mean change in CGAS scores at 6-week follow-up in the group who received risperidone 1–3 mg per day (+9.0 versus placebo; p = 0.006) and risperidone 4–6 mg per day (+11.0 versus placebo; p <0.001). The aripiprazole trial also reported increases in mean change in CGAS scores at 6-week follow-up in the group who received aripiprazole 10 mg per day (+4.9 versus placebo; p = 0.006) and aripiprazole 30 mg per day (+5.0 versus placebo; p = 0.005).
The trials for each comparator all reported data on weight. The difference in weight gain at 6-week follow-up was lowest in the groups who received aripiprazole 10 mg per day (+0.8 kg versus placebo) and aripiprazole 30 mg per day (+1.0 kg versus placebo), followed by the groups who received risperidone 0.5–2.5 mg per day (+1.18 kg versus placebo) and risperidone 3–6 mg per day (+1.38 kg versus placebo) and those who received quetiapine 400 mg per day (+2.6 kg versus placebo) and quetiapine 800 mg per day (+2.2 kg versus placebo). The highest weight gain was reported in the olanzapine trial (+4.2 kg versus placebo).
Increases in the level of prolactin at 6-week follow-up were reported in the group who received risperidone 0.5–2.5 mg per day (+46.1 ng/ml in females and +19.2 ng/ml in males, versus placebo), risperidone 3–6 mg per day (+86.5 ng/ml in females and +29.6 ng/ml in males, versus placebo), olanzapine 2.5–20 mg per day (+12.1 ng/ml versus placebo), quetiapine 400 mg per day (+7.7 ng/ml versus placebo) and quetiapine 800 mg per day (+10.42 ng/ml versus placebo). Reductions in prolactin levels were reported only in the groups who received aripiprazole 10 mg per day (−3.4 ng/ml versus placebo) and aripiprazole 30 mg per day (−6.6 ng/ml versus placebo). No differences in akathisia compared with placebo were reported in the group who received aripiprazole 10 mg per day. Differences in akathisia were reported in the groups who received aripiprazole 30 mg per day (+7.0% versus placebo), risperidone 0.5–2.5 mg per day (+5.0% versus placebo), quetiapine 400 mg per day (+1.4% versus placebo) and quetiapine 800 mg per day (+1.4% versus placebo).
The ERG noted that the additional studies identified by the manufacturer include people aged 13 to 17 years with schizophrenia, which is wider than the population defined in the scope (people aged 15 to 17 years). The ERG also noted that the systematic review and the two other data sources identified by the manufacturer encompassed people with conditions other than schizophrenia and included non-randomised studies. The ERG concurred with the manufacturer that data on the use of aripiprazole specifically for people with learning difficulties are unlikely to be available.
The ERG commented that comparable data on PANSS scores for aripiprazole, quetiapine, risperidone and olanzapine could have been included in an indirect comparison. It noted that the manufacturer provided no explanation of its calculation or interpretation of the odds ratios for the indirect comparison. The ERG also noted that three of the RCTs reported prolactin concentration in a standard format that could have been included in an indirect comparison. Comparable data on weight change from the risperidone trial could also have been included in an indirect comparison. The ERG agreed with the manufacturer that there were insufficient data for analysis of the other clinical outcomes.
# Cost effectiveness
## Original submission
The manufacturer carried out a systematic review of the literature to identify cost-effectiveness studies of aripiprazole for the treatment of schizophrenia in adolescents. No such studies were identified; however, four economic evaluations that included aripiprazole in adults with schizophrenia were identified and reviewed. Given that there were no economic evaluations assessing the cost effectiveness of aripiprazole in adolescents, the manufacturer carried out a de novo economic evaluation.
The manufacturer presented a decision tree followed by a Markov model to estimate the cost effectiveness of first-line aripiprazole compared with first-line olanzapine for the treatment of schizophrenia in adolescents. The model incorporates first-line, second-line and third-line treatments and allows people to switch to the next treatment when one treatment is discontinued or a relapse occurs. In the first two cycles of the model, people undergoing treatment may discontinue and switch to another antipsychotic drug (from aripiprazole to olanzapine or vice versa). These cycles are represented as two health states in the decision tree: stable schizophrenia and withdrawal (because of lack of efficacy, adverse events or other reasons). In the second cycle there may also be a relapse, which is reflected as an additional health state in this cycle. People in whom there is no relapse or who discontinue treatment are assumed to continue treatment in the stable schizophrenia state. Discontinuation is assumed to occur only in the first two cycles. From the third treatment cycle onwards, people are assumed to either continue in a stable condition or a relapse occurs and they may subsequently switch antipsychotic treatment. This is reflected by using a Markov process that involves only two states – maintenance on treatment and relapse. People who discontinue treatment or in whom a relapse occurs on the second treatment are assumed to receive clozapine as a last-resort treatment and to continue receiving clozapine after relapse. The model adopted a 3-year time horizon on the basis that this is the maximum duration an individual would remain in this group before being considered an adult (at which point other treatment options may be available). Death was not modelled because of the short time horizon and a lack of efficacy data on death rates.
The manufacturer's base-case analysis compared first-line aripiprazole with first-line olanzapine in people aged 13 to 17 years with schizophrenia, which is broader than the UK marketing authorisation for aripiprazole (which is for adolescents aged 15 to 17 years with schizophrenia). Results were presented in terms of total and incremental costs and quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) for the two strategies.
The model used withdrawal and adverse event data, but not primary outcome data, from published RCTs and the indirect comparison. The probabilities of withdrawals and adverse events were calculated directly from study 31-03-239 on aripiprazole and from the manufacturer's adjusted indirect comparison. The manufacturer stated that no long-term data on treatment effects, including rates of relapse with aripiprazole and olanzapine, were identified in the literature for the adolescent population. Data on rates of relapse were therefore taken from a study of adults with schizophrenia that compared aripiprazole with other atypical antipsychotics. The study reported a relative risk of relapse with aripiprazole of 0.92 (95% CI 0.67 to 1.26) compared with other atypical antipsychotics. However, the manufacturer stated that this value is an error, as it does not equal the ratio of the proportion of people in whom there is a relapse after treatment with other atypical antipsychotics divided by the proportion of people in whom there is a relapse after treatment with aripiprazole. The manufacturer adjusted the value (which was provided as commercial in confidence) and used this higher adjusted relative risk of relapse (that is, a relapse is more likely to occur) in the economic model.
The manufacturer also found limited or no data on adolescents with schizophrenia concerning utility values and resource use. Utilities for the health states were taken from a study of adults with schizophrenia in the UK. The study reported separate utilities for patients and non-patients. The manufacturer used the utilities derived from patients in its economic model.
The model included four types of resource use and costs: drug acquisition, on-treatment monitoring and switching of medication, management of adverse events, and health state costs. Treatment costs were calculated using daily drug dosages from the SPCs supported by the mean and median dosages in study 31-03-239 and the RCT reported by Kryzhanovskaya et al. (2009) respectively. Resource use associated with switching medication was based on three 20-minute visits to a psychiatrist. Resource use associated with adverse treatment effects was based on assumptions made in NICE clinical guideline 82 (CG82), 'Schizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care' (2009) about weight gain and extrapyramidal symptoms, and clinical opinion on somnolence. Resource use associated with relapse was also based on CG82.
In the manufacturer's base-case analyses, first-line treatment with aripiprazole is estimated to dominate first-line treatment with olanzapine (that is, first-line treatment with aripiprazole is more effective and less costly than first-line treatment with olanzapine; incremental cost −£69.21, incremental benefit 0.004). The manufacturer conducted a number of one-way deterministic sensitivity analyses, which showed that varying the relative risk of relapse and the daily cost of aripiprazole had the greatest effect on the ICERs. The ICERs varied between −£123,663 and £628,706 per QALY gained for a relative risk of relapse of 0.679 to 1.261 and from −£64,755 and £130,723 per QALY gained for a daily cost of aripiprazole of £2.28 to £6.84. The probabilistic sensitivity analysis suggested that first-line aripiprazole had a 96% probability of being cost effective at £20,000 per QALY gained when compared with first-line olanzapine.
The ERG considered that in general the manufacturer's approach to the economic evaluation was appropriate. However, the ERG noted a number of concerns about the cost-effectiveness analysis, including the approach used to compare sequential treatment strategies. These concerns included:
for both treatment strategies the major contribution to the total cost was the cost of managing relapses
the exclusion of risperidone, which is currently the most common first-line treatment for schizophrenia in adolescent populations in the UK
the exclusion of relevant adverse events such as extrapyramidal symptoms and sexual dysfunction in the economic model
the appropriateness of applying data derived from adult populations, such as relative risk values, to adolescents, and the uncertainty this generates in the model
the appropriateness of using a re-derived relative risk value based on crude relative risk reported in the published paper.
The ERG made revisions to the manufacturer's model to correct errors (relating to the cost of relapse in cycle 2 and the Health Resource Group cost code that was applied). When the cost of relapse in cycle 2 was revised it resulted in a higher ICER than was reported in the manufacturer's base case for the comparison of first-line aripiprazole with first-line olanzapine (£6231 per QALY gained; incremental cost £27.15, incremental benefit 0.004). Revising the HRG cost code had no effect on the result (aripiprazole dominated olanzapine in the revised result and the base case). The ERG also noted there was an error in the presentation of all the probabilistic sensitivity results relating to the inclusion of total undiscounted cost for first-line olanzapine. Revising this error resulted in considerably higher ICERs than those reported in the manufacturer's base case (ranging from £22,182 per QALY gained in the ERG analysis after correcting for this error to £47,103 per QALY gained after correcting for this error and applying a relative risk of relapse of 0.92).
The ERG performed a number of analyses on the corrected model to apply alternative estimates for parameter inputs and explore the impact of alternative structural assumptions and the methods used in the adjusted indirect comparison. The cumulative results presented by the ERG showed that adjusting medication costs for people with schizophrenia in whom there is a relapse approximately doubles the incremental costs without affecting the incremental QALYs, increasing the ICER from £6231 to £13,763 per QALY gained. The ICER increases from £13,763 to £23,144 per QALY gained when the disutility for people discontinuing treatment because of adverse events is reduced and the disutility associated with weight gain is continued while people remain on a given treatment. When the proportion of people in whom there is a relapse and who are admitted as inpatients is increased to 50% and applied to the assumptions already considered, it results in aripiprazole dominating olanzapine (that is, aripiprazole is more effective and less expensive than olanzapine). However, when the length of stay for admitted patients is increased to 107.7 days, the ICER increases to £69,638 QALY gained, and increases further to £232,981 per QALY gained when the relative risk of relapse of 0.92 reported by Moeller and colleagues is used.
The ERG also presented exploratory analyses in which the unit costs of risperidone for the treatment of adolescents with schizophrenia and the odds ratios relating to early discontinuations with risperidone (based on an adjusted indirect comparison) were applied to the manufacturer's economic model. In the first analysis, the cost of first-line treatment with risperidone was substituted for the cost of first-line treatment with olanzapine in the manufacturer's model. This caused the ICERs for aripiprazole as a first-line treatment to increase significantly, rising to £89,114–£112,012 per QALY gained compared with risperidone. The ERG noted that this analysis did not use any clinical data specific to risperidone, and implicitly assumed that the odds ratios derived for olanzapine (relative to aripiprazole) could be applied to risperidone. To examine the impact of applying odds ratios derived from an alternative data source, an adjusted indirect comparison was conducted using data from an RCT on the use of risperidone in adolescents aged 13 to 17 years reported by Haas and colleagues (2009) to estimate the odds ratios for discontinuation (due to adverse events, lack of efficacy and other reasons) and for treatment-related adverse effects (weight gain, somnolence and extrapyramidal symptoms). The ERG noted that the risperidone RCT was not placebo controlled; rather, it compared the standard dosage of risperidone (1.5–6.0 mg/day) with a dosage that (although not proven ineffective) was tenfold lower (0.15–0.6 mg/day). The ERG therefore cautioned that the occurrence of treatment discontinuations associated with risperidone may have been underestimated in the study, and hence the odds ratios derived in the adjusted indirect comparison may be biased against aripiprazole. Using these data in the manufacturer's economic model, the ERG's analysis suggested that first-line risperidone dominated first-line aripiprazole (that is, first-line aripiprazole is a less cost-effective option compared with first-line risperidone).
## Additional submission after consultation
In response to the Appraisal Consultation Document issued in July 2010 in which the Committee was minded not to recommend aripiprazole for the treatment of schizophrenia in adolescents aged 15 to 17 years, the manufacturer provided a revised economic model. The revised model contained four additional treatment sequences specified in the Appraisal Consultation Document:
treatment strategy A (aripiprazole then risperidone then olanzapine then clozapine )
treatment strategy B (risperidone then aripiprazole then olanzapine then clozapine )
treatment strategy C (risperidone then olanzapine then aripiprazole then clozapine )
treatment strategy D (risperidone then olanzapine then quetiapine then clozapine ).
The revised economic model also included a range of doses for the comparators, including low doses (which are commonly prescribed for adolescents), lay utility values (rather than patient values) from Briggs and colleagues (2008), an unadjusted relative risk of relapse of 0.937 (rather than an adjusted value), and additional adverse treatment effects (akathisia, tremor and agitation). The manufacturer's submission stated that, although requested by the Committee, sexual dysfunction could not be included in the model because this outcome was not reported in the studies identified and that prolactin levels (which are thought to be related to sexual dysfunction) were reported in different ways. Furthermore, data on aggression were not consistently reported in the studies identified, although rates of agitation were available for aripiprazole, risperidone and quetiapine and included as a sensitivity analysis. The manufacturer's submission justified the exclusion of PANSS scores in the revised model on the basis that clinicians do not use the PANSS questionnaire in clinical practice and that in CG82 PANSS was used to inform utility values and not as a separate outcome measure. The manufacturer carried out corrections for inaccuracies identified by the ERG in the original model, which included the cost of an acute hospital stay (changed to £513 per day), the costs during the second cycle of the model, the values for the proportion of patients with an acute hospitalisation, and the number of patients receiving olanzapine following relapse.
The manufacturer's revised model included a number of assumptions to inform gaps in the outcome measures. If data were not available for any outcome measure, equivalence with aripiprazole was assumed (that is, relative risk = 1.0). For quetiapine, the odds ratio of withdrawal due to lack of efficacy was assumed to be captured in withdrawal due to other reasons. Costs and disutility associated with extrapyramidal symptoms were applied to other adverse events included in the model (akathisia, benzodiazepine use, agitation and tremor). The manufacturer's model included several available formulations of each of the antipsychotic treatments. In the base-case analysis, UK prescription cost analysis was used to provide the most commonly prescribed formulation, which was then used to calculate the daily cost of the antipsychotics included in the analysis. The most commonly prescribed formulation of aripiprazole was the 28-tablet pack of 10 mg at a cost of £95.74. Based on a dose of 10 mg per day (dose escalated according to the SPC and according to the dose used in the clinical trial), aripiprazole was costed at £3.42 per day in the model. The most commonly prescribed formulation of olanzapine was the 28-tablet pack of 10 mg at a cost of £79.45. Based on a dose of 12.5 mg per day (mean modal dose according to the clinical trial), olanzapine was costed at £3.55 per day in the model. The most commonly prescribed formulation of quetiapine was the 60-tablet pack of 25 mg at a cost of £33.83. Based on a dose of 400 mg per day, quetiapine was costed at £9.02 per day in the model. The most commonly prescribed formulation of risperidone was the 20-tablet pack of 0.5 mg at a cost of £1.06. Based on a dose of 2 mg per day, risperidone was costed at £0.21 per day in the model. The most commonly prescribed clozapine formulation was 100 mg tablets. At a dose of 325 mg per day (based on a usual dose for people aged under 18 years of 200– 450 mg daily), clozapine was costed at £2.86 per day in the model.
The manufacturer's revised model included deterministic sensitivity analyses of the doses for each treatment:
Dosing scenario 1 examined the following: aripiprazole 10 mg, olanzapine 12.5 mg (as in the base case), risperidone 4–6 mg and quetiapine 800 mg (both costs and efficacy were varied).
Dosing scenario 2 examined the following: aripiprazole 10 mg, olanzapine 10 mg (tablets are available in 10 mg doses; efficacy remains the same as in the base case), risperidone 4–6 mg and quetiapine 800 mg (both costs and efficacy were varied).
The manufacturer also carried out sensitivity analyses of adverse events including weight gain, somnolence, extrapyramidal symptoms (represented by tremor and akathisia) and agitation.
The results of the manufacturer's revised deterministic base case showed that treatment strategy D (R, O, Q, C) was dominated by strategy C (R, O, A, C), and treatment strategies B (R, A, O, C) and A (A, R, O, C) resulted in ICERs ranging from £51,600 per QALY gained to £108,800 per QALY gained respectively compared with treatment strategy C (R, O, A, C). The results of the manufacturer's sensitivity analyses showed that treatment strategy D (R, O, Q, C) was dominated by treatment strategy C (R, O, A, C) in all scenarios presented. Results of the manufacturer's dosing scenarios showed that in the first scenario, treatment strategies A (A, R, O, C) and B (R, A, O, C) resulted in ICERs ranging from £38,500 to £49,000 per QALY gained respectively compared with treatment strategy C (R, O, A, C). In the second dosing scenario, treatment strategies B (R, A, O, C) and A (A, R, O, C) resulted in ICERs ranging from £203,000 to £350,000 per QALY gained respectively compared with treatment strategy C (R, O, A, C). The results of the manufacturer's sensitivity analysis of adverse events showed that treatment strategies A (A, R, O, C) and B (R, A, O, C) resulted in ICERs ranging from £38,300 per QALY gained to £49,000 per QALY gained respectively compared with treatment strategy C (R, O, A, C).
The ERG commented that its original concern regarding the application of disutility due to weight gain only in the first cycle of each line of treatment was not addressed in the manufacturer's revised model. The ERG noted that the manufacturer's revised deterministic analyses showed that treatment strategy D (R, O, Q, C) was dominated by first-line risperidone strategies B (R, A, O, C) and C (R, O, A, C), and that aripiprazole was associated with higher ICERs compared with first-line risperidone sequences. The ERG noted that the results of the manufacturer's revised probabilistic sensitivity analysis showed consistently better outcomes (total QALYs increased by 0.05 and 0.06 for each strategy) and slightly lower costs than the deterministic analysis, and that small changes in the model resulted in large changes in the results.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Committee reviewed the data available on the clinical and cost effectiveness of aripiprazole, having considered evidence on the nature of schizophrenia in people aged 15 to 17 years and the value placed on the benefits of aripiprazole by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee discussed current standard clinical management of schizophrenia in adolescents. It heard from clinical specialists and patient experts that antipsychotics are prescribed only after a psychological assessment and a discussion with the person with schizophrenia together with their family or carer. The choice of treatment is negotiated with the person and depends on a number of factors, including adverse events associated with the treatment, previous treatments the person has received and their responses to them, and adverse events experienced while on those treatments. Adolescents with schizophrenia are usually treated with atypical antipsychotics at a low dose and are closely monitored.
The clinical specialists noted that the main aim of treatment is to maximise the control of schizophrenia and minimise the adverse events that are the most troublesome for each individual. The Committee heard from the patient experts that effective control of schizophrenia with aripiprazole would allow adolescents to return to normal functioning in terms of work or schooling. The Committee understood from the clinical specialists that no single atypical antipsychotic drug is considered to be more clinically effective than the others. Risperidone is the most widely used first-line atypical antipsychotic in UK clinical practice because clinicians have extensive experience of using it to treat schizophrenia, and often achieve control with low doses and without troublesome adverse events. The clinical specialists stated that when an atypical antipsychotic medication is prescribed, control of schizophrenia and adverse events is assessed over a period of 6 weeks or more and an alternative atypical antipsychotic can be considered if the first antipsychotic proves unsatisfactory. Other atypical antipsychotics such as aripiprazole, olanzapine, quetiapine or amisulpride may be used if control of schizophrenia is not achieved with risperidone. The clinical specialists also explained that clozapine is sometimes prescribed; however, because it needs careful monitoring for particular side effects, it is prescribed as rescue therapy only if the schizophrenia is refractory to at least three other antipsychotic treatments. The Committee noted that some of the atypical antipsychotics described by the clinical specialists do not have a marketing authorisation for the treatment of schizophrenia in adolescents, but acknowledged that specific licensing in adolescents is not a prerequisite to prescribing licensed adult medicines, particularly if there is widespread experience of their use. The Committee agreed with the clinical specialists that it is important for adolescents with schizophrenia to have a range of treatment options before considering rescue therapy with clozapine, and therefore considered that aripiprazole may be a suitable treatment option for people aged 15 to 17 years with schizophrenia.
The Committee heard from the clinical specialists and patient experts that there are a number of dose-related adverse events associated with atypical antipsychotic treatments, including weight gain, hyperprolactinaemia and sexual dysfunction, aggression and akathisia/extrapyramidal symptoms. Adolescents are often less tolerant of adverse events than adults, leading to problems with adherence to medication. The Committee heard from the clinical specialists that some treatments are more likely to be associated with particular adverse events than others: olanzapine is more likely associated with weight gain, risperidone and amisulpride are more likely associated with hyperprolactinaemia, and aripiprazole is more likely associated with akathisia and a subjective feeling of aggression (for which benzodiazepine co-treatment may be used). The clinical specialists stated that these adverse events are dose related and therefore it is preferable to start prescribing any atypical antipsychotic at a low dose. The Committee accepted that all atypical antipsychotics are associated with adverse events and that accounts from the clinical specialists on the use of aripiprazole suggest that it may be as safe and well tolerated as the other treatments.
# Clinical effectiveness
The Committee noted that the clinical effectiveness evidence presented in the manufacturer's submission was derived mainly from one RCT (study 31-03-239) that studied treatment with aripiprazole at two different doses compared with placebo, with supporting data on adverse events from two open-label single-arm extension studies. The Committee noted that the 31-03-239 study was placebo controlled and did not provide a head-to-head comparison of aripiprazole with any other atypical antipsychotics.
The Committee noted that the 31-03-239 study showed a reduction in total PANSS score (that is, an improvement in symptoms) at week 6 in all three study arms. Statistically significant differences in the degree of improvement were observed in the aripiprazole groups compared with the placebo group (p = 0.0414 and p = 0.0061 for the 10 mg and 30 mg doses versus placebo). The Committee heard from the clinical specialists that the PANSS score is a well-recognised tool used in clinical trials for the measurement of positive, negative and general psychopathology symptoms in schizophrenia. However, the results are often difficult to relate to UK clinical practice as the tool is not routinely used by clinicians. The Committee accepted that the PANSS score is a valid tool for the measurement of positive, negative and general psychopathology symptoms and that evidence from the 31-03-239 study demonstrates a reduction in schizophrenic symptoms in the aripiprazole groups.
The Committee was aware that the manufacturer's original submission included a very limited evidence base. However, the manufacturer's additional analyses provided some evidence for each of the atypical antipsychotics (risperidone, quetiapine and olanzapine) routinely used in UK clinical practice. The Committee noted that the trials for olanzapine, quetiapine and, most notably, risperidone showed greater relative risks in PANSS positive and negative scores in their treatment arms compared with their placebo arms than were seen in the aripiprazole trial. The Committee also noted that there appears to be a large placebo effect in the aripiprazole trial, but heard from the manufacturer that the precise cause of this effect is unknown. The Committee was aware that, insofar as evidence is available, the CGI and CGAS findings from the trials are not better for aripiprazole than for the comparator treatments.
The Committee considered the evidence on adverse events for aripiprazole and each of the comparators presented in the manufacturer's additional analyses. The Committee noted that there is substantial variation between the atypical antipsychotics in the adverse events associated with each treatment. The Committee was aware of the clinical specialists' view that it is important for adolescents with schizophrenia to have a range of treatment options before considering rescue therapy with clozapine, in order to individualise treatment and to minimise adverse treatment effects. The Committee noted that olanzapine is associated with substantial weight gain, as to a lesser extent are quetiapine and risperidone, but that only very small changes in weight gain are seen with aripiprazole. It considered that weight gain may be of considerable importance to adolescents and was concerned that weight gain associated with olanzapine may not be just a short-term problem, but could be a long-term health risk. In terms of changes in prolactin levels, the Committee heard from the clinical specialists that risperidone is associated with higher levels of prolactin, as to a lesser extent is olanzapine. Prolactin levels with aripiprazole treatment are generally lower than seen with the other comparator treatments. The Committee heard that a change in prolactin level is one of a number of contributors to potential sexual dysfunction.
# Cost effectiveness
The Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG. It noted that the manufacturer used a decision tree, followed by a Markov model, to estimate the cost effectiveness of first-line aripiprazole compared with first-line olanzapine for the treatment of schizophrenia in adolescents. Data were derived from the manufacturer's adjusted indirect comparison using secondary outcome data for aripiprazole and olanzapine. The Committee also considered an updated adjusted indirect comparison from the manufacturer that incorporated risperidone, quetiapine and olanzapine as comparators.
The Committee had concerns about a number of aspects of the economic model, including the exclusion of comparators specified in the final scope, primary (PANSS) outcome data and data on relevant adverse events (such as extrapyramidal symptoms and sexual dysfunction). The Committee was also aware that the ERG had identified a number of technical errors in the manufacturer's model. The Committee heard from the ERG that in the absence of data specific to the population in the scope, data on health state utility at relapse, disutility associated with treatment-related adverse events and resource use assumptions were all derived from studies of adults rather than adolescents.
The Committee noted that the manufacturer's initial base-case ICER (provided for the first Appraisal Committee meeting and following revisions from the ERG) for first-line aripiprazole (in a three-drug sequence) compared with first-line olanzapine of £6200 per QALY gained (incremental costs −£69, incremental QALYs 0.004) was based on a number of assumptions that were inappropriate; and that sensitivity analyses conducted by the ERG suggested the ICER could be as high as £233,000 per QALY gained if certain assumptions were varied. Furthermore, it noted that aripiprazole is dominated by risperidone in all of the ERG's exploratory analyses. It concluded that the ICERs presented by the manufacturer could not be accepted without revision. The Committee requested further clarification from the manufacturer.
The Committee considered the manufacturer's updated economic model that compared sequences of treatments starting with aripiprazole with sequences starting with risperidone. The Committee still had concerns about the primary outcome data not being included in the model. It did not agree with the manufacturer's argument that this omission could be justified on the grounds that trial outcomes were not used in ordinary clinical practice; nor did it agree with the manufacturer's reference to NICE clinical guideline 82 ('Core interventions in the treatment and management of schizophrenia in primary and secondary care (update)'), in which PANSS scores were used to inform utility values and not considered as a separate outcome measure as an argument for not including PANSS scores in the model. The Committee noted that as aripiprazole is associated with smaller changes in PANSS scores than risperidone, olanzapine and quetiapine, the omission clearly favoured aripiprazole. The Committee also noted that some adverse events (sexual dysfunction and aggression) were not included in the model, and was aware that there was an error in the manufacturer's adjusted indirect comparison that resulted in the odds ratios of withdrawals (for other reasons) from risperidone compared with withdrawals from aripiprazole being higher in the manufacturer's analysis. The Committee noted that the manufacturer's updated base-case analysis shows that treatment sequences in which aripiprazole is used first result in ICERs ranging from £52,750 per QALY gained to £108,800 per QALY gained when compared with treatment sequences in which risperidone is used first. It considered that, in view of the PANSS scores not being included in the model, these ICERs were likely to be underestimated. Furthermore, they are outside the range considered to be a cost-effective use of NHS resources.
In view of the results from the manufacturer's updated base-case analysis and the testimony of the clinical specialists, which highlighted that routine clinical practice is to start treatment with risperidone, the Committee concluded that starting treatment with aripiprazole rather than risperidone would not be a cost-effective use of NHS resources.
However the Committee was mindful that in people aged 15 to 17 years with schizophrenia who are intolerant of or have a contraindication to risperidone, or whose schizophrenia has not been adequately controlled with risperidone, the case for aripiprazole is more plausible. The Committee considered whether there was any evidence to suggest that aripiprazole should be used ahead of, or only after olanzapine or quietapine in the treatment pathway for schizophrenia. It noted that the economic analyses suggest little difference between sequences in which aripiprazole precedes olanzapine and vice versa; and although sequences that contain aripiprazole are suggested to be more cost effective than the sequence that contains quetiapine (sequence D), the Committee was concerned that the cost of quetiapine was unfairly calculated in the manufacturer's economic model, as optimal packs and doses may not have been considered. The Committee agreed that the differences in side effects between these drugs were a more important consideration than the (small) differences in their costs and primary outcomes. Therefore the Committee agreed that aripiprazole should be available on equal terms with other antipsychotic comparators (apart from risperidone), given its good side-effect profile and comparable price to olanzapine and quetiapine
The Committee considered whether its recommendations were associated with any potential issues related to equality. The Committee was aware that consultees and commentators suggested that one area of potential discrimination was that the diagnosis of schizophrenia requires a definitive methodological approach using precise diagnostic criteria detailed in a number of tools, including DSM-IV and K-SADS-PL. The Committee noted that although some people with learning difficulties may exhibit psychoses, unless they fulfil the DSM-IV and K-SADS-PL criteria for schizophrenia they do not (by definition) have schizophrenia, and therefore are not appropriate for inclusion in this technology appraisal. It noted that both the DSM-IV and K-SADS-PL criteria are used in clinical practice, as well as in studies of schizophrenia. The Committee concluded that there are not sufficient data to provide evidence on how the clinical and cost effectiveness of aripiprazole may differ for people with schizophrenia who have learning difficulties.
# Summary of Appraisal Committee's key conclusions
TA213 (STA)
Appraisal title: Aripiprazole for the treatment of schizophrenia in people aged 15 to 17 years
FAD section
Key conclusions
Aripiprazole is recommended as an option for the treatment of schizophrenia in people aged 15 to 17 years who are intolerant of risperidone, or for whom risperidone is contraindicated, or whose schizophrenia has not been adequately controlled with risperidone.
People aged 15 to 17 years currently receiving aripiprazole for the treatment of schizophrenia who do not meet the criteria specified in 1.1 should have the option to continue treatment until it is considered appropriate to stop. This decision should be made jointly by the clinician, the person with schizophrenia, and if appropriate, their parents or carers.
Current practice
Clinical need of patients including the availability of alternative treatments
The Committee agreed with the clinical specialists that it is important for adolescents with schizophrenia to have a range of treatment options before considering rescue therapy with clozapine, and therefore considered that aripiprazole may be a suitable treatment option for people aged 15 to 17 years with schizophrenia.
The technology
Proposed benefits of the technology
The Committee heard from the patient experts that effective control of schizophrenia with aripiprazole would allow adolescents to return to normal functioning in terms of work or schooling.
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee understood from the clinical specialists that no single atypical antipsychotic drug is considered to be more clinically effective than the others.
What is the position of the treatment in the pathway of care for the condition?
The Committee heard from the clinical specialists that risperidone is the most widely used first-line atypical antipsychotic in UK clinical practice for adolescents with schizophrenia. Other atypical antipsychotics, such as aripiprazole, olanzapine, quetiapine or amisulpride may be used if control of schizophrenia is not achieved with risperidone. It was noted that clozapine is prescribed as a rescue therapy only if the schizophrenia is refractory to at least three other antipsychotic treatments.
Adverse events
The Committee heard from the clinical specialists and patient experts that there are a number of dose-related adverse events associated with atypical antipsychotic treatments, including weight gain, hyperprolactinaemia and sexual dysfunction, aggression and akathisia/extrapyramidal symptoms. The Committee heard from the clinical specialists that some treatments are more frequently associated with particular adverse events than others. The Committee accepted that accounts from the clinical specialists on of the use of aripiprazole suggest that it may be as safe and well tolerated as the other treatments.
Evidence for clinical effectiveness
Availability, nature and quality of the evidence
The clinical evidence presented in the manufacturer's submission was derived mainly from one RCT (study 31-03-239) that studied treatment with aripiprazole at two different doses compared with placebo. Supporting data on adverse events was obtained from two open-label single-arm extension studies.
An indirect comparison was also conducted to compare first-line aripiprazole with first-line olanzapine.
The 31-03-239 study was placebo controlled and did not provide a head-to-head comparison of aripiprazole with any other atypical antipsychotics.
The Committee was aware that the manufacturer's original submission included a very limited evidence base. However, the manufacturer's additional analyses provided some evidence for each of the atypical antipsychotics (risperidone, quetiapine and olanzapine) routinely used in UK clinical practice. The Committee noted that the trials for olanzapine, quetiapine and, most notably, risperidone showed greater relative risks in PANSS positive and negative scores in their treatment arms compared with their placebo arms than were seen in the aripiprazole trial. The Committee also noted that there appears to be a large placebo effect in the aripiprazole trial, but heard from the manufacturer that the precise cause of this effect is unknown. The Committee was aware that, insofar as evidence is available, the CGI and CGAS findings are not better for aripiprazole than for the comparator treatments.
The Committee noted that there is substantial variation between the atypical antipsychotics in the adverse events associated with each treatment.
The Committee heard that a change in prolactin level is one of a number of contributors to potential sexual dysfunction. The Commitee considered that weight gain may be of considerable importance to adolescents and was concerned that weight gain associated with olanzapine may not be just a short-term problem, but could be a long-term health risk.
Relevance to general clinical practice in the NHS
The Committee heard from the clinical specialists that choice of treatment depends on a number of factors. Adolescents with schizophrenia are usually treated with atypical antipsychotics at a low dose and are closely monitored.
Uncertainties generated by the evidence
The Committee heard from the clinical specialists that the PANSS score (primary outcome) is a well-recognised tool used in clinical trials, however the results are often difficult to relate to UK clinical practice as the tool is not routinely used by clinicians.
The Committee noted that there appears to be a large placebo effect in the aripiprazole trial, but heard from the manufacturer that the precise cause of this effect is unknown.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
Not applicable.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee accepted that PANSS score is a valid tool for the measurement of positive, negative and general psychopathology symptoms and that evidence from the 31-03-239 study demonstrates a reduction in schizophrenic symptoms in the aripiprazole groups.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG.
The Committee heard from the ERG that some data used in the model were derived from adults rather than adolescent populations in the absence of data specific to adolescents.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee had concerns about a number of aspects of the economic model, such as the exclusion of comparators specified in the final scope, primary PANSS outcome data, and data on relevant adverse events (such as EPS and sexual dysfunction).
The Committee considered the manufacturer's updated economic model that compared sequences of treatments starting with aripiprazole with sequences starting with risperidone. The Committee still had concerns about the primary outcome data not being included in the model. It did not agree with the manufacturer's argument that this omission could be justified on the grounds that trial outcomes were not used in ordinary clinical practice; nor did it agree with the manufacturer's reference to NICE clinical guideline 82 ('Core interventions in the treatment and management of schizophrenia in primary and secondary care (update)'), in which PANSS scores were used to inform utility values and not considered as a separate outcome measure as an argument for not including PANSS scores in the model. The Committee noted that as aripiprazole is associated with smaller changes in PANSS scores than risperidone, olanzapine and quetiapine, the omission clearly favoured aripiprazole. The Committee also noted that some adverse events (sexual dysfunction and aggression) were not included in the model, and was aware that there is an error in the adjusted indirect comparison that results in the odds ratios of withdrawals (for other reasons) from risperidone compared with withdrawals from aripiprazole being higher in the manufacturer's analysis.
Incorporation of health-related quality of life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee heard from the ERG that in the absence of data specific to the population in the scope, data on health state utility at relapse, disutility associated with treatment-related adverse events and resource use assumptions were all derived from studies of adult rather than adolescent populations.
Are there specific groups of people for whom the technology is particularly cost-effective?
Not applicable.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee noted that the manufacturer's updated base-case analysis shows that treatment sequences in which aripiprazole is used first result in ICERs ranging from £52,750 per QALY gained to £108,800 per QALY gained when compared with treatment sequences in which risperidone is used first. It considered that, in view of the PANSS scores not being included in the model, these ICERs were likely to be underestimated. Furthermore, they are outside the range considered to be a cost-effective use of NHS resources.
In view of the results from the manufacturer's updated base-case analysis and the testimony of the clinical specialists, which highlighted that routine clinical practice is to start treatment with risperidone, the Committee concluded that starting treatment with aripiprazole rather than risperidone would not be a cost-effective use of NHS resources.
The Committee was mindful that in people aged 15 to 17 years with schizophrenia who are intolerant of or have a contraindication to risperidone, or whose schizophrenia has not been adequately controlled with risperidone, the case for aripiprazole is more plausible. The Committee considered whether there was any evidence to suggest that aripiprazole should be used ahead of, or only after olanzapine or quietapine in the treatment pathway for schizophrenia. It noted that the economic analyses suggest little difference between sequences in which aripiprazole precedes olanzapine and vice versa; and although sequences that contain aripiprazole are suggested to be more cost-effective than the sequence that contains quetiapine (sequence D), the Committee was concerned that the cost of quetiapine was unfairly calculated in the manufacturer's economic model, as optimal packs and doses may not have been considered. The Committee agreed that the differences in side effects between these drugs were a more important consideration than the (small) differences in their costs and primary outcomes. Therefore the Committee agreed that aripiprazole should be available on equal terms with other antipsychotic comparators (apart from risperidone), given its good side-effect profile and comparable price to olanzapine and quetiapine.
Additional factors taken into account
Patient Access Schemes
(PPRS)
Not applicable to this appraisal.
End-of-life considerations
Not applicable to this appraisal.
Equalities considerations, social value judgements
The Committee was aware that consultees and commentators suggested that one area of potential discrimination was that the diagnosis of schizophrenia requires a definitive methodological approach using precise diagnostic criteria which may not be met by people with learning difficulties. The Committee concluded that there are not sufficient data to provide evidence on how the clinical and cost effectiveness of aripiprazole may differ for people with schizophrenia who have learning difficulties.
# Related NICE guidance
# Published
Schizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care. NICE clinical guideline 82 (2009).
Guidance on the use of electroconvulsive therapy.NICE technology appraisal guidance 59 (2003).
# Under development
Schizophrenia: the recognition and management of schizophrenia in children and young people. NICE clinical guideline.# Review of guidance
The guidance on this technology will be considered for review in November 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveJanuary 2011# Changes after publication
February 2014: implementation section updated to clarify that aripiprazole is recommended as an option for treating schizophrenia. Additional minor maintenance update also carried out.
March 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Aripiprazole is recommended as an option for the treatment of schizophrenia in people aged 15 to 17\xa0years who are intolerant of risperidone, or for whom risperidone is contraindicated, or whose schizophrenia has not been adequately controlled with risperidone.\n\nPeople aged 15 to 17\xa0years currently receiving aripiprazole for the treatment of schizophrenia who do not meet the criteria specified in 1.1 should have the option to continue treatment until it is considered appropriate to stop. This decision should be made jointly by the clinician and the person with schizophrenia, and if appropriate, their parents or carers.', 'The technology ': "Aripiprazole (Abilify, Bristol-Myers Squibb and Otsuka Pharmaceuticals) has a UK marketing authorisation for the treatment of schizophrenia in people aged 15\xa0years and older. The initial marketing authorisation for aripiprazole was for the treatment of schizophrenia in adults. Subsequently an extension was sought to include the treatment of schizophrenia in adolescents aged 13 to 17\xa0years. The Committee for Human Medicinal Products concluded that the proposed extension was approvable provided the population is restricted to people aged 15\xa0years and older.\n\nAripiprazole is administered orally. The summary of product characteristics (SPC) states that the recommended dosage for aripiprazole is '10\xa0mg/day administered on a once-a-day schedule without regard to meals'. It also states: 'Treatment should be initiated at 2\xa0mg (using aripiprazole oral solution 1\xa0mg/ml) for 2\xa0days, titrated to 5\xa0mg for 2\xa0additional days to reach the recommended daily dose of 10\xa0mg. When appropriate, subsequent dose increases should be administered in 5\xa0mg increments without exceeding the maximum daily dose of 30\xa0mg'.\n\nThe SPC lists the most commonly reported adverse reactions associated with aripiprazole treatment to include akathisia and nausea. For full details of adverse reactions, contraindications, special warnings and precautions for use, see the SPC.\n\nAripiprazole is available in 5\xa0mg, 10\xa0mg, 15\xa0mg and 30\xa0mg tablets. The acquisition cost of aripiprazole 5\xa0mg, 10\xa0mg and 15\xa0mg is £97.67 for 28\xa0tablets. The acquisition cost of aripiprazole 30\xa0mg is £195.33 for 28\xa0tablets. The acquisition cost of aripiprazole oral solution 1\xa0mg/ml is £104.64 for 150\xa0ml. Costs exclude VAT and are from the British national formulary [BNF] 59th edition. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submissions": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of aripiprazole and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\n# Clinical effectiveness\n\n## Original submission\n\nThe decision problem defined the population as people with schizophrenia aged 15 to 17\xa0years, in line with the marketing authorisation. Consideration of the population with schizophrenia aged 18\xa0years and older was outside the remit of this appraisal. The manufacturer considered only one antipsychotic treatment, olanzapine, as a comparator to aripiprazole, despite the decision problem listing risperidone, quetiapine and amisulpride as other comparators. The manufacturer justified these omissions on the grounds that data for these comparators from randomised controlled trials (RCTs) in adolescents were not available.\n\nThe manufacturer performed a systematic review to identify RCTs comparing aripiprazole with antipsychotic drugs (olanzapine, risperidone, quetiapine, haloperidol, and amisulpride) or with placebo. Clozapine was listed as a comparator in the decision problem but was excluded from the systematic review because the manufacturer received clinical advice that clozapine is not routinely prescribed for the first-line treatment of schizophrenia in adolescents.\n\nSix RCTs were identified, none of which compared aripiprazole with another antipsychotic drug. Only one RCT on the use of aripiprazole in adolescents (study 31-03-239) compared with placebo was identified. Study 31-03-239 was a phase III, multicentre, randomised, double-blind, placebo-controlled trial that enrolled 302\xa0people aged between 13 and 17\xa0years with schizophrenia (diagnosed using the 'Diagnostic and statistical manual of mental disorders, 4th edition' ['DSM-IV'] and confirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version [K-SADS-PL]). Participants were randomly assigned to one of three study arms: a once-daily fixed dose of either 10\xa0mg or 30\xa0mg of aripiprazole, or matching placebo. Supporting data on adverse events were from two open-label single-arm extension studies.\n\nThe primary outcome in study 31-03-239 was mean change from baseline in Positive and Negative Syndrome Scale (PANSS) total score at 6-week follow-up. PANSS scores range from 7 (symptoms absent) to 49 (extreme symptoms), with reductions in score indicating improvements in symptoms. Secondary outcomes included PANSS positive and negative subscale scores, Children's Global Assessment Scale (CGAS), Clinical Global Impression for Severity (CGI-severity) and Improvement (CGI-improvement), and time to discontinuation (for all reasons). The number of hospitalisations was also included. Health-related quality of life was assessed using the Paediatric Quality of Life and Enjoyment and Satisfaction Questionnaire (P-QLES-Q) total and overall scores at baseline and at 6-week follow-up.\n\nThe results from study 31-03-239 showed that at 6-week follow-up reductions in PANSS score (that is, improvements in symptoms) occurred in all three groups. Statistically significant differences in the degree of improvement versus placebo were observed in the group who received aripiprazole 10\xa0mg (−5.5; p\xa0=\xa00.05) and the group who received aripiprazole 30\xa0mg (−7.4; p\xa0=\xa00.007). At 6-week follow-up all three groups showed reductions in PANSS positive subscale scores, and these reductions were statistically significant in the two groups who received aripiprazole compared with the group who received placebo. All three groups also showed reductions in PANSS negative subscale scores at 6-week follow-up; compared with placebo these reductions were statistically significant only in the group who received 10\xa0mg aripiprazole.\n\nAt 6-week follow-up mean change in CGAS scores showed statistically significant increases (improvements) from baseline in the groups in study 31-03-239 who received 10\xa0mg and 30\xa0mg aripiprazole compared with the group who received placebo. Mean CGI-severity and CGI-improvement scores at 6-week follow-up showed statistically significant decreases (improvements) from baseline in the groups who received 10\xa0mg or 30\xa0mg aripiprazole compared with the group who received placebo. Health-related quality of life as assessed by P-QLES-Q total and overall scores at baseline and at 6-week follow-up showed statistically significant changes in both the group who received 10\xa0mg aripiprazole and the group who received 30\xa0mg aripiprazole compared with the group who received placebo.\n\nThe manufacturer presented a post-hoc subgroup analysis of the results in participants aged 15 to 17\xa0years in study 31-03-239 (which included participants as young as 13\xa0years). The manufacturer used a cut-off age of 15\xa0years to separate participants aged 15 to 17\xa0years from those aged 13 to 14\xa0years in the trial. From this analysis the manufacturer concluded that efficacy improvements in the subgroup aged 15 to 17\xa0years were comparable to those in the overall dataset, and that the observed effect was maintained during the trial period. The manufacturer also compared side effects in adolescents aged 15 to 17\xa0years with side effects in adults treated with aripiprazole for schizophrenia and concluded that the tolerability and safety profiles were similar in the two age groups.\n\nData on adverse events were taken from study 31-03-239 comparing aripiprazole with placebo and from two open-label single-arm extension studies (31-03-241 and 31-05-243). Participants who completed study 31-03-239 were eligible to enter an open-label extension study of aripiprazole for 6\xa0months (31-03-241). The second open-label extension study (31-05-243) included participants who had completed the first extension study (31-03-241).\n\nThe most common treatment-related adverse events observed in study 31-03-239 comparing aripiprazole with placebo were extrapyramidal disorder, somnolence and tremor. Overall, a higher percentage of participants in the groups who received aripiprazole experienced treatment-related adverse events (71.0% of those who received 10\xa0mg aripiprazole and 72.5% of those who received 30\xa0mg aripiprazole) compared with the placebo group (57.0%). The majority of treatment-related adverse events were mild or moderate in severity. The rates of serious treatment-emergent adverse events were low for all groups; with an incidence of 3% in the placebo group and 4% in the groups who received 10\xa0mg and 30\xa0mg aripiprazole. Mean weight and body mass index z-scores at each visit were within 0.5\xa0standard deviations of the general population for all three groups. A 'significant' weight gain (defined as a weight gain of 7% or more from baseline) was seen at 6-week follow-up in 4% of the participants who received 10\xa0mg aripiprazole, 5.2% of those who received 30\xa0mg aripiprazole and 1% of participants in the placebo group. A 'significant' weight loss (defined as a weight loss of 7% or more from baseline) was seen at 6-week follow-up in 3% of the participants who received 10\xa0mg aripiprazole, 2.1% of those who received 30\xa0mg aripiprazole and 6.1% of participants in the placebo group.\n\nChanges from baseline in extrapyramidal symptoms as shown by the Simpson–Angus scale showed a statistically significant difference between the aripiprazole groups and the placebo group (0.5 in the group who received aripiprazole 10\xa0mg [p\xa0<\xa00.007], 0.3 in the group who received aripiprazole 30\xa0mg [p\xa0<\xa00.05] and −0.3 in the placebo group). In this study, the Barnes scale and the Abnormal Involuntary Movement scale were also analysed and showed no statistically significant differences (data not reported). Mean serum prolactin levels relative to baseline were −8.45\xa0ng/ml for the group who received placebo, −11.93\xa0ng/ml for the group who received 10\xa0mg aripiprazole and −15.14\xa0ng/ml for the group who received 30\xa0mg aripiprazole. The aripiprazole groups showed significantly greater changes in prolactin levels compared with the placebo groups (10\xa0mg aripiprazole group, p\xa0=\xa00.003; 30\xa0mg aripiprazole group, p\xa0<\xa00.0001). The manufacturer's submission stated that overall, aripiprazole has no impact on cardiac conduction, and the available literature suggests that the impact on metabolic parameters and prolactin levels appears to be less than with other atypical antipsychotics.\n\nThe results of the first open-label study (31-03-241) showed that the majority of treatment-related adverse events were mild or moderate in severity. In the subgroup of participants with schizophrenia, 69% had at least one treatment-related adverse event and 5.9% had a serious adverse event. At 6-week follow-up, 24.5% of participants had a weight gain from baseline of 7% or more and 4.6% had a weight loss from baseline of 7% or more. There were no clinically meaningful changes reported in mean QT or QTc intervals or other ECG abnormalities.\n\nThe results of the second open-label extension study (31-05-243) showed that the majority of treatment-related adverse events were mild or moderate in severity. Approximately 48% of participants who received long-term treatment with aripiprazole reported at least one treatment-related adverse event. Influenza, vomiting and headache were the only treatment-related adverse events reported by 5% or more of the participants. Serious adverse events occurred in 5.9% of participants. The manufacturer's submission stated that data were insufficient to draw conclusions about the impact of aripiprazole treatment on clinical chemistry parameters such as prolactin levels. At 6-week follow-up 12.7% of participants had a weight gain from baseline of 7% or more and 7.0% had a weight loss from baseline of 7% or more. No clinically meaningful changes in mean QT or QTc intervals or other ECG abnormalities were observed.\n\nThe manufacturer's systematic review also attempted to identify studies that could be included in an adjusted indirect comparison to provide data comparing aripiprazole with olanzapine, the chosen comparator in the manufacturer's submission. Of the six trials identified, two were deemed eligible for inclusion in an indirect comparison by the manufacturer: study 31-03-239 that compared aripiprazole with placebo, and an RCT by Kryzhanovskaya et al. (2009) that compared olanzapine with placebo; both studies were in adolescents with schizophrenia aged 13 to 17\xa0years. The other four trials identified were deemed by the manufacturer to be unsuitable for inclusion in the indirect comparison as they either did not include a placebo group or did not contain sufficient data for comparison. The olanzapine RCT was a phase III, multicentre, randomised, double-blind, placebo-controlled trial that enrolled 107\xa0participants aged between 13 and 17\xa0years with schizophrenia (diagnosed using the 'Diagnostic and statistical manual of mental disorders, 4th edition text revision' ['DSM-IV-TR']). Participants were randomly assigned to either flexible doses of olanzapine (2.5–20\xa0mg/day) or placebo.\n\nData on clinical efficacy (withdrawals because of adverse events, lack of efficacy or other reasons, weight gain of 7% or more, somnolence and treatment with benzodiazepines [used as a surrogate for extrapyramidal symptoms]) were extracted from the RCTs and analysed for use in the economic evaluation. Data from the study of olanzapine were compared with data from the study of aripiprazole using the placebo arm of each trial as a common comparator. Data were also extracted from the clinical study reports for aripiprazole. No further details on the methodological approach taken to data extraction for the indirect comparison were provided in the manufacturer's submission.\n\nThe results of the adjusted indirect comparison were reported as an odds ratio (OR) and relative risk (RR), each with 95% confidence intervals (CI). The manufacturer's submission did not provide further details on how these results were generated from the ORs and RRs of the individual RCTs. The estimates of the effectiveness of aripiprazole relative to olanzapine were used primarily to inform the economic model. These estimates included the probability of discontinuation of olanzapine compared with aripiprazole 10\xa0mg (due to adverse events OR\xa01.57, lack of efficacy OR\xa05.00, and other reasons OR\xa04.00), the probability of adverse events with olanzapine compared with aripiprazole 10\xa0mg (weight gain OR\xa00.51 and somnolence OR 5.34) and the probability of relapse with aripiprazole or olanzapine (information provided as commercial in confidence).\n\nThe ERG noted that the evidence of clinical effectiveness was based on only one RCT (study 31-03-239), which compared aripiprazole with placebo. The ERG considered that the RCT was relevant to the decision problem and provided evidence that is generalisable to the UK population. However, the trial included adolescents aged 13 to 17\xa0years, which is broader than the population defined in the decision problem and in the UK marketing authorisation for aripiprazole (which is for people aged 15\xa0years and older). The ERG also noted that there were differences in the three treatment arms of the trial, with a greater proportion of white people, people who had previously received antipsychotic treatment and females in the 10\xa0mg aripiprazole group compared with the 30\xa0mg aripiprazole group. The ERG noted that the two open-label extension studies included adolescents and adults with schizophrenia and with bipolar disorder.\n\nThe ERG commented on the clinical outcomes presented in the manufacturer's submission. The ERG noted that there are no agreed parameters by which clinically meaningful changes or differences in PANSS, CGI, CGAS, and P-QLES-Q can be pre-defined. The ERG noted that the clinical significance of the differences observed in PANSS score, which was the manufacturer's chosen primary outcome, was not explained by the manufacturer. The ERG commented that no explanation was given by the manufacturer of the apparent placebo effect observed in the trial. The ERG also noted that data from three scales used to assess the clinical effects of aripiprazole were reported in the 31-03-239 study and clinical study report, but were not included in the manufacturer's submission.\n\nThe ERG noted that only a subset of the relevant outcomes reported in the RCTs was used in the indirect comparison. The ERG also commented that no formal assessment of heterogeneity was carried out on the indirect comparison by the manufacturer. The ERG further noted that the manufacturer's submission did not provide an interpretation of the results of the adjusted indirect comparison or any critical assessment of the results of the analysis. It noted that a trial reported by Haas and colleagues comparing standard and subtherapeutic (that is, lower doses than the indicated dosage regimen) doses of risperidone in adolescents with schizophrenia was not identified in the systematic review or included in the indirect comparison because it was published after the manufacturer's systematic review of the literature was carried out.\n\n## Additional submission after consultation\n\nIn response to the appraisal consultation document issued in July 2010 in which the Committee was minded not to recommend aripiprazole for the treatment of schizophrenia in people aged 15 to 17\xa0years, the manufacturer was asked to submit further clinical data to incorporate into an updated indirect comparison. Data from two additional RCTs were provided, one comparing quetiapine with placebo (Findling et al. 2008) and the other comparing risperidone with placebo (Haas et al. 2009). Both RCTs included people aged 13 to 17\xa0years with schizophrenia, a wider population than that defined in the decision problem (which specified an age range of 15 to 17\xa0years). No studies were identified that compared amisulpride with placebo. Three studies were identified that compared clozapine with placebo. However, the manufacturer did not consider clozapine to be a main comparator and therefore deemed these three studies unsuitable for inclusion in its analysis. No clinical data on the use of aripiprazole in adolescents with learning difficulties were identified.\n\nThe manufacturer also reported conclusions from a systematic review of head-to-head and placebo-controlled comparisons of atypical antipsychotics in children and adolescents with psychotic and bipolar spectrum disorders (Fraguas et al. 2010). The systematic review found differences in mean weight gain across second-generation antipsychotics. Olanzapine was associated with the largest mean weight gain (3.8 to 16.2\xa0kg) and aripiprazole was associated with the smallest (0 to 4.4\xa0kg). The systematic review also reported that the greatest increase in prolactin levels occurred in people receiving risperidone (mean change from 8.3 to 49.6\xa0ng/ml) followed by people receiving olanzapine (−1.5 to 13.7\xa0ng/ml). The manufacturer also presented results from a study of children and adolescents aged 4 to 19\xa0years that reported hyperprolactinaemia (>\xa025.7\xa0ng/ml) in 84.1% of participants who received risperidone, 52.9% of those who received olanzapine, 14.4% of those who received quetiapine and 9.5% of those who received aripiprazole (Correll 2007).\n\nThe trials for each comparator all reported significant differences in PANSS total score at 6-week follow-up. The largest differences were reported in the trials with risperidone 1–3\xa0mg per day (−12.7 versus placebo; p\xa0=\xa0<0.001) and risperidone 4–6\xa0mg per day (−13.4 versus placebo; p\xa0=\xa0<0.001), followed by the trial with olanzapine 2.5–20\xa0mg per day (−12.5 versus placebo; p\xa0=\xa00.005) and the trial with quetiapine 800\xa0mg per day (−9.29 versus placebo; p\xa0=\xa00.009) and 400\xa0mg per day (−8.16 versus placebo; p\xa0=\xa00.043). The smallest differences were reported in the trials with aripiprazole 10\xa0mg per day (−5.5 versus placebo; p\xa0=\xa00.05) and aripiprazole 30\xa0mg per day (−7.4 versus placebo; p\xa0=\xa00.007).\n\nThe trials for each comparator (except quetiapine) reported data on PANSS subscores. Reductions in PANSS positive subscores at 6-week follow-up were reported in each of these trials: olanzapine 2.5–20\xa0mg per day (−3.9 versus placebo), risperidone 1–3\xa0mg per day (−3.3 versus placebo), risperidone 4–6\xa0mg per day (−3.5 versus placebo), aripiprazole 10\xa0mg per day (−2.0 versus placebo) and aripiprazole 30\xa0mg per day (−2.5 versus placebo). Similarly, reductions in PANSS negative subscores at 6-week follow-up were reported in each of these trials: risperidone 1–3\xa0mg per day (−3.5 versus placebo), risperidone 4–6\xa0mg per day (−3.0 versus placebo), olanzapine 2.5–20\xa0mg per day (−2.0 versus placebo), aripiprazole 10\xa0mg per day (−1.5 versus placebo) and aripiprazole 30\xa0mg per day (−1.2 versus placebo). PANSS subscores were not reported in the trial comparing quetiapine with placebo (Findling et al. 2008).\n\nCGI-severity and CGI-improvement scores were reported only in the trials that compared olanzapine and aripiprazole with placebo. The reported mean CGI-severity scores at 6-week follow-up showed a decrease (improvement) in the group who received olanzapine 2.5–20\xa0mg per day (−0.6 versus placebo; p\xa0=\xa00.004), the group who received aripiprazole 10\xa0mg per day (−0.3 versus placebo; p\xa0=\xa00.008) and the group who received aripiprazole 30\xa0mg per day (−0.4 versus placebo; p\xa0=\xa00.002). The reported mean CGI-improvement scores at 6-week follow-up showed a decrease in the group who received olanzapine 2.5–20\xa0mg per day (−1.1 versus placebo; p\xa0<\xa00.001). Reductions in CGI-improvement scores at 6-week follow-up were also reported in the groups who received aripiprazole 10\xa0mg per day (−0.4 versus placebo; p\xa0=\xa00.02) and aripiprazole 30\xa0mg per day (−0.6 versus placebo; p\xa0=\xa00.0004). CGAS scores were reported only in the risperidone and aripiprazole trials. The risperidone trial reported increases (improvements) in mean change in CGAS scores at 6-week follow-up in the group who received risperidone 1–3\xa0mg per day (+9.0 versus placebo; p\xa0=\xa00.006) and risperidone 4–6\xa0mg per day (+11.0 versus placebo; p\xa0<0.001). The aripiprazole trial also reported increases in mean change in CGAS scores at 6-week follow-up in the group who received aripiprazole 10\xa0mg per day (+4.9 versus placebo; p\xa0=\xa00.006) and aripiprazole 30\xa0mg per day (+5.0 versus placebo; p\xa0=\xa00.005).\n\nThe trials for each comparator all reported data on weight. The difference in weight gain at 6-week follow-up was lowest in the groups who received aripiprazole 10\xa0mg per day (+0.8\xa0kg versus placebo) and aripiprazole 30\xa0mg per day (+1.0\xa0kg versus placebo), followed by the groups who received risperidone 0.5–2.5\xa0mg per day (+1.18\xa0kg versus placebo) and risperidone 3–6\xa0mg per day (+1.38\xa0kg versus placebo) and those who received quetiapine 400\xa0mg per day (+2.6\xa0kg versus placebo) and quetiapine 800\xa0mg per day (+2.2\xa0kg versus placebo). The highest weight gain was reported in the olanzapine trial (+4.2\xa0kg versus placebo).\n\nIncreases in the level of prolactin at 6-week follow-up were reported in the group who received risperidone 0.5–2.5\xa0mg per day (+46.1\xa0ng/ml in females and +19.2\xa0ng/ml in males, versus placebo), risperidone 3–6\xa0mg per day (+86.5\xa0ng/ml in females and +29.6\xa0ng/ml in males, versus placebo), olanzapine 2.5–20\xa0mg per day (+12.1\xa0ng/ml versus placebo), quetiapine 400\xa0mg per day (+7.7\xa0ng/ml versus placebo) and quetiapine 800\xa0mg per day (+10.42\xa0ng/ml versus placebo). Reductions in prolactin levels were reported only in the groups who received aripiprazole 10\xa0mg per day (−3.4\xa0ng/ml versus placebo) and aripiprazole 30\xa0mg per day (−6.6\xa0ng/ml versus placebo). No differences in akathisia compared with placebo were reported in the group who received aripiprazole 10\xa0mg per day. Differences in akathisia were reported in the groups who received aripiprazole 30\xa0mg per day (+7.0% versus placebo), risperidone 0.5–2.5\xa0mg per day (+5.0% versus placebo), quetiapine 400\xa0mg per day (+1.4% versus placebo) and quetiapine 800\xa0mg per day (+1.4% versus placebo).\n\nThe ERG noted that the additional studies identified by the manufacturer include people aged 13 to 17\xa0years with schizophrenia, which is wider than the population defined in the scope (people aged 15 to 17\xa0years). The ERG also noted that the systematic review and the two other data sources identified by the manufacturer encompassed people with conditions other than schizophrenia and included non-randomised studies. The ERG concurred with the manufacturer that data on the use of aripiprazole specifically for people with learning difficulties are unlikely to be available.\n\nThe ERG commented that comparable data on PANSS scores for aripiprazole, quetiapine, risperidone and olanzapine could have been included in an indirect comparison. It noted that the manufacturer provided no explanation of its calculation or interpretation of the odds ratios for the indirect comparison. The ERG also noted that three of the RCTs reported prolactin concentration in a standard format that could have been included in an indirect comparison. Comparable data on weight change from the risperidone trial could also have been included in an indirect comparison. The ERG agreed with the manufacturer that there were insufficient data for analysis of the other clinical outcomes.\n\n# Cost effectiveness\n\n## Original submission\n\nThe manufacturer carried out a systematic review of the literature to identify cost-effectiveness studies of aripiprazole for the treatment of schizophrenia in adolescents. No such studies were identified; however, four economic evaluations that included aripiprazole in adults with schizophrenia were identified and reviewed. Given that there were no economic evaluations assessing the cost effectiveness of aripiprazole in adolescents, the manufacturer carried out a de novo economic evaluation.\n\nThe manufacturer presented a decision tree followed by a Markov model to estimate the cost effectiveness of first-line aripiprazole compared with first-line olanzapine for the treatment of schizophrenia in adolescents. The model incorporates first-line, second-line and third-line treatments and allows people to switch to the next treatment when one treatment is discontinued or a relapse occurs. In the first two cycles of the model, people undergoing treatment may discontinue and switch to another antipsychotic drug (from aripiprazole to olanzapine or vice versa). These cycles are represented as two health states in the decision tree: stable schizophrenia and withdrawal (because of lack of efficacy, adverse events or other reasons). In the second cycle there may also be a relapse, which is reflected as an additional health state in this cycle. People in whom there is no relapse or who discontinue treatment are assumed to continue treatment in the stable schizophrenia state. Discontinuation is assumed to occur only in the first two cycles. From the third treatment cycle onwards, people are assumed to either continue in a stable condition or a relapse occurs and they may subsequently switch antipsychotic treatment. This is reflected by using a Markov process that involves only two states – maintenance on treatment and relapse. People who discontinue treatment or in whom a relapse occurs on the second treatment are assumed to receive clozapine as a last-resort treatment and to continue receiving clozapine after relapse. The model adopted a 3-year time horizon on the basis that this is the maximum duration an individual would remain in this group before being considered an adult (at which point other treatment options may be available). Death was not modelled because of the short time horizon and a lack of efficacy data on death rates.\n\nThe manufacturer's base-case analysis compared first-line aripiprazole with first-line olanzapine in people aged 13 to 17\xa0years with schizophrenia, which is broader than the UK marketing authorisation for aripiprazole (which is for adolescents aged 15 to 17\xa0years with schizophrenia). Results were presented in terms of total and incremental costs and quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) for the two strategies.\n\nThe model used withdrawal and adverse event data, but not primary outcome data, from published RCTs and the indirect comparison. The probabilities of withdrawals and adverse events were calculated directly from study 31-03-239 on aripiprazole and from the manufacturer's adjusted indirect comparison. The manufacturer stated that no long-term data on treatment effects, including rates of relapse with aripiprazole and olanzapine, were identified in the literature for the adolescent population. Data on rates of relapse were therefore taken from a study of adults with schizophrenia that compared aripiprazole with other atypical antipsychotics. The study reported a relative risk of relapse with aripiprazole of 0.92 (95% CI 0.67 to 1.26) compared with other atypical antipsychotics. However, the manufacturer stated that this value is an error, as it does not equal the ratio of the proportion of people in whom there is a relapse after treatment with other atypical antipsychotics divided by the proportion of people in whom there is a relapse after treatment with aripiprazole. The manufacturer adjusted the value (which was provided as commercial in confidence) and used this higher adjusted relative risk of relapse (that is, a relapse is more likely to occur) in the economic model.\n\nThe manufacturer also found limited or no data on adolescents with schizophrenia concerning utility values and resource use. Utilities for the health states were taken from a study of adults with schizophrenia in the UK. The study reported separate utilities for patients and non-patients. The manufacturer used the utilities derived from patients in its economic model.\n\nThe model included four types of resource use and costs: drug acquisition, on-treatment monitoring and switching of medication, management of adverse events, and health state costs. Treatment costs were calculated using daily drug dosages from the SPCs supported by the mean and median dosages in study 31-03-239 and the RCT reported by Kryzhanovskaya et al. (2009) respectively. Resource use associated with switching medication was based on three 20-minute visits to a psychiatrist. Resource use associated with adverse treatment effects was based on assumptions made in NICE clinical guideline 82 (CG82), 'Schizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care' (2009) about weight gain and extrapyramidal symptoms, and clinical opinion on somnolence. Resource use associated with relapse was also based on CG82.\n\nIn the manufacturer's base-case analyses, first-line treatment with aripiprazole is estimated to dominate first-line treatment with olanzapine (that is, first-line treatment with aripiprazole is more effective and less costly than first-line treatment with olanzapine; incremental cost −£69.21, incremental benefit 0.004). The manufacturer conducted a number of one-way deterministic sensitivity analyses, which showed that varying the relative risk of relapse and the daily cost of aripiprazole had the greatest effect on the ICERs. The ICERs varied between −£123,663 and £628,706 per QALY gained for a relative risk of relapse of 0.679 to 1.261 and from −£64,755 and £130,723 per QALY gained for a daily cost of aripiprazole of £2.28 to £6.84. The probabilistic sensitivity analysis suggested that first-line aripiprazole had a 96% probability of being cost effective at £20,000 per QALY gained when compared with first-line olanzapine.\n\nThe ERG considered that in general the manufacturer's approach to the economic evaluation was appropriate. However, the ERG noted a number of concerns about the cost-effectiveness analysis, including the approach used to compare sequential treatment strategies. These concerns included:\n\nfor both treatment strategies the major contribution to the total cost was the cost of managing relapses\n\nthe exclusion of risperidone, which is currently the most common first-line treatment for schizophrenia in adolescent populations in the UK\n\nthe exclusion of relevant adverse events such as extrapyramidal symptoms and sexual dysfunction in the economic model\n\nthe appropriateness of applying data derived from adult populations, such as relative risk values, to adolescents, and the uncertainty this generates in the model\n\nthe appropriateness of using a re-derived relative risk value based on crude relative risk reported in the published paper.\n\nThe ERG made revisions to the manufacturer's model to correct errors (relating to the cost of relapse in cycle 2 and the Health Resource Group [HRG] cost code that was applied). When the cost of relapse in cycle 2 was revised it resulted in a higher ICER than was reported in the manufacturer's base case for the comparison of first-line aripiprazole with first-line olanzapine (£6231 per QALY gained; incremental cost £27.15, incremental benefit 0.004). Revising the HRG cost code had no effect on the result (aripiprazole dominated olanzapine in the revised result and the base case). The ERG also noted there was an error in the presentation of all the probabilistic sensitivity results relating to the inclusion of total undiscounted cost for first-line olanzapine. Revising this error resulted in considerably higher ICERs than those reported in the manufacturer's base case (ranging from £22,182 per QALY gained in the ERG analysis after correcting for this error to £47,103 per QALY gained after correcting for this error and applying a relative risk of relapse of 0.92).\n\nThe ERG performed a number of analyses on the corrected model to apply alternative estimates for parameter inputs and explore the impact of alternative structural assumptions and the methods used in the adjusted indirect comparison. The cumulative results presented by the ERG showed that adjusting medication costs for people with schizophrenia in whom there is a relapse approximately doubles the incremental costs without affecting the incremental QALYs, increasing the ICER from £6231 to £13,763 per QALY gained. The ICER increases from £13,763 to £23,144 per QALY gained when the disutility for people discontinuing treatment because of adverse events is reduced and the disutility associated with weight gain is continued while people remain on a given treatment. When the proportion of people in whom there is a relapse and who are admitted as inpatients is increased to 50% and applied to the assumptions already considered, it results in aripiprazole dominating olanzapine (that is, aripiprazole is more effective and less expensive than olanzapine). However, when the length of stay for admitted patients is increased to 107.7\xa0days, the ICER increases to £69,638 QALY gained, and increases further to £232,981 per QALY gained when the relative risk of relapse of 0.92 reported by Moeller and colleagues is used.\n\nThe ERG also presented exploratory analyses in which the unit costs of risperidone for the treatment of adolescents with schizophrenia and the odds ratios relating to early discontinuations with risperidone (based on an adjusted indirect comparison) were applied to the manufacturer's economic model. In the first analysis, the cost of first-line treatment with risperidone was substituted for the cost of first-line treatment with olanzapine in the manufacturer's model. This caused the ICERs for aripiprazole as a first-line treatment to increase significantly, rising to £89,114–£112,012 per QALY gained compared with risperidone. The ERG noted that this analysis did not use any clinical data specific to risperidone, and implicitly assumed that the odds ratios derived for olanzapine (relative to aripiprazole) could be applied to risperidone. To examine the impact of applying odds ratios derived from an alternative data source, an adjusted indirect comparison was conducted using data from an RCT on the use of risperidone in adolescents aged 13 to 17\xa0years reported by Haas and colleagues (2009) to estimate the odds ratios for discontinuation (due to adverse events, lack of efficacy and other reasons) and for treatment-related adverse effects (weight gain, somnolence and extrapyramidal symptoms). The ERG noted that the risperidone RCT was not placebo controlled; rather, it compared the standard dosage of risperidone (1.5–6.0\xa0mg/day) with a dosage that (although not proven ineffective) was tenfold lower (0.15–0.6\xa0mg/day). The ERG therefore cautioned that the occurrence of treatment discontinuations associated with risperidone may have been underestimated in the study, and hence the odds ratios derived in the adjusted indirect comparison may be biased against aripiprazole. Using these data in the manufacturer's economic model, the ERG's analysis suggested that first-line risperidone dominated first-line aripiprazole (that is, first-line aripiprazole is a less cost-effective option compared with first-line risperidone).\n\n## Additional submission after consultation\n\nIn response to the Appraisal Consultation Document issued in July 2010 in which the Committee was minded not to recommend aripiprazole for the treatment of schizophrenia in adolescents aged 15 to 17\xa0years, the manufacturer provided a revised economic model. The revised model contained four additional treatment sequences specified in the Appraisal Consultation Document:\n\ntreatment strategy A (aripiprazole then risperidone then olanzapine then clozapine [A, R, O, C])\n\ntreatment strategy B (risperidone then aripiprazole then olanzapine then clozapine [R, A, O, C])\n\ntreatment strategy C (risperidone then olanzapine then aripiprazole then clozapine [R, O, A, C])\n\ntreatment strategy D (risperidone then olanzapine then quetiapine then clozapine [R, O, Q, C]).\n\nThe revised economic model also included a range of doses for the comparators, including low doses (which are commonly prescribed for adolescents), lay utility values (rather than patient values) from Briggs and colleagues (2008), an unadjusted relative risk of relapse of 0.937 (rather than an adjusted value), and additional adverse treatment effects (akathisia, tremor and agitation). The manufacturer's submission stated that, although requested by the Committee, sexual dysfunction could not be included in the model because this outcome was not reported in the studies identified and that prolactin levels (which are thought to be related to sexual dysfunction) were reported in different ways. Furthermore, data on aggression were not consistently reported in the studies identified, although rates of agitation were available for aripiprazole, risperidone and quetiapine and included as a sensitivity analysis. The manufacturer's submission justified the exclusion of PANSS scores in the revised model on the basis that clinicians do not use the PANSS questionnaire in clinical practice and that in CG82 PANSS was used to inform utility values and not as a separate outcome measure. The manufacturer carried out corrections for inaccuracies identified by the ERG in the original model, which included the cost of an acute hospital stay (changed to £513 per day), the costs during the second cycle of the model, the values for the proportion of patients with an acute hospitalisation, and the number of patients receiving olanzapine following relapse.\n\nThe manufacturer's revised model included a number of assumptions to inform gaps in the outcome measures. If data were not available for any outcome measure, equivalence with aripiprazole was assumed (that is, relative risk\xa0=\xa01.0). For quetiapine, the odds ratio of withdrawal due to lack of efficacy was assumed to be captured in withdrawal due to other reasons. Costs and disutility associated with extrapyramidal symptoms were applied to other adverse events included in the model (akathisia, benzodiazepine use, agitation and tremor). The manufacturer's model included several available formulations of each of the antipsychotic treatments. In the base-case analysis, UK prescription cost analysis was used to provide the most commonly prescribed formulation, which was then used to calculate the daily cost of the antipsychotics included in the analysis. The most commonly prescribed formulation of aripiprazole was the 28-tablet pack of 10\xa0mg at a cost of £95.74. Based on a dose of 10\xa0mg per day (dose escalated according to the SPC and according to the dose used in the clinical trial), aripiprazole was costed at £3.42 per day in the model. The most commonly prescribed formulation of olanzapine was the 28-tablet pack of 10\xa0mg at a cost of £79.45. Based on a dose of 12.5\xa0mg per day (mean modal dose according to the clinical trial), olanzapine was costed at £3.55 per day in the model. The most commonly prescribed formulation of quetiapine was the 60-tablet pack of 25\xa0mg at a cost of £33.83. Based on a dose of 400\xa0mg per day, quetiapine was costed at £9.02 per day in the model. The most commonly prescribed formulation of risperidone was the 20-tablet pack of 0.5\xa0mg at a cost of £1.06. Based on a dose of 2\xa0mg per day, risperidone was costed at £0.21 per day in the model. The most commonly prescribed clozapine formulation was 100\xa0mg tablets. At a dose of 325\xa0mg per day (based on a usual dose for people aged under 18\xa0years of 200– 450\xa0mg daily), clozapine was costed at £2.86 per day in the model.\n\nThe manufacturer's revised model included deterministic sensitivity analyses of the doses for each treatment:\n\nDosing scenario 1 examined the following: aripiprazole 10\xa0mg, olanzapine 12.5\xa0mg (as in the base case), risperidone 4–6\xa0mg and quetiapine 800\xa0mg (both costs and efficacy were varied).\n\nDosing scenario 2 examined the following: aripiprazole 10\xa0mg, olanzapine 10\xa0mg (tablets are available in 10\xa0mg doses; efficacy remains the same as in the base case), risperidone 4–6\xa0mg and quetiapine 800\xa0mg (both costs and efficacy were varied).\n\nThe manufacturer also carried out sensitivity analyses of adverse events including weight gain, somnolence, extrapyramidal symptoms (represented by tremor and akathisia) and agitation.\n\nThe results of the manufacturer's revised deterministic base case showed that treatment strategy D (R, O, Q, C) was dominated by strategy C (R, O, A, C), and treatment strategies B (R, A, O, C) and A (A, R, O, C) resulted in ICERs ranging from £51,600 per QALY gained to £108,800 per QALY gained respectively compared with treatment strategy C (R, O, A, C). The results of the manufacturer's sensitivity analyses showed that treatment strategy D (R, O, Q, C) was dominated by treatment strategy C (R, O, A, C) in all scenarios presented. Results of the manufacturer's dosing scenarios showed that in the first scenario, treatment strategies A (A, R, O, C) and B (R, A, O, C) resulted in ICERs ranging from £38,500 to £49,000 per QALY gained respectively compared with treatment strategy C (R, O, A, C). In the second dosing scenario, treatment strategies B (R, A, O, C) and A (A, R, O, C) resulted in ICERs ranging from £203,000 to £350,000 per QALY gained respectively compared with treatment strategy C (R, O, A, C). The results of the manufacturer's sensitivity analysis of adverse events showed that treatment strategies A (A, R, O, C) and B (R, A, O, C) resulted in ICERs ranging from £38,300 per QALY gained to £49,000 per QALY gained respectively compared with treatment strategy C (R, O, A, C).\n\nThe ERG commented that its original concern regarding the application of disutility due to weight gain only in the first cycle of each line of treatment was not addressed in the manufacturer's revised model. The ERG noted that the manufacturer's revised deterministic analyses showed that treatment strategy D (R, O, Q, C) was dominated by first-line risperidone strategies B (R, A, O, C) and C (R, O, A, C), and that aripiprazole was associated with higher ICERs compared with first-line risperidone sequences. The ERG noted that the results of the manufacturer's revised probabilistic sensitivity analysis showed consistently better outcomes (total QALYs increased by 0.05 and 0.06 for each strategy) and slightly lower costs than the deterministic analysis, and that small changes in the model resulted in large changes in the results.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Committee reviewed the data available on the clinical and cost effectiveness of aripiprazole, having considered evidence on the nature of schizophrenia in people aged 15 to 17\xa0years and the value placed on the benefits of aripiprazole by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed current standard clinical management of schizophrenia in adolescents. It heard from clinical specialists and patient experts that antipsychotics are prescribed only after a psychological assessment and a discussion with the person with schizophrenia together with their family or carer. The choice of treatment is negotiated with the person and depends on a number of factors, including adverse events associated with the treatment, previous treatments the person has received and their responses to them, and adverse events experienced while on those treatments. Adolescents with schizophrenia are usually treated with atypical antipsychotics at a low dose and are closely monitored.\n\nThe clinical specialists noted that the main aim of treatment is to maximise the control of schizophrenia and minimise the adverse events that are the most troublesome for each individual. The Committee heard from the patient experts that effective control of schizophrenia with aripiprazole would allow adolescents to return to normal functioning in terms of work or schooling. The Committee understood from the clinical specialists that no single atypical antipsychotic drug is considered to be more clinically effective than the others. Risperidone is the most widely used first-line atypical antipsychotic in UK clinical practice because clinicians have extensive experience of using it to treat schizophrenia, and often achieve control with low doses and without troublesome adverse events. The clinical specialists stated that when an atypical antipsychotic medication is prescribed, control of schizophrenia and adverse events is assessed over a period of 6\xa0weeks or more and an alternative atypical antipsychotic can be considered if the first antipsychotic proves unsatisfactory. Other atypical antipsychotics such as aripiprazole, olanzapine, quetiapine or amisulpride may be used if control of schizophrenia is not achieved with risperidone. The clinical specialists also explained that clozapine is sometimes prescribed; however, because it needs careful monitoring for particular side effects, it is prescribed as rescue therapy only if the schizophrenia is refractory to at least three other antipsychotic treatments. The Committee noted that some of the atypical antipsychotics described by the clinical specialists do not have a marketing authorisation for the treatment of schizophrenia in adolescents, but acknowledged that specific licensing in adolescents is not a prerequisite to prescribing licensed adult medicines, particularly if there is widespread experience of their use. The Committee agreed with the clinical specialists that it is important for adolescents with schizophrenia to have a range of treatment options before considering rescue therapy with clozapine, and therefore considered that aripiprazole may be a suitable treatment option for people aged 15 to 17\xa0years with schizophrenia.\n\nThe Committee heard from the clinical specialists and patient experts that there are a number of dose-related adverse events associated with atypical antipsychotic treatments, including weight gain, hyperprolactinaemia and sexual dysfunction, aggression and akathisia/extrapyramidal symptoms. Adolescents are often less tolerant of adverse events than adults, leading to problems with adherence to medication. The Committee heard from the clinical specialists that some treatments are more likely to be associated with particular adverse events than others: olanzapine is more likely associated with weight gain, risperidone and amisulpride are more likely associated with hyperprolactinaemia, and aripiprazole is more likely associated with akathisia and a subjective feeling of aggression (for which benzodiazepine co-treatment may be used). The clinical specialists stated that these adverse events are dose related and therefore it is preferable to start prescribing any atypical antipsychotic at a low dose. The Committee accepted that all atypical antipsychotics are associated with adverse events and that accounts from the clinical specialists on the use of aripiprazole suggest that it may be as safe and well tolerated as the other treatments.\n\n# Clinical effectiveness\n\nThe Committee noted that the clinical effectiveness evidence presented in the manufacturer's submission was derived mainly from one RCT (study 31-03-239) that studied treatment with aripiprazole at two different doses compared with placebo, with supporting data on adverse events from two open-label single-arm extension studies. The Committee noted that the 31-03-239 study was placebo controlled and did not provide a head-to-head comparison of aripiprazole with any other atypical antipsychotics.\n\nThe Committee noted that the 31-03-239 study showed a reduction in total PANSS score (that is, an improvement in symptoms) at week\xa06 in all three study arms. Statistically significant differences in the degree of improvement were observed in the aripiprazole groups compared with the placebo group (p\xa0=\xa00.0414 and p\xa0=\xa00.0061 for the 10\xa0mg and 30\xa0mg doses versus placebo). The Committee heard from the clinical specialists that the PANSS score is a well-recognised tool used in clinical trials for the measurement of positive, negative and general psychopathology symptoms in schizophrenia. However, the results are often difficult to relate to UK clinical practice as the tool is not routinely used by clinicians. The Committee accepted that the PANSS score is a valid tool for the measurement of positive, negative and general psychopathology symptoms and that evidence from the 31-03-239 study demonstrates a reduction in schizophrenic symptoms in the aripiprazole groups.\n\nThe Committee was aware that the manufacturer's original submission included a very limited evidence base. However, the manufacturer's additional analyses provided some evidence for each of the atypical antipsychotics (risperidone, quetiapine and olanzapine) routinely used in UK clinical practice. The Committee noted that the trials for olanzapine, quetiapine and, most notably, risperidone showed greater relative risks in PANSS positive and negative scores in their treatment arms compared with their placebo arms than were seen in the aripiprazole trial. The Committee also noted that there appears to be a large placebo effect in the aripiprazole trial, but heard from the manufacturer that the precise cause of this effect is unknown. The Committee was aware that, insofar as evidence is available, the CGI and CGAS findings from the trials are not better for aripiprazole than for the comparator treatments.\n\nThe Committee considered the evidence on adverse events for aripiprazole and each of the comparators presented in the manufacturer's additional analyses. The Committee noted that there is substantial variation between the atypical antipsychotics in the adverse events associated with each treatment. The Committee was aware of the clinical specialists' view that it is important for adolescents with schizophrenia to have a range of treatment options before considering rescue therapy with clozapine, in order to individualise treatment and to minimise adverse treatment effects. The Committee noted that olanzapine is associated with substantial weight gain, as to a lesser extent are quetiapine and risperidone, but that only very small changes in weight gain are seen with aripiprazole. It considered that weight gain may be of considerable importance to adolescents and was concerned that weight gain associated with olanzapine may not be just a short-term problem, but could be a long-term health risk. In terms of changes in prolactin levels, the Committee heard from the clinical specialists that risperidone is associated with higher levels of prolactin, as to a lesser extent is olanzapine. Prolactin levels with aripiprazole treatment are generally lower than seen with the other comparator treatments. The Committee heard that a change in prolactin level is one of a number of contributors to potential sexual dysfunction.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG. It noted that the manufacturer used a decision tree, followed by a Markov model, to estimate the cost effectiveness of first-line aripiprazole compared with first-line olanzapine for the treatment of schizophrenia in adolescents. Data were derived from the manufacturer's adjusted indirect comparison using secondary outcome data for aripiprazole and olanzapine. The Committee also considered an updated adjusted indirect comparison from the manufacturer that incorporated risperidone, quetiapine and olanzapine as comparators.\n\nThe Committee had concerns about a number of aspects of the economic model, including the exclusion of comparators specified in the final scope, primary (PANSS) outcome data and data on relevant adverse events (such as extrapyramidal symptoms and sexual dysfunction). The Committee was also aware that the ERG had identified a number of technical errors in the manufacturer's model. The Committee heard from the ERG that in the absence of data specific to the population in the scope, data on health state utility at relapse, disutility associated with treatment-related adverse events and resource use assumptions were all derived from studies of adults rather than adolescents.\n\nThe Committee noted that the manufacturer's initial base-case ICER (provided for the first Appraisal Committee meeting and following revisions from the ERG) for first-line aripiprazole (in a three-drug sequence) compared with first-line olanzapine of £6200 per QALY gained (incremental costs −£69, incremental QALYs 0.004) was based on a number of assumptions that were inappropriate; and that sensitivity analyses conducted by the ERG suggested the ICER could be as high as £233,000 per QALY gained if certain assumptions were varied. Furthermore, it noted that aripiprazole is dominated by risperidone in all of the ERG's exploratory analyses. It concluded that the ICERs presented by the manufacturer could not be accepted without revision. The Committee requested further clarification from the manufacturer.\n\nThe Committee considered the manufacturer's updated economic model that compared sequences of treatments starting with aripiprazole with sequences starting with risperidone. The Committee still had concerns about the primary outcome data not being included in the model. It did not agree with the manufacturer's argument that this omission could be justified on the grounds that trial outcomes were not used in ordinary clinical practice; nor did it agree with the manufacturer's reference to NICE clinical guideline 82 ('Core interventions in the treatment and management of schizophrenia in primary and secondary care (update)'), in which PANSS scores were used to inform utility values and not considered as a separate outcome measure as an argument for not including PANSS scores in the model. The Committee noted that as aripiprazole is associated with smaller changes in PANSS scores than risperidone, olanzapine and quetiapine, the omission clearly favoured aripiprazole. The Committee also noted that some adverse events (sexual dysfunction and aggression) were not included in the model, and was aware that there was an error in the manufacturer's adjusted indirect comparison that resulted in the odds ratios of withdrawals (for other reasons) from risperidone compared with withdrawals from aripiprazole being higher in the manufacturer's analysis. The Committee noted that the manufacturer's updated base-case analysis shows that treatment sequences in which aripiprazole is used first result in ICERs ranging from £52,750 per QALY gained to £108,800 per QALY gained when compared with treatment sequences in which risperidone is used first. It considered that, in view of the PANSS scores not being included in the model, these ICERs were likely to be underestimated. Furthermore, they are outside the range considered to be a cost-effective use of NHS resources.\n\nIn view of the results from the manufacturer's updated base-case analysis and the testimony of the clinical specialists, which highlighted that routine clinical practice is to start treatment with risperidone, the Committee concluded that starting treatment with aripiprazole rather than risperidone would not be a cost-effective use of NHS resources.\n\nHowever the Committee was mindful that in people aged 15 to 17\xa0years with schizophrenia who are intolerant of or have a contraindication to risperidone, or whose schizophrenia has not been adequately controlled with risperidone, the case for aripiprazole is more plausible. The Committee considered whether there was any evidence to suggest that aripiprazole should be used ahead of, or only after olanzapine or quietapine in the treatment pathway for schizophrenia. It noted that the economic analyses suggest little difference between sequences in which aripiprazole precedes olanzapine and vice versa; and although sequences that contain aripiprazole are suggested to be more cost effective than the sequence that contains quetiapine (sequence D), the Committee was concerned that the cost of quetiapine was unfairly calculated in the manufacturer's economic model, as optimal packs and doses may not have been considered. The Committee agreed that the differences in side effects between these drugs were a more important consideration than the (small) differences in their costs and primary outcomes. Therefore the Committee agreed that aripiprazole should be available on equal terms with other antipsychotic comparators (apart from risperidone), given its good side-effect profile and comparable price to olanzapine and quetiapine\n\nThe Committee considered whether its recommendations were associated with any potential issues related to equality. The Committee was aware that consultees and commentators suggested that one area of potential discrimination was that the diagnosis of schizophrenia requires a definitive methodological approach using precise diagnostic criteria detailed in a number of tools, including DSM-IV and K-SADS-PL. The Committee noted that although some people with learning difficulties may exhibit psychoses, unless they fulfil the DSM-IV and K-SADS-PL criteria for schizophrenia they do not (by definition) have schizophrenia, and therefore are not appropriate for inclusion in this technology appraisal. It noted that both the DSM-IV and K-SADS-PL criteria are used in clinical practice, as well as in studies of schizophrenia. The Committee concluded that there are not sufficient data to provide evidence on how the clinical and cost effectiveness of aripiprazole may differ for people with schizophrenia who have learning difficulties.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA213 (STA)\n\n\n\nAppraisal title: Aripiprazole for the treatment of schizophrenia in people aged 15 to 17\xa0years\n\n\n\nFAD section\n\nKey conclusions\n\nAripiprazole is recommended as an option for the treatment of schizophrenia in people aged 15 to 17\xa0years who are intolerant of risperidone, or for whom risperidone is contraindicated, or whose schizophrenia has not been adequately controlled with risperidone.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nPeople aged 15 to 17\xa0years currently receiving aripiprazole for the treatment of schizophrenia who do not meet the criteria specified in 1.1 should have the option to continue treatment until it is considered appropriate to stop. This decision should be made jointly by the clinician, the person with schizophrenia, and if appropriate, their parents or carers.\n\n\n\nCurrent practice\n\nClinical need of patients including the availability of alternative treatments\n\n\n\nThe Committee agreed with the clinical specialists that it is important for adolescents with schizophrenia to have a range of treatment options before considering rescue therapy with clozapine, and therefore considered that aripiprazole may be a suitable treatment option for people aged 15 to 17\xa0years with schizophrenia.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\n\n\n\n\nThe Committee heard from the patient experts that effective control of schizophrenia with aripiprazole would allow adolescents to return to normal functioning in terms of work or schooling.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\n\n\nThe Committee understood from the clinical specialists that no single atypical antipsychotic drug is considered to be more clinically effective than the others.\n\n\n\n\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\n\n\nThe Committee heard from the clinical specialists that risperidone is the most widely used first-line atypical antipsychotic in UK clinical practice for adolescents with schizophrenia. Other atypical antipsychotics, such as aripiprazole, olanzapine, quetiapine or amisulpride may be used if control of schizophrenia is not achieved with risperidone. It was noted that clozapine is prescribed as a rescue therapy only if the schizophrenia is refractory to at least three other antipsychotic treatments.\n\n\n\nAdverse events\n\n\n\nThe Committee heard from the clinical specialists and patient experts that there are a number of dose-related adverse events associated with atypical antipsychotic treatments, including weight gain, hyperprolactinaemia and sexual dysfunction, aggression and akathisia/extrapyramidal symptoms. The Committee heard from the clinical specialists that some treatments are more frequently associated with particular adverse events than others. The Committee accepted that accounts from the clinical specialists on of the use of aripiprazole suggest that it may be as safe and well tolerated as the other treatments.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of the evidence\n\n\n\nThe clinical evidence presented in the manufacturer's submission was derived mainly from one RCT (study 31-03-239) that studied treatment with aripiprazole at two different doses compared with placebo. Supporting data on adverse events was obtained from two open-label single-arm extension studies.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAn indirect comparison was also conducted to compare first-line aripiprazole with first-line olanzapine.\n\n\n\n\n\n\n\nThe 31-03-239 study was placebo controlled and did not provide a head-to-head comparison of aripiprazole with any other atypical antipsychotics.\n\n\n\n\n\n\n\nThe Committee was aware that the manufacturer's original submission included a very limited evidence base. However, the manufacturer's additional analyses provided some evidence for each of the atypical antipsychotics (risperidone, quetiapine and olanzapine) routinely used in UK clinical practice. The Committee noted that the trials for olanzapine, quetiapine and, most notably, risperidone showed greater relative risks in PANSS positive and negative scores in their treatment arms compared with their placebo arms than were seen in the aripiprazole trial. The Committee also noted that there appears to be a large placebo effect in the aripiprazole trial, but heard from the manufacturer that the precise cause of this effect is unknown. The Committee was aware that, insofar as evidence is available, the CGI and CGAS findings are not better for aripiprazole than for the comparator treatments.\n\n\n\n\n\n\n\n\n\nThe Committee noted that there is substantial variation between the atypical antipsychotics in the adverse events associated with each treatment.\n\n\n\n\n\n\n\nThe Committee heard that a change in prolactin level is one of a number of contributors to potential sexual dysfunction. The Commitee considered that weight gain may be of considerable importance to adolescents and was concerned that weight gain associated with olanzapine may not be just a short-term problem, but could be a long-term health risk.\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\n\n\nThe Committee heard from the clinical specialists that choice of treatment depends on a number of factors. Adolescents with schizophrenia are usually treated with atypical antipsychotics at a low dose and are closely monitored.\n\n\n\nUncertainties generated by the evidence\n\n\n\nThe Committee heard from the clinical specialists that the PANSS score (primary outcome) is a well-recognised tool used in clinical trials, however the results are often difficult to relate to UK clinical practice as the tool is not routinely used by clinicians.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee noted that there appears to be a large placebo effect in the aripiprazole trial, but heard from the manufacturer that the precise cause of this effect is unknown.\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNot applicable.\n\n-\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\n\n\nThe Committee accepted that PANSS score is a valid tool for the measurement of positive, negative and general psychopathology symptoms and that evidence from the 31-03-239 study demonstrates a reduction in schizophrenic symptoms in the aripiprazole groups.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nThe Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG.\n\n\n\n\n\n\n\n\n\n\n\nThe Committee heard from the ERG that some data used in the model were derived from adults rather than adolescent populations in the absence of data specific to adolescents.\n\n\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee had concerns about a number of aspects of the economic model, such as the exclusion of comparators specified in the final scope, primary PANSS outcome data, and data on relevant adverse events (such as EPS and sexual dysfunction).\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee considered the manufacturer's updated economic model that compared sequences of treatments starting with aripiprazole with sequences starting with risperidone. The Committee still had concerns about the primary outcome data not being included in the model. It did not agree with the manufacturer's argument that this omission could be justified on the grounds that trial outcomes were not used in ordinary clinical practice; nor did it agree with the manufacturer's reference to NICE clinical guideline 82 ('Core interventions in the treatment and management of schizophrenia in primary and secondary care (update)'), in which PANSS scores were used to inform utility values and not considered as a separate outcome measure as an argument for not including PANSS scores in the model. The Committee noted that as aripiprazole is associated with smaller changes in PANSS scores than risperidone, olanzapine and quetiapine, the omission clearly favoured aripiprazole. The Committee also noted that some adverse events (sexual dysfunction and aggression) were not included in the model, and was aware that there is an error in the adjusted indirect comparison that results in the odds ratios of withdrawals (for other reasons) from risperidone compared with withdrawals from aripiprazole being higher in the manufacturer's analysis.\n\n\n\nIncorporation of health-related quality of life benefits and utility values\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee heard from the ERG that in the absence of data specific to the population in the scope, data on health state utility at relapse, disutility associated with treatment-related adverse events and resource use assumptions were all derived from studies of adult rather than adolescent populations.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost-effective?\n\nNot applicable.\n\n-\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nThe Committee noted that the manufacturer's updated base-case analysis shows that treatment sequences in which aripiprazole is used first result in ICERs ranging from £52,750 per QALY gained to £108,800 per QALY gained when compared with treatment sequences in which risperidone is used first. It considered that, in view of the PANSS scores not being included in the model, these ICERs were likely to be underestimated. Furthermore, they are outside the range considered to be a cost-effective use of NHS resources.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nIn view of the results from the manufacturer's updated base-case analysis and the testimony of the clinical specialists, which highlighted that routine clinical practice is to start treatment with risperidone, the Committee concluded that starting treatment with aripiprazole rather than risperidone would not be a cost-effective use of NHS resources.\n\n\n\nThe Committee was mindful that in people aged 15 to 17\xa0years with schizophrenia who are intolerant of or have a contraindication to risperidone, or whose schizophrenia has not been adequately controlled with risperidone, the case for aripiprazole is more plausible. The Committee considered whether there was any evidence to suggest that aripiprazole should be used ahead of, or only after olanzapine or quietapine in the treatment pathway for schizophrenia. It noted that the economic analyses suggest little difference between sequences in which aripiprazole precedes olanzapine and vice versa; and although sequences that contain aripiprazole are suggested to be more cost-effective than the sequence that contains quetiapine (sequence D), the Committee was concerned that the cost of quetiapine was unfairly calculated in the manufacturer's economic model, as optimal packs and doses may not have been considered. The Committee agreed that the differences in side effects between these drugs were a more important consideration than the (small) differences in their costs and primary outcomes. Therefore the Committee agreed that aripiprazole should be available on equal terms with other antipsychotic comparators (apart from risperidone), given its good side-effect profile and comparable price to olanzapine and quetiapine.\n\n\n\nAdditional factors taken into account\n\nPatient Access Schemes\n\n(PPRS)\n\n\n\nNot applicable to this appraisal.\n\n-\n\nEnd-of-life considerations\n\nNot applicable to this appraisal.\n\n-\n\nEqualities considerations, social value judgements\n\n\n\nThe Committee was aware that consultees and commentators suggested that one area of potential discrimination was that the diagnosis of schizophrenia requires a definitive methodological approach using precise diagnostic criteria which may not be met by people with learning difficulties. The Committee concluded that there are not sufficient data to provide evidence on how the clinical and cost effectiveness of aripiprazole may differ for people with schizophrenia who have learning difficulties.\n\n", 'Related NICE guidance': '# Published\n\nSchizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care. NICE clinical guideline 82 (2009).\n\nGuidance on the use of electroconvulsive therapy.NICE technology appraisal guidance 59 (2003).\n\n# Under development\n\nSchizophrenia: the recognition and management of schizophrenia in children and young people. NICE clinical guideline.', 'Review of guidance': 'The guidance on this technology will be considered for review in November 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveJanuary 2011', 'Changes after publication': 'February 2014: implementation section updated to clarify that aripiprazole is recommended as an option for treating schizophrenia. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta213
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Evidence-based recommendations on aripiprazole for treating schizophrenia in young people aged 15 to 17.
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53d4f199c27f219268f06f575e82a21f3fdc7316
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Extracorporeal shockwave therapy for refractory greater trochanteric pain syndrome
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Extracorporeal shockwave therapy for refractory greater trochanteric pain syndrome
The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Extracorporeal shockwave therapy for refractory greater trochanteric pain syndrome.
# Guidance
Evidence on the efficacy and safety of extracorporeal shockwave therapy (ESWT) for refractory greater trochanteric pain syndrome is limited in quality and quantity. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake ESWT for refractory greater trochanteric pain syndrome should take the following actions.
Inform the clinical governance leads in their Trusts.
Ensure that patients understand the uncertainty about the procedure's safety and efficacy. In particular, patients should be informed about the possibility of pain during and after treatment, and the risk that symptoms may worsen. They should be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.
Audit and review clinical outcomes of all patients having ESWT for refractory greater trochanteric pain syndrome (see section 3.1).
This procedure should only be carried out by clinicians with specific training in the administration of ESWT for refractory greater trochanteric pain syndrome and in accordance with manufacturer's instructions.
NICE encourages further research into ESWT for refractory greater trochanteric pain syndrome. Research studies should clearly describe patient selection, imaging, and treatment protocols. Outcomes should include functional and quality-of-life scores with at least 1 year of follow-up.# The procedure
# Indications and current treatments
Greater trochanteric pain syndrome is a disorder that affects the (lateral) side of the hip or hips. Greater trochanteric pain may be associated with inflammation of the trochanteric bursa (also known as trochanteric bursitis). The trochanteric bursa is a small fluid-filled sac that separates the greater trochanter of the femur and the overlying fascia lata to allow smooth movement. Greater trochanteric pain may also be associated with direct injury, tendon damage, infection, differences in leg length or hip-replacement surgery.
Greater trochanteric pain syndrome is usually managed conservatively with rest, physiotherapy, anti-inflammatory medication and corticosteroid injections (often combined with local anaesthesia). In patients refractory to conservative treatments, surgical options such as supratrochanteric fasciotomy or trochanteric bursectomy may be used.
# Outline of the procedure
Extracorporeal shockwave therapy (ESWT) is a non-invasive treatment in which a device is used to pass acoustic shockwaves through the skin to the affected area. Ultrasound guidance can be used to assist with positioning of the device.
ESWT may be applied in one or several sessions. Local anaesthesia may be used because high-energy ESWT can be painful. Different energies and frequencies of shockwaves can be used.
The mechanism by which this therapy might have an effect on greater trochanteric pain syndrome is unknown.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A non-randomised comparative study of 229 patients treated by several ESWT sessions (n = 78), a single local corticosteroid injection (n = 75) or 'home training' (n = 76) reported that the percentage of patients who had either recovered completely or had improved symptoms (assessed using a 6-point Likert scale) following ESWT were 13% (10/78) at 1 month, 68% (53/78) at 4 months and 74% (58/78) at 15 months. In the corticosteroid injection group, 75% (56/75) of patients reported complete recovery or improved symptoms at 1 month, 51% (38/75) at 4 months and 48% (36/75) at 15 months. In the home-training group, 7% (5/76) of patients reported complete recovery or improved symptoms at 1 month, 41% (31/76) at 4 months and 80% (61/76) at 15 months.
The non-randomised comparative study of 229 patients reported significantly higher mean pain scores (measured on a visual analogue scale from 0 to 10; 10 indicates worst conceivable pain) in the ESWT (5.6) and the home-training groups (5.9) compared with the steroid injection group (2.2) at 1 month (p < 0.001). However, at 15 months the scores were 2.4 after ESWT, 2.7 after home training and 5.3 after injection (p < 0.001). All groups had similar pain scores at baseline (range 5.8–6.3).
The non-randomised comparative study of 229 patients reported that 64% (50/78) of patients in the ESWT group, 49% (37/75) in the steroid injection group and 34% (26/76) in the home-training group had returned to previous sporting or recreational activity at 4 months (ESWT vs home training, p < 0.001).
The Specialist Advisers listed key efficacy outcomes as recovery measured on a 6-point Likert scale, severity of pain measured using a visual analogue scale and improved function.
# Safety
Increased pain for more than 1 day was reported in 3% (2/78) of patients treated by ESWT, 24% (18/75) treated by steroid injection and 20% (15/76) treated with home training in the non-randomised comparative study of 229 patients.
Skin irritation during the first month of follow-up was reported in 33% (26/78) of patients treated by ESWT and 3% (2/75) treated by steroid injection in the non-randomised comparative study of 229 patients.
The Specialist Advisers considered theoretical adverse events to include pain, tendon rupture, haematoma and nerve damage.
# Other comments
NICE received 30 completed questionnaires from patients treated by the procedure. Thirty percent (9/30) stated that they would not have ESWT again; 3 of these patients reported that the procedure had made their condition worse with increased pain and decreased mobility. The remaining 70% (21/30) of patients would recommend this procedure to others.# Further information
This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
For related NICE guidance see our website.
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Changes since publication
January 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': "Evidence on the efficacy and safety of extracorporeal shockwave therapy (ESWT) for refractory greater trochanteric pain syndrome is limited in quality and quantity. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake ESWT for refractory greater trochanteric pain syndrome should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy. In particular, patients should be informed about the possibility of pain during and after treatment, and the risk that symptoms may worsen. They should be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having ESWT for refractory greater trochanteric pain syndrome (see section 3.1).\n\nThis procedure should only be carried out by clinicians with specific training in the administration of ESWT for refractory greater trochanteric pain syndrome and in accordance with manufacturer's instructions.\n\nNICE encourages further research into ESWT for refractory greater trochanteric pain syndrome. Research studies should clearly describe patient selection, imaging, and treatment protocols. Outcomes should include functional and quality-of-life scores with at least 1 year of follow-up.", 'The procedure': "# Indications and current treatments\n\nGreater trochanteric pain syndrome is a disorder that affects the (lateral) side of the hip or hips. Greater trochanteric pain may be associated with inflammation of the trochanteric bursa (also known as trochanteric bursitis). The trochanteric bursa is a small fluid-filled sac that separates the greater trochanter of the femur and the overlying fascia lata to allow smooth movement. Greater trochanteric pain may also be associated with direct injury, tendon damage, infection, differences in leg length or hip-replacement surgery.\n\nGreater trochanteric pain syndrome is usually managed conservatively with rest, physiotherapy, anti-inflammatory medication and corticosteroid injections (often combined with local anaesthesia). In patients refractory to conservative treatments, surgical options such as supratrochanteric fasciotomy or trochanteric bursectomy may be used.\n\n# Outline of the procedure\n\nExtracorporeal shockwave therapy (ESWT) is a non-invasive treatment in which a device is used to pass acoustic shockwaves through the skin to the affected area. Ultrasound guidance can be used to assist with positioning of the device.\n\nESWT may be applied in one or several sessions. Local anaesthesia may be used because high-energy ESWT can be painful. Different energies and frequencies of shockwaves can be used.\n\nThe mechanism by which this therapy might have an effect on greater trochanteric pain syndrome is unknown.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA non-randomised comparative study of 229 patients treated by several ESWT sessions (n = 78), a single local corticosteroid injection (n = 75) or 'home training' (n = 76) reported that the percentage of patients who had either recovered completely or had improved symptoms (assessed using a 6-point Likert scale) following ESWT were 13% (10/78) at 1 month, 68% (53/78) at 4 months and 74% (58/78) at 15 months. In the corticosteroid injection group, 75% (56/75) of patients reported complete recovery or improved symptoms at 1 month, 51% (38/75) at 4\xa0months and 48% (36/75) at 15 months. In the home-training group, 7% (5/76) of patients reported complete recovery or improved symptoms at 1 month, 41% (31/76) at 4 months and 80% (61/76) at 15 months.\n\nThe non-randomised comparative study of 229 patients reported significantly higher mean pain scores (measured on a visual analogue scale from 0 to 10; 10 indicates worst conceivable pain) in the ESWT (5.6) and the home-training groups (5.9) compared with the steroid injection group (2.2) at 1 month (p\xa0<\xa00.001). However, at 15 months the scores were 2.4 after ESWT, 2.7 after home training and 5.3 after injection (p\xa0<\xa00.001). All groups had similar pain scores at baseline (range 5.8–6.3).\n\nThe non-randomised comparative study of 229 patients reported that 64% (50/78) of patients in the ESWT group, 49% (37/75) in the steroid injection group and 34% (26/76) in the home-training group had returned to previous sporting or recreational activity at 4\xa0months (ESWT vs home training, p\xa0<\xa00.001).\n\nThe Specialist Advisers listed key efficacy outcomes as recovery measured on a 6-point Likert scale, severity of pain measured using a visual analogue scale and improved function.\n\n# Safety\n\nIncreased pain for more than 1 day was reported in 3% (2/78) of patients treated by ESWT, 24% (18/75) treated by steroid injection and 20% (15/76) treated with home training in the non-randomised comparative study of 229 patients.\n\nSkin irritation during the first month of follow-up was reported in 33% (26/78) of patients treated by ESWT and 3% (2/75) treated by steroid injection in the non-randomised comparative study of 229 patients.\n\nThe Specialist Advisers considered theoretical adverse events to include pain, tendon rupture, haematoma and nerve damage.\n\n# Other comments\n\nNICE received 30 completed questionnaires from patients treated by the procedure. Thirty percent (9/30) stated that they would not have ESWT again; 3 of these patients reported that the procedure had made their condition worse with increased pain and decreased mobility. The remaining 70% (21/30) of patients would recommend this procedure to others.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg376
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The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Extracorporeal shockwave therapy for refractory greater trochanteric pain syndrome.
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3b659adff1177cf06bb81c7cffcdeefd47a51cfc
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nice
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Off-pump coronary artery bypass grafting
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Off-pump coronary artery bypass grafting
The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Off-pump coronary artery bypass grafting.
# Guidance
This document replaces previous guidance on off-pump coronary artery bypass grafting (interventional procedure guidance 35).
Current evidence on the safety and efficacy of off-pump coronary artery bypass grafting (CABG) is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.
During the consent process, patients should be informed that they will be offered off-pump CABG rather than on-pump surgery, but that on-pump surgery may be a possibility. They should be informed about the uncertainties in relation to longer-term risks of graft occlusion and mortality, as well as the likely advantages of off-pump CABG, including the lower incidence of stroke.
Patient selection and treatment should be carried out by cardiac surgical teams who are skilled in both off-pump and on-pump surgery.
NICE encourages clinicians to submit data on patients having off-pump CABG to the UK Central Cardiac Audit Database, with a view to ultimately providing information about longer-term outcomes by linking the database to national statistics records.# The procedure
# Indications and current treatments
Coronary artery disease (CAD) refers to the hardening and narrowing of the coronary arteries as a result of atherosclerosis. It can cause angina, myocardial infarction and heart failure. One treatment option is CABG, most often performed 'on pump', maintaining the circulation and oxygenation of the blood extracorporeally using a cardiopulmonary bypass machine, while the heart is arrested (not beating).
# Outline of the procedure
Off-pump CABG aims to avoid the potential hazards of cardiopulmonary bypass, mainly in relation to the risk of stroke. With the patient under general anaesthesia, after a thoracotomy, the heart is displaced and snares are placed around target coronary arteries to occlude them while bypass grafts are sutured in place. An immobilising device is used to minimise movement of the beating heart while the anastomoses are performed. Donor vessel harvesting is performed in the standard way.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
Some studies reported outcomes that could be interpreted as relating either to efficacy or to safety, depending on their timing, which was not documented. Outcomes with uncertain timing of occurrence have been considered as efficacy outcomes. It is assumed that these occurred after the immediate postoperative period because they were reported with long-term follow-up data.
A meta-analysis of 5537 patients reported no significant difference in mortality rate between off-pump and on-pump CABG (relative risk 0.98, 95% CI 0.66 to 1.44) (follow-up not stated). A non-randomised controlled study of 3014 patients treated by off-pump or on-pump CABG reported major adverse events (death, stroke or myocardial infarction) in 11% (72/637) and 15% (367/2377) of patients respectively at 1-year follow-up (p = 0.012). A randomised controlled trial (RCT) of 2203 patients treated by off-pump or on-pump CABG reported death, myocardial infarction or revascularisation between 1-month and 1-year follow-up in 10% (105/1104) and 7% (78/1099) of patients respectively (p = 0.04).
A UK national register report of 86,047 patients treated since 1999 reported that 1-year survival for patients treated in the period 2004 to 2008 was 97% for off-pump CABG and 96% for on-pump CABG. By 5-year follow-up (for patients who had reached that time point), survival was 89% for off-pump CABG and 89% for on-pump CABG (significance and absolute figures not stated).
The meta-analysis of 5537 patients and a meta-analysis of 297,000 patients reported no significant difference between off-pump and on-pump CABG in relative risk of revascularisation: 1.35 (95% CI 0.83 to 2.18) and 1.35 (95% CI 0.76 to 2.39) respectively (follow-up not stated).
The non-randomised controlled study of 3014 patients reported graft failure (≥ 75% stenosis) in 45% (181/402) of patients in the off-pump group and in 46% (697/1518) of patients in the on-pump group at 12 to 18 months follow-up (p = 0.75). An RCT of 2203 patients treated by off-pump or on-pump CABG reported that fewer grafts were inserted than were planned pre-operatively in 18% of patients in the off-pump group and 11% in the on-pump group (p < 0.001) (absolute figures not stated).
In a case series of 312 patients, off-pump CABG was converted to on-pump CABG in 4% (12/312) of patients.
The Specialist Advisers listed key efficacy outcomes as requirement for additional revascularisation, symptom relief and length of stay.
# Safety
A meta-analysis of 297,000 patients reported that 30-day mortality was significantly lower following off-pump rather than on-pump CABG (pooled odds ratio 0.72, 95% CI 0.66 to 0.78) (p < 0.00001). The RCT of 2203 patients reported no significant difference in 30-day mortality between the off-pump group and the on-pump group (2% and 1% respectively, p = 0.47).
Stroke occurred significantly less frequently following off-pump CABG than on-pump CABG in the meta analysis of 297,000 patients (pooled odds ratio 0.62, 95% CI 0.55 to 0.69) (p < 0.00001) (follow-up not stated).
The Specialist Advisers listed theoretical adverse events as infection, bleeding and renal dysfunction. They commented that inaccurate suturing may lead to graft failure.
# Other comments
This review of existing guidance was precipitated by recent evidence of higher graft occlusion rates in the longer term after off-pump CABG compared with on-pump surgery (see the RCT of 2203 patients). The Committee considered this evidence carefully in the context of other evidence on large numbers of patients for whom off-pump CABG had shown advantages without additional safety concerns.
The Committee was advised that off-pump CABG may have a particular role in the management of patients with gross calcification of the ascending aorta and those with low ejection fractions.# Further information
For related NICE guidance see our website.
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
It updates and replaces NICE interventional procedure guidance 35.
We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.
Changes since publication
May 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': 'This document replaces previous guidance on off-pump coronary artery bypass grafting (interventional procedure guidance 35).\n\nCurrent evidence on the safety and efficacy of off-pump coronary artery bypass grafting (CABG) is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nDuring the consent process, patients should be informed that they will be offered off-pump CABG rather than on-pump surgery, but that on-pump surgery may be a possibility. They should be informed about the uncertainties in relation to longer-term risks of graft occlusion and mortality, as well as the likely advantages of off-pump CABG, including the lower incidence of stroke.\n\nPatient selection and treatment should be carried out by cardiac surgical teams who are skilled in both off-pump and on-pump surgery.\n\nNICE encourages clinicians to submit data on patients having off-pump CABG to the UK Central Cardiac Audit Database, with a view to ultimately providing information about longer-term outcomes by linking the database to national statistics records.', 'The procedure': "# Indications and current treatments\n\nCoronary artery disease (CAD) refers to the hardening and narrowing of the coronary arteries as a result of atherosclerosis. It can cause angina, myocardial infarction and heart failure. One treatment option is CABG, most often performed 'on pump', maintaining the circulation and oxygenation of the blood extracorporeally using a cardiopulmonary bypass machine, while the heart is arrested (not beating).\n\n# Outline of the procedure\n\nOff-pump CABG aims to avoid the potential hazards of cardiopulmonary bypass, mainly in relation to the risk of stroke. With the patient under general anaesthesia, after a thoracotomy, the heart is displaced and snares are placed around target coronary arteries to occlude them while bypass grafts are sutured in place. An immobilising device is used to minimise movement of the beating heart while the anastomoses are performed. Donor vessel harvesting is performed in the standard way.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nSome studies reported outcomes that could be interpreted as relating either to efficacy or to safety, depending on their timing, which was not documented. Outcomes with uncertain timing of occurrence have been considered as efficacy outcomes. It is assumed that these occurred after the immediate postoperative period because they were reported with long-term follow-up data.\n\nA meta-analysis of 5537 patients reported no significant difference in mortality rate between off-pump and on-pump CABG (relative risk 0.98, 95% CI 0.66 to 1.44) (follow-up not stated). A non-randomised controlled study of 3014 patients treated by off-pump or on-pump CABG reported major adverse events (death, stroke or myocardial infarction) in 11% (72/637) and 15% (367/2377) of patients respectively at 1-year follow-up (p\xa0=\xa00.012). A randomised controlled trial (RCT) of 2203 patients treated by off-pump or on-pump CABG reported death, myocardial infarction or revascularisation between 1-month and 1-year follow-up in 10% (105/1104) and 7% (78/1099) of patients respectively (p\xa0=\xa00.04).\n\nA UK national register report of 86,047 patients treated since 1999 reported that 1-year survival for patients treated in the period 2004 to 2008 was 97% for off-pump CABG and 96% for on-pump CABG. By 5-year follow-up (for patients who had reached that time point), survival was 89% for off-pump CABG and 89% for on-pump CABG (significance and absolute figures not stated).\n\nThe meta-analysis of 5537 patients and a meta-analysis of 297,000 patients reported no significant difference between off-pump and on-pump CABG in relative risk of revascularisation: 1.35 (95% CI 0.83 to 2.18) and 1.35 (95% CI 0.76 to 2.39) respectively (follow-up not stated).\n\nThe non-randomised controlled study of 3014 patients reported graft failure (≥\xa075% stenosis) in 45% (181/402) of patients in the off-pump group and in 46% (697/1518) of patients in the on-pump group at 12 to 18 months follow-up (p\xa0=\xa00.75). An RCT of 2203 patients treated by off-pump or on-pump CABG reported that fewer grafts were inserted than were planned pre-operatively in 18% of patients in the off-pump group and 11% in the on-pump group (p\xa0<\xa00.001) (absolute figures not stated).\n\nIn a case series of 312 patients, off-pump CABG was converted to on-pump CABG in 4% (12/312) of patients.\n\nThe Specialist Advisers listed key efficacy outcomes as requirement for additional revascularisation, symptom relief and length of stay.\n\n# Safety\n\nA meta-analysis of 297,000 patients reported that 30-day mortality was significantly lower following off-pump rather than on-pump CABG (pooled odds ratio 0.72, 95% CI\xa00.66 to 0.78) (p\xa0<\xa00.00001). The RCT of 2203 patients reported no significant difference in 30-day mortality between the off-pump group and the on-pump group (2% [18/1104] and 1% [13/1099] respectively, p\xa0=\xa00.47).\n\nStroke occurred significantly less frequently following off-pump CABG than on-pump CABG in the meta analysis of 297,000 patients (pooled odds ratio 0.62, 95% CI 0.55 to 0.69) (p\xa0<\xa00.00001) (follow-up not stated).\n\nThe Specialist Advisers listed theoretical adverse events as infection, bleeding and renal dysfunction. They commented that inaccurate suturing may lead to graft failure.\n\n# Other comments\n\nThis review of existing guidance was precipitated by recent evidence of higher graft occlusion rates in the longer term after off-pump CABG compared with on-pump surgery (see the RCT of 2203 patients). The Committee considered this evidence carefully in the context of other evidence on large numbers of patients for whom off-pump CABG had shown advantages without additional safety concerns.\n\nThe Committee was advised that off-pump CABG may have a particular role in the management of patients with gross calcification of the ascending aorta and those with low ejection fractions.", 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 35.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nMay 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg377
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The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Off-pump coronary artery bypass grafting.
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fcfefaaa8a033065b3a4b4b47337a0db05a67c24
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nice
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Percutaneous laser coronary angioplasty
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Percutaneous laser coronary angioplasty
The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Percutaneous laser coronary angioplasty.
# Guidance
Current evidence on the safety and efficacy of percutaneous laser coronary angioplasty is adequate to support the use of this procedure in carefully selected patients for whom conventional angioplasty would otherwise be technically difficult, provided that normal arrangements are in place for clinical governance, consent and audit.# The procedure
# Indications and current treatments
Coronary artery disease (CAD) refers to the narrowing and occlusion of the coronary arteries as a result of atherosclerosis. This can cause angina, myocardial infarction and heart failure.
Treatment options for patients with CAD with severe stenosis or occlusion include thrombolysis, percutaneous balloon angioplasty, stent placement, percutaneous cutting balloon or coronary artery bypass grafting.
Percutaneous laser coronary angioplasty has been used for CAD with severe stenosis or atherosclerotic occlusion, when standard techniques for recannalisation are unlikely to succeed or have failed.
# Outline of the procedure
Percutaneous laser coronary angioplasty aims to penetrate plaque within coronary arteries that is not amenable to standard techniques such as balloon angioplasty or stenting alone.
A thin, flexible fibre-optic catheter connected to a laser-generating source outside the body is introduced via the femoral artery. The catheter is advanced over a guidewire through the artery to the blockage in the coronary artery, under fluoroscopic guidance. The tip of the catheter system emits pulses of laser light to vaporise the plaque while being slowly advanced across the lesion.
Percutaneous laser coronary angioplasty has also been done using a laser guidewire system but that method is not now in regular use.
This procedure is often used with adjunctive balloon angioplasty and followed by angiography to document the results.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A randomised controlled trial (RCT) of 303 patients treated with laser guidewire or mechanical guidewire reported procedural success (defined as the ability to cross the target lesion at the first attempt) in 53% (76/144) and 47% (75/159) of patients respectively (p = 0.33). A non-randomised controlled study of 3733 procedures reported that 'lesion success' assessed angiographically was achieved in 89% and 94% of native vessels treated with laser angioplasty using 2 different laser devices, and in 91% and 95% of saphenous vein grafts for which laser treatment was attempted (absolute figures not stated). A case series of 958 patients reported that among 55 patients who underwent immediate postoperative angiographic assessment, coronary stenosis (assessed by the percentage of artery diameter blocked) decreased from 83% at baseline to 49% following laser angioplasty and to 38% following adjunctive balloon angioplasty (absolute figures not stated).
The RCT of 303 patients treated with laser guidewire or mechanical guidewire reported no major adverse cardiac events in 54% (78/144) and 67% (106/159) of patients respectively at 400-day follow-up (p = 0.026).
Major adverse cardiac events (death, myocardial infarction or revascularisation) were more frequent after laser angioplasty compared with balloon angioplasty in the meta-analysis of 9222 patients at up to 1-year follow-up (odds ratio 1.32; 95% confidence interval 1.01 to 1.73).
A case series of 1862 patients reported that 71% of patients had an improvement in their angina symptoms, 13% had unchanged symptoms and 16% had worse symptoms at 6-month median follow-up (absolute figures not stated).
A meta-analysis of 16 studies including a total of 9222 patients reported that angiographically measured restenosis occurred more frequently after laser angioplasty than after balloon angioplasty (OR 1.55; 95% CI 1.09 to 2.20) at follow-up of between 3 months and 1 year. An RCT of 96 patients treated by laser angioplasty and adjunctive balloon angioplasty or by balloon angioplasty alone reported restenosis in 52% and 47% of patients respectively at 163 days median follow-up (p = not significant; absolute figures not stated).
The case series of 1862 patients reported restenosis greater than 50% of the artery diameter in 54% (434/797) of eligible patients undergoing angiographic assessment at 6-month median follow-up. A case series of 495 stenosed saphenous vein grafts treated by laser angioplasty reported restenosis in 55% of the 161 patients who had angiographic assessment at 6-month follow-up (absolute figures not stated).
The Specialist Advisers listed key efficacy outcomes as procedural success, angiographic success, quality-of-life scores, target vessel revascularisation and cardiac enzyme level post procedure.
# Safety
The meta-analysis of 9222 patients treated by laser angioplasty or balloon angioplasty reported no difference between the groups in the rate of myocardial infarction at 30-day follow-up (OR 1.39; 95% CI 0.69 to 2.82). A meta-analysis of 3012 patients being treated for in-stent restenosis reported that the pooled mean rate of major adverse cardiac events was 35% for laser angioplasty, 29% for balloon angioplasty and 31% for stent-in-stent treatment (absolute figures not stated).
A non-randomised controlled study of 8932 procedures reported that the rate of arterial perforation was 2% (5/242) for laser angioplasty, less than 1% (11/7905) for balloon angioplasty and 0% (0/116) for mechanical rotational atherectomy.
The Specialist Advisers listed theoretical adverse events as death, coronary dissection, abrupt vessel closure, thermal damage to the vessel and restenosis.# Further information
For related NICE guidance see our website.
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.
Changes since publication
January 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': 'Current evidence on the safety and efficacy of percutaneous laser coronary angioplasty is adequate to support the use of this procedure in carefully selected patients for whom conventional angioplasty would otherwise be technically difficult, provided that normal arrangements are in place for clinical governance, consent and audit.', 'The procedure': "# Indications and current treatments\n\nCoronary artery disease (CAD) refers to the narrowing and occlusion of the coronary arteries as a result of atherosclerosis. This can cause angina, myocardial infarction and heart failure.\n\nTreatment options for patients with CAD with severe stenosis or occlusion include thrombolysis, percutaneous balloon angioplasty, stent placement, percutaneous cutting balloon or coronary artery bypass grafting.\n\nPercutaneous laser coronary angioplasty has been used for CAD with severe stenosis or atherosclerotic occlusion, when standard techniques for recannalisation are unlikely to succeed or have failed.\n\n# Outline of the procedure\n\nPercutaneous laser coronary angioplasty aims to penetrate plaque within coronary arteries that is not amenable to standard techniques such as balloon angioplasty or stenting alone.\n\nA thin, flexible fibre-optic catheter connected to a laser-generating source outside the body is introduced via the femoral artery. The catheter is advanced over a guidewire through the artery to the blockage in the coronary artery, under fluoroscopic guidance. The tip of the catheter system emits pulses of laser light to vaporise the plaque while being slowly advanced across the lesion.\n\nPercutaneous laser coronary angioplasty has also been done using a laser guidewire system but that method is not now in regular use.\n\nThis procedure is often used with adjunctive balloon angioplasty and followed by angiography to document the results.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 303 patients treated with laser guidewire or mechanical guidewire reported procedural success (defined as the ability to cross the target lesion at the first attempt) in 53% (76/144) and 47% (75/159) of patients respectively (p\xa0=\xa00.33). A non-randomised controlled study of 3733 procedures reported that 'lesion success' assessed angiographically was achieved in 89% and 94% of native vessels treated with laser angioplasty using 2 different laser devices, and in 91% and 95% of saphenous vein grafts for which laser treatment was attempted (absolute figures not stated). A case series of 958 patients reported that among 55 patients who underwent immediate postoperative angiographic assessment, coronary stenosis (assessed by the percentage of artery diameter blocked) decreased from 83% at baseline to 49% following laser angioplasty and to 38% following adjunctive balloon angioplasty (absolute figures not stated).\n\nThe RCT of 303 patients treated with laser guidewire or mechanical guidewire reported no major adverse cardiac events in 54% (78/144) and 67% (106/159) of patients respectively at 400-day follow-up (p\xa0=\xa00.026).\n\nMajor adverse cardiac events (death, myocardial infarction or revascularisation) were more frequent after laser angioplasty compared with balloon angioplasty in the meta-analysis of 9222 patients at up to 1-year follow-up (odds ratio [OR] 1.32; 95% confidence interval [CI] 1.01 to 1.73).\n\nA case series of 1862 patients reported that 71% of patients had an improvement in their angina symptoms, 13% had unchanged symptoms and 16% had worse symptoms at 6-month median follow-up (absolute figures not stated).\n\nA meta-analysis of 16 studies including a total of 9222 patients reported that angiographically measured restenosis occurred more frequently after laser angioplasty than after balloon angioplasty (OR 1.55; 95% CI 1.09 to 2.20) at follow-up of between 3 months and 1 year. An RCT of 96 patients treated by laser angioplasty and adjunctive balloon angioplasty or by balloon angioplasty alone reported restenosis in 52% and 47% of patients respectively at 163 days median follow-up (p = not significant; absolute figures not stated).\n\nThe case series of 1862 patients reported restenosis greater than 50% of the artery diameter in 54% (434/797) of eligible patients undergoing angiographic assessment at 6-month median follow-up. A case series of 495 stenosed saphenous vein grafts treated by laser angioplasty reported restenosis in 55% of the 161 patients who had angiographic assessment at 6-month follow-up (absolute figures not stated).\n\nThe Specialist Advisers listed key efficacy outcomes as procedural success, angiographic success, quality-of-life scores, target vessel revascularisation and cardiac enzyme level post procedure.\n\n# Safety\n\nThe meta-analysis of 9222 patients treated by laser angioplasty or balloon angioplasty reported no difference between the groups in the rate of myocardial infarction at 30-day follow-up (OR 1.39; 95% CI 0.69 to 2.82). A meta-analysis of 3012 patients being treated for in-stent restenosis reported that the pooled mean rate of major adverse cardiac events was 35% for laser angioplasty, 29% for balloon angioplasty and 31% for stent-in-stent treatment (absolute figures not stated).\n\nA non-randomised controlled study of 8932 procedures reported that the rate of arterial perforation was 2% (5/242) for laser angioplasty, less than 1% (11/7905) for balloon angioplasty and 0% (0/116) for mechanical rotational atherectomy.\n\nThe Specialist Advisers listed theoretical adverse events as death, coronary dissection, abrupt vessel closure, thermal damage to the vessel and restenosis.", 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg378
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The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Percutaneous laser coronary angioplasty.
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1e50b4c515503002b718a104432ecbcfe726884e
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nice
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Distal iliotibial band lengthening for refractory greater trochanteric pain syndrome
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Distal iliotibial band lengthening for refractory greater trochanteric pain syndrome
The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Distal iliotibial band lengthening for refractory greater trochanteric pain syndrome.
# Guidance
Current evidence on the efficacy and safety of distal iliotibial band lengthening for refractory greater trochanteric pain syndrome is inadequate in quantity and quality. Therefore this procedure should only be used in the context of research. Research studies should clearly define patient selection, and outcomes should include measures of function and quality of life.# The procedure
# Indications and current treatments
Greater trochanteric pain syndrome is a disorder that affects the (lateral) side of the hip or hips. Greater trochanteric pain may be associated with inflammation of the trochanteric bursa (also known as trochanteric bursitis). The trochanteric bursa is a small fluid-filled sac that separates the greater trochanter of the femur and the overlying fascia lata to allow smooth movement. Greater trochanteric pain may also be associated with direct injury, tendon damage, infection, differences in leg length or hip-replacement surgery.
Greater trochanteric pain syndrome is usually managed conservatively with rest, physiotherapy, anti-inflammatory medication and corticosteroid injections. In patients refractory to conservative treatment, surgical options such as bursectomy or supratrochanteric fasciotomy may be used.
# Outline of the procedure
The aim of distal iliotibial band lengthening for refractory greater trochanteric pain syndromeis to relieve the pressure between the greater trochanter and the fascia lata by lengthening the iliotibial band (a thickened and reinforced part of the fascia lata which runs longitudinally throughout its length).
Distal iliotibial band lengthening for greater trochanteric pain syndrome is carried out with the patient under local or general anaesthesia. Through a short lateral incision above the knee a 'Z' lengthening of the iliotibial band of approximately 1.5–2 cm is performed. The fascia is repaired with sutures.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A case series of 11 patients reported a mean Harris hip score of 61 before the procedure and 91 at a mean 43-month follow-up (the Harris hip score measures functional ability, hip dynamics and range of movement on a scale from 0 to 100, in which a higher score indicates a better health outcome).
The case series of 11 patients reported a mean pain score (measured on a scale from 0 to 100; a higher score indicates worse pain) of 83 before the procedure and 13 at a mean follow-up of 43 months.
A case series of 12 patients reported a significant increase in mean EQ-5D score (a standardised assessment of mobility, self care, usual activities, pain and/or discomfort and anxiety and/or depression; a higher score indicates a better health outcome) from 0.26 before the procedure to 0.67 at a mean 28-month follow-up (p < 0.005).
The Specialist Advisers expressed doubt about the conceptual mechanism of action of this procedure. They listed key efficacy outcomes as pain relief, patient satisfaction, hip function (measured using the isokinetic strength Harris hip score) and quality of life (measured using SF-36 or Euroqol scores).
# Safety
Seroma was reported in 1 patient in the case series of 11 patients (timing of event not stated): this was successfully treated by surgical drainage.
The Specialist Advisers considered that loss of strength in the lower limb was a theoretical adverse event.# Further information
For related NICE guidance see our website.
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.
Changes since publication
January 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': 'Current evidence on the efficacy and safety of distal iliotibial band lengthening for refractory greater trochanteric pain syndrome is inadequate in quantity and quality. Therefore this procedure should only be used in the context of research. Research studies should clearly define patient selection, and outcomes should include measures of function and quality of life.', 'The procedure': "# Indications and current treatments\n\nGreater trochanteric pain syndrome is a disorder that affects the (lateral) side of the hip or hips. Greater trochanteric pain may be associated with inflammation of the trochanteric bursa (also known as trochanteric bursitis). The trochanteric bursa is a small fluid-filled sac that separates the greater trochanter of the femur and the overlying fascia lata to allow smooth movement. Greater trochanteric pain may also be associated with direct injury, tendon damage, infection, differences in leg length or hip-replacement surgery.\n\nGreater trochanteric pain syndrome is usually managed conservatively with rest, physiotherapy, anti-inflammatory medication and corticosteroid injections. In patients refractory to conservative treatment, surgical options such as bursectomy or supratrochanteric fasciotomy may be used.\n\n# Outline of the procedure\n\nThe aim of distal iliotibial band lengthening for refractory greater trochanteric pain syndromeis to relieve the pressure between the greater trochanter and the fascia lata by lengthening the iliotibial band (a thickened and reinforced part of the fascia lata which runs longitudinally throughout its length).\n\nDistal iliotibial band lengthening for greater trochanteric pain syndrome is carried out with the patient under local or general anaesthesia. Through a short lateral incision above the knee a 'Z' lengthening of the iliotibial band of approximately 1.5–2 cm is performed. The fascia is repaired with sutures.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 11 patients reported a mean Harris hip score of 61 before the procedure and 91 at a mean 43-month follow-up (the Harris hip score measures functional ability, hip dynamics and range of movement on a scale from 0 to 100, in which a higher score indicates a better health outcome).\n\nThe case series of 11 patients reported a mean pain score (measured on a scale from 0 to 100; a higher score indicates worse pain) of 83 before the procedure and 13 at a mean follow-up of 43 months.\n\nA case series of 12 patients reported a significant increase in mean EQ-5D score (a standardised assessment of mobility, self care, usual activities, pain and/or discomfort and anxiety and/or depression; a higher score indicates a better health outcome) from 0.26 before the procedure to 0.67 at a mean 28-month follow-up (p\xa0<\xa00.005).\n\nThe Specialist Advisers expressed doubt about the conceptual mechanism of action of this procedure. They listed key efficacy outcomes as pain relief, patient satisfaction, hip function (measured using the isokinetic strength Harris hip score) and quality of life (measured using SF-36 or Euroqol scores).\n\n# Safety\n\nSeroma was reported in 1 patient in the case series of 11 patients (timing of event not stated): this was successfully treated by surgical drainage.\n\nThe Specialist Advisers considered that loss of strength in the lower limb was a theoretical adverse event.", 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg375
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The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Distal iliotibial band lengthening for refractory greater trochanteric pain syndrome.
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2f359e97efb33455735d3287e3c6b74306106821
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nice
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Thoracoscopic repair of congenital diaphragmatic hernia in neonates
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Thoracoscopic repair of congenital diaphragmatic hernia in neonates
The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Thoracoscopic repair of congenital diaphragmatic hernia in neonates.
# Guidance
Current evidence on the safety and efficacy of thoracoscopic repair of congenital diaphragmatic hernia (CDH) in neonates is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance and audit.
During the consent process, parents should be informed in particular about the possibility of conversion to abdominal repair and about the risk of recurrence.
This procedure should only be carried out by surgeons with specific training and experience in laparoscopic and thoracoscopic surgery in neonates and children.
NICE encourages collaboration between the units performing this procedure in the collection of data and publication of results.# The procedure
# Indications and current treatments
Congenital diaphragmatic hernia results from failure of complete fusion of the developing fetal diaphragm – a process that normally occurs between gestational weeks 6 and 8. The defect may be anterior (Morgagni's hernia) or posterolateral (Bochdalek hernia). Migration of abdominal organs into the thoracic cavity, pulmonary hypoplasia and respiratory failure at birth can occur.
Current management of CDH in neonates usually involves initial ventilatory support and supportive care, to allow labile cardiopulmonary physiology to improve, followed by surgical reduction of the hernia, usually through an abdominal approach, and repair of the diaphragmatic defect.
# Outline of the procedure
The aim of this procedure is to reduce the herniated abdominal organs and repair the diaphragmatic defect. It is normally carried out for posterolateral Bochdalek defects.
Thoracoscopic repair of CDH in neonates is carried out with the patient under general anaesthesia and in the lateral decubitus position. Between 2 and 4 trocars can be used, with CO2 insufflation of the pleural space to partially collapse the lung sufficiently to achieve good exposure of the defect and to reduce the herniated viscera within the abdomen. Following reduction, the diaphragm is repaired using non-absorbable interrupted sutures or patches (if defects are relatively large). Where technically possible, posterolateral diaphragm stitches are passed around the ribs and tied extracorporeally. Patients usually require temporary chest drain insertion and ventilatory support.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A meta-analysis of 3 non-randomised comparative studies including a total of 143 patients treated by thoracoscopic (n = 62) or open (n = 81) repair reported recurrence rates of 16% (10/62) and 5% (4/81) respectively (follow-up not stated), and a risk ratio of 3.21 (95% confidence interval 1.11 to 9.29).
A non-randomised comparative study of 30 patients treated by thoracoscopic (n = 18) or laparoscopic repair (n = 12) reported 'easy reduction' in 83% (15/18) and 42% (5/12) of patients respectively; 'difficult reduction' in 11% (2/18) and 33% (4/12); and that it was impossible to reduce the hernia in 6% (1/18) and 25% (3/12) of patients respectively. A case series of 45 patients reported that reduction of hernia contents was 'easily accomplished' in 67% (30/45) of patients.
A non-randomised comparative study of 57 patients reported conversion from a thoracoscopic to an open procedure in 1 patient (the liver could not be reduced into the abdomen). The case series of 45 patients reported conversion to an open procedure in 9% (4/45) of patients (3 conversions were due to difficulty in reducing the hernia and 1 was due to a decrease in oxygen saturation).
Median duration of postoperative ventilation was 2 and 4 days after thoracoscopic and open repair, respectively, in the non-randomised comparative study of 73 patients (p = 0.04) but was similar in the 2 groups in the study of 57 patients (5 days in each group; p = 0.56).
The Specialist Advisers listed key efficacy outcomes as reduction in postoperative abdominal adhesions, improved postoperative pain, duration of hospital stay, resumption of enteral nutrition and cosmetic appearance.
# Safety
A mortality rate of 3% (2/62) in the thoracoscopic group compared with 12% (10/81) in the open group, and a mortality risk ratio of 0.33 (95% CI 0.01 to 1.13) was reported in the meta-analysis of 143 patients (follow-up not stated).
Death due to haemorrhage in 1 patient was reported in the open group of the non-randomised comparative study of 73 patients. Death after severe bronchopneumonia and pneumothorax was reported in 1 patient each in the case series of 45 patients (timing not stated).
The non-randomised comparative study of 57 patients reported no significant difference in major infection rates (defined as abscess, systemic sepsis or abdominal wall patch infection) in the thoracoscopic group compared with the open group (17% vs 4% , p = 0.19) (not otherwise described).
Gastrointestinal perforation rates of 7% (2/29) in the thoracoscopic group and 7% (2/28) in the open group were reported in the non-randomised comparative study of 57 patients.
The Specialist Advisers considered theoretical adverse events to include solid/hollow visceral injury, physiological instability and hypercarbia if not carefully insufflated.
# Other comments
The Committee considered evidence that included infants over 30 days but less than 12 months.# Further information
For related NICE guidance see our website.
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.
Changes since publication
January 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': 'Current evidence on the safety and efficacy of thoracoscopic repair of congenital diaphragmatic hernia (CDH) in neonates is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance and audit.\n\nDuring the consent process, parents should be informed in particular about the possibility of conversion to abdominal repair and about the risk of recurrence.\n\nThis procedure should only be carried out by surgeons with specific training and experience in laparoscopic and thoracoscopic surgery in neonates and children.\n\nNICE encourages collaboration between the units performing this procedure in the collection of data and publication of results.', 'The procedure': "# Indications and current treatments\n\nCongenital diaphragmatic hernia results from failure of complete fusion of the developing fetal diaphragm – a process that normally occurs between gestational weeks 6 and 8. The defect may be anterior (Morgagni's hernia) or posterolateral (Bochdalek hernia). Migration of abdominal organs into the thoracic cavity, pulmonary hypoplasia and respiratory failure at birth can occur.\n\nCurrent management of CDH in neonates usually involves initial ventilatory support and supportive care, to allow labile cardiopulmonary physiology to improve, followed by surgical reduction of the hernia, usually through an abdominal approach, and repair of the diaphragmatic defect.\n\n# Outline of the procedure\n\nThe aim of this procedure is to reduce the herniated abdominal organs and repair the diaphragmatic defect. It is normally carried out for posterolateral Bochdalek defects.\n\nThoracoscopic repair of CDH in neonates is carried out with the patient under general anaesthesia and in the lateral decubitus position. Between 2 and 4 trocars can be used, with CO2 insufflation of the pleural space to partially collapse the lung sufficiently to achieve good exposure of the defect and to reduce the herniated viscera within the abdomen. Following reduction, the diaphragm is repaired using non-absorbable interrupted sutures or patches (if defects are relatively large). Where technically possible, posterolateral diaphragm stitches are passed around the ribs and tied extracorporeally. Patients usually require temporary chest drain insertion and ventilatory support.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA meta-analysis of 3 non-randomised comparative studies including a total of 143 patients treated by thoracoscopic (n = 62) or open (n = 81) repair reported recurrence rates of 16% (10/62) and 5% (4/81) respectively (follow-up not stated), and a risk ratio of 3.21 (95%\xa0confidence interval [CI] 1.11 to 9.29).\n\nA non-randomised comparative study of 30 patients treated by thoracoscopic (n = 18) or laparoscopic repair (n = 12) reported 'easy reduction' in 83% (15/18) and 42% (5/12) of patients respectively; 'difficult reduction' in 11% (2/18) and 33% (4/12); and that it was impossible to reduce the hernia in 6% (1/18) and 25% (3/12) of patients respectively. A case series of 45 patients reported that reduction of hernia contents was 'easily accomplished' in 67% (30/45) of patients.\n\nA non-randomised comparative study of 57 patients reported conversion from a thoracoscopic to an open procedure in 1 patient (the liver could not be reduced into the abdomen). The case series of 45 patients reported conversion to an open procedure in 9% (4/45) of patients (3 conversions were due to difficulty in reducing the hernia and 1 was due to a decrease in oxygen saturation).\n\nMedian duration of postoperative ventilation was 2 and 4 days after thoracoscopic and open repair, respectively, in the non-randomised comparative study of 73 patients (p\xa0= 0.04) but was similar in the 2 groups in the study of 57 patients (5 days in each group; p\xa0=\xa00.56).\n\nThe Specialist Advisers listed key efficacy outcomes as reduction in postoperative abdominal adhesions, improved postoperative pain, duration of hospital stay, resumption of enteral nutrition and cosmetic appearance.\n\n# Safety\n\nA mortality rate of 3% (2/62) in the thoracoscopic group compared with 12% (10/81) in the open group, and a mortality risk ratio of 0.33 (95%\xa0CI 0.01 to 1.13) was reported in the meta-analysis of 143 patients (follow-up not stated).\n\nDeath due to haemorrhage in 1 patient was reported in the open group of the non-randomised comparative study of 73 patients. Death after severe bronchopneumonia and pneumothorax was reported in 1 patient each in the case series of 45 patients (timing not stated).\n\nThe non-randomised comparative study of 57 patients reported no significant difference in major infection rates (defined as abscess, systemic sepsis or abdominal wall patch infection) in the thoracoscopic group compared with the open group (17% [5/29] vs 4% [1/28], p\xa0=\xa00.19) (not otherwise described).\n\nGastrointestinal perforation rates of 7% (2/29) in the thoracoscopic group and 7% (2/28) in the open group were reported in the non-randomised comparative study of 57 patients.\n\nThe Specialist Advisers considered theoretical adverse events to include solid/hollow visceral injury, physiological instability and hypercarbia if not carefully insufflated.\n\n# Other comments\n\nThe Committee considered evidence that included infants over 30 days but less than 12 months.", 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2011. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg379
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The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Thoracoscopic repair of congenital diaphragmatic hernia in neonates.
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c3640fa16fe8007c450ef160c4882238b75c2fda
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nice
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Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events
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Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events
Evidence-based recommendations on clopidogrel and modified-release dipyridamole for preventing occlusive vascular events in adults.
# Guidance
This guidance replaces 'NICE technology appraisal guidance 90' issued in May 2005. For details, see 'About this guidance'.
This guidance applies to people who have had an occlusive vascular event, or who have established peripheral arterial disease. For people who have had a myocardial infarction, this guidance follows on from the recommendations for clopidogrel in combination with low-dose aspirin in NICE clinical guideline 48 and NICE clinical guideline 94. This guidance does not apply to people who have had, or are at risk of, a stroke associated with atrial fibrillation, or who need treatment to prevent occlusive events after coronary revascularisation or carotid artery procedures.
Clopidogrel is recommended as an option to prevent occlusive vascular events:
for people who have had an ischaemic stroke or who have peripheral arterial disease or multivascular disease or
for people who have had a myocardial infarction only if aspirin is contraindicated or not tolerated.
Modified-release dipyridamole in combination with aspirin is recommended as an option to prevent occlusive vascular events:
for people who have had a transient ischaemic attack or
for people who have had an ischaemic stroke only if clopidogrel is contraindicated or not tolerated.
Modified-release dipyridamole alone is recommended as an option to prevent occlusive vascular events:
for people who have had an ischaemic stroke only if aspirin and clopidogrel are contraindicated or not tolerated or
for people who have had a transient ischaemic attack only if aspirin is contraindicated or not tolerated.
Treatment with clopidogrel to prevent occlusive vascular events should be started with the least costly licensed preparation.
People currently receiving clopidogrel or modified-release dipyridamole either with or without aspirin outside the criteria in 1.1, 1.2 and 1.3 should have the option to continue treatment until they and their clinicians consider it appropriate to stop.# Clinical need and practice
Occlusive vascular events include ischaemic stroke, transient ischaemic attack and myocardial infarction. They occur when blood flow is impeded because an artery is blocked or restricted because of atherosclerosis and atherothrombosis. Atherosclerotic plaques form in artery walls because of damage to the vascular endothelium. Damage is caused by a number of factors working together over a long period, such as elevated low-density lipoproteins, smoking, high blood pressure and diabetes mellitus. If an atherosclerotic plaque is suddenly disrupted, platelet activation and thrombus (clot) formation follows, leading to atherothrombosis. The thrombus can block an artery, either at the original site of the plaque formation or further down the artery. People who have had an occlusive vascular event are at increased risk of another.
Peripheral arterial disease is a condition in which the arteries that carry blood to the arms or legs become narrowed or clogged, slowing or stopping the flow of blood. It occurs most often because of atherosclerosis. People who have peripheral arterial disease are at high risk of having an occlusive vascular event. People with cardiovascular disease who have disease in more than one vascular site are said to have multivascular disease. These people are at increased risk of death, myocardial infarction or stroke, compared with people with disease in a single vascular bed.
Each year in the UK an estimated 98,000 people have a first ischaemic stroke, between 46,000 and 65,000 people have a transient ischaemic attack, and 146,000 have a myocardial infarction. Approximately 2% of the population of England and Wales have had a stroke and about 70% of all strokes are ischaemic. In the UK, in total around 510,000 people have had a transient ischaemic attack and over 1.4 million have had a myocardial infarction. About 20% of the UK population aged 55–75 years have evidence of lower extremity peripheral arterial disease, equating to a prevalence of 850,000 people, of whom 5% have symptoms. An estimated 16% of people with cardiovascular disease have multivascular disease.
Ischaemic stroke and myocardial infarction are associated with high mortality rates. Approximately 23% of people die within 30 days of having a stroke, and of the people who survive, 60% to 70% die within 3 years. Thirty per cent of people die from their first myocardial infarction. In terms of morbidity, an occlusive vascular event can lead to a stay in hospital, reduced health-related quality of life and long-term disability, with a resulting impact on caregivers. Stroke is the leading cause of disability in the UK and it is thought that more than 900,000 people in England are living with the effects of stroke, with about half dependent on others for support with everyday activities.
The aim of treatment is to prevent occlusive vascular events, and their recurrence. This can include pharmacological therapy with one or more antiplatelet agents. Antiplatelet agents include aspirin, clopidogrel and modified-release dipyridamole.
For people who have had a non-ST-segment-elevation myocardial infarction (NSTEMI), 'Unstable angina and NSTEMI' (NICE clinical guideline 94) recommends that aspirin should be started and continued indefinitely, unless contraindicated. In people with predicted 6-month mortality greater than 1.5%, clopidogrel should be considered in addition to aspirin, unless contraindicated, and continued for 12 months. For people who have had an ST-segment-elevation myocardial infarction (STEMI), 'MI: secondary prevention' (NICE clinical guideline 48) recommends that patients treated with a combination of aspirin and clopidogrel during the first 24 hours after the myocardial infarction should continue this treatment for at least 4 weeks. Thereafter, standard treatment including low-dose aspirin should be given, unless there are other indications to continue dual antiplatelet therapy.
The 'National service framework for coronary heart disease' states that GPs and primary care trusts should identify all people with established cardiovascular disease and offer them comprehensive advice and appropriate treatment to reduce their risk of recurrent occlusive vascular events. GP contracts include points for the number of people with coronary heart disease or who have had a stroke and who are taking antiplatelet therapy for secondary prevention.# The technologies
Clopidogrel (Plavix, Sanofi-Aventis, Bristol-Myers Squibb) is an irreversible adenosine diphosphate-receptor antagonist with antiplatelet properties. Clopidogrel is available as branded and generic preparations and has a marketing authorisation for 'the prevention of atherothrombotic events in patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease'.
Contraindications to clopidogrel include severe liver impairment and active pathological bleeding such as peptic ulcer or intracranial haemorrhage. For full details of side effects and contraindications, see the summary of product characteristics.
The cost of branded clopidogrel for 30 days at a dose of 75 mg daily is £35.64 per person (British national formulary , edition 60). The cost of generic clopidogrel 75 mg in the NHS Drug Tariff (October 2010) is £3.40 for 30 days. Costs may vary in different settings because of negotiated procurement discounts.
Modified-release dipyridamole (Persantin Retard and Asasantin Retard, Boehringer Ingelheim) has both antiplatelet and vasodilating properties and is thought to inhibit the uptake of adenosine into blood and vascular cells. Dipyridamole may also inhibit the breakdown of cyclic guanosine monophosphate. Modified-release dipyridamole has a marketing authorisation for the 'secondary prevention of ischaemic stroke and transient ischaemic attacks either alone or in conjunction with aspirin'. It is available either on its own as Persantin Retard, or in a combination tablet with aspirin as Asasantin Retard.
Dipyridamole has activity as a vasodilator; therefore it should be used with caution in people with severe coronary artery disease, including unstable angina and/or recent myocardial infarction, left ventricular outflow obstruction or haemodynamic instability (for example, decompensated heart failure). For full details of side effects and contraindications, see the summary of product characteristics.
The cost of treatment for 30 days with modified-release dipyridamole alone is £7.50 and modified-release dipyridamole plus aspirin is £7.79 per person (BNF, edition 60). Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
# Clinical effectiveness
Four randomised controlled trials (RCTs) were identified by the Assessment Group. Two of these were included in NICE technology appraisal guidance 90 (CAPRIE and ESPS-2) and two were published later (ESPRIT and PRoFESS). The RCTs were considered by the Assessment Group to be of good quality. Three of the trials were double blind and one was an open-label study (ESPRIT).
CAPRIE (n = 19,185) compared clopidogrel with aspirin and ESPRIT (n = 2736) compared modified-release dipyridamole plus aspirin with aspirin. ESPS-2 (n = 6602) had four groups and compared modified-release dipyridamole with modified-release dipyridamole plus aspirin, and with aspirin and with placebo. PRoFESS (n = 20,332) made a head-to-head comparison of clopidogrel and modified-release dipyridamole plus aspirin. A wide range of dosages of aspirin were used in the trials.
All the trials included people who had experienced an ischaemic stroke and two trials included people who had experienced a transient ischaemic attack (ESPS-2 and ESPRIT). CAPRIE was the only trial to include people who had a prior myocardial infarction or who had peripheral arterial disease. The mean length of follow-up in the trials was between 1.91 and 3.5 years. The CAPRIE and ESPRIT trials each used composite endpoints of first occurrence of ischaemic stroke, myocardial infarction, or vascular death (CAPRIE); and first occurrence of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication (ESPRIT). In the ESPS-2 trial, three discrete primary endpoints were reported: stroke, all-cause death, and stroke and/or all-cause death. The PRoFESS trial had a single primary endpoint of recurrent stroke.
## Modified-release dipyridamole compared with aspirin
The ESPS-2 trial compared modified-release dipyridamole with aspirin. The study reported no statistically significant differences in risk reduction for the primary outcomes of stroke (relative risk 1.02; 95% confidence interval 0.85 to 1.22), stroke and/or all-cause death (RR 0.97; 95% CI 0.85 to 1.11), and all-cause death (RR 1.03; 95% CI 0.85 to 1.25). Additionally, no statistically significant differences were reported for secondary outcomes.
## Modified-release dipyridamole plus aspirin compared with aspirin
Two trials (ESPS-2 and ESPRIT) compared modified-release dipyridamole plus aspirin with aspirin.
In the ESPS-2 trial, people receiving modified-release dipyridamole plus aspirin had a reduced risk of stroke (RR 0.76; 95% CI 0.63 to 0.93) compared with the aspirin group. The other primary outcomes in this study did not report statistically significant results for stroke and/or all-cause death (RR 0.87; 95% CI 0.75 to 1.00) and all-cause death (RR 1.02; 95% CI 0.84 to 1.23). For the secondary outcomes, statistically significant results favouring the group receiving modified-release dipyridamole plus aspirin were reported for stroke or transient ischaemic attack (RR 0.80; 95% CI 0.70 to 0.92), other vascular events (RR 0.55; 95% CI 0.33 to 0.94), ischaemic events (RR 0.77; 95% CI 0.65 to 0.92) and vascular events (RR 0.78; 95% CI 0.67 to 0.91). For other outcomes, no statistically significant differences were reported between the treatments.
The ESPRIT trial reported a statistically significant result for the primary outcome (that is, first occurrence of non-fatal stroke, non-fatal myocardial infarction, major bleeding complication or death from all vascular causes), favouring people receiving modified-release dipyridamole plus aspirin (hazard ratio 0.80; 95%CI 0.66 to 0.98). For the secondary outcomes, statistically significant results were reported for death from all vascular causes and non-fatal stroke (HR 0.78; 95% CI 0.62 to 0.97) and all vascular events (HR 0.78; 95% CI 0.63 to 0.97). For other outcomes, no statistically significant differences were reported between the treatments.
## Modified-release dipyridamole plus aspirin compared with modified-release dipyridamole
In the ESPS-2 trial, modified-release dipyridamole plus aspirin compared with modified-release dipyridamole alone reduced the risk of stroke (RR 0.75; 95% CI 0.61 to 0.91). The other primary outcomes in this study did not report statistically significant results. These were stroke and/or all-cause death (RR 0.89; 95% CI 0.77 to 1.03) and all-cause death (RR 0.99; 95% CI 0.81 to 1.19). For the secondary outcomes, statistically significant results were reported for transient ischaemic attack (RR 0.80; 95% CI 0.66 to 0.97), ischaemic events (RR 0.76; 95% CI 0.64 to 0.90) and vascular events (RR 0.76; 95% CI 0.65 to 0.89). For other outcomes, no statistically significant differences were reported between the treatments.
## Clopidogrel compared with aspirin
The CAPRIE trial compared clopidogrel with aspirin. For the primary outcome, the trial reported that clopidogrel compared with aspirin reduced the risk of a first occurrence of ischaemic stroke, myocardial infarction or vascular death in two groups. These were the all patients group (8.7% relative risk reduction; 95% CI 0.3 to 16.5) and a subgroup of people with peripheral arterial disease (23.8% relative risk reduction; 95% CI 8.9 to 36.2). No risk reduction was seen between treatments in subgroups defined by prior stroke (7.3% relative risk reduction; 95% CI –5.7 to 18.7) or by prior experience of a myocardial infarction (–3.7% relative risk reduction; 95% CI –22.1 to 12). For other outcomes, no statistically significant differences were reported between the treatments.
Data from the CAPRIE trial also allowed for a post-hoc subgroup analysis of data for people with multivascular disease (defined by the Assessment Group as people with experience of at least two of the following conditions: ischaemic stroke, myocardial infarction and symptomatic peripheral arterial disease). The analysis suggested that clopidogrel (compared with aspirin) reduced the risk of a first occurrence of ischaemic stroke, myocardial infarction or vascular death (14.9% relative risk reduction; 95% CI 0.3 to 27.3, p = 0.045).
## Modified-release dipyridamole plus aspirin compared with clopidogrel
The PRoFESS trial investigated the non-inferiority of modified-release dipyridamole plus aspirin compared with clopidogrel. The trial reported no statistically significant difference in the primary outcome of recurrent stroke of any type (HR 1.01; 95% CI 0.92 to 1.11). For the secondary outcomes, there was a statistically significant reduction in the risk of events in the modified-release dipyridamole group compared with the clopidogrel group for new or worsening congestive heart failure (HR 0.78; 95% CI 0.62 to 0.96) and a statistically significant increase in the risk of events in the modified-release dipyridamole group compared with the clopidogrel group for intracranial haemorrhage (HR 1.42; 95% CI 1.11 to 1.83).
## Indirect comparisons
The Assessment Group completed an indirect comparison that compared clopidogrel, modified- release dipyridamole plus aspirin, modified-release dipyridamole alone and aspirin using data from the four RCTs. Comparisons were made in a population of people with a history of ischaemic stroke or transient ischaemic attack.
The Assessment Group reported that the results from the mixed treatment comparison showed no statistical difference between the pairs of drug interventions, except for the outcomes of 'any recurrent stroke' and major bleeding. Compared with people assigned to treatment with aspirin, there was evidence of a risk reduction for 'any recurrent stroke' in people taking either clopidogrel (RR 0.75; 95% CI 0.60 to 0.93) or modified-release dipyridamole plus aspirin (RR 0.76; 95% CI 0.62 to 0.92). People treated with modified-release dipyridamole alone were at statistically significant higher risk of 'any recurrent stroke' than people treated with either clopidogrel or modified-release dipyridamole plus aspirin. The direct and indirect evidence was consistent.
# Cost effectiveness
## Bristol-Myers Squibb and Sanofi-Aventis model (clopidogrel)
The Bristol-Myers Squibb and Sanofi-Aventis model estimated the cost effectiveness of four treatments for the secondary prevention of occlusive vascular events. These treatments were aspirin, clopidogrel, modified-release dipyridamole plus aspirin and modified-release dipyridamole alone. In line with the licensed indications for the products, all four treatments were compared for use in people with a prior ischaemic stroke. In people with a history of myocardial infarction, peripheral arterial disease or multivascular disease, clopidogrel was compared with aspirin.
The manufacturers submitted a Markov model that comprised six health states: no event in model, history of stroke, history of myocardial infarction, TA80 state (an intermediate state reflecting NICE technology appraisal guidance 80 which recommended clopidogrel plus aspirin for up to 12 months after an NSTEMI event), history of stroke and myocardial infarction, and death (split into vascular and non-vascular death). People entering the model could remain stable, have a myocardial infarction or stroke, or die. The modelled patient population was aged 65 years. The model was run with 3-month cycles for 35 years. The perspective adopted was that of the UK NHS in line with the NICE reference case. Costs and utility values were discounted at a rate of 3.5%.
Each patient population was modelled in the same way, with the exception that the baseline risks of vascular events differed by cohort (ischaemic stroke, myocardial infarction, peripheral arterial disease and multivascular disease). Event rates were different for years 1, 2 and 3 of the model. Event rates in year 3 were used to inform the model from year 3 onwards. Relative treatment effects for clopidogrel, modified-release dipyridamole and modified-release dipyridamole plus aspirin were based on either direct evidence or indirect evidence, using a network meta-analysis. The non-treatment costs used in the model were based on information from published burden of illness studies. Treatment costs were sourced from MIMS. All costs were inflated to 2007/08 prices, if necessary. The model included the branded price of clopidogrel. Utility values were derived from the published literature and were between 0.61 and 0.87. A disutility associated with adverse events of between −0.3 and −0.001 was also applied in the model.
In people who have had an ischaemic stroke, modified-release dipyridamole plus aspirin was associated with an additional cost of £107 and an additional quality-adjusted life year (QALY) of 0.45, producing an incremental cost-effectiveness ratio (ICER) of £237 per QALY gained compared with aspirin. Clopidogrel was associated with an additional cost of £2324 and an additional QALY of 0.07, producing an ICER of £31,204 per QALY gained compared with aspirin. Clopidogrel was associated with greater costs and fewer QALYs than modified-release dipyridamole plus aspirin.
In people who have had a myocardial infarction, clopidogrel was associated with an additional cost of £2643 and an additional QALY of 0.13, producing an ICER of £20,662 per QALY gained compared with aspirin. For people with peripheral arterial disease, clopidogrel was associated with an additional cost of £2470 and an additional QALY of 0.13, producing an ICER of £18,854 per QALY gained compared with aspirin. For people with multivascular disease, clopidogrel was associated with an additional cost of £1805 and an additional QALY of 0.12, producing an ICER of £15,524 per QALY gained compared with aspirin.
## Boehringer Ingelheim model (modified-release dipyridamole)
The Boehringer Ingelheim model estimated the cost effectiveness of modified-release dipyridamole plus aspirin compared with aspirin, clopidogrel and no treatment. The manufacturer did not estimate the cost effectiveness of modified-release dipyridamole alone, because no new trial data were available for this treatment since NICE technology appraisal guidance 90. Separate analyses were conducted for people who have had an ischaemic stroke, and for people who have had a transient ischaemic attack. Only people tolerant to aspirin were considered in the analysis.
The manufacturer submitted a Markov model based on the Assessment Group model from NICE technology appraisal guidance 90. The model had five health states: no recurrent stroke, haemorrhagic stroke, recurrent ischaemic stroke, vascular death and non-vascular death. People entered the model at the 'no recurrent stroke' state and after each cycle of 6 months could move to any of the other four states, or remain in the current state. After each cycle, transitions could occur to the other states.
The baseline age in the model was 66 years, with a time horizon of 50 years. The perspective adopted was that of the NHS and personal social services. Transition probabilities between the states in the model for the first 4 years were taken from the PRoFESS, ESPRIT and ESPS-2 trials. Different transition probabilities were calculated for each 6-month period over the 4 years. Transition probabilities in subsequent years for the stroke states were based on the final 6-month period of the 4 years. Transition probabilities to death were estimated based on a factor of 1.5 applied to Office for National Statistics death rate data for the general population.
Costs of stroke events were calculated from the literature and varied according to disabled or non-disabled status. Costs of hospital stay following congestive heart failure and other haemorrhagic events were sourced from the 2006/07 National Reference Costs. Drug acquisition costs were based on branded drug costs for modified-release dipyridamole and aspirin, and clopidogrel, and on the generic price for aspirin (2009 prices). Utility data from the PRoFESS trial at 1 year were used, which was provided as commercial in confidence. A short-term disutility associated with different events was also included in the model. Costs and utility values were discounted at a rate of 3.5% per year.
In people who have had an ischaemic stroke, treatment with modified-release dipyridamole plus aspirin was associated with an additional cost of £704, and 0.131 additional QALYs per person with a corresponding ICER of £5377 per QALY gained, compared with aspirin. Treatment with clopidogrel compared with modified-release dipyridamole plus aspirin was associated with additional costs of £1808 and 0.015 additional QALYs per person with an ICER of £114,628 per QALY gained. The results were similar in people who have had a transient ischaemic attack. In this population, treatment with modified-release dipyridamole plus aspirin compared with aspirin was associated with an additional cost of £732 and 0.121 additional QALYs per person with an ICER of £6053 per QALY gained. The manufacturer reported that its model suggested that at a cost-effectiveness threshold of £20,000 per QALY gained, modified-release dipyridamole plus aspirin would no longer be cost effective compared with clopidogrel if the price of generic clopidogrel reduced to approximately 50% of that of branded clopidogrel.
## Assessment Group model
The Assessment Group developed an individual patient sampling model, in which a series of individual profiles were generated whose combined characteristics were representative of the specified population. Analyses were split by population: ischaemic stroke, myocardial infarction, peripheral arterial disease and multivascular disease. The ischaemic stroke and transient ischaemic attack populations were assumed to be equivalent in risk and outcomes and so were modelled together. Within the myocardial infarction group, treatment strategies as described in the clinical guidelines on STEMI and NSTEMI (NICE clinical guideline 48 and NICE clinical guideline 94) were modelled initially. Once initial treatment was completed according to the guidelines, potential treatment strategies for this appraisal were considered as follow-on treatment.
The Assessment Group presented different treatment strategies, depending on the population and intolerances. The Assessment Group considered that this approach reflected the real world, because people may switch between different treatments. For each person in the model, age, sex and disability status was set. According to these variables, estimates of time to first event were applied. These events determined the event history of the person and included a fatal or new non-fatal ischaemic stroke event, a fatal or new non-fatal non-ischaemic stroke event, a fatal or new non-fatal myocardial infarction, death from other vascular causes, death from non-vascular causes and person discontinues current preventive medication for any reason. Only one event could occur at any one time. If the event was non-fatal then the person continued in the model, with an updated age, sex and disability status and updated risks, with the potential to incur additional events over time, moving through the model over a lifetime. Each person was modelled in the same way. Data provided by the manufacturers from the CAPRIE and PRoFESS trials were used to develop risk models for the economic model and to work out event fatality. An exponential survival function was used to model medication continuance over time. Adverse events were incorporated into the model.
Resource use was measured in terms of clinical events and time spent in chronic states, and differed by disability status. Drug costs were taken from the BNF58 and from the NHS Drug Tariff (January 2010) for generic clopidogrel, which at that point reported that the price of 30 tablets was £10.90. Unit costs were drawn from various sources, including the manufacturers' submissions, and inflated if necessary to 2009. The costs were £6410 for non-fatal ischaemic or haemorrhagic stroke if the person was not disabled and £13,647 if they were disabled, £8768 for fatal ischaemic or haemorrhagic stroke, £5762 for non-fatal myocardial infarction, £2218 for fatal myocardial infarction and £2225 for other vascular or non-vascular death.
Utility values were also drawn from a variety of sources, including the manufacturers' submissions and additional analyses requested from the manufacturer. Mean utility values were assigned to each chronic health state and a specific utility decrement effect was applied for each modelled event. Utility values for the myocardial infarction and peripheral arterial disease groups were 0.87 and 0.80 respectively. Utility values for the ischaemic stroke group and all utility decrements were taken from the Boehringer Ingelheim submission. Discounting at 3.5% was applied to costs and benefits after the first year. A lifetime horizon was used.
Deterministic and probabilistic sensitivity analyses were conducted to explore the impact of uncertainty on the cost-effectiveness estimates.
For people who have had an ischaemic stroke or transient ischaemic attack, when the branded price for clopidogrel was used, the Assessment Group reported that the optimal treatment strategy was modified-release dipyridamole plus aspirin, followed by aspirin and finally clopidogrel. This produced an ICER of £16,894 per QALY gained and incremental costs of £354 and 0.021 QALYs compared with treatment with the next best strategy of modified-release dipyridamole plus aspirin, followed by aspirin.
When the generic price for clopidogrel was used, the optimal treatment strategy changed so that it began with clopidogrel, followed by modified-release dipyridamole plus aspirin and finally aspirin. This produced an ICER of £13,558 per QALY gained, compared with the next best strategy of clopidogrel, followed by aspirin, followed by modified-release dipyridamole plus aspirin. This strategy was associated with an additional cost of £334 and 0.024 additional QALYs.
For people with intolerance to aspirin, clopidogrel followed by modified-release dipyridamole was the optimal treatment strategy with an ICER of £7142 per QALY gained compared with treatment with clopidogrel alone. This strategy was associated with an additional cost of £616 and 0.086 additional QALYs. It could be calculated from the data that for people with intolerance to aspirin and clopidogrel or for whom clopidogrel wasn't licensed, the optimal treatment strategy was modified-release dipyridamole alone with an ICER of £314 per QALY gained compared with no preventive treatment. This strategy was associated with an additional cost of £167 and 0.531 additional QALYs.
For people with intolerance to modified-release dipyridamole, the optimal treatment strategy depended on the price of clopidogrel. At the branded price, the preferred strategy was aspirin followed by clopidogrel with an ICER of £6797 per QALY gained, compared with clopidogrel alone. This strategy was associated with an additional cost of £628 and 0.092 additional QALYs. At the generic price, the optimal strategy was clopidogrel followed by aspirin, compared with aspirin followed by clopidogrel, with an ICER of £3970 per QALY gained, an additional cost of £224 and 0.056 additional QALYs. For people with intolerance to both aspirin and modified-release dipyridamole, only clopidogrel is available for long-term prevention. It was considered optimal by the Assessment Group compared with no preventive therapy, with an ICER of £275 per QALY gained. This strategy was associated with an additional cost of £163 and 0.591 additional QALYs.
From the Assessment Group's analysis of the ischaemic stroke data, the ICERs could be calculated for people with intolerance to clopidogrel or for whom treatment with clopidogrel is not licensed, such as people who have had a transient ischaemic attack. Treatment with modified-release dipyridamole plus aspirin followed by aspirin had an ICER of £9145 per QALY gained, compared with treatment with aspirin followed by modified-release dipyridamole. This strategy was associated with an additional cost of £567 and 0.062 additional QALYs.
The Assessment Group reported that for people who have had a myocardial infarction the optimal treatment strategies were the same regardless of the price of clopidogrel. Aspirin followed by clopidogrel, compared with aspirin alone, was the optimal strategy for this population, with an ICER of £1964 per QALY gained (using the price of generic clopidogrel) and a difference in costs of £185 and QALYs of 0.094. For people with intolerance to aspirin, treatment with clopidogrel was likely to be the optimal treatment, compared with no preventive therapy, with an ICER of £2020 per QALY gained (using the price of generic clopidogrel) and a difference in cost of £468 and 0.232 additional QALYs.
After consultation on the appraisal consultation document, the Assessment Group provided a reanalysis of the data for people who have had a myocardial infarction. This analysis used a price of clopidogrel of £5.13, reflecting the NHS tariff price for August 2010. The results showed that the lower price had no effect on the optimal treatment strategy: aspirin followed by clopidogrel remained the optimal treatment strategy.
The Assessment Group reported that for people with peripheral arterial disease the optimal treatment strategies were the same regardless of the price of clopidogrel. Clopidogrel followed by aspirin was the optimal strategy for this group, with an ICER of £2815 per QALY gained. It was associated with an additional cost of £983 and an additional 0.349 QALYs compared with treatment with aspirin alone followed by treatment with clopidogrel. In people with intolerance to aspirin, clopidogrel alone was the optimal treatment strategy. Compared with no preventive therapy, clopidogrel gave an additional 0.773 QALYs at a cost of £557, with an ICER of £721 per QALY gained.
The Assessment Group reported that for people with multivascular disease the optimal treatment strategies were the same regardless of the price of clopidogrel. Clopidogrel followed by aspirin was the optimal strategy for this group, compared with aspirin followed by clopidogrel. For the optimal strategy, treatment was associated with an ICER of £2604 per QALY gained, and incremental costs of £595 and incremental QALYs of 0.228. In people with intolerance to aspirin, clopidogrel alone was the optimal treatment strategy and was associated with lower total costs of –£548 compared with no preventive therapy, 0.723 additional QALYS and a corresponding ICER of –£758 per QALY gained.
# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of clopidogrel and modified-release dipyridamole, having considered evidence on the nature of occlusive vascular events and peripheral arterial disease and the value placed on the benefits of clopidogrel and modified-release dipyridamole by people who have had an occlusive vascular event or are at risk of one, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee discussed current clinical management for the prevention of occlusive vascular events. The Committee heard from clinical specialists that they would value clear, straightforward guidance so that treatment could be started at the earliest possible point, when the risk of recurrent events is highest. Patient experts explained that treatment with clopidogrel or modified-release dipyridamole plus aspirin was an important part of treatment for the prevention of occlusive vascular events but is just one part of a wider programme of management involving both pharmacological and non-pharmacological treatment. The Committee heard from the patient experts that people are often on a number of treatments and would value a reduction in the number of tablets that need to be taken. The Committee heard from the patient experts that they considered that clopidogrel had fewer severe side effects than aspirin or modified-release dipyridamole. The Committee recognised that antiplatelet therapy such as clopidogrel and modified-release dipyridamole was one part of clinical management and that people valued treatments with ease of administration and few side effects.
The Committee discussed the results of the ESPRIT and PRoFESS trials, which became available after the publication of NICE technology appraisal guidance 90. The Committee noted that these trials included people who have had an ischaemic stroke or a transient ischaemic attack and there was no new evidence for people with peripheral arterial disease or for people who have had a myocardial infarction. The Committee discussed the results of the PRoFESS trial and considered that it had not shown that clopidogrel provided greater benefits than modified-release dipyridamole plus aspirin. But the Committee also considered that the trial had not shown that modified-release dipyridamole plus aspirin provided greater benefits than clopidogrel. The Committee noted comments made in the consultation on the appraisal consultation document about the exclusion of the MATCH and CHARISMA trials, but considered that these trials studied a combination of clopidogrel plus aspirin that was outside the scope of this appraisal. Likewise, it noted comments made about the EARLY trial that compared early and standard initiation of treatment, but considered that this had been appropriately excluded from the Assessment Group's review. The Committee concluded that the data published after NICE technology appraisal guidance 90 supported the conclusions in that guidance.
The Committee specifically discussed the duration of follow-up in the ESPRIT and PRoFESS trials, recognising that in NICE technology appraisal guidance 90 the evidence was limited to 2 years' follow-up. It noted that the ESPRIT trial had a mean follow-up of 3.5 years and the PRoFESS trial had a mean follow-up of 2.5 years. The Committee heard from the clinical specialists that in clinical practice the length of time people stayed on treatment varied, but it could be longer than 2 years. The clinical specialists discussed evidence from the ESPRIT trial that showed that Kaplan-Meier curves by treatment group continued to diverge over time. While the clinical specialists recognised that the study and its results have limitations, they considered that this provided evidence of a continued treatment effect beyond the 2 years used in NICE technology appraisal guidance 90. The Committee was persuaded that it was appropriate to examine the Assessment Group's analyses of cost effectiveness without specifying a limit on the duration of treatment.
The Committee considered the subgroup of people with multivascular disease. It noted that there is a range of definitions of multivascular disease, but heard from the clinical specialists that identifying the subgroup of people with multivascular disease was important and clinically meaningful. The Committee discussed the post-hoc analyses from the CAPRIE trial that suggested that this group is at high risk of occlusive vascular events and may need more intensive treatment. The Committee was aware of the limitations of post-hoc analyses but noted that the subgroups were based on large numbers of people. On balance, it considered multivascular disease to be appropriate to consider in the cost-effectiveness analysis.
The Committee recognised that after the publication of NICE technology appraisal guidance 90, clopidogrel became available in a number of generic preparations. The Assessment Group's analyses used both the branded and generic prices. The Committee was aware that after the assessment report was written the price of clopidogrel was reduced further from approximately £10 to approximately £5 per month. It noted that this would affect the cost-effectiveness results, because treatment with generic clopidogrel would cost less than previously stated. The Committee considered that it was appropriate to take account of the generic price of clopidogrel in its considerations and that any treatment with clopidogrel should use the least costly licensed preparation.
The Committee discussed the cost-effectiveness results from the two manufacturers' models. The Committee considered the Boehringer Ingelheim model, which reported that in people who have had an ischaemic stroke or a transient ischaemic attack, treatment with modified-release dipyridamole plus aspirin was cost effective compared with aspirin, with ICERs of around £5400 and £6100 per QALY gained, respectively. The Committee considered the Bristol-Myers Squibb and Sanofi-Aventis model, which found that in people who have had an ischaemic stroke, treatment with modified-release dipyridamole plus aspirin was cost effective with an ICER of around £240 per QALY gained compared with aspirin. In people who have had a myocardial infarction, or who have peripheral arterial disease and for people with multivascular disease, the ICERs were all below £21,000 per QALY gained, compared with aspirin. The Committee discussed the limitations of the models, noting that in the submissions neither model used the generic price of clopidogrel. However, the Committee was aware that the manufacturer of modified-release dipyridamole had commented that at a cost-effectiveness threshold of £20,000 per QALY gained, if the price of generic clopidogrel was about 50% of that of branded clopidogrel, modified-release dipyridamole plus aspirin would no longer be cost effective compared with clopidogrel. Furthermore, the Committee was aware of comments in response to consultation on the Assessment Report from the manufacturer of clopidogrel that for people who have had an ischaemic stroke, using a price of £10.90 for clopidogrel produced an ICER of under £500 per QALY gained for clopidogrel in comparison with modified-release dipyridamole.
The Committee discussed the results of the Assessment Group's model for the subgroup of people with peripheral arterial disease. It noted that a treatment strategy of clopidogrel followed by aspirin had an ICER of around £2800 per QALY gained, compared with aspirin alone. For people with intolerance to aspirin, treatment with clopidogrel had an ICER of around £720 per QALY gained compared with no preventive therapy. The Committee considered that for people with peripheral arterial disease clopidogrel was a cost-effective use of NHS resources.
The Committee discussed the results of the Assessment Group's model for the subgroup of people with multivascular disease. It noted that a treatment strategy of clopidogrel followed by aspirin had an ICER of around £2600 per QALY gained, compared with aspirin alone. In people with intolerance to aspirin, clopidogrel was a cost-saving strategy, costing less and producing more benefits than no preventive therapy. The Committee considered that for people with multivascular disease clopidogrel was a cost-effective use of NHS resources.
The Committee discussed the results of the Assessment Group's model for the subgroup of people who have had a myocardial infarction. It recognised that the model had incorporated the current NICE clinical guideline 48 and NICE clinical guideline 94 on the use of clopidogrel plus aspirin for the treatment of people with STEMI and NSTEMI, and modelled the use of clopidogrel monotherapy after its use as a combination therapy for acute coronary syndromes. The treatment strategy of aspirin followed by clopidogrel had an ICER of £2000 per QALY gained, compared with aspirin alone. A treatment strategy of clopidogrel followed by aspirin was associated with greater costs and fewer QALYs than starting with aspirin. In people with intolerance to aspirin, clopidogrel had an ICER of £2000 per QALY gained compared with no preventive therapy. The Committee discussed the re-analysis provided by the Assessment Group after the consultation on the appraisal consultation document, which showed that the further reduction of the price of clopidogrel to £5.13 (the price in July 2010) had no effect on the optimal treatment strategy. The Committee concluded that for people who have had a myocardial infarction, when treatment with combined clopidogrel and aspirin therapy is no longer appropriate, clopidogrel was a cost-effective use of NHS resources only for people who have a contraindication to aspirin or intolerance to it.
The Committee discussed the results of the Assessment Group's model for people who have had an ischaemic stroke. The Committee noted that the optimal treatment strategy changed depending on whether the branded or generic price of clopidogrel was used. When the generic price of clopidogrel was used, the Assessment Group model found that clopidogrel followed by modified-release dipyridamole plus aspirin and then aspirin alone had an ICER of £13,600 per QALY gained, compared with clopidogrel followed by aspirin, followed by modified-release dipryidamole plus aspirin. In people with intolerance to modified-release dipyridamole, clopidogrel followed by aspirin had an ICER of £4000 per QALY gained compared with aspirin alone. In people with intolerance to aspirin, clopidogrel followed by modified-release dipyridamole alone had an ICER of £7100 per QALY gained, compared with treatment with clopidogrel alone. For people who had intolerance to clopidogrel and aspirin, treatment with modified-release dipyridamole alone had an ICER of £314 per QALY gained in comparison with no preventive treatment. The Committee recognised that the differences in the total costs and QALYs for the different treatment strategies each including clopidogrel, modified-release dipyridamole plus aspirin and aspirin were small. However, it noted that these were consistent in all analyses, and with a further reduction in the price of clopidogrel the differences in costs would be larger. The Committee concluded that using clopidogrel at the generic price was a cost-effective use of NHS resources. Modified-release dipyridamole plus aspirin was a cost-effective use of NHS resources only when it was used for people who had a contraindication or intolerance to clopidogrel. Modified-release dipyridamole alone was a cost-effective use of NHS resources only when it was used in people who had a contraindication or intolerance to aspirin and clopidogrel.
The Committee heard from the clinical specialists that people who have had a transient ischaemic attack are sometimes treated with clopidogrel. However, the Committee recognised that recommendations could not be made for the use of clopidogrel for people who have had a transient ischaemic attack because clopidogrel is not licensed for this indication. For people who have had a transient ischaemic attack, treatment with modified-release dipyridamole plus aspirin followed by aspirin had an ICER of £9,100 per QALY gained compared with treatment with aspirin alone. For people who had intolerance to aspirin, treatment with modified-release dipyridamole alone had an ICER of £314 per QALY gained in comparison with no preventive treatment. The Committee considered that for people who have had a transient ischaemic attack, treatment with modified-release dipyridamole plus aspirin could be considered a cost-effective use of NHS resources. Modified-release dipyridamole alone was considered to be a cost-effective use of NHS resources for people who have had a transient ischaemic attack only if aspirin is contraindicated or not tolerated.
# Summary of the Appraisal Committee's key conclusions
TA210 (STA)
Appraisal title: Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of technology appraisal guidance 90)
FAD section
Key conclusions
For people who have had an ischaemic stroke, clopidogrel is recommended as a treatment option. For people who have a contraindication or intolerance to clopidogrel, modified-release dipyridamole plus aspirin is recommended as a treatment option. For people who have a contraindication or intolerance to both clopidogrel and aspirin, modified-release dipyridamole alone is recommended as a treatment option.
For people who have had a transient ischaemic attack, modified-release dipyridamole plus aspirin is recommended as a treatment option. For people who have a contraindication or intolerance to aspirin, modified-release dipyridamole alone is recommended as a treatment option.
For people who have had a myocardial infarction, clopidogrel is recommended only when treatment with aspirin is contraindicated or not tolerated.
For people with peripheral arterial disease, clopidogrel is recommended as a treatment option.
For people with multivascular disease, clopidogrel is recommended as a treatment option.
Treatment with clopidogrel to prevent occlusive vascular events should be started with the least costly licensed preparation.
Current practice
Clinical need of patients including the availability of alternative treatments
Patients are often on a number of treatments and would value a reduction in the number of tablets that need to be taken.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits
This is a review of established technologies.
n/a
What is the position of the treatment in the pathway of care for the condition
Treatment with clopidogrel or modified-release dipyridamole plus aspirin is an important part of treatment for the prevention of occlusive vascular events, but is just one part of a wider programme of management involving both pharmacological and non-pharmacological treatment.
Clopidogrel is not licensed for the treatment of transient ischaemic attack, and therefore recommendations could not be made about the use of clopidogrel in this patient population.
Adverse effects
The Committee heard from patient experts that they considered that clopidogrel had fewer severe side effects than aspirin or modified-release dipyridamole.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
Two trials (ESPRIT and PRoFESS) became available since the publication of NICE technology appraisal guidance 90.
Relevance to general clinical practice in the NHS
The clinical specialists cited evidence from the ESPRIT trial that showed that Kaplan-Meier curves by treatment group continued to diverge over time. While the clinical specialists recognised that the study and its results have limitations, they considered that this provided evidence of a continued treatment effect beyond the 2 years recommended in NICE technology appraisal guidance 90.
Uncertainties generated by the evidence
The ESPRIT and PRoFESS trials included people who have had an ischaemic stroke or a transient ischaemic attack, and there was no new evidence relating to people with peripheral arterial disease or people who have had a myocardial infarction.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness
NICE technology appraisal guidance 90 considered subgroups of people who had experienced ischaemic stroke, transient ischaemic attack or myocardial infarction, or who had peripheral arterial disease.
n/a
Additionally, the Committee considered multivascular disease to be appropriate to consider in the cost-effectiveness analysis.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The data published after NICE technology appraisal guidance 90 were supportive of the conclusions in that guidance.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee discussed the manufacturers' models, noting that neither model used the generic price of clopidogrel.
Uncertainties around and plausibility of assumptions and inputs in the economic model
Since the assessment report was written, the price of clopidogrel has been reduced further from approximately £10 to £5 a month.
Incorporation of health-related quality of life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
This was not an issue in the analyses.
n/a
Are there specific groups of people for whom the technology is particularly cost-effective?
NICE technology appraisal guidance 90 includes subgroups of people who had experienced ischaemic stroke, transient ischaemic attack or myocardial infarction, or who had peripheral arterial disease.
n/a
Additionally, the Committee considered multivascular disease to be appropriate to consider in the cost-effectiveness analysis because in post-hoc analyses of the CAPRIE trial, people with multivascular disease were found to be at high risk of occlusive vascular events.
What are the key drivers of cost effectiveness?
Since the publication of NICE technology appraisal guidance 90, clopidogrel has become available in a number of generic formulations.
For people who have had an ischaemic stroke, the optimal strategy for treatment changed depending on whether the branded or generic price of clopidogrel was used.
Most likely cost-effectiveness estimate (given as an ICER)
For the subgroup of people with peripheral arterial disease, a treatment strategy of clopidogrel followed by aspirin had an ICER of around £2800 per QALY gained compared with aspirin alone. In people with intolerance to aspirin, treatment with clopidogrel had an ICER of around £720 per QALY gained compared with no preventive therapy.
For the subgroup of people with multivascular disease, a treatment strategy of clopidogrel followed by aspirin had an ICER of around £2600 per QALY gained compared with treatment with aspirin alone. In people with intolerance to aspirin, clopidogrel was a cost-saving strategy, costing less and producing more benefits than no preventive therapy.
For the subgroup of people who have had a myocardial infarction, the treatment strategy of aspirin followed by clopidogrel had an ICER of £2000 per QALY gained, compared with treatment with aspirin alone. In people with intolerance to aspirin, clopidogrel had an ICER of £2000 per QALY gained compared with no preventive therapy
For people who have had an ischaemic stroke, when the generic price of clopidogrel was used, the treatment strategy of clopidogrel followed by modified-release dipyridamole plus aspirin and then aspirin alone had an ICER of £13,600 per QALY gained compared with treatment with clopidogrel followed by aspirin, followed by modified-release dipyridamole plus aspirin. In people with intolerance to modified-release dipyridamole, the treatment strategy of clopidogrel followed by aspirin had an ICER of £4000 per QALY gained compared with aspirin alone. In people with intolerance to aspirin, the treatment strategy of clopidogrel followed by modified-release dipyridamole alone had an ICER of £7,100 per QALY gained, compared with treatment with clopidogrel alone. For people who had intolerance to clopidogrel and aspirin, treatment with modified-release dipyridamole alone had an ICER of £314 per QALY gained in comparison with no preventive therapy.
For people who have had a transient ischaemic attack, treatment with modified-release dipyridamole plus aspirin had an ICER of £9,100 per QALY gained compared with treatment with aspirin alone. For people who had intolerance to aspirin, treatment with modified-release dipyridamole alone had an ICER of £314 per QALY gained in comparison with no preventive therapy.
Additional factors taken into account
Patient Access Schemes
(PPRS)
No patient access schemes were submitted.
n/a
End of life considerations
End-of-life considerations were not discussed.
n/a
Equalities considerations, social value judgements
No equalities issues were raised in the submissions.
n/a# Related NICE guidance
Unstable angina and NSTEMI: the early management of unstable angina and non-ST-segment-elevation myocardial infarction. NICE clinical guideline 94 (2010).
MI: secondary prevention. Secondary prevention in primary and secondary care for patients following a myocardial infarction. NICE clinical guideline 48 (2007).# Review of guidance
The guidance on this technology will be considered for review by the Guidance Executive in July 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveNovember 2010# Changes after publication
February 2014: implementation section updated to clarify that clopidogrel and modified-release dipyridamole is recommended as an option for preventing occlusive vascular events. Additional minor maintenance update also carried out.
March 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE multiple technology appraisal process.
It replaces NICE technology appraisal guidance 90 (published May 2005).
The review and re-appraisal of clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events has resulted in a change in the guidance. Specifically:
Treatment with modified-release dipyridamole in combination with aspirin for people who have had an ischaemic stroke is now recommended only if clopidogrel is contraindicated or not tolerated.
Treatment with modified-release dipyridamole in combination with aspirin for people who have had an ischaemic stroke or a transient ischaemic attack is no longer limited to 2 years' duration from the most recent event.
Clopidogrel is no longer recommended only for people who are intolerant of aspirin and have had an occlusive vascular event or have peripheral arterial disease (see section 1 for new guidance).
Modified-release dipyridamole alone is now recommended as an option to prevent occlusive vascular events (see sections 1.2 and 1.3).
The recommendations from this guideline have been incorporated into a NICE Pathway. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': "This guidance replaces 'NICE technology appraisal guidance 90' issued in May 2005. For details, see 'About this guidance'.\n\nThis guidance applies to people who have had an occlusive vascular event, or who have established peripheral arterial disease. For people who have had a myocardial infarction, this guidance follows on from the recommendations for clopidogrel in combination with low-dose aspirin in NICE clinical guideline 48 and NICE clinical guideline 94. This guidance does not apply to people who have had, or are at risk of, a stroke associated with atrial fibrillation, or who need treatment to prevent occlusive events after coronary revascularisation or carotid artery procedures.\n\nClopidogrel is recommended as an option to prevent occlusive vascular events:\n\nfor people who have had an ischaemic stroke or who have peripheral arterial disease or multivascular disease or\n\nfor people who have had a myocardial infarction only if aspirin is contraindicated or not tolerated.\n\nModified-release dipyridamole in combination with aspirin is recommended as an option to prevent occlusive vascular events:\n\nfor people who have had a transient ischaemic attack or\n\nfor people who have had an ischaemic stroke only if clopidogrel is contraindicated or not tolerated.\n\nModified-release dipyridamole alone is recommended as an option to prevent occlusive vascular events:\n\nfor people who have had an ischaemic stroke only if aspirin and clopidogrel are contraindicated or not tolerated or\n\nfor people who have had a transient ischaemic attack only if aspirin is contraindicated or not tolerated.\n\nTreatment with clopidogrel to prevent occlusive vascular events should be started with the least costly licensed preparation.\n\nPeople currently receiving clopidogrel or modified-release dipyridamole either with or without aspirin outside the criteria in 1.1, 1.2 and 1.3 should have the option to continue treatment until they and their clinicians consider it appropriate to stop.", 'Clinical need and practice': "Occlusive vascular events include ischaemic stroke, transient ischaemic attack and myocardial infarction. They occur when blood flow is impeded because an artery is blocked or restricted because of atherosclerosis and atherothrombosis. Atherosclerotic plaques form in artery walls because of damage to the vascular endothelium. Damage is caused by a number of factors working together over a long period, such as elevated low-density lipoproteins, smoking, high blood pressure and diabetes mellitus. If an atherosclerotic plaque is suddenly disrupted, platelet activation and thrombus (clot) formation follows, leading to atherothrombosis. The thrombus can block an artery, either at the original site of the plaque formation or further down the artery. People who have had an occlusive vascular event are at increased risk of another.\n\nPeripheral arterial disease is a condition in which the arteries that carry blood to the arms or legs become narrowed or clogged, slowing or stopping the flow of blood. It occurs most often because of atherosclerosis. People who have peripheral arterial disease are at high risk of having an occlusive vascular event. People with cardiovascular disease who have disease in more than one vascular site are said to have multivascular disease. These people are at increased risk of death, myocardial infarction or stroke, compared with people with disease in a single vascular bed.\n\nEach year in the UK an estimated 98,000 people have a first ischaemic stroke, between 46,000 and 65,000 people have a transient ischaemic attack, and 146,000 have a myocardial infarction. Approximately 2% of the population of England and Wales have had a stroke and about 70% of all strokes are ischaemic. In the UK, in total around 510,000 people have had a transient ischaemic attack and over 1.4 million have had a myocardial infarction. About 20% of the UK population aged 55–75\xa0years have evidence of lower extremity peripheral arterial disease, equating to a prevalence of 850,000 people, of whom 5% have symptoms. An estimated 16% of people with cardiovascular disease have multivascular disease.\n\nIschaemic stroke and myocardial infarction are associated with high mortality rates. Approximately 23% of people die within 30\xa0days of having a stroke, and of the people who survive, 60% to 70% die within 3\xa0years. Thirty per cent of people die from their first myocardial infarction. In terms of morbidity, an occlusive vascular event can lead to a stay in hospital, reduced health-related quality of life and long-term disability, with a resulting impact on caregivers. Stroke is the leading cause of disability in the UK and it is thought that more than 900,000 people in England are living with the effects of stroke, with about half dependent on others for support with everyday activities.\n\nThe aim of treatment is to prevent occlusive vascular events, and their recurrence. This can include pharmacological therapy with one or more antiplatelet agents. Antiplatelet agents include aspirin, clopidogrel and modified-release dipyridamole.\n\nFor people who have had a non-ST-segment-elevation myocardial infarction (NSTEMI), 'Unstable angina and NSTEMI' (NICE clinical guideline 94) recommends that aspirin should be started and continued indefinitely, unless contraindicated. In people with predicted 6-month mortality greater than 1.5%, clopidogrel should be considered in addition to aspirin, unless contraindicated, and continued for 12\xa0months. For people who have had an ST-segment-elevation myocardial infarction (STEMI), 'MI: secondary prevention' (NICE clinical guideline 48) recommends that patients treated with a combination of aspirin and clopidogrel during the first 24 hours after the myocardial infarction should continue this treatment for at least 4 weeks. Thereafter, standard treatment including low-dose aspirin should be given, unless there are other indications to continue dual antiplatelet therapy.\n\nThe 'National service framework for coronary heart disease' states that GPs and primary care trusts should identify all people with established cardiovascular disease and offer them comprehensive advice and appropriate treatment to reduce their risk of recurrent occlusive vascular events. GP contracts include points for the number of people with coronary heart disease or who have had a stroke and who are taking antiplatelet therapy for secondary prevention.", 'The technologies': "Clopidogrel (Plavix, Sanofi-Aventis, Bristol-Myers Squibb) is an irreversible adenosine diphosphate-receptor antagonist with antiplatelet properties. Clopidogrel is available as branded and generic preparations and has a marketing authorisation for 'the prevention of atherothrombotic events in patients suffering from myocardial infarction (from a few days until less than 35\xa0days), ischaemic stroke (from 7\xa0days until less than 6\xa0months) or established peripheral arterial disease'.\n\nContraindications to clopidogrel include severe liver impairment and active pathological bleeding such as peptic ulcer or intracranial haemorrhage. For full details of side effects and contraindications, see the summary of product characteristics.\n\nThe cost of branded clopidogrel for 30\xa0days at a dose of 75\xa0mg daily is £35.64 per person (British national formulary [BNF], edition 60). The cost of generic clopidogrel 75\xa0mg in the NHS Drug Tariff (October 2010) is £3.40 for 30\xa0days. Costs may vary in different settings because of negotiated procurement discounts.\n\nModified-release dipyridamole (Persantin Retard and Asasantin Retard, Boehringer Ingelheim) has both antiplatelet and vasodilating properties and is thought to inhibit the uptake of adenosine into blood and vascular cells. Dipyridamole may also inhibit the breakdown of cyclic guanosine monophosphate. Modified-release dipyridamole has a marketing authorisation for the 'secondary prevention of ischaemic stroke and transient ischaemic attacks either alone or in conjunction with aspirin'. It is available either on its own as Persantin Retard, or in a combination tablet with aspirin as Asasantin Retard.\n\nDipyridamole has activity as a vasodilator; therefore it should be used with caution in people with severe coronary artery disease, including unstable angina and/or recent myocardial infarction, left ventricular outflow obstruction or haemodynamic instability (for example, decompensated heart failure). For full details of side effects and contraindications, see the summary of product characteristics.\n\nThe cost of treatment for 30\xa0days with modified-release dipyridamole alone is £7.50 and modified-release dipyridamole plus aspirin is £7.79 per person (BNF, edition 60). Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nFour randomised controlled trials (RCTs) were identified by the Assessment Group. Two of these were included in NICE technology appraisal guidance 90 (CAPRIE and ESPS-2) and two were published later (ESPRIT and PRoFESS). The RCTs were considered by the Assessment Group to be of good quality. Three of the trials were double blind and one was an open-label study (ESPRIT).\n\nCAPRIE (n\xa0=\xa019,185) compared clopidogrel with aspirin and ESPRIT (n\xa0=\xa02736) compared modified-release dipyridamole plus aspirin with aspirin. ESPS-2 (n\xa0=\xa06602) had four groups and compared modified-release dipyridamole with modified-release dipyridamole plus aspirin, and with aspirin and with placebo. PRoFESS (n\xa0=\xa020,332) made a head-to-head comparison of clopidogrel and modified-release dipyridamole plus aspirin. A wide range of dosages of aspirin were used in the trials.\n\nAll the trials included people who had experienced an ischaemic stroke and two trials included people who had experienced a transient ischaemic attack (ESPS-2 and ESPRIT). CAPRIE was the only trial to include people who had a prior myocardial infarction or who had peripheral arterial disease. The mean length of follow-up in the trials was between 1.91 and 3.5\xa0years. The CAPRIE and ESPRIT trials each used composite endpoints of first occurrence of ischaemic stroke, myocardial infarction, or vascular death (CAPRIE); and first occurrence of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication (ESPRIT). In the ESPS-2 trial, three discrete primary endpoints were reported: stroke, all-cause death, and stroke and/or all-cause death. The PRoFESS trial had a single primary endpoint of recurrent stroke.\n\n## Modified-release dipyridamole compared with aspirin\n\nThe ESPS-2 trial compared modified-release dipyridamole with aspirin. The study reported no statistically significant differences in risk reduction for the primary outcomes of stroke (relative risk [RR] 1.02; 95% confidence interval [CI] 0.85 to 1.22), stroke and/or all-cause death (RR 0.97; 95% CI 0.85 to 1.11), and all-cause death (RR 1.03; 95% CI 0.85 to 1.25). Additionally, no statistically significant differences were reported for secondary outcomes.\n\n## Modified-release dipyridamole plus aspirin compared with aspirin\n\nTwo trials (ESPS-2 and ESPRIT) compared modified-release dipyridamole plus aspirin with aspirin.\n\nIn the ESPS-2 trial, people receiving modified-release dipyridamole plus aspirin had a reduced risk of stroke (RR 0.76; 95% CI 0.63 to 0.93) compared with the aspirin group. The other primary outcomes in this study did not report statistically significant results for stroke and/or all-cause death (RR 0.87; 95% CI 0.75 to 1.00) and all-cause death (RR 1.02; 95% CI 0.84 to 1.23). For the secondary outcomes, statistically significant results favouring the group receiving modified-release dipyridamole plus aspirin were reported for stroke or transient ischaemic attack (RR 0.80; 95% CI 0.70 to 0.92), other vascular events (RR 0.55; 95% CI 0.33 to 0.94), ischaemic events (RR 0.77; 95% CI 0.65 to 0.92) and vascular events (RR 0.78; 95% CI 0.67 to 0.91). For other outcomes, no statistically significant differences were reported between the treatments.\n\nThe ESPRIT trial reported a statistically significant result for the primary outcome (that is, first occurrence of non-fatal stroke, non-fatal myocardial infarction, major bleeding complication or death from all vascular causes), favouring people receiving modified-release dipyridamole plus aspirin (hazard ratio [HR] 0.80; 95%CI 0.66 to 0.98). For the secondary outcomes, statistically significant results were reported for death from all vascular causes and non-fatal stroke (HR 0.78; 95% CI 0.62 to 0.97) and all vascular events (HR 0.78; 95% CI 0.63 to 0.97). For other outcomes, no statistically significant differences were reported between the treatments.\n\n## Modified-release dipyridamole plus aspirin compared with modified-release dipyridamole\n\nIn the ESPS-2 trial, modified-release dipyridamole plus aspirin compared with modified-release dipyridamole alone reduced the risk of stroke (RR 0.75; 95% CI 0.61 to 0.91). The other primary outcomes in this study did not report statistically significant results. These were stroke and/or all-cause death (RR 0.89; 95% CI 0.77 to 1.03) and all-cause death (RR 0.99; 95% CI 0.81 to 1.19). For the secondary outcomes, statistically significant results were reported for transient ischaemic attack (RR 0.80; 95% CI 0.66 to 0.97), ischaemic events (RR 0.76; 95% CI 0.64 to 0.90) and vascular events (RR 0.76; 95% CI 0.65 to 0.89). For other outcomes, no statistically significant differences were reported between the treatments.\n\n## Clopidogrel compared with aspirin\n\nThe CAPRIE trial compared clopidogrel with aspirin. For the primary outcome, the trial reported that clopidogrel compared with aspirin reduced the risk of a first occurrence of ischaemic stroke, myocardial infarction or vascular death in two groups. These were the all patients group (8.7% relative risk reduction; 95% CI 0.3 to 16.5) and a subgroup of people with peripheral arterial disease (23.8% relative risk reduction; 95% CI 8.9 to 36.2). No risk reduction was seen between treatments in subgroups defined by prior stroke (7.3% relative risk reduction; 95% CI –5.7 to 18.7) or by prior experience of a myocardial infarction (–3.7% relative risk reduction; 95% CI –22.1 to 12). For other outcomes, no statistically significant differences were reported between the treatments.\n\nData from the CAPRIE trial also allowed for a post-hoc subgroup analysis of data for people with multivascular disease (defined by the Assessment Group as people with experience of at least two of the following conditions: ischaemic stroke, myocardial infarction and symptomatic peripheral arterial disease). The analysis suggested that clopidogrel (compared with aspirin) reduced the risk of a first occurrence of ischaemic stroke, myocardial infarction or vascular death (14.9% relative risk reduction; 95% CI 0.3 to 27.3, p\xa0=\xa00.045).\n\n## Modified-release dipyridamole plus aspirin compared with clopidogrel\n\nThe PRoFESS trial investigated the non-inferiority of modified-release dipyridamole plus aspirin compared with clopidogrel. The trial reported no statistically significant difference in the primary outcome of recurrent stroke of any type (HR 1.01; 95% CI 0.92 to 1.11). For the secondary outcomes, there was a statistically significant reduction in the risk of events in the modified-release dipyridamole group compared with the clopidogrel group for new or worsening congestive heart failure (HR 0.78; 95% CI 0.62 to 0.96) and a statistically significant increase in the risk of events in the modified-release dipyridamole group compared with the clopidogrel group for intracranial haemorrhage (HR 1.42; 95% CI 1.11 to 1.83).\n\n## Indirect comparisons\n\nThe Assessment Group completed an indirect comparison that compared clopidogrel, modified- release dipyridamole plus aspirin, modified-release dipyridamole alone and aspirin using data from the four RCTs. Comparisons were made in a population of people with a history of ischaemic stroke or transient ischaemic attack.\n\nThe Assessment Group reported that the results from the mixed treatment comparison showed no statistical difference between the pairs of drug interventions, except for the outcomes of 'any recurrent stroke' and major bleeding. Compared with people assigned to treatment with aspirin, there was evidence of a risk reduction for 'any recurrent stroke' in people taking either clopidogrel (RR 0.75; 95% CI 0.60 to 0.93) or modified-release dipyridamole plus aspirin (RR 0.76; 95% CI 0.62 to 0.92). People treated with modified-release dipyridamole alone were at statistically significant higher risk of 'any recurrent stroke' than people treated with either clopidogrel or modified-release dipyridamole plus aspirin. The direct and indirect evidence was consistent.\n\n# Cost effectiveness\n\n## Bristol-Myers Squibb and Sanofi-Aventis model (clopidogrel)\n\nThe Bristol-Myers Squibb and Sanofi-Aventis model estimated the cost effectiveness of four treatments for the secondary prevention of occlusive vascular events. These treatments were aspirin, clopidogrel, modified-release dipyridamole plus aspirin and modified-release dipyridamole alone. In line with the licensed indications for the products, all four treatments were compared for use in people with a prior ischaemic stroke. In people with a history of myocardial infarction, peripheral arterial disease or multivascular disease, clopidogrel was compared with aspirin.\n\nThe manufacturers submitted a Markov model that comprised six health states: no event in model, history of stroke, history of myocardial infarction, TA80 state (an intermediate state reflecting NICE technology appraisal guidance 80 [now updated in CG94] which recommended clopidogrel plus aspirin for up to 12\xa0months after an NSTEMI event), history of stroke and myocardial infarction, and death (split into vascular and non-vascular death). People entering the model could remain stable, have a myocardial infarction or stroke, or die. The modelled patient population was aged 65\xa0years. The model was run with 3-month cycles for 35\xa0years. The perspective adopted was that of the UK NHS in line with the NICE reference case. Costs and utility values were discounted at a rate of 3.5%.\n\nEach patient population was modelled in the same way, with the exception that the baseline risks of vascular events differed by cohort (ischaemic stroke, myocardial infarction, peripheral arterial disease and multivascular disease). Event rates were different for years 1, 2 and 3 of the model. Event rates in year\xa03 were used to inform the model from year 3 onwards. Relative treatment effects for clopidogrel, modified-release dipyridamole and modified-release dipyridamole plus aspirin were based on either direct evidence or indirect evidence, using a network meta-analysis. The non-treatment costs used in the model were based on information from published burden of illness studies. Treatment costs were sourced from MIMS. All costs were inflated to 2007/08 prices, if necessary. The model included the branded price of clopidogrel. Utility values were derived from the published literature and were between 0.61 and 0.87. A disutility associated with adverse events of between −0.3 and −0.001 was also applied in the model.\n\nIn people who have had an ischaemic stroke, modified-release dipyridamole plus aspirin was associated with an additional cost of £107 and an additional quality-adjusted life year (QALY) of 0.45, producing an incremental cost-effectiveness ratio (ICER) of £237 per QALY gained compared with aspirin. Clopidogrel was associated with an additional cost of £2324 and an additional QALY of 0.07, producing an ICER of £31,204 per QALY gained compared with aspirin. Clopidogrel was associated with greater costs and fewer QALYs than modified-release dipyridamole plus aspirin.\n\nIn people who have had a myocardial infarction, clopidogrel was associated with an additional cost of £2643 and an additional QALY of 0.13, producing an ICER of £20,662 per QALY gained compared with aspirin. For people with peripheral arterial disease, clopidogrel was associated with an additional cost of £2470 and an additional QALY of 0.13, producing an ICER of £18,854 per QALY gained compared with aspirin. For people with multivascular disease, clopidogrel was associated with an additional cost of £1805 and an additional QALY of 0.12, producing an ICER of £15,524 per QALY gained compared with aspirin.\n\n## Boehringer Ingelheim model (modified-release dipyridamole)\n\nThe Boehringer Ingelheim model estimated the cost effectiveness of modified-release dipyridamole plus aspirin compared with aspirin, clopidogrel and no treatment. The manufacturer did not estimate the cost effectiveness of modified-release dipyridamole alone, because no new trial data were available for this treatment since NICE technology appraisal guidance 90. Separate analyses were conducted for people who have had an ischaemic stroke, and for people who have had a transient ischaemic attack. Only people tolerant to aspirin were considered in the analysis.\n\nThe manufacturer submitted a Markov model based on the Assessment Group model from NICE technology appraisal guidance 90. The model had five health states: no recurrent stroke, haemorrhagic stroke, recurrent ischaemic stroke, vascular death and non-vascular death. People entered the model at the 'no recurrent stroke' state and after each cycle of 6\xa0months could move to any of the other four states, or remain in the current state. After each cycle, transitions could occur to the other states.\n\nThe baseline age in the model was 66\xa0years, with a time horizon of 50\xa0years. The perspective adopted was that of the NHS and personal social services. Transition probabilities between the states in the model for the first 4\xa0years were taken from the PRoFESS, ESPRIT and ESPS-2 trials. Different transition probabilities were calculated for each 6-month period over the 4\xa0years. Transition probabilities in subsequent years for the stroke states were based on the final 6-month period of the 4\xa0years. Transition probabilities to death were estimated based on a factor of 1.5 applied to Office for National Statistics death rate data for the general population.\n\nCosts of stroke events were calculated from the literature and varied according to disabled or non-disabled status. Costs of hospital stay following congestive heart failure and other haemorrhagic events were sourced from the 2006/07 National Reference Costs. Drug acquisition costs were based on branded drug costs for modified-release dipyridamole and aspirin, and clopidogrel, and on the generic price for aspirin (2009 prices). Utility data from the PRoFESS trial at 1\xa0year were used, which was provided as commercial in confidence. A short-term disutility associated with different events was also included in the model. Costs and utility values were discounted at a rate of 3.5% per year.\n\nIn people who have had an ischaemic stroke, treatment with modified-release dipyridamole plus aspirin was associated with an additional cost of £704, and 0.131 additional QALYs per person with a corresponding ICER of £5377 per QALY gained, compared with aspirin. Treatment with clopidogrel compared with modified-release dipyridamole plus aspirin was associated with additional costs of £1808 and 0.015 additional QALYs per person with an ICER of £114,628 per QALY gained. The results were similar in people who have had a transient ischaemic attack. In this population, treatment with modified-release dipyridamole plus aspirin compared with aspirin was associated with an additional cost of £732 and 0.121 additional QALYs per person with an ICER of £6053 per QALY gained. The manufacturer reported that its model suggested that at a cost-effectiveness threshold of £20,000 per QALY gained, modified-release dipyridamole plus aspirin would no longer be cost effective compared with clopidogrel if the price of generic clopidogrel reduced to approximately 50% of that of branded clopidogrel.\n\n## Assessment Group model\n\nThe Assessment Group developed an individual patient sampling model, in which a series of individual profiles were generated whose combined characteristics were representative of the specified population. Analyses were split by population: ischaemic stroke, myocardial infarction, peripheral arterial disease and multivascular disease. The ischaemic stroke and transient ischaemic attack populations were assumed to be equivalent in risk and outcomes and so were modelled together. Within the myocardial infarction group, treatment strategies as described in the clinical guidelines on STEMI and NSTEMI (NICE clinical guideline 48 and NICE clinical guideline 94) were modelled initially. Once initial treatment was completed according to the guidelines, potential treatment strategies for this appraisal were considered as follow-on treatment.\n\nThe Assessment Group presented different treatment strategies, depending on the population and intolerances. The Assessment Group considered that this approach reflected the real world, because people may switch between different treatments. For each person in the model, age, sex and disability status was set. According to these variables, estimates of time to first event were applied. These events determined the event history of the person and included a fatal or new non-fatal ischaemic stroke event, a fatal or new non-fatal non-ischaemic stroke event, a fatal or new non-fatal myocardial infarction, death from other vascular causes, death from non-vascular causes and person discontinues current preventive medication for any reason. Only one event could occur at any one time. If the event was non-fatal then the person continued in the model, with an updated age, sex and disability status and updated risks, with the potential to incur additional events over time, moving through the model over a lifetime. Each person was modelled in the same way. Data provided by the manufacturers from the CAPRIE and PRoFESS trials were used to develop risk models for the economic model and to work out event fatality. An exponential survival function was used to model medication continuance over time. Adverse events were incorporated into the model.\n\nResource use was measured in terms of clinical events and time spent in chronic states, and differed by disability status. Drug costs were taken from the BNF58 and from the NHS Drug Tariff (January 2010) for generic clopidogrel, which at that point reported that the price of 30\xa0tablets was £10.90. Unit costs were drawn from various sources, including the manufacturers' submissions, and inflated if necessary to 2009. The costs were £6410 for non-fatal ischaemic or haemorrhagic stroke if the person was not disabled and £13,647 if they were disabled, £8768 for fatal ischaemic or haemorrhagic stroke, £5762 for non-fatal myocardial infarction, £2218 for fatal myocardial infarction and £2225 for other vascular or non-vascular death.\n\nUtility values were also drawn from a variety of sources, including the manufacturers' submissions and additional analyses requested from the manufacturer. Mean utility values were assigned to each chronic health state and a specific utility decrement effect was applied for each modelled event. Utility values for the myocardial infarction and peripheral arterial disease groups were 0.87 and 0.80 respectively. Utility values for the ischaemic stroke group and all utility decrements were taken from the Boehringer Ingelheim submission. Discounting at 3.5% was applied to costs and benefits after the first year. A lifetime horizon was used.\n\nDeterministic and probabilistic sensitivity analyses were conducted to explore the impact of uncertainty on the cost-effectiveness estimates.\n\nFor people who have had an ischaemic stroke or transient ischaemic attack, when the branded price for clopidogrel was used, the Assessment Group reported that the optimal treatment strategy was modified-release dipyridamole plus aspirin, followed by aspirin and finally clopidogrel. This produced an ICER of £16,894 per QALY gained and incremental costs of £354 and 0.021 QALYs compared with treatment with the next best strategy of modified-release dipyridamole plus aspirin, followed by aspirin.\n\nWhen the generic price for clopidogrel was used, the optimal treatment strategy changed so that it began with clopidogrel, followed by modified-release dipyridamole plus aspirin and finally aspirin. This produced an ICER of £13,558 per QALY gained, compared with the next best strategy of clopidogrel, followed by aspirin, followed by modified-release dipyridamole plus aspirin. This strategy was associated with an additional cost of £334 and 0.024 additional QALYs.\n\nFor people with intolerance to aspirin, clopidogrel followed by modified-release dipyridamole was the optimal treatment strategy with an ICER of £7142 per QALY gained compared with treatment with clopidogrel alone. This strategy was associated with an additional cost of £616 and 0.086 additional QALYs. It could be calculated from the data that for people with intolerance to aspirin and clopidogrel or for whom clopidogrel wasn't licensed, the optimal treatment strategy was modified-release dipyridamole alone with an ICER of £314 per QALY gained compared with no preventive treatment. This strategy was associated with an additional cost of £167 and 0.531 additional QALYs.\n\nFor people with intolerance to modified-release dipyridamole, the optimal treatment strategy depended on the price of clopidogrel. At the branded price, the preferred strategy was aspirin followed by clopidogrel with an ICER of £6797 per QALY gained, compared with clopidogrel alone. This strategy was associated with an additional cost of £628 and 0.092 additional QALYs. At the generic price, the optimal strategy was clopidogrel followed by aspirin, compared with aspirin followed by clopidogrel, with an ICER of £3970 per QALY gained, an additional cost of £224 and 0.056 additional QALYs. For people with intolerance to both aspirin and modified-release dipyridamole, only clopidogrel is available for long-term prevention. It was considered optimal by the Assessment Group compared with no preventive therapy, with an ICER of £275 per QALY gained. This strategy was associated with an additional cost of £163 and 0.591 additional QALYs.\n\nFrom the Assessment Group's analysis of the ischaemic stroke data, the ICERs could be calculated for people with intolerance to clopidogrel or for whom treatment with clopidogrel is not licensed, such as people who have had a transient ischaemic attack. Treatment with modified-release dipyridamole plus aspirin followed by aspirin had an ICER of £9145 per QALY gained, compared with treatment with aspirin followed by modified-release dipyridamole. This strategy was associated with an additional cost of £567 and 0.062 additional QALYs.\n\nThe Assessment Group reported that for people who have had a myocardial infarction the optimal treatment strategies were the same regardless of the price of clopidogrel. Aspirin followed by clopidogrel, compared with aspirin alone, was the optimal strategy for this population, with an ICER of £1964 per QALY gained (using the price of generic clopidogrel) and a difference in costs of £185 and QALYs of 0.094. For people with intolerance to aspirin, treatment with clopidogrel was likely to be the optimal treatment, compared with no preventive therapy, with an ICER of £2020 per QALY gained (using the price of generic clopidogrel) and a difference in cost of £468 and 0.232 additional QALYs.\n\nAfter consultation on the appraisal consultation document, the Assessment Group provided a reanalysis of the data for people who have had a myocardial infarction. This analysis used a price of clopidogrel of £5.13, reflecting the NHS tariff price for August 2010. The results showed that the lower price had no effect on the optimal treatment strategy: aspirin followed by clopidogrel remained the optimal treatment strategy.\n\nThe Assessment Group reported that for people with peripheral arterial disease the optimal treatment strategies were the same regardless of the price of clopidogrel. Clopidogrel followed by aspirin was the optimal strategy for this group, with an ICER of £2815 per QALY gained. It was associated with an additional cost of £983 and an additional 0.349 QALYs compared with treatment with aspirin alone followed by treatment with clopidogrel. In people with intolerance to aspirin, clopidogrel alone was the optimal treatment strategy. Compared with no preventive therapy, clopidogrel gave an additional 0.773 QALYs at a cost of £557, with an ICER of £721 per QALY gained.\n\nThe Assessment Group reported that for people with multivascular disease the optimal treatment strategies were the same regardless of the price of clopidogrel. Clopidogrel followed by aspirin was the optimal strategy for this group, compared with aspirin followed by clopidogrel. For the optimal strategy, treatment was associated with an ICER of £2604 per QALY gained, and incremental costs of £595 and incremental QALYs of 0.228. In people with intolerance to aspirin, clopidogrel alone was the optimal treatment strategy and was associated with lower total costs of –£548 compared with no preventive therapy, 0.723 additional QALYS and a corresponding ICER of –£758 per QALY gained.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of clopidogrel and modified-release dipyridamole, having considered evidence on the nature of occlusive vascular events and peripheral arterial disease and the value placed on the benefits of clopidogrel and modified-release dipyridamole by people who have had an occlusive vascular event or are at risk of one, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed current clinical management for the prevention of occlusive vascular events. The Committee heard from clinical specialists that they would value clear, straightforward guidance so that treatment could be started at the earliest possible point, when the risk of recurrent events is highest. Patient experts explained that treatment with clopidogrel or modified-release dipyridamole plus aspirin was an important part of treatment for the prevention of occlusive vascular events but is just one part of a wider programme of management involving both pharmacological and non-pharmacological treatment. The Committee heard from the patient experts that people are often on a number of treatments and would value a reduction in the number of tablets that need to be taken. The Committee heard from the patient experts that they considered that clopidogrel had fewer severe side effects than aspirin or modified-release dipyridamole. The Committee recognised that antiplatelet therapy such as clopidogrel and modified-release dipyridamole was one part of clinical management and that people valued treatments with ease of administration and few side effects.\n\nThe Committee discussed the results of the ESPRIT and PRoFESS trials, which became available after the publication of NICE technology appraisal guidance 90. The Committee noted that these trials included people who have had an ischaemic stroke or a transient ischaemic attack and there was no new evidence for people with peripheral arterial disease or for people who have had a myocardial infarction. The Committee discussed the results of the PRoFESS trial and considered that it had not shown that clopidogrel provided greater benefits than modified-release dipyridamole plus aspirin. But the Committee also considered that the trial had not shown that modified-release dipyridamole plus aspirin provided greater benefits than clopidogrel. The Committee noted comments made in the consultation on the appraisal consultation document about the exclusion of the MATCH and CHARISMA trials, but considered that these trials studied a combination of clopidogrel plus aspirin that was outside the scope of this appraisal. Likewise, it noted comments made about the EARLY trial that compared early and standard initiation of treatment, but considered that this had been appropriately excluded from the Assessment Group's review. The Committee concluded that the data published after NICE technology appraisal guidance 90 supported the conclusions in that guidance.\n\nThe Committee specifically discussed the duration of follow-up in the ESPRIT and PRoFESS trials, recognising that in NICE technology appraisal guidance 90 the evidence was limited to 2\xa0years' follow-up. It noted that the ESPRIT trial had a mean follow-up of 3.5\xa0years and the PRoFESS trial had a mean follow-up of 2.5\xa0years. The Committee heard from the clinical specialists that in clinical practice the length of time people stayed on treatment varied, but it could be longer than 2\xa0years. The clinical specialists discussed evidence from the ESPRIT trial that showed that Kaplan-Meier curves by treatment group continued to diverge over time. While the clinical specialists recognised that the study and its results have limitations, they considered that this provided evidence of a continued treatment effect beyond the 2 years used in NICE technology appraisal guidance 90. The Committee was persuaded that it was appropriate to examine the Assessment Group's analyses of cost effectiveness without specifying a limit on the duration of treatment.\n\nThe Committee considered the subgroup of people with multivascular disease. It noted that there is a range of definitions of multivascular disease, but heard from the clinical specialists that identifying the subgroup of people with multivascular disease was important and clinically meaningful. The Committee discussed the post-hoc analyses from the CAPRIE trial that suggested that this group is at high risk of occlusive vascular events and may need more intensive treatment. The Committee was aware of the limitations of post-hoc analyses but noted that the subgroups were based on large numbers of people. On balance, it considered multivascular disease to be appropriate to consider in the cost-effectiveness analysis.\n\nThe Committee recognised that after the publication of NICE technology appraisal guidance 90, clopidogrel became available in a number of generic preparations. The Assessment Group's analyses used both the branded and generic prices. The Committee was aware that after the assessment report was written the price of clopidogrel was reduced further from approximately £10 to approximately £5 per month. It noted that this would affect the cost-effectiveness results, because treatment with generic clopidogrel would cost less than previously stated. The Committee considered that it was appropriate to take account of the generic price of clopidogrel in its considerations and that any treatment with clopidogrel should use the least costly licensed preparation.\n\nThe Committee discussed the cost-effectiveness results from the two manufacturers' models. The Committee considered the Boehringer Ingelheim model, which reported that in people who have had an ischaemic stroke or a transient ischaemic attack, treatment with modified-release dipyridamole plus aspirin was cost effective compared with aspirin, with ICERs of around £5400 and £6100 per QALY gained, respectively. The Committee considered the Bristol-Myers Squibb and Sanofi-Aventis model, which found that in people who have had an ischaemic stroke, treatment with modified-release dipyridamole plus aspirin was cost effective with an ICER of around £240 per QALY gained compared with aspirin. In people who have had a myocardial infarction, or who have peripheral arterial disease and for people with multivascular disease, the ICERs were all below £21,000 per QALY gained, compared with aspirin. The Committee discussed the limitations of the models, noting that in the submissions neither model used the generic price of clopidogrel. However, the Committee was aware that the manufacturer of modified-release dipyridamole had commented that at a cost-effectiveness threshold of £20,000 per QALY gained, if the price of generic clopidogrel was about 50% of that of branded clopidogrel, modified-release dipyridamole plus aspirin would no longer be cost effective compared with clopidogrel. Furthermore, the Committee was aware of comments in response to consultation on the Assessment Report from the manufacturer of clopidogrel that for people who have had an ischaemic stroke, using a price of £10.90 for clopidogrel produced an ICER of under £500 per QALY gained for clopidogrel in comparison with modified-release dipyridamole.\n\nThe Committee discussed the results of the Assessment Group's model for the subgroup of people with peripheral arterial disease. It noted that a treatment strategy of clopidogrel followed by aspirin had an ICER of around £2800 per QALY gained, compared with aspirin alone. For people with intolerance to aspirin, treatment with clopidogrel had an ICER of around £720 per QALY gained compared with no preventive therapy. The Committee considered that for people with peripheral arterial disease clopidogrel was a cost-effective use of NHS resources.\n\nThe Committee discussed the results of the Assessment Group's model for the subgroup of people with multivascular disease. It noted that a treatment strategy of clopidogrel followed by aspirin had an ICER of around £2600 per QALY gained, compared with aspirin alone. In people with intolerance to aspirin, clopidogrel was a cost-saving strategy, costing less and producing more benefits than no preventive therapy. The Committee considered that for people with multivascular disease clopidogrel was a cost-effective use of NHS resources.\n\nThe Committee discussed the results of the Assessment Group's model for the subgroup of people who have had a myocardial infarction. It recognised that the model had incorporated the current NICE clinical guideline 48 and NICE clinical guideline 94 on the use of clopidogrel plus aspirin for the treatment of people with STEMI and NSTEMI, and modelled the use of clopidogrel monotherapy after its use as a combination therapy for acute coronary syndromes. The treatment strategy of aspirin followed by clopidogrel had an ICER of £2000 per QALY gained, compared with aspirin alone. A treatment strategy of clopidogrel followed by aspirin was associated with greater costs and fewer QALYs than starting with aspirin. In people with intolerance to aspirin, clopidogrel had an ICER of £2000 per QALY gained compared with no preventive therapy. The Committee discussed the re-analysis provided by the Assessment Group after the consultation on the appraisal consultation document, which showed that the further reduction of the price of clopidogrel to £5.13 (the price in July 2010) had no effect on the optimal treatment strategy. The Committee concluded that for people who have had a myocardial infarction, when treatment with combined clopidogrel and aspirin therapy is no longer appropriate, clopidogrel was a cost-effective use of NHS resources only for people who have a contraindication to aspirin or intolerance to it.\n\nThe Committee discussed the results of the Assessment Group's model for people who have had an ischaemic stroke. The Committee noted that the optimal treatment strategy changed depending on whether the branded or generic price of clopidogrel was used. When the generic price of clopidogrel was used, the Assessment Group model found that clopidogrel followed by modified-release dipyridamole plus aspirin and then aspirin alone had an ICER of £13,600 per QALY gained, compared with clopidogrel followed by aspirin, followed by modified-release dipryidamole plus aspirin. In people with intolerance to modified-release dipyridamole, clopidogrel followed by aspirin had an ICER of £4000 per QALY gained compared with aspirin alone. In people with intolerance to aspirin, clopidogrel followed by modified-release dipyridamole alone had an ICER of £7100 per QALY gained, compared with treatment with clopidogrel alone. For people who had intolerance to clopidogrel and aspirin, treatment with modified-release dipyridamole alone had an ICER of £314 per QALY gained in comparison with no preventive treatment. The Committee recognised that the differences in the total costs and QALYs for the different treatment strategies each including clopidogrel, modified-release dipyridamole plus aspirin and aspirin were small. However, it noted that these were consistent in all analyses, and with a further reduction in the price of clopidogrel the differences in costs would be larger. The Committee concluded that using clopidogrel at the generic price was a cost-effective use of NHS resources. Modified-release dipyridamole plus aspirin was a cost-effective use of NHS resources only when it was used for people who had a contraindication or intolerance to clopidogrel. Modified-release dipyridamole alone was a cost-effective use of NHS resources only when it was used in people who had a contraindication or intolerance to aspirin and clopidogrel.\n\nThe Committee heard from the clinical specialists that people who have had a transient ischaemic attack are sometimes treated with clopidogrel. However, the Committee recognised that recommendations could not be made for the use of clopidogrel for people who have had a transient ischaemic attack because clopidogrel is not licensed for this indication. For people who have had a transient ischaemic attack, treatment with modified-release dipyridamole plus aspirin followed by aspirin had an ICER of £9,100 per QALY gained compared with treatment with aspirin alone. For people who had intolerance to aspirin, treatment with modified-release dipyridamole alone had an ICER of £314 per QALY gained in comparison with no preventive treatment. The Committee considered that for people who have had a transient ischaemic attack, treatment with modified-release dipyridamole plus aspirin could be considered a cost-effective use of NHS resources. Modified-release dipyridamole alone was considered to be a cost-effective use of NHS resources for people who have had a transient ischaemic attack only if aspirin is contraindicated or not tolerated.\n\n# Summary of the Appraisal Committee's key conclusions\n\nTA210 (STA)\n\n\n\nAppraisal title: Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of technology appraisal guidance 90)\n\nFAD section\n\nKey conclusions\n\nFor people who have had an ischaemic stroke, clopidogrel is recommended as a treatment option. For people who have a contraindication or intolerance to clopidogrel, modified-release dipyridamole plus aspirin is recommended as a treatment option. For people who have a contraindication or intolerance to both clopidogrel and aspirin, modified-release dipyridamole alone is recommended as a treatment option.\n\nFor people who have had a transient ischaemic attack, modified-release dipyridamole plus aspirin is recommended as a treatment option. For people who have a contraindication or intolerance to aspirin, modified-release dipyridamole alone is recommended as a treatment option.\n\nFor people who have had a myocardial infarction, clopidogrel is recommended only when treatment with aspirin is contraindicated or not tolerated.\n\nFor people with peripheral arterial disease, clopidogrel is recommended as a treatment option.\n\nFor people with multivascular disease, clopidogrel is recommended as a treatment option.\n\nTreatment with clopidogrel to prevent occlusive vascular events should be started with the least costly licensed preparation.\n\n\n\n\n\n\n\n\n\nCurrent practice\n\nClinical need of patients including the availability of alternative treatments\n\n\n\nPatients are often on a number of treatments and would value a reduction in the number of tablets that need to be taken.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits\n\n\n\nThis is a review of established technologies.\n\nn/a\n\nWhat is the position of the treatment in the pathway of care for the condition\n\n\n\nTreatment with clopidogrel or modified-release dipyridamole plus aspirin is an important part of treatment for the prevention of occlusive vascular events, but is just one part of a wider programme of management involving both pharmacological and non-pharmacological treatment.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nClopidogrel is not licensed for the treatment of transient ischaemic attack, and therefore recommendations could not be made about the use of clopidogrel in this patient population.\n\n\n\n\n\nAdverse effects\n\n\n\nThe Committee heard from patient experts that they considered that clopidogrel had fewer severe side effects than aspirin or modified-release dipyridamole.\n\n\n\n\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\n\n\nTwo trials (ESPRIT and PRoFESS) became available since the publication of NICE technology appraisal guidance 90.\n\n\n\nRelevance to general clinical practice in the NHS\n\n\n\nThe clinical specialists cited evidence from the ESPRIT trial that showed that Kaplan-Meier curves by treatment group continued to diverge over time. While the clinical specialists recognised that the study and its results have limitations, they considered that this provided evidence of a continued treatment effect beyond the 2 years recommended in NICE technology appraisal guidance 90.\n\n\n\nUncertainties generated by the evidence\n\n\n\nThe ESPRIT and PRoFESS trials included people who have had an ischaemic stroke or a transient ischaemic attack, and there was no new evidence relating to people with peripheral arterial disease or people who have had a myocardial infarction.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness\n\n\n\nNICE technology appraisal guidance 90 considered subgroups of people who had experienced ischaemic stroke, transient ischaemic attack or myocardial infarction, or who had peripheral arterial disease.\n\n\n\n\n\nn/a\n\n\n\n\n\n\n\n\n\nAdditionally, the Committee considered multivascular disease to be appropriate to consider in the cost-effectiveness analysis.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\n\n\nThe data published after NICE technology appraisal guidance 90 were supportive of the conclusions in that guidance.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nThe Committee discussed the manufacturers' models, noting that neither model used the generic price of clopidogrel.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nSince the assessment report was written, the price of clopidogrel has been reduced further from approximately £10 to £5 a month.\n\n\n\nIncorporation of health-related quality of life benefits and utility values\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\n\n\nThis was not an issue in the analyses.\n\nn/a\n\n\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost-effective?\n\nNICE technology appraisal guidance 90 includes subgroups of people who had experienced ischaemic stroke, transient ischaemic attack or myocardial infarction, or who had peripheral arterial disease.\n\n\n\n\n\nn/a\n\n\n\n\n\n\n\n\n\nAdditionally, the Committee considered multivascular disease to be appropriate to consider in the cost-effectiveness analysis because in post-hoc analyses of the CAPRIE trial, people with multivascular disease were found to be at high risk of occlusive vascular events.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\n\n\nSince the publication of NICE technology appraisal guidance 90, clopidogrel has become available in a number of generic formulations.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nFor people who have had an ischaemic stroke, the optimal strategy for treatment changed depending on whether the branded or generic price of clopidogrel was used.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nFor the subgroup of people with peripheral arterial disease, a treatment strategy of clopidogrel followed by aspirin had an ICER of around £2800 per QALY gained compared with aspirin alone. In people with intolerance to aspirin, treatment with clopidogrel had an ICER of around £720 per QALY gained compared with no preventive therapy.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nFor the subgroup of people with multivascular disease, a treatment strategy of clopidogrel followed by aspirin had an ICER of around £2600 per QALY gained compared with treatment with aspirin alone. In people with intolerance to aspirin, clopidogrel was a cost-saving strategy, costing less and producing more benefits than no preventive therapy.\n\n\n\n\n\n\n\nFor the subgroup of people who have had a myocardial infarction, the treatment strategy of aspirin followed by clopidogrel had an ICER of £2000 per QALY gained, compared with treatment with aspirin alone. In people with intolerance to aspirin, clopidogrel had an ICER of £2000 per QALY gained compared with no preventive therapy\n\n\n\n\n\n\n\n\n\nFor people who have had an ischaemic stroke, when the generic price of clopidogrel was used, the treatment strategy of clopidogrel followed by modified-release dipyridamole plus aspirin and then aspirin alone had an ICER of £13,600 per QALY gained compared with treatment with clopidogrel followed by aspirin, followed by modified-release dipyridamole plus aspirin. In people with intolerance to modified-release dipyridamole, the treatment strategy of clopidogrel followed by aspirin had an ICER of £4000 per QALY gained compared with aspirin alone. In people with intolerance to aspirin, the treatment strategy of clopidogrel followed by modified-release dipyridamole alone had an ICER of £7,100 per QALY gained, compared with treatment with clopidogrel alone. For people who had intolerance to clopidogrel and aspirin, treatment with modified-release dipyridamole alone had an ICER of £314 per QALY gained in comparison with no preventive therapy.\n\n\n\n\n\n\n\nFor people who have had a transient ischaemic attack, treatment with modified-release dipyridamole plus aspirin had an ICER of £9,100 per QALY gained compared with treatment with aspirin alone. For people who had intolerance to aspirin, treatment with modified-release dipyridamole alone had an ICER of £314 per QALY gained in comparison with no preventive therapy.\n\n\n\nAdditional factors taken into account\n\nPatient Access Schemes\n\n(PPRS)\n\nNo patient access schemes were submitted.\n\nn/a\n\nEnd of life considerations\n\n\n\nEnd-of-life considerations were not discussed.\n\nn/a\n\nEqualities considerations, social value judgements\n\n\n\nNo equalities issues were raised in the submissions.\n\nn/a", 'Related NICE guidance': 'Unstable angina and NSTEMI: the early management of unstable angina and non-ST-segment-elevation myocardial infarction. NICE clinical guideline 94 (2010).\n\nMI: secondary prevention. Secondary prevention in primary and secondary care for patients following a myocardial infarction. NICE clinical guideline 48 (2007).', 'Review of guidance': 'The guidance on this technology will be considered for review by the Guidance Executive in July 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveNovember 2010', 'Changes after publication': 'February 2014: implementation section updated to clarify that clopidogrel and modified-release dipyridamole is recommended as an option for preventing occlusive vascular events. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': "NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nIt replaces NICE technology appraisal guidance 90 (published May 2005).\n\nThe review and re-appraisal of clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events has resulted in a change in the guidance. Specifically:\n\nTreatment with modified-release dipyridamole in combination with aspirin for people who have had an ischaemic stroke is now recommended only if clopidogrel is contraindicated or not tolerated.\n\nTreatment with modified-release dipyridamole in combination with aspirin for people who have had an ischaemic stroke or a transient ischaemic attack is no longer limited to 2 years' duration from the most recent event.\n\nClopidogrel is no longer recommended only for people who are intolerant of aspirin and have had an occlusive vascular event or have peripheral arterial disease (see section 1 for new guidance).\n\nModified-release dipyridamole alone is now recommended as an option to prevent occlusive vascular events (see sections 1.2 and 1.3).\n\nThe recommendations from this guideline have been incorporated into a NICE Pathway. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE."}
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https://www.nice.org.uk/guidance/ta210
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Evidence-based recommendations on clopidogrel and modified-release dipyridamole for preventing occlusive vascular events in adults.
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Prucalopride for the treatment of chronic constipation in women
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Prucalopride for the treatment of chronic constipation in women
Evidence-based recommendations on prucalopride (Resolor) for treating chronic constipation in women.
# Guidance
Prucalopride is recommended as an option for the treatment of chronic constipation only in women for whom treatment with at least two laxatives from different classes, at the highest tolerated recommended doses for at least 6 months, has failed to provide adequate relief and invasive treatment for constipation is being considered.
If treatment with prucalopride is not effective after 4 weeks, the woman should be re-examined and the benefit of continuing treatment reconsidered.
Prucalopride should only be prescribed by a clinician with experience of treating chronic constipation, who has carefully reviewed the woman's previous courses of laxative treatments specified in 1.1.# The technology
Prucalopride (Resolor, Movetis) is a selective serotonin (5-HT4) receptor agonist that predominantly stimulates colonic motility. Prucalopride has a UK marketing authorisation for the 'symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief'.
Prucalopride is administered orally. The summary of product characteristics (SPC) states that the recommended dose of prucalopride is 2 mg once daily for adult women (up to 65 years old) and 1 mg once daily for older women (over 65 years). The dose for older women can be increased to 2 mg once daily if needed. If once-daily prucalopride is not effective after 4 weeks, the patient should be re-examined and the benefit of continuing treatment reconsidered.
The SPC reports that the most common adverse effects that may be associated with prucalopride treatment include headache and gastrointestinal symptoms (abdominal pain, nausea or diarrhoea). Most adverse effects occur at the start of treatment and usually subside within a few days of continued treatment. For full details of side effects and contraindications, see the SPC.
Prucalopride is available in 1-mg and 2-mg tablets. The acquisition cost of prucalopride 1 mg is £38.69 for a pack of 28 tablets. The acquisition cost of prucalopride 2 mg is £59.52 for a pack of 28 tablets (excluding VAT; 'British National Formulary' , 60th edition). The manufacturer estimated that the annual cost of treatment with prucalopride is £622 for adult women and £403 for older women (excluding any monitoring costs), assuming that each woman receives treatment for an average of 220 days each year. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of prucalopride and a review of this submission by the Evidence Review Group (ERG; appendix B).
The manufacturer described nine trials that provided evidence on the clinical effectiveness of prucalopride in people with chronic constipation. There were three pivotal phase III randomised, double-blind, placebo-controlled trials in adults (aged 18–65 years) with chronic constipation (PRU-INT-6, PRU-USA-11 and PRU-USA-13), one phase III, randomised, double-blind, placebo-controlled trial in older people (65 years or older, PRU-INT-12), one trial in adults (18 years or older) with opioid-induced constipation (PRU-INT-8), one retreatment study (PRU-USA-28) and three extended, open-label, single-arm, observational studies (PRU-INT-10, PRU-USA-22 and PRU-INT-17). The key clinical evidence presented by the manufacturer was derived from the three pivotal trials, which reported the efficacy of prucalopride compared with placebo in adults, and PRU-INT-12, which reported the efficacy of prucalopride compared with placebo in older people. The number of people randomised to PRU-INT-6, PRU-USA-11, PRU-USA-13 and PRU-INT-12 was 720, 628, 651 and 305 respectively. Approximately 90% of people in the pivotal trials were women. The manufacturer also presented other trials, which reported additional safety considerations and response rates (see section 3.8). The manufacturer's submission stated that people were enrolled in the pivotal trials and PRU-INT-12 if they had a history of chronic constipation (defined as no more than two spontaneous complete bowel movements per week) and one or more of the following for at least 6 months before the screening visit:
straining during at least 25% of bowel movements
very hard or hard stools in at least 25% of bowel movements
sensation of incomplete evacuation for at least 25% of bowel movements.
There was a 2-week run-in period for each pivotal trial and for PRU-INT-12, in which no laxative medication (except for rescue medication) was allowed. People in the pivotal trials were then randomised 1:1:1 to prucalopride 2 mg, prucalopride 4 mg or placebo. People in PRU-INT-12 were also randomised to prucalopride 1 mg. If people had not had a bowel movement for 3 days or more, they could receive a single dose of 15 mg bisacodyl as rescue medication (medications used for quick relief of symptoms). If a bowel movement did not occur, the dose of bisacodyl could be increased; if there was still no bowel movement after this, an enema could be administered. In the pivotal trials people were treated for 12 weeks and in PRU-INT-12 people were treated for 4 weeks. Data were collected at 4- and 12-week time points in the pivotal trials and at 4 weeks in PRU-INT-12.
The primary outcome measure in the pivotal trials was three or more spontaneous complete bowel movements per week which was evaluated over the first 4 weeks of treatment and averaged over the full 12 weeks of the trial. The proportion of people with an average increase of one or more spontaneous complete bowel movements per week compared with baseline was measured as a secondary outcome in the trials. The proportion of people treated with prucalopride 2 mg in the pivotal trials who had three or more spontaneous complete bowel movements per week during weeks 1–4 ranged from 23.7% to 32.1%, compared with 9.8% to 11.5% for placebo (all p ≤ 0.001). During weeks 1–12, the proportion of people treated with prucalopride 2 mg who had three or more spontaneous complete bowel movements per week ranged from 19.5% to 28.9% compared with 9.6% to 13.0% for placebo (all p ≤ 0.01).
The proportion of people treated with prucalopride 2 mg in the pivotal trials who had an average increase of one or more spontaneous complete bowel movements per week (the secondary outcome measure) during weeks 1–4 ranged from 41.0% to 56.5% compared with 20.9% to 25.5% for placebo (all p ≤ 0.001). During weeks 1–12 of treatment, the proportion of people who had an average increase of one or more spontaneous complete bowel movements per week ranged from 38.1% to 50.3% for prucalopride 2 mg compared with 20.9% to 27.5% for placebo (all p ≤ 0.001).
In PRU-INT-12 the proportion of people treated with prucalopride who had an average of three or more spontaneous complete bowel movements per week during weeks 1–4 was 39.5% for prucalopride 1 mg and 32.0% for prucalopride 2 mg, compared with 20.0% for placebo (p ≤ 0.05). In addition, the proportion of people treated with prucalopride who had an average increase of one or more spontaneous complete bowel movements per week during weeks 1–4 was 61.1% for prucalopride 1 mg and 56.9% for prucalopride 2 mg compared with 33.8% for placebo (p ≤ 0.05).
The manufacturer's submission reported quality-of-life data from the pivotal trials, which were derived from Patient Assessment of Constipation – Symptoms (PAC-SYM) and Patient Assessment of Constipation – Quality of Life (PAC-QOL) scores. All pivotal trials showed a significantly greater improvement in PAC-QOL scores for people treated with prucalopride compared with placebo at weeks 1–4 and weeks 1–12 (both p < 0.001 compared with placebo). Statistically significant improvements in PAC-SYM scores were also seen in all three trials at weeks 1–4 (p ≤ 0.001 compared with placebo) and in all trials except PRU-INT-6 at weeks 1–12 (p ≤ 0.05). PRU-INT-12 also reported quality-of-life data for older women derived from PAC-SYM and PAC-QOL scores. Statistically significant improvements in PAC-SYM and PAC-QOL scores were shown for prucalopride 1 mg compared with placebo at week 4 (both p ≤ 0.05). Improvements in PAC-SYM and PAC-QOL scores for prucalopride 2 mg compared with placebo were seen at week 4 but they did not reach statistical significance.
Surveys of the SF-36 mental component summary and the SF-36 physical component summary were taken during the run-in period and at weeks 4 and 12 of the pivotal trials. No trials showed statistically significantly greater improvements in SF-36 scores for prucalopride 2 mg compared with placebo at week 12. A statistically significant improvement in the SF-36 physical component summary at week 4 was only seen in the PRU-INT-6 study for prucalopride 2 mg compared with placebo (p ≤ 0.05). Additional evidence provided by the manufacturer in response to the appraisal consultation document suggested, however, that when only the cohort of patients who responded to treatment was compared with placebo, a statistically significant difference between the effect of prucalopride and placebo was seen. The SF-36 data were not used in further sections of the manufacturer's submission.
The following three single-arm extension studies were designed to assess the long-term tolerability and safety of prucalopride:
PRU-INT-10: included people from PRU-INT-6 (pivotal trial) and PRU-INT-12 (trial in older people).
PRU-USA-22: included people from PRU-USA-3 (phase II dose–response trial), PRU-USA-11 and PRU-USA-13 (pivotal trials), PRU-USA-21 (phase II dose–response trial), PRU-USA-25 (phase III dose–titration trial), PRU-USA-27 (opioid-induced chronic constipation trial) and PRU-USA-28 (phase III retreatment trial).
PRU-INT-17: included people from PRU-INT-8 and PRU-INT-14 (both opioid-induced chronic constipation trials). Studies PRU-INT-10, PRU-USA-22 and PRU-INT-17 had durations of 24, 36 and 12 months respectively. People received prucalopride doses ranging from 0 to 4 mg. Results from these studies reported that prucalopride treatment was associated with an improvement in constipation from baseline at all time points (this was statistically significant in PRU-INT-10 and PRU-USA-22) and a decrease in the use of laxatives. At 12 months, on average, less than 50% of people remained in these trials. The reasons for stopping treatment included insufficient treatment response (18%), withdrawal of consent (15%) and adverse events (9%). However for the three trials, most people (approximately 45%) discontinued treatment because the previous trial sponsor decided to stop the prucalopride development programme worldwide.
The manufacturer reported that prucalopride was generally well tolerated and that the majority of adverse events in the clinical trials were mild or moderate. In PRU-INT-6, 80.8% of people in the prucalopride 2 mg arm reported at least one adverse event, compared with 66.0% in the placebo arm. The incidence of serious adverse events was 2.1% in both the prucalopride and placebo arms. The most frequently reported adverse events included headache, nausea and abdominal pain. The incidence of diarrhoea in the prucalopride 2 mg arm (13.0%) was more than twice that of the placebo arm (5.4%). The adverse event profiles in the PRU-USA-11 and PRU-USA-13 trials were similar to those in the PRU-INT-6 trial. The onset of these adverse events was most frequently reported on the day after the start of treatment ('day one') and the duration was short. The manufacturer reported that when day one was excluded from the analysis, the incidence of adverse events was comparable among the treatment groups.
The manufacturer developed a decision analytic model based on patient-level data from the clinical trials. All data from the included trials, for men and women, were used in the model, however all analyses presented by the manufacturer were derived using data from women only. The model compared prucalopride 1 mg daily (for older women) and prucalopride 2 mg daily (for adult women) with placebo for up to 52 weeks. In both arms, bisacodyl as rescue medication was allowed, and if it was used, any bowel movements in the following 48 hours were not included in the analysis. In the base case, results were presented for all women (that is, adult women and older women). Treatment duration was 4 weeks, after which women could only continue treatment if they had three or more spontaneous complete bowel movements per week.
Two additional analyses were presented. One incorporated data for adult women only and one incorporated data for older women only. For the first 12 weeks, the model for adult women included randomised controlled trial data for all women treated with prucalopride 2 mg. Additional observational trial data were incorporated up to a further 40 weeks after the initial trial period. The model in older women incorporated randomised controlled trial data for women treated with prucalopride 1 mg in the first 4 weeks followed by observational data for up to 1 year.
No discounting was applied in the model because both costs and utility values were modelled for 52 weeks. The only costs incorporated in the economic model were the list prices of prucalopride 2 mg (£2.13 per tablet) and prucalopride 1 mg (£1.38 per tablet). Costs and utility values for placebo plus rescue therapy were not included in the model. The manufacturer assumed that women would take their treatment for only part of the year (220 days). Adverse events and their associated costs were not included in the model. The manufacturer acknowledged that the rates of adverse events were comparable between prucalopride and placebo and therefore they considered that including these events would not affect the outcome of the analysis.
Clinical data incorporated in the model were derived from the three pivotal trials, two trials in older people (PRU-INT-12 and PRU-USA-26) and the extension studies. Patient characteristics from these studies were used to inform the disease states in the model. Further patient characteristics were obtained from other trials not fully described in the manufacturer's submission, including three additional dose–response trials (PRU-INT-1, PRU-INT-2 and PRU-USA-3) and two phase II trials (PRU-FRA-1 and PRU-GBR-4). No methods or results for these trials were included in the submission. PAC-SYM and PAC-QOL data from the clinical trials were mapped to EQ-5D through SF-36 scores using the generalised least squares regression method. People who had chronic constipation who did not respond to prucalopride were assumed to have no quality-adjusted life year (QALY) gain.
The manufacturer's base case presented an average cost-effectiveness ratio because no cost for the comparator was included in the model. The average cost of prucalopride for all women was £498 with an average QALY gain of 0.0316, resulting in an average incremental cost-effectiveness ratio (ICER) of £15,700 per QALY gained. The average cost of prucalopride for adult women (18–64 years) was £622 with an average QALY gain of 0.0369, resulting in an ICER of £16,800 per QALY gained. The average cost of prucalopride for older women (65 years or older) was £403 with an average QALY gain of 0.0342, resulting in an ICER of £11,700 per QALY gained.
The manufacturer also presented an analysis that included all women who had an additional bowel movement per week (the secondary outcome measure in the pivotal trials). The manufacturer estimated that, for all women, the annual cost per person to reach this secondary outcome would be £498 with an average QALY gain of 0.0277, resulting in an ICER of £18,000 per QALY gained. For adult women, the cost would be £622 with an average QALY gain of 0.0342, resulting in an ICER of £18,000 per QALY gained. The cost for older women was £403 with a QALY gain of 0.0255, resulting in an ICER of £15,800 per QALY gained.
The manufacturer presented probabilistic sensitivity analyses for all women, adult women and older women, with and without an adjustment for baseline severity of constipation. The probabilistic sensitivity analysis results showed that the probabilities of the ICERs for prucalopride exceeding £20,000 per QALY gained were approximately 45%, 44% and 47% for all women, adult women and older women respectively. The probabilities of the ICERs for prucalopride exceeding £30,000 per QALY gained were approximately 40%, 36% and 45% for all women, adult women and older women respectively. The manufacturer reported that the main factors affecting cost effectiveness were:
the effect of constipation severity at baseline on treatment effectiveness (that is, if the treatment effect is assumed to be the same regardless of baseline severity, the probability of prucalopride being cost effective at £20,000 per QALY gained is increased)
the ability to identify women whose constipation did not respond to prucalopride at a very early stage of treatment
the acquisition cost of prucalopride
the utility values derived from mapping PAC outcome measures (PAC-SYM and PAC-QOL) to EQ-5D scores.
The ERG reviewed the evidence submitted by the manufacturer on the clinical and cost effectiveness of prucalopride. It noted that the three pivotal trials (PRU-INT-6, PRU-USA-11 and PRU-USA-13) formed the basis of the manufacturer's assessment of clinical effectiveness. The ERG was unclear how people from the original trials were selected for the extension studies because no baseline data were provided in the manufacturer's submission. The ERG considered it possible that the people in the extension studies had constipation that was not necessarily refractory to laxative treatment. The ERG further noted that the extension studies included both older people and people with opioid-induced chronic constipation and that the results were not separated. The ERG was also concerned that the high rate of withdrawal from the extension studies (more than 50% of people at 12 months) was likely to have resulted in people who were relatively more satisfied with their treatment continuing with treatment compared with those dropping out.
Overall, the ERG noted that there was a considerable quantity of clinical-effectiveness evidence in adults that suggested an improvement in chronic constipation for people treated with prucalopride compared with placebo. The ERG calculated the weighted average of the effect of prucalopride across the pivotal trials and estimated that 28% of people reached the primary outcome of three or more spontaneous complete bowel movements per week after treatment with prucalopride 2 mg compared with 10.6% of people treated with placebo after 14 weeks. After 112 weeks, 23.8% of people treated with prucalopride 2 mg reached the primary outcome compared with 11.4% of people treated with placebo.
The ERG was uncertain whether the population in the trials reflected the population covered by the marketing authorisation or decision problem for prucalopride. It noted that in the three pivotal trials, 17% of people at baseline answered that they had found their previous laxative treatment adequate and may not have been eligible for the trials (that is, not laxative refractory). The ERG further considered that people who have one or two bowel movements per week while on laxative treatment were likely to be having beneficial effects from laxatives and therefore their constipation may not have been refractory to laxatives. It also considered that any two of the criteria used alone by the manufacturer to describe chronic constipation (section 3.1 above) would be unlikely to be sufficient evidence of treatment failure with laxatives.
The ERG considered that the comparator used in the pivotal trials (placebo plus rescue medication with bisacodyl) did not represent standard clinical practice for chronic constipation. It suggested that a more appropriate comparator would have been a variety of oral laxative treatments, at the discretion of the treating clinician. It further commented that the manufacturer's submission did not consider some of the comparators outlined in the decision problem, including invasive procedures (such as rectal interventions) and bowel surgery.
The ERG assessed the manufacturer's cost-effectiveness analysis and considered its methodological approach acceptable. It noted that the manufacturer's decision to exclude the cost of the comparator from the analysis was conservative. However, the ERG was concerned that precise details of the trials used to inform the inputs in the economic model were not given or did not fully correspond with those described in the manufacturer's submission. It noted that five trials used for the economic model (PRU-INT-1, PRU-INT-2, PRU-USA-3, PRU-FRA-1 and PRU-GBR-4) were not fully described in the submission.
The ERG noted that quality of life data from PAC-QOL and PAC-SYM scores were mapped to the EQ-5D using SF-36 scores obtained from the trials. The ERG was concerned that the SF-36 data did not directly contribute to EQ-5D scores, even though these results were available from the trials, and no sensitivity analysis was undertaken by the manufacturer to test the impact of using SF-36 results.
The ERG noted that the manufacturer's model only allowed for variation in the response rate and mean treatment rates to be analysed. It also noted that no explicit allowance was made for withdrawal from treatment at any time after 4 weeks and that the assumption that the last measured QALY gain was sustained for the rest of the year was not tested in the model.
The ERG noted there were more adverse events in the prucalopride arms than in the placebo arms of the trials. It was concerned that adverse events, including rare events, and their associated costs were not included in the model.
The ERG ran the manufacturer's model using alternative scenarios and assumptions including the following:
Assuming that people who responded to treatment with prucalopride would receive treatment for a mean of 220 days or 365 days.
Using response rates taken from pooled trial estimates at week 4 calculated in the effectiveness review.
Allowing for the possibility that adverse events may be higher in the prucalopride arm than the placebo arm by increasing costs by 5% and reducing QALY gain by 5% in the prucalopride arm.
Reducing the effectiveness (QALY) of prucalopride and placebo uniformly by 25%, 50% and 75% to allow for possible variation in the regression method used to calculate the QALYs.The ERG concluded that the results from its sensitivity analysis were not significantly different from those provided by the manufacturer.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of prucalopride, having considered evidence on the nature of chronic constipation and the value placed on the benefits of prucalopride by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
# Clinical effectiveness
The Committee discussed the nature of chronic constipation and current clinical practice for the treatment of people with laxative-refractory chronic constipation. The clinical specialists stated that chronic constipation has a wide spectrum of severity and that for a minority of people with intractable constipation there can be very low quality of life and feelings of hopelessness. The Committee understood that current practice is a stepped approach to management starting with lifestyle and dietary changes. If these changes provide inadequate relief, different classes of oral laxatives are available. For some people chronic constipation can become intractable, and relatively invasive procedures (such as suppositories, enemas, rectal irrigation and manual disimpaction) may be tried. The Committee heard from the manufacturer that the intended position of prucalopride in the treatment pathway for chronic constipation is after failure of oral laxatives because of inadequate efficacy or intolerance. The Committee noted the clinical specialists' advice that people who have had an inadequate response to an oral laxative often try many different types before considering invasive options. The Committee was aware that the scope for this appraisal was to consider the use of prucalopride in women with chronic constipation in whom standard laxative regimens have failed to provide adequate relief, and for whom invasive procedures are being considered.
The Committee discussed patient selection and the conduct of the clinical trials. The Committee noted that the inclusion criteria in the trials were people with chronic constipation in whom laxatives failed to provide adequate relief. The Committee also noted that it was unclear how inadequate relief had been defined in the trials. In addition, the Committee heard from the ERG that up to 30% of the people in the trials responded to laxatives, so their constipation may not have fitted these inclusion criteria. The Committee was also aware of concerns raised during consultation that because adequate relief had not been properly defined by the manufacturer, this could contribute to widespread use of prucalopride in people in whom laxatives had not necessarily failed. However, the Committee heard from the clinical specialists that it is often difficult to differentiate between people for whom laxatives do not provide adequate relief and those who no longer want to use laxatives because of the side effects, despite any treatment benefit they may achieve. Based on advice from the clinical specialists, the Committee concluded that inadequate relief from previous laxative treatments could be defined by duration of follow-up and by the number of laxatives previously used.
The Committee considered the comparator, placebo plus rescue medication with bisacodyl, used in the clinical trials. The Committee noted the concerns of the NHS representatives that the use of placebo as a comparator did not reflect current clinical practice for chronic constipation and that prucalopride had not been compared with some of the less expensive oral laxatives commonly used in the NHS. It was aware that similar concerns had been raised during consultation. The Committee also noted that bisacodyl was used as rescue medication in the clinical trials and it could have been a comparator. However it heard from the manufacturer that in clinical practice, people for whom laxatives fail to provide adequate relief sometimes adopt a 'do nothing' approach and later present with faecal impaction. At this stage, invasive procedures (such as rectal irrigation and faecal disimpaction) and occasionally surgery are used to resolve the constipation. The Committee also heard from the clinical specialists that people whose constipation has not responded adequately to laxatives would usually be encouraged to stop all current treatments and then restart their laxative regimen in a stepwise manner. The clinical specialists further stated that in clinical trials for studies of chronic constipation, placebo is often the comparator. The clinical specialists noted that invasive procedures have risks and provide only temporary relief, and are therefore not appropriate comparators to prucalopride. In view of the different classes of laxatives used in clinical practice and the fact that many of these are often used in rotation to avoid tolerance, the Committee agreed that it would be difficult to define a standard laxative regimen as a comparator for people with laxative-refractory chronic constipation.
The Committee discussed the clinical effectiveness of prucalopride. It was aware of the data presented by the manufacturer that showed prucalopride to be more effective than placebo in women with chronic constipation during the trial periods of 4 weeks for older women (65 years and older) and 12 weeks for adult women (18–64 years). The Committee was aware of concerns from consultees that the short duration of the clinical trials may not adequately reflect the efficacy of a drug that treats a long-term condition. It was also aware of the open-label extension studies that showed that prucalopride was efficacious in the long term. The Committee questioned how well the extension studies proved that the clinical effectiveness of prucalopride is sustained, given the high drop-out rate. However, it heard from the manufacturer that 90% of the people whose constipation did not respond to treatment in the extension studies also had no response in the randomised trial period (that is, were already non-responders), which suggests that for people whose constipation does not respond early with prucalopride, their condition will not respond with continued treatment. The Committee heard from the manufacturer that people whose constipation responds to treatment with prucalopride are likely to have a response within 28 days of treatment, and that people whose constipation does not respond in that period are unlikely to have a response with treatment longer than 28 days. The Committee also heard from the clinical specialists that prucalopride's mechanism of action is on the gut muscle rather than the mucosa and that this mechanism of action means that efficacy could be sustained in the long term. Although some consultees argued that the mechanism of action of prucalopride is not unique and that it did not prove that tolerance to prucalopride (and subsequent dose increases) did not occur, the Committee was persuaded that some people may benefit from continued use of prucalopride. The Committee was persuaded that the stopping rule in the SPC for prucalopride, which restricts treatment after 4 weeks in women who gained normal bowel movements while on treatment, would be followed by prescribing clinicians and limit use in people who do not respond early to treatment with prucalopride.
The Committee noted from the ERG's analysis that a substantial proportion of people with chronic constipation in the pivotal trials responded to placebo (see section 3.18). The clinical specialists stated that it was not unusual for people with gastrointestinal conditions to respond to placebo, and that they were not surprised by the high response to placebo in the trials. The Committee was assured that in clinical practice, any treatment that provides at least a 10% improvement in response over placebo is considered to be clinically meaningful. The Committee considered that the available data demonstrated that prucalopride was clinically effective in providing relief to women with laxative-refractory chronic constipation.
The Committee considered the adverse effects of prucalopride. It noted that diarrhoea and headaches were common in the clinical trials but that most side effects were mild to moderate in severity. The Committee heard from the clinical specialists that these side effects are often symptoms of chronic constipation and may not always be caused by prucalopride. It also heard that people regularly have their medication reviewed by their clinicians to make sure that their constipation is not a side effect of any treatments they are receiving (prescription and non-prescription). The Committee was aware that prucalopride belongs to the same class of drugs as cisapride, which is associated with serious cardiovascular side effects. The Committee heard from clinical specialists that prucalopride has a selective mechanism of action and may not have the same cardiovascular side effects as cisapride. However, the Committee was concerned that some side effects of prucalopride, such as possible cardiovascular effects, may only be apparent after long-term treatment and were not observed in the clinical trials conducted.
# Cost effectiveness
The Committee considered the quality-of-life data presented in the manufacturer's submission. The Committee noted that disease specific quality-of-life measures (PAC-QOL and PAC-SYM) were mapped to EQ-5D using SF-36 scores obtained from the trials. The Committee heard from the clinical specialists that people with a PAC-QOL score of 4 (equating to an EQ-5D of 0.585), as observed in the clinical trials, have substantially limited quality of life. Although PAC-QOL and therefore EQ-5D improved with prucalopride treatment, the Committee noted that this was not reflected in the SF-36 data directly measured in the trials. The Committee was aware of the concerns raised by the ERG that the assumptions used in the mapping equation could not be tested and may therefore not be robust. It questioned if SF-36 data from the trials would give similar EQ-5D improvement had they been used in the model; and why this had not been tested in a sensitivity analysis. The manufacturer stated that further SF-36 data (not in the submission) for people whose constipation responded to treatment showed statistically significant improvement for prucalopride compared with placebo. Sensitivity analyses of these outcomes were conducted by the manufacturer and were considered to be consistent with results from the ERG's analyses when assumptions about the acquisition cost of prucalopride and the number of days on treatment were varied. The Committee concluded that changing the mapping equation to include SF-36 instead of PAC-QOL would be unlikely to alter the results of the model substantially.
The Committee discussed the manufacturer's ICER calculations and the ERG's exploratory analysis, in which the ERG ran the manufacturer's model using different alternative scenarios and assumptions. The Committee noted that in the base case presented by the manufacturer, the average cost of prucalopride for all women was £498 with a QALY gain of 0.0316, resulting in an ICER of £15,700 per QALY gained. The average cost of prucalopride for adult women was £622 with a QALY gain of 0.0369, resulting in an ICER of £16,800 per QALY gained. The average cost of prucalopride for older women was £403 with a QALY gain of 0.0342, resulting in an ICER of £11,700 per QALY gained. Although the Committee had concerns about the generalisability of the populations selected for the clinical trials to the decision problem and about the extrapolation of benefits beyond the trials, the Committee concluded that the ERG had shown the manufacturer's cost-effectiveness estimates to be reasonably stable under varied assumptions.
The Committee considered the true resource costs of treating chronic constipation when laxatives fail to provide adequate relief, such as referrals to secondary care, rectal irrigation and surgery. It agreed that these costs could be reduced by using prucalopride. Based on these considerations, the Committee agreed that the costs of chronic constipation presented by the manufacturer in its economic model were probably conservative and if the true resource costs were included, it was likely that the ICERs presented by the manufacturer would be reduced.
The Committee was persuaded that the most plausible ICER for prucalopride compared with placebo plus rescue medication was likely to be below £20,000 per QALY gained. Therefore, the Committee agreed that prucalopride would be an appropriate use of NHS resources and recommended that prucalopride should be considered as an option for the treatment of chronic constipation in women only when they have used the highest tolerated recommended doses of at least two laxatives from different classes for at least 6 months, without having adequate relief of their constipation, and invasive treatment is being considered. The Committee acknowledged that if treatment with prucalopride is not effective after 4 weeks, the woman should be re-examined and the benefit of continuing treatment reconsidered, in line with current advice in the marketing authorisation. The Committee agreed with the clinical specialists that women suitable for treatment with prucalopride should be treated by a clinician with experience in managing chronic constipation who has carefully reviewed the woman's previous courses of laxative treatments.
# Summary of Appraisal Committee's key conclusions
TA211(STA)
Appraisal title: Prucalopride for the treatment of chronic constipation in women
FAD section(s)
Key conclusion
Prucalopride is recommended as an option for the treatment of chronic constipation only in women for whom treatment with at least two laxatives from different classes, at the highest tolerated recommended doses for at least 6 months, has failed to provide adequate relief and invasive treatment for constipation is being considered.
If treatment with prucalopride is not effective after 4 weeks, the woman should be re-examined and the benefit of continuing treatment reconsidered.
Prucalopride should only be prescribed by a clinician with experience of treating chronic constipation, who has carefully reviewed the woman's previous courses of laxative treatments as specified in the first paragraph above.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee noted that for some people chronic constipation can become intractable, and relatively invasive procedures (such as suppositories, enemas, rectal irrigation and manual disimpaction) may be tried when oral laxatives fail to provide adequate relief. However these measures are associated with risks and only provide temporary relief.
The clinical specialists stated that chronic constipation has a wide spectrum of severity and that for a minority of people with intractable constipation there can be very low quality of life and feelings of hopelessness.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee was aware that the scope for this appraisal was to consider the use of prucalopride in women with chronic constipation in whom standard laxative regimens have failed to provide adequate relief, and for whom invasive procedures are being considered. The Committee heard from the clinical specialists that in clinical practice, any treatment that provides at least a 10% improvement in response over placebo is considered to be clinically meaningful. The Committee considered that the available data demonstrated that prucalopride was clinically effective in providing relief to women with laxative-refractory chronic constipation.
What is the position of the treatment in the pathway of care for the condition?
The Committee heard from the manufacturer that the intended position of prucalopride in the treatment pathway for chronic constipation is after failure of oral laxatives because of inadequate efficacy or intolerance.
The Committee recommended that prucalopride should only be offered to women who have used the highest tolerated recommended doses of at least two laxatives from different classes for at least 6 months, without having adequate relief, and for whom invasive treatment is being considered for their constipation.
Adverse effects
The Committee noted that diarrhoea and headaches were common in people who were treated with prucalopride in clinical trials, but that most side effects were mild to moderate in severity. The Committee was concerned that some side effects of prucalopride, such as possible cardiovascular effects, may only be apparent after long-term treatment and were not observed in the clinical trials conducted.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee considered that the available data demonstrated that prucalopride was clinically effective in providing relief to women with laxative-refractory chronic constipation.
The Committee was aware of concerns from consultees that the short duration of the clinical trials may not adequately reflect the efficacy of a drug that treats a long-term condition.
Relevance to general clinical practice in the NHS
The Committee was aware that the scope for this appraisal was to consider the use of prucalopride in women with chronic constipation in whom standard laxative regimens have failed to provide adequate relief, and for whom invasive procedures are being considered. The Committee noted that the comparator used in clinical trials was placebo plus rescue medication with bisacodyl, which did not reflect current practice for chronic constipation in the NHS. The Committee heard that more invasive procedures such as rectal irrigation and occasionally surgery are used to treat people with laxative-refractory constipation. It heard from the clinical specialists that generally people whose constipation has not responded adequately to laxatives would usually be encouraged to stop all current treatments, and then restart their laxative regimen in a stepwise manner. The Committee agreed that it would be difficult to define a standard laxative regimen as a comparator for people with laxative-refractory chronic constipation.
The Committee agreed that the resource costs of treating chronic constipation, such as referrals to secondary care and invasive procedures, could be reduced by using prucalopride.
Uncertainties generated by the evidence
The Committee noted the concerns of the NHS representatives that the use of placebo as a comparator did not reflect current clinical practice for chronic constipation.
The Committee noted that it was unclear how inadequate relief had been defined in the trials. The Committee also noted that up to 30% of the people in the trials responded to laxatives, so their constipation may not have been laxative-refractory.
The Committee questioned how well the extension studies proved that the clinical effectiveness of prucalopride is sustained, given the high drop-out rate.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The manufacturer provided separate analyses of adult women (18–64 years), older women (65 years or older) and all women combined. The marketing authorisation states that the recommended dose of prucalopride is 2 mg once daily for adult women (up to 65 years) and 1 mg once daily for older women (over 65 years). The dose for older women can be increased to 2 mg once daily if needed.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee considered that the available data demonstrated that prucalopride was clinically effective in providing relief to women with laxative-refractory chronic constipation.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee considered evidence on the cost effectiveness of prucalopride compared with placebo, including quality-of-life estimates, costs and ICERs presented by the manufacturer.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee noted that disease specific quality-of life measures (PAC-QOL and PAC-SYM) were mapped to EQ-5D using SF-36 scores obtained from the trials. The Committee was aware of the concerns raised by the ERG about the mapping process.
The Committee had concerns about the generalisability of the populations who were selected for the clinical trials to the decision problem, and about the extrapolation of benefits beyond the trials.
The Committee noted the sensitivity analysis conducted by the ERG showed the model results to be stable under various assumptions.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee noted that disease specific quality-of-life measures (PAC-QOL and PAC-SYM) were mapped to EQ-5D using SF-36 scores obtained from the trials. Although PAC-QOL and therefore EQ-5D improved with prucalopride treatment, the Committee noted that this was not reflected in the SF-36 data directly measured in the trials. The Committee was aware that the SF-36 data presented in the manufacturer's submission were not used in the model and were not tested in a sensitivity analysis.
The Committee heard from the manufacturer that further SF-36 data that were not in their submission for people whose constipation responded to treatment showed statistically significant improvement in chronic constipation for those treated with prucalopride compared with placebo.
Sensitivity analyses of these outcomes were conducted by the manufacturer and were considered to be consistent with results from the ERG's analyses when assumptions about the acquisition cost of prucalopride and the number of days on treatment were varied.
Are there specific groups of people for whom the technology is particularly cost effective?
For adult women the ICER was £16,800 per QALY gained. For older women, the ICER was £11,700 per QALY gained.
What are the key drivers of cost effectiveness?
The Committee considered the true resource costs of treating chronic constipation when laxatives fail to provide adequate relief, such as referrals to secondary care, rectal irrigation and surgery. It agreed that the costs of chronic constipation presented by the manufacturer in its economic model were probably conservative and if the true resource costs were included, it was likely that the ICERs presented by the manufacturer would be reduced.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee was persuaded that the most plausible ICER for prucalopride compared with placebo plus rescue medication was likely to be below £20,000 per QALY gained.
Additional factors taken into account
Patient access schemes
(PPRS)
Not applicable to this appraisal.
End-of-life considerations
Not applicable to this appraisal.
Equalities considerations
No equality issues were raised during the scoping exercise or through the course of this appraisal.
-# Related NICE guidance
Irritable bowel syndrome in adults: diagnosis and management of irritable bowel syndrome in primary care. NICE clinical guideline 61 (2008).
Constipation in children and young people: diagnosis and management of idiopathic childhood constipation in primary and secondary care. NICE clinical guideline 99 (2010).# Review of guidance
The guidance on this technology will be considered for review in October 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveDecember 2010# Changes after publication
February 2014: implementation section updated to clarify that prucalopride is recommended as an option for treating chronic constipation in women. Additional minor maintenance update also carried out.
March 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': "Prucalopride is recommended as an option for the treatment of chronic constipation only in women for whom treatment with at least two laxatives from different classes, at the highest tolerated recommended doses for at least 6 months, has failed to provide adequate relief and invasive treatment for constipation is being considered.\n\nIf treatment with prucalopride is not effective after 4 weeks, the woman should be re-examined and the benefit of continuing treatment reconsidered.\n\nPrucalopride should only be prescribed by a clinician with experience of treating chronic constipation, who has carefully reviewed the woman's previous courses of laxative treatments specified in 1.1.", 'The technology ': "Prucalopride (Resolor, Movetis) is a selective serotonin (5-HT4) receptor agonist that predominantly stimulates colonic motility. Prucalopride has a UK marketing authorisation for the 'symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief'.\n\nPrucalopride is administered orally. The summary of product characteristics (SPC) states that the recommended dose of prucalopride is 2\xa0mg once daily for adult women (up to 65\xa0years old) and 1\xa0mg once daily for older women (over 65\xa0years). The dose for older women can be increased to 2\xa0mg once daily if needed. If once-daily prucalopride is not effective after 4\xa0weeks, the patient should be re-examined and the benefit of continuing treatment reconsidered.\n\nThe SPC reports that the most common adverse effects that may be associated with prucalopride treatment include headache and gastrointestinal symptoms (abdominal pain, nausea or diarrhoea). Most adverse effects occur at the start of treatment and usually subside within a few days of continued treatment. For full details of side effects and contraindications, see the SPC.\n\nPrucalopride is available in 1-mg and 2-mg tablets. The acquisition cost of prucalopride 1\xa0mg is £38.69 for a pack of 28\xa0tablets. The acquisition cost of prucalopride 2\xa0mg is £59.52 for a pack of 28\xa0tablets (excluding VAT; 'British National Formulary' [BNF], 60th edition). The manufacturer estimated that the annual cost of treatment with prucalopride is £622 for adult women and £403 for older women (excluding any monitoring costs), assuming that each woman receives treatment for an average of 220\xa0days each year. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of prucalopride and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer described nine trials that provided evidence on the clinical effectiveness of prucalopride in people with chronic constipation. There were three pivotal phase III randomised, double-blind, placebo-controlled trials in adults (aged 18–65 years) with chronic constipation (PRU-INT-6, PRU-USA-11 and PRU-USA-13), one phase III, randomised, double-blind, placebo-controlled trial in older people (65 years or older, PRU-INT-12), one trial in adults (18 years or older) with opioid-induced constipation (PRU-INT-8), one retreatment study (PRU-USA-28) and three extended, open-label, single-arm, observational studies (PRU-INT-10, PRU-USA-22 and PRU-INT-17). The key clinical evidence presented by the manufacturer was derived from the three pivotal trials, which reported the efficacy of prucalopride compared with placebo in adults, and PRU-INT-12, which reported the efficacy of prucalopride compared with placebo in older people. The number of people randomised to PRU-INT-6, PRU-USA-11, PRU-USA-13 and PRU-INT-12 was 720, 628, 651 and 305 respectively. Approximately 90% of people in the pivotal trials were women. The manufacturer also presented other trials, which reported additional safety considerations and response rates (see section 3.8). The manufacturer's submission stated that people were enrolled in the pivotal trials and PRU-INT-12 if they had a history of chronic constipation (defined as no more than two spontaneous complete bowel movements per week) and one or more of the following for at least 6\xa0months before the screening visit:\n\nstraining during at least 25% of bowel movements\n\nvery hard or hard stools in at least 25% of bowel movements\n\nsensation of incomplete evacuation for at least 25% of bowel movements.\n\nThere was a 2-week run-in period for each pivotal trial and for PRU-INT-12, in which no laxative medication (except for rescue medication) was allowed. People in the pivotal trials were then randomised 1:1:1 to prucalopride 2\xa0mg, prucalopride 4\xa0mg or placebo. People in PRU-INT-12 were also randomised to prucalopride 1\xa0mg. If people had not had a bowel movement for 3\xa0days or more, they could receive a single dose of 15\xa0mg bisacodyl as rescue medication (medications used for quick relief of symptoms). If a bowel movement did not occur, the dose of bisacodyl could be increased; if there was still no bowel movement after this, an enema could be administered. In the pivotal trials people were treated for 12\xa0weeks and in PRU-INT-12 people were treated for 4\xa0weeks. Data were collected at 4- and 12-week time points in the pivotal trials and at 4\xa0weeks in PRU-INT-12.\n\nThe primary outcome measure in the pivotal trials was three or more spontaneous complete bowel movements per week which was evaluated over the first 4\xa0weeks of treatment and averaged over the full 12\xa0weeks of the trial. The proportion of people with an average increase of one or more spontaneous complete bowel movements per week compared with baseline was measured as a secondary outcome in the trials. The proportion of people treated with prucalopride 2\xa0mg in the pivotal trials who had three or more spontaneous complete bowel movements per week during weeks 1–4 ranged from 23.7% to 32.1%, compared with 9.8% to 11.5% for placebo (all p\xa0≤\xa00.001). During weeks 1–12, the proportion of people treated with prucalopride 2\xa0mg who had three or more spontaneous complete bowel movements per week ranged from 19.5% to 28.9% compared with 9.6% to 13.0% for placebo (all p\xa0≤\xa00.01).\n\nThe proportion of people treated with prucalopride 2\xa0mg in the pivotal trials who had an average increase of one or more spontaneous complete bowel movements per week (the secondary outcome measure) during weeks 1–4 ranged from 41.0% to 56.5% compared with 20.9% to 25.5% for placebo (all p\xa0≤\xa00.001). During weeks 1–12 of treatment, the proportion of people who had an average increase of one or more spontaneous complete bowel movements per week ranged from 38.1% to 50.3% for prucalopride 2\xa0mg compared with 20.9% to 27.5% for placebo (all p\xa0≤\xa00.001).\n\nIn PRU-INT-12 the proportion of people treated with prucalopride who had an average of three or more spontaneous complete bowel movements per week during weeks 1–4 was 39.5% for prucalopride 1\xa0mg and 32.0% for prucalopride 2\xa0mg, compared with 20.0% for placebo (p\xa0≤\xa00.05). In addition, the proportion of people treated with prucalopride who had an average increase of one or more spontaneous complete bowel movements per week during weeks 1–4 was 61.1% for prucalopride 1\xa0mg and 56.9% for prucalopride 2\xa0mg compared with 33.8% for placebo (p\xa0≤\xa00.05).\n\nThe manufacturer's submission reported quality-of-life data from the pivotal trials, which were derived from Patient Assessment of Constipation – Symptoms (PAC-SYM) and Patient Assessment of Constipation – Quality of Life (PAC-QOL) scores. All pivotal trials showed a significantly greater improvement in PAC-QOL scores for people treated with prucalopride compared with placebo at weeks 1–4 and weeks 1–12 (both p\xa0<\xa00.001 compared with placebo). Statistically significant improvements in PAC-SYM scores were also seen in all three trials at weeks 1–4 (p\xa0≤\xa00.001 compared with placebo) and in all trials except PRU-INT-6 at weeks 1–12 (p\xa0≤\xa00.05). PRU-INT-12 also reported quality-of-life data for older women derived from PAC-SYM and PAC-QOL scores. Statistically significant improvements in PAC-SYM and PAC-QOL scores were shown for prucalopride 1\xa0mg compared with placebo at week 4 (both p\xa0≤\xa00.05). Improvements in PAC-SYM and PAC-QOL scores for prucalopride 2\xa0mg compared with placebo were seen at week\xa04 but they did not reach statistical significance.\n\nSurveys of the SF-36 mental component summary and the SF-36 physical component summary were taken during the run-in period and at weeks 4 and 12 of the pivotal trials. No trials showed statistically significantly greater improvements in SF-36 scores for prucalopride 2\xa0mg compared with placebo at week 12. A statistically significant improvement in the SF-36 physical component summary at week 4 was only seen in the PRU-INT-6 study for prucalopride 2\xa0mg compared with placebo (p\xa0≤\xa00.05). Additional evidence provided by the manufacturer in response to the appraisal consultation document suggested, however, that when only the cohort of patients who responded to treatment was compared with placebo, a statistically significant difference between the effect of prucalopride and placebo was seen. The SF-36 data were not used in further sections of the manufacturer's submission.\n\nThe following three single-arm extension studies were designed to assess the long-term tolerability and safety of prucalopride:\n\nPRU-INT-10: included people from PRU-INT-6 (pivotal trial) and PRU-INT-12 (trial in older people).\n\nPRU-USA-22: included people from PRU-USA-3 (phase II dose–response trial), PRU-USA-11 and PRU-USA-13 (pivotal trials), PRU-USA-21 (phase II dose–response trial), PRU-USA-25 (phase III dose–titration trial), PRU-USA-27 (opioid-induced chronic constipation trial) and PRU-USA-28 (phase III retreatment trial).\n\nPRU-INT-17: included people from PRU-INT-8 and PRU-INT-14 (both opioid-induced chronic constipation trials). Studies PRU-INT-10, PRU-USA-22 and PRU-INT-17 had durations of 24, 36 and 12\xa0months respectively. People received prucalopride doses ranging from 0 to 4\xa0mg. Results from these studies reported that prucalopride treatment was associated with an improvement in constipation from baseline at all time points (this was statistically significant in PRU-INT-10 and PRU-USA-22) and a decrease in the use of laxatives. At 12\xa0months, on average, less than 50% of people remained in these trials. The reasons for stopping treatment included insufficient treatment response (18%), withdrawal of consent (15%) and adverse events (9%). However for the three trials, most people (approximately 45%) discontinued treatment because the previous trial sponsor decided to stop the prucalopride development programme worldwide.\n\nThe manufacturer reported that prucalopride was generally well tolerated and that the majority of adverse events in the clinical trials were mild or moderate. In PRU-INT-6, 80.8% of people in the prucalopride 2\xa0mg arm reported at least one adverse event, compared with 66.0% in the placebo arm. The incidence of serious adverse events was 2.1% in both the prucalopride and placebo arms. The most frequently reported adverse events included headache, nausea and abdominal pain. The incidence of diarrhoea in the prucalopride 2\xa0mg arm (13.0%) was more than twice that of the placebo arm (5.4%). The adverse event profiles in the PRU-USA-11 and PRU-USA-13 trials were similar to those in the PRU-INT-6 trial. The onset of these adverse events was most frequently reported on the day after the start of treatment ('day one') and the duration was short. The manufacturer reported that when day one was excluded from the analysis, the incidence of adverse events was comparable among the treatment groups.\n\nThe manufacturer developed a decision analytic model based on patient-level data from the clinical trials. All data from the included trials, for men and women, were used in the model, however all analyses presented by the manufacturer were derived using data from women only. The model compared prucalopride 1 mg daily (for older women) and prucalopride 2 mg daily (for adult women) with placebo for up to 52 weeks. In both arms, bisacodyl as rescue medication was allowed, and if it was used, any bowel movements in the following 48 hours were not included in the analysis. In the base case, results were presented for all women (that is, adult women and older women). Treatment duration was 4\xa0weeks, after which women could only continue treatment if they had three or more spontaneous complete bowel movements per week.\n\nTwo additional analyses were presented. One incorporated data for adult women only and one incorporated data for older women only. For the first 12\xa0weeks, the model for adult women included randomised controlled trial data for all women treated with prucalopride 2\xa0mg. Additional observational trial data were incorporated up to a further 40\xa0weeks after the initial trial period. The model in older women incorporated randomised controlled trial data for women treated with prucalopride 1\xa0mg in the first 4\xa0weeks followed by observational data for up to 1\xa0year.\n\nNo discounting was applied in the model because both costs and utility values were modelled for 52 weeks. The only costs incorporated in the economic model were the list prices of prucalopride 2\xa0mg (£2.13 per tablet) and prucalopride 1\xa0mg (£1.38 per tablet). Costs and utility values for placebo plus rescue therapy were not included in the model. The manufacturer assumed that women would take their treatment for only part of the year (220\xa0days). Adverse events and their associated costs were not included in the model. The manufacturer acknowledged that the rates of adverse events were comparable between prucalopride and placebo and therefore they considered that including these events would not affect the outcome of the analysis.\n\nClinical data incorporated in the model were derived from the three pivotal trials, two trials in older people (PRU-INT-12 and PRU-USA-26) and the extension studies. Patient characteristics from these studies were used to inform the disease states in the model. Further patient characteristics were obtained from other trials not fully described in the manufacturer's submission, including three additional dose–response trials (PRU-INT-1, PRU-INT-2 and PRU-USA-3) and two phase II trials (PRU-FRA-1 and PRU-GBR-4). No methods or results for these trials were included in the submission. PAC-SYM and PAC-QOL data from the clinical trials were mapped to EQ-5D through SF-36 scores using the generalised least squares regression method. People who had chronic constipation who did not respond to prucalopride were assumed to have no quality-adjusted life year (QALY) gain.\n\nThe manufacturer's base case presented an average cost-effectiveness ratio because no cost for the comparator was included in the model. The average cost of prucalopride for all women was £498 with an average QALY gain of 0.0316, resulting in an average incremental cost-effectiveness ratio (ICER) of £15,700 per QALY gained. The average cost of prucalopride for adult women (18–64 years) was £622 with an average QALY gain of 0.0369, resulting in an ICER of £16,800 per QALY gained. The average cost of prucalopride for older women (65 years or older) was £403 with an average QALY gain of 0.0342, resulting in an ICER of £11,700 per QALY gained.\n\nThe manufacturer also presented an analysis that included all women who had an additional bowel movement per week (the secondary outcome measure in the pivotal trials). The manufacturer estimated that, for all women, the annual cost per person to reach this secondary outcome would be £498 with an average QALY gain of 0.0277, resulting in an ICER of £18,000 per QALY gained. For adult women, the cost would be £622 with an average QALY gain of 0.0342, resulting in an ICER of £18,000 per QALY gained. The cost for older women was £403 with a QALY gain of 0.0255, resulting in an ICER of £15,800 per QALY gained.\n\nThe manufacturer presented probabilistic sensitivity analyses for all women, adult women and older women, with and without an adjustment for baseline severity of constipation. The probabilistic sensitivity analysis results showed that the probabilities of the ICERs for prucalopride exceeding £20,000 per QALY gained were approximately 45%, 44% and 47% for all women, adult women and older women respectively. The probabilities of the ICERs for prucalopride exceeding £30,000 per QALY gained were approximately 40%, 36% and 45% for all women, adult women and older women respectively. The manufacturer reported that the main factors affecting cost effectiveness were:\n\nthe effect of constipation severity at baseline on treatment effectiveness (that is, if the treatment effect is assumed to be the same regardless of baseline severity, the probability of prucalopride being cost effective at £20,000 per QALY gained is increased)\n\nthe ability to identify women whose constipation did not respond to prucalopride at a very early stage of treatment\n\nthe acquisition cost of prucalopride\n\nthe utility values derived from mapping PAC outcome measures (PAC-SYM and PAC-QOL) to EQ-5D scores.\n\nThe ERG reviewed the evidence submitted by the manufacturer on the clinical and cost effectiveness of prucalopride. It noted that the three pivotal trials (PRU-INT-6, PRU-USA-11 and PRU-USA-13) formed the basis of the manufacturer's assessment of clinical effectiveness. The ERG was unclear how people from the original trials were selected for the extension studies because no baseline data were provided in the manufacturer's submission. The ERG considered it possible that the people in the extension studies had constipation that was not necessarily refractory to laxative treatment. The ERG further noted that the extension studies included both older people and people with opioid-induced chronic constipation and that the results were not separated. The ERG was also concerned that the high rate of withdrawal from the extension studies (more than 50% of people at 12\xa0months) was likely to have resulted in people who were relatively more satisfied with their treatment continuing with treatment compared with those dropping out.\n\nOverall, the ERG noted that there was a considerable quantity of clinical-effectiveness evidence in adults that suggested an improvement in chronic constipation for people treated with prucalopride compared with placebo. The ERG calculated the weighted average of the effect of prucalopride across the pivotal trials and estimated that 28% of people reached the primary outcome of three or more spontaneous complete bowel movements per week after treatment with prucalopride 2\xa0mg compared with 10.6% of people treated with placebo after 1\xad4 weeks. After 1\xad12 weeks, 23.8% of people treated with prucalopride 2\xa0mg reached the primary outcome compared with 11.4% of people treated with placebo.\n\nThe ERG was uncertain whether the population in the trials reflected the population covered by the marketing authorisation or decision problem for prucalopride. It noted that in the three pivotal trials, 17% of people at baseline answered that they had found their previous laxative treatment adequate and may not have been eligible for the trials (that is, not laxative refractory). The ERG further considered that people who have one or two bowel movements per week while on laxative treatment were likely to be having beneficial effects from laxatives and therefore their constipation may not have been refractory to laxatives. It also considered that any two of the criteria used alone by the manufacturer to describe chronic constipation (section 3.1 above) would be unlikely to be sufficient evidence of treatment failure with laxatives.\n\nThe ERG considered that the comparator used in the pivotal trials (placebo plus rescue medication with bisacodyl) did not represent standard clinical practice for chronic constipation. It suggested that a more appropriate comparator would have been a variety of oral laxative treatments, at the discretion of the treating clinician. It further commented that the manufacturer's submission did not consider some of the comparators outlined in the decision problem, including invasive procedures (such as rectal interventions) and bowel surgery.\n\nThe ERG assessed the manufacturer's cost-effectiveness analysis and considered its methodological approach acceptable. It noted that the manufacturer's decision to exclude the cost of the comparator from the analysis was conservative. However, the ERG was concerned that precise details of the trials used to inform the inputs in the economic model were not given or did not fully correspond with those described in the manufacturer's submission. It noted that five trials used for the economic model (PRU-INT-1, PRU-INT-2, PRU-USA-3, PRU-FRA-1 and PRU-GBR-4) were not fully described in the submission.\n\nThe ERG noted that quality of life data from PAC-QOL and PAC-SYM scores were mapped to the EQ-5D using SF-36 scores obtained from the trials. The ERG was concerned that the SF-36 data did not directly contribute to EQ-5D scores, even though these results were available from the trials, and no sensitivity analysis was undertaken by the manufacturer to test the impact of using SF-36 results.\n\nThe ERG noted that the manufacturer's model only allowed for variation in the response rate and mean treatment rates to be analysed. It also noted that no explicit allowance was made for withdrawal from treatment at any time after 4\xa0weeks and that the assumption that the last measured QALY gain was sustained for the rest of the year was not tested in the model.\n\nThe ERG noted there were more adverse events in the prucalopride arms than in the placebo arms of the trials. It was concerned that adverse events, including rare events, and their associated costs were not included in the model.\n\nThe ERG ran the manufacturer's model using alternative scenarios and assumptions including the following:\n\nAssuming that people who responded to treatment with prucalopride would receive treatment for a mean of 220\xa0days or 365\xa0days.\n\nUsing response rates taken from pooled trial estimates at week\xa04 calculated in the effectiveness review.\n\nAllowing for the possibility that adverse events may be higher in the prucalopride arm than the placebo arm by increasing costs by 5% and reducing QALY gain by 5% in the prucalopride arm.\n\nReducing the effectiveness (QALY) of prucalopride and placebo uniformly by 25%, 50% and 75% to allow for possible variation in the regression method used to calculate the QALYs.The ERG concluded that the results from its sensitivity analysis were not significantly different from those provided by the manufacturer.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of prucalopride, having considered evidence on the nature of chronic constipation and the value placed on the benefits of prucalopride by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee discussed the nature of chronic constipation and current clinical practice for the treatment of people with laxative-refractory chronic constipation. The clinical specialists stated that chronic constipation has a wide spectrum of severity and that for a minority of people with intractable constipation there can be very low quality of life and feelings of hopelessness. The Committee understood that current practice is a stepped approach to management starting with lifestyle and dietary changes. If these changes provide inadequate relief, different classes of oral laxatives are available. For some people chronic constipation can become intractable, and relatively invasive procedures (such as suppositories, enemas, rectal irrigation and manual disimpaction) may be tried. The Committee heard from the manufacturer that the intended position of prucalopride in the treatment pathway for chronic constipation is after failure of oral laxatives because of inadequate efficacy or intolerance. The Committee noted the clinical specialists' advice that people who have had an inadequate response to an oral laxative often try many different types before considering invasive options. The Committee was aware that the scope for this appraisal was to consider the use of prucalopride in women with chronic constipation in whom standard laxative regimens have failed to provide adequate relief, and for whom invasive procedures are being considered.\n\nThe Committee discussed patient selection and the conduct of the clinical trials. The Committee noted that the inclusion criteria in the trials were people with chronic constipation in whom laxatives failed to provide adequate relief. The Committee also noted that it was unclear how inadequate relief had been defined in the trials. In addition, the Committee heard from the ERG that up to 30% of the people in the trials responded to laxatives, so their constipation may not have fitted these inclusion criteria. The Committee was also aware of concerns raised during consultation that because adequate relief had not been properly defined by the manufacturer, this could contribute to widespread use of prucalopride in people in whom laxatives had not necessarily failed. However, the Committee heard from the clinical specialists that it is often difficult to differentiate between people for whom laxatives do not provide adequate relief and those who no longer want to use laxatives because of the side effects, despite any treatment benefit they may achieve. Based on advice from the clinical specialists, the Committee concluded that inadequate relief from previous laxative treatments could be defined by duration of follow-up and by the number of laxatives previously used.\n\nThe Committee considered the comparator, placebo plus rescue medication with bisacodyl, used in the clinical trials. The Committee noted the concerns of the NHS representatives that the use of placebo as a comparator did not reflect current clinical practice for chronic constipation and that prucalopride had not been compared with some of the less expensive oral laxatives commonly used in the NHS. It was aware that similar concerns had been raised during consultation. The Committee also noted that bisacodyl was used as rescue medication in the clinical trials and it could have been a comparator. However it heard from the manufacturer that in clinical practice, people for whom laxatives fail to provide adequate relief sometimes adopt a 'do nothing' approach and later present with faecal impaction. At this stage, invasive procedures (such as rectal irrigation and faecal disimpaction) and occasionally surgery are used to resolve the constipation. The Committee also heard from the clinical specialists that people whose constipation has not responded adequately to laxatives would usually be encouraged to stop all current treatments and then restart their laxative regimen in a stepwise manner. The clinical specialists further stated that in clinical trials for studies of chronic constipation, placebo is often the comparator. The clinical specialists noted that invasive procedures have risks and provide only temporary relief, and are therefore not appropriate comparators to prucalopride. In view of the different classes of laxatives used in clinical practice and the fact that many of these are often used in rotation to avoid tolerance, the Committee agreed that it would be difficult to define a standard laxative regimen as a comparator for people with laxative-refractory chronic constipation.\n\nThe Committee discussed the clinical effectiveness of prucalopride. It was aware of the data presented by the manufacturer that showed prucalopride to be more effective than placebo in women with chronic constipation during the trial periods of 4\xa0weeks for older women (65\xa0years and older) and 12\xa0weeks for adult women (18–64\xa0years). The Committee was aware of concerns from consultees that the short duration of the clinical trials may not adequately reflect the efficacy of a drug that treats a long-term condition. It was also aware of the open-label extension studies that showed that prucalopride was efficacious in the long term. The Committee questioned how well the extension studies proved that the clinical effectiveness of prucalopride is sustained, given the high drop-out rate. However, it heard from the manufacturer that 90% of the people whose constipation did not respond to treatment in the extension studies also had no response in the randomised trial period (that is, were already non-responders), which suggests that for people whose constipation does not respond early with prucalopride, their condition will not respond with continued treatment. The Committee heard from the manufacturer that people whose constipation responds to treatment with prucalopride are likely to have a response within 28\xa0days of treatment, and that people whose constipation does not respond in that period are unlikely to have a response with treatment longer than 28\xa0days. The Committee also heard from the clinical specialists that prucalopride's mechanism of action is on the gut muscle rather than the mucosa and that this mechanism of action means that efficacy could be sustained in the long term. Although some consultees argued that the mechanism of action of prucalopride is not unique and that it did not prove that tolerance to prucalopride (and subsequent dose increases) did not occur, the Committee was persuaded that some people may benefit from continued use of prucalopride. The Committee was persuaded that the stopping rule in the SPC for prucalopride, which restricts treatment after 4\xa0weeks in women who gained normal bowel movements while on treatment, would be followed by prescribing clinicians and limit use in people who do not respond early to treatment with prucalopride.\n\nThe Committee noted from the ERG's analysis that a substantial proportion of people with chronic constipation in the pivotal trials responded to placebo (see section 3.18). The clinical specialists stated that it was not unusual for people with gastrointestinal conditions to respond to placebo, and that they were not surprised by the high response to placebo in the trials. The Committee was assured that in clinical practice, any treatment that provides at least a 10% improvement in response over placebo is considered to be clinically meaningful. The Committee considered that the available data demonstrated that prucalopride was clinically effective in providing relief to women with laxative-refractory chronic constipation.\n\nThe Committee considered the adverse effects of prucalopride. It noted that diarrhoea and headaches were common in the clinical trials but that most side effects were mild to moderate in severity. The Committee heard from the clinical specialists that these side effects are often symptoms of chronic constipation and may not always be caused by prucalopride. It also heard that people regularly have their medication reviewed by their clinicians to make sure that their constipation is not a side effect of any treatments they are receiving (prescription and non-prescription). The Committee was aware that prucalopride belongs to the same class of drugs as cisapride, which is associated with serious cardiovascular side effects. The Committee heard from clinical specialists that prucalopride has a selective mechanism of action and may not have the same cardiovascular side effects as cisapride. However, the Committee was concerned that some side effects of prucalopride, such as possible cardiovascular effects, may only be apparent after long-term treatment and were not observed in the clinical trials conducted.\n\n# Cost effectiveness\n\nThe Committee considered the quality-of-life data presented in the manufacturer's submission. The Committee noted that disease specific quality-of-life measures (PAC-QOL and PAC-SYM) were mapped to EQ-5D using SF-36 scores obtained from the trials. The Committee heard from the clinical specialists that people with a PAC-QOL score of 4 (equating to an EQ-5D of 0.585), as observed in the clinical trials, have substantially limited quality of life. Although PAC-QOL and therefore EQ-5D improved with prucalopride treatment, the Committee noted that this was not reflected in the SF-36 data directly measured in the trials. The Committee was aware of the concerns raised by the ERG that the assumptions used in the mapping equation could not be tested and may therefore not be robust. It questioned if SF-36 data from the trials would give similar EQ-5D improvement had they been used in the model; and why this had not been tested in a sensitivity analysis. The manufacturer stated that further SF-36 data (not in the submission) for people whose constipation responded to treatment showed statistically significant improvement for prucalopride compared with placebo. Sensitivity analyses of these outcomes were conducted by the manufacturer and were considered to be consistent with results from the ERG's analyses when assumptions about the acquisition cost of prucalopride and the number of days on treatment were varied. The Committee concluded that changing the mapping equation to include SF-36 instead of PAC-QOL would be unlikely to alter the results of the model substantially.\n\nThe Committee discussed the manufacturer's ICER calculations and the ERG's exploratory analysis, in which the ERG ran the manufacturer's model using different alternative scenarios and assumptions. The Committee noted that in the base case presented by the manufacturer, the average cost of prucalopride for all women was £498 with a QALY gain of 0.0316, resulting in an ICER of £15,700 per QALY gained. The average cost of prucalopride for adult women was £622 with a QALY gain of 0.0369, resulting in an ICER of £16,800 per QALY gained. The average cost of prucalopride for older women was £403 with a QALY gain of 0.0342, resulting in an ICER of £11,700 per QALY gained. Although the Committee had concerns about the generalisability of the populations selected for the clinical trials to the decision problem and about the extrapolation of benefits beyond the trials, the Committee concluded that the ERG had shown the manufacturer's cost-effectiveness estimates to be reasonably stable under varied assumptions.\n\nThe Committee considered the true resource costs of treating chronic constipation when laxatives fail to provide adequate relief, such as referrals to secondary care, rectal irrigation and surgery. It agreed that these costs could be reduced by using prucalopride. Based on these considerations, the Committee agreed that the costs of chronic constipation presented by the manufacturer in its economic model were probably conservative and if the true resource costs were included, it was likely that the ICERs presented by the manufacturer would be reduced.\n\nThe Committee was persuaded that the most plausible ICER for prucalopride compared with placebo plus rescue medication was likely to be below £20,000 per QALY gained. Therefore, the Committee agreed that prucalopride would be an appropriate use of NHS resources and recommended that prucalopride should be considered as an option for the treatment of chronic constipation in women only when they have used the highest tolerated recommended doses of at least two laxatives from different classes for at least 6\xa0months, without having adequate relief of their constipation, and invasive treatment is being considered. The Committee acknowledged that if treatment with prucalopride is not effective after 4 weeks, the woman should be re-examined and the benefit of continuing treatment reconsidered, in line with current advice in the marketing authorisation. The Committee agreed with the clinical specialists that women suitable for treatment with prucalopride should be treated by a clinician with experience in managing chronic constipation who has carefully reviewed the woman's previous courses of laxative treatments.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA211(STA)\n\n\n\nAppraisal title: Prucalopride for the treatment of chronic constipation in women\n\nFAD section(s)\n\nKey conclusion\n\nPrucalopride is recommended as an option for the treatment of chronic constipation only in women for whom treatment with at least two laxatives from different classes, at the highest tolerated recommended doses for at least 6 months, has failed to provide adequate relief and invasive treatment for constipation is being considered.\n\n\n\nIf treatment with prucalopride is not effective after 4 weeks, the woman should be re-examined and the benefit of continuing treatment reconsidered.\n\n\n\nPrucalopride should only be prescribed by a clinician with experience of treating chronic constipation, who has carefully reviewed the woman's previous courses of laxative treatments as specified in the first paragraph above.\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee noted that for some people chronic constipation can become intractable, and relatively invasive procedures (such as suppositories, enemas, rectal irrigation and manual disimpaction) may be tried when oral laxatives fail to provide adequate relief. However these measures are associated with risks and only provide temporary relief.\n\nThe clinical specialists stated that chronic constipation has a wide spectrum of severity and that for a minority of people with intractable constipation there can be very low quality of life and feelings of hopelessness.\n\n, 4.4\n\nThe technology\n\nProposed benefits of the technology\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe Committee was aware that the scope for this appraisal was to consider the use of prucalopride in women with chronic constipation in whom standard laxative regimens have failed to provide adequate relief, and for whom invasive procedures are being considered. The Committee heard from the clinical specialists that in clinical practice, any treatment that provides at least a 10% improvement in response over placebo is considered to be clinically meaningful. The Committee considered that the available data demonstrated that prucalopride was clinically effective in providing relief to women with laxative-refractory chronic constipation.\n\n, 4.6\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee heard from the manufacturer that the intended position of prucalopride in the treatment pathway for chronic constipation is after failure of oral laxatives because of inadequate efficacy or intolerance.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee recommended that prucalopride should only be offered to women who have used the highest tolerated recommended doses of at least two laxatives from different classes for at least 6\xa0months, without having adequate relief, and for whom invasive treatment is being considered for their constipation.\n\n\n\nAdverse effects\n\n\n\nThe Committee noted that diarrhoea and headaches were common in people who were treated with prucalopride in clinical trials, but that most side effects were mild to moderate in severity. The Committee was concerned that some side effects of prucalopride, such as possible cardiovascular effects, may only be apparent after long-term treatment and were not observed in the clinical trials conducted.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\n\n\nThe Committee considered that the available data demonstrated that prucalopride was clinically effective in providing relief to women with laxative-refractory chronic constipation.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee was aware of concerns from consultees that the short duration of the clinical trials may not adequately reflect the efficacy of a drug that treats a long-term condition.\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\n\n\nThe Committee was aware that the scope for this appraisal was to consider the use of prucalopride in women with chronic constipation in whom standard laxative regimens have failed to provide adequate relief, and for whom invasive procedures are being considered. The Committee noted that the comparator used in clinical trials was placebo plus rescue medication with bisacodyl, which did not reflect current practice for chronic constipation in the NHS. The Committee heard that more invasive procedures such as rectal irrigation and occasionally surgery are used to treat people with laxative-refractory constipation. It heard from the clinical specialists that generally people whose constipation has not responded adequately to laxatives would usually be encouraged to stop all current treatments, and then restart their laxative regimen in a stepwise manner. The Committee agreed that it would be difficult to define a standard laxative regimen as a comparator for people with laxative-refractory chronic constipation.\n\n\n\n\n\n, 4.4\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee agreed that the resource costs of treating chronic constipation, such as referrals to secondary care and invasive procedures, could be reduced by using prucalopride.\n\n\n\n\n\nUncertainties generated by the evidence\n\n\n\nThe Committee noted the concerns of the NHS representatives that the use of placebo as a comparator did not reflect current clinical practice for chronic constipation.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee noted that it was unclear how inadequate relief had been defined in the trials. The Committee also noted that up to 30% of the people in the trials responded to laxatives, so their constipation may not have been laxative-refractory.\n\n\n\n\n\n\n\nThe Committee questioned how well the extension studies proved that the clinical effectiveness of prucalopride is sustained, given the high drop-out rate.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe manufacturer provided separate analyses of adult women (18–64 years), older women (65 years or older) and all women combined. The marketing authorisation states that the recommended dose of prucalopride is 2\xa0mg once daily for adult women (up to 65\xa0years) and 1\xa0mg once daily for older women (over 65\xa0years). The dose for older women can be increased to 2\xa0mg once daily if needed.\n\n-\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee considered that the available data demonstrated that prucalopride was clinically effective in providing relief to women with laxative-refractory chronic constipation.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nThe Committee considered evidence on the cost effectiveness of prucalopride compared with placebo, including quality-of-life estimates, costs and ICERs presented by the manufacturer.\n\n– 4.11\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that disease specific quality-of life measures (PAC-QOL and PAC-SYM) were mapped to EQ-5D using SF-36 scores obtained from the trials. The Committee was aware of the concerns raised by the ERG about the mapping process.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee had concerns about the generalisability of the populations who were selected for the clinical trials to the decision problem, and about the extrapolation of benefits beyond the trials.\n\n\n\n\n\n\n\nThe Committee noted the sensitivity analysis conducted by the ERG showed the model results to be stable under various assumptions.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe Committee noted that disease specific quality-of-life measures (PAC-QOL and PAC-SYM) were mapped to EQ-5D using SF-36 scores obtained from the trials. Although PAC-QOL and therefore EQ-5D improved with prucalopride treatment, the Committee noted that this was not reflected in the SF-36 data directly measured in the trials. The Committee was aware that the SF-36 data presented in the manufacturer's submission were not used in the model and were not tested in a sensitivity analysis.\n\n\n\nThe Committee heard from the manufacturer that further SF-36 data that were not in their submission for people whose constipation responded to treatment showed statistically significant improvement in chronic constipation for those treated with prucalopride compared with placebo.\n\n\n\nSensitivity analyses of these outcomes were conducted by the manufacturer and were considered to be consistent with results from the ERG's analyses when assumptions about the acquisition cost of prucalopride and the number of days on treatment were varied.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nFor adult women the ICER was £16,800 per QALY gained. For older women, the ICER was £11,700 per QALY gained.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee considered the true resource costs of treating chronic constipation when laxatives fail to provide adequate relief, such as referrals to secondary care, rectal irrigation and surgery. It agreed that the costs of chronic constipation presented by the manufacturer in its economic model were probably conservative and if the true resource costs were included, it was likely that the ICERs presented by the manufacturer would be reduced.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nThe Committee was persuaded that the most plausible ICER for prucalopride compared with placebo plus rescue medication was likely to be below £20,000 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes\n\n(PPRS)\n\nNot applicable to this appraisal.\n\n-\n\nEnd-of-life considerations\n\n\n\nNot applicable to this appraisal.\n\n-\n\nEqualities considerations\n\n\n\nNo equality issues were raised during the scoping exercise or through the course of this appraisal.\n\n-", 'Related NICE guidance': 'Irritable bowel syndrome in adults: diagnosis and management of irritable bowel syndrome in primary care. NICE clinical guideline 61 (2008).\n\nConstipation in children and young people: diagnosis and management of idiopathic childhood constipation in primary and secondary care. NICE clinical guideline 99 (2010).', 'Review of guidance': 'The guidance on this technology will be considered for review in October 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveDecember 2010', 'Changes after publication': 'February 2014: implementation section updated to clarify that prucalopride is recommended as an option for treating chronic constipation in women. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta211
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Evidence-based recommendations on prucalopride (Resolor) for treating chronic constipation in women.
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12f54a936ca264de26dc230eab62edc7c14093be
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Bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer
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Bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer
Evidence-based recommendations on bevacizumab (Avastin), with other drugs, for treating metastatic colorectal cancer in adults.
# Guidance
Bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine is not recommended for the treatment of metastatic colorectal cancer.
People currently receiving bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer should have the option to continue treatment until they and their clinicians consider it appropriate to stop.# The technology
Bevacizumab (Avastin, Roche Products) is a recombinant humanised monoclonal IgG1 antibody that inhibits the formation of blood vessels (angiogenesis inhibitor). It targets the biological activity of human vascular endothelial growth factor (VEGF), which stimulates new blood vessel formation in the tumour. Bevacizumab in combination with fluoropyrimidine-based chemotherapy has a UK marketing authorisation for the treatment of patients with metastatic carcinoma of the colon or the rectum.
The summary of product characteristics (SPC) lists the following conditions that may be associated with bevacizumab treatment: gastrointestinal perforations, fistulae, wound healing complications, hypertension, proteinuria, arterial and venous thromboembolism, haemorrhage, pulmonary haemorrhage/haemoptysis, congestive heart failure, reversible posterior leucoencephalopathy and neutropenia. For full details of side effects and contraindications, see the SPC.
Bevacizumab is administered as an intravenous infusion. Bevacizumab treatment is given in combination with chemotherapy and is licensed for use until progression of the underlying disease. The recommended dosage for metastatic carcinoma of the colon or rectum is 5 mg/kg or 10 mg/kg of body weight once every 2 weeks when given with oxaliplatin and fluorouracil plus folinic acid (FOLFOX) or 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks when given with oxaliplatin and capecitabine (XELOX). Bevacizumab is available in 100-mg and 400-mg vials at net prices of £242.66 and £924.40 respectively (excluding VAT; 'British national formulary' edition 58). For first-line treatment with bevacizumab, the manufacturer's economic model assumed a dosage of 5 mg/kg of body weight once every 2 weeks when given with FOLFOX and 7.5 mg/kg of body weight given once every 3 weeks XELOX, in line with the NO16966 trial. The acquisition cost of bevacizumab (excluding VAT and assuming wastage) for a patient weighing 70 kg is £924.40 at a dosage of 5 mg/kg every 2 weeks and £1409.72 at a dosage of 7.5 mg/kg every 3 weeks. The manufacturer of bevacizumab (Roche Products) proposed a patient access scheme to the Department of Health for the use of bevacizumab in metastatic colorectal cancer. The Department of Health was content for NICE to consider the patient access scheme proposed by Roche. However, it had concerns about the scheme's complexity and believed that the administrative burden of the scheme was greater than that originally set out by the manufacturer.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of bevacizumab and a review of this submission by the Evidence Review Group (ERG; appendix B).
The manufacturer's approach to the decision problem compared bevacizumab plus FOLFOX (B-FOLFOX) or bevacizumab plus XELOX (B-XELOX) with FOLFOX and XELOX without bevacizumab as a first-line treatment. The manufacturer stated that the use of irinotecan in combination with folinic acid and fluorouracil (FOLFIRI) is decreasing and that it is mainly used in the small minority of patients in whom oxaliplatin is contraindicated or who cannot tolerate oxaliplatin. This was based on market research analysis, which indicated that combination chemotherapy regimens including oxaliplatin are the most commonly used in UK clinical practice. However, for completeness, the manufacturer performed an economic evaluation comparing B-FOLFOX or B-XELOX with FOLFIRI. The manufacturer stated that the cost effectiveness of bevacizumab as a second-line treatment could not be demonstrated.
The manufacturer undertook a systematic review of the literature and identified two randomised controlled trials: one assessed bevacizumab as a first-line therapy (NO16966) and one assessed bevacizumab as a second-line therapy (E3200). No evidence of bevacizumab used in lines of treatment beyond second-line therapy was provided by the manufacturer.
The NO16966 study started as a phase III, multinational, two-arm, randomised, open-label study. This study was originally designed to demonstrate the non-inferiority of XELOX compared with FOLFOX-4 (that is, the FOLFOX regimen given every 2 weeks, with two long infusions in the first 48 hours) in adult patients with histologically confirmed metastatic colorectal cancer who had not been treated before with chemotherapy. After randomisation of 634 patients to XELOX or FOLFOX-4, the original protocol design was amended to include a 2 x 2 factorial randomised study in which patients were subsequently randomised to either XELOX or FOLFOX plus either bevacizumab or placebo. A further 1401 patients were then recruited (blinded to the allocation of bevacizumab or placebo), and a final total of 2035 patients were randomised in the NO16966 study. The study amendment included an additional objective of demonstrating superiority of bevacizumab in combination with chemotherapy (B-XELOX or B-FOLFOX-4) over placebo in combination with chemotherapy (P-XELOX or P FOLFOX-4). The dosage of bevacizumab was 5 mg/kg every 2 weeks (B-FOLFOX-4) or 7.5 mg/kg every 3 weeks (B-XELOX). Treatment was planned to continue until disease progression, unacceptable toxicity, resection of metastatic disease or for 48 weeks, whichever came first (this being at the discretion of the investigator). Patients who completed the 48-week study treatment phase without progressive disease were eligible to enter the post-study treatment phase and continue their allocated treatment until their disease progressed. Patients whose disease became operable, and underwent resection, were eligible to enter the post-study treatment phase. The NO16966 protocol also allowed continuation of allocated treatment (bevacizumab or placebo) until disease progression (in line with the bevacizumab SPC, which was produced after the NO16966 study) if oxaliplatin treatment was terminated because of adverse events.
All patients in the study had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The study was stratified to ensure that study arms were balanced with regards to ECOG performance status (0 versus 1), number of organs with metastases at baseline (one versus more than one), alkaline phosphatase level at baseline (within normal range versus above normal range), liver as a site of metastasis (yes versus no) and geographic region. The median follow-up was 28 months. The manufacturer acknowledged that patients in the study were slightly younger and fitter than patients with metastatic colorectal cancer in the UK who are, on average, over 60 years of age.
The primary pooled analysis of non-inferiority of the NO16966 study (that is, pooling of all XELOX arms compared with pooling of all FOLFOX-4 arms) showed that the XELOX and FOLFOX-4 regimens were equivalent for overall and progression-free survival. The primary pooled analysis of superiority for the NO16966 study (that is, pooling of the initial two-arm study and the 2 x 2 factorial part of the study) showed that the addition of bevacizumab to chemotherapy (B-XELOX and B-FOLFOX-4) significantly improved progression-free survival compared with chemotherapy alone (P XELOX and P-FOLFOX-4 and XELOX and FOLFOX-4 combined). The median progression-free survival was 7.7 months in the placebo plus chemotherapy group and 9.4 months in the bevacizumab plus chemotherapy group (intention-to-treat analysis, hazard ratio 0.79; 95% confidence interval 0.72 to 0.87, p = 0.0001). The median overall survival was 18.9 months in the placebo plus chemotherapy group compared with 21.2 months in the bevacizumab plus chemotherapy group (HR 0.83; 95% CI 0.74 to 0.93, p = 0.0019).
The manufacturer provided a secondary pooled analysis of superiority based only on the 2 x 2 factorial design (according to the original statistical plan, that is B-XELOX and B-FOLFOX-4 combined compared with P-XELOX and P-FOLFOX-4 combined). The median progression-free survival was 8.0 months in the placebo plus chemotherapy group and 9.4 months in the bevacizumab plus chemotherapy group (HR 0.83; 95% CI 0.72 to 0.95, p = 0.0023). The median overall survival was 19.9 months in the placebo plus chemotherapy group and 21.3 months in the bevacizumab plus chemotherapy group (HR 0.89; 95% CI 0.76 to 1.03, p = 0.0769).
The manufacturer reported that the difference in progression-free survival was statistically significant for bevacizumab versus placebo in the XELOX subgroup (HR 0.80; 97.5% CI 0.66 to 0.96, p = 0.0059) but not in the FOLFOX-4 subgroup (HR 0.89; 97.5% CI 0.74 to 1.06, p = 0.1312). An exploratory analysis submitted by the manufacturer suggested that bevacizumab did not deliver a benefit to patients in the FOLFOX-4 group who had received prior adjuvant treatment (HR 1.75; 97.5% CI 1.15 to 2.65, p value not reported), whereas it did give a benefit to patients in the FOLFOX-4 group who had not had adjuvant therapy (HR 0.72; 97.5% CI 0.58 to 0.90, p value not reported). The manufacturer stated that this difference could be because the patients in the P-FOLFOX-4 group had a greater time between adjuvant treatment and development of metastatic disease than all of the other groups. This suggested that there was an imbalance in the data due to the better prognosis in the P-FOLFOX-4 group because the cancers in this group were growing more slowly than in the other groups. Additional exploratory analyses showed that when the data for all patients who had received adjuvant treatment were removed from all treatment groups (and thereby including the removal of the subgroup of patients that may have had slower tumour progression), the hazard ratios for overall survival and for progression-free survival ranged from 0.83 to 0.85 (all p values < 0.03) and from 0.74 to 0.77 (all p values < 0.0001).
The manufacturer also conducted a post-hoc subgroup analysis of the impact of bevacizumab treatment on liver resection rates. This analysis suggested that bevacizumab improved liver resection rates, although this was not statistically significant. No analyses of KRAS or other mutations were submitted.
The rates of discontinuation in the NO16966 study were higher in the bevacizumab plus chemotherapy groups than in the placebo plus chemotherapy groups. In the 2 x 2 factorial part of the study, 29% (203/699) of patients receiving bevacizumab plus chemotherapy and 47% (329/701) of patients receiving chemotherapy alone were treated until progression (despite the protocol allowing treatment to be continued until disease progression, in line with the SPC of bevacizumab).
In the NO16966 study, the most common adverse events of bevacizumab treatment were thromboembolic (7.8% venous thromboembolic events compared with 5.1% in the placebo plus chemotherapy groups and 1.7% arterial thromboembolic events compared with 0.9% in the placebo plus chemotherapy groups). Grade 3 or 4 hypertension, proteinuria and bleeding were more common in the bevacizumab groups than in the placebo plus chemotherapy groups (4% versus 0.8%, 3.5% versus 0.9% and 1.9% versus 1.5% respectively). The incidence of serious and life-threatening (grade 3 and 4) adverse events was higher in the bevacizumab plus chemotherapy groups (79.9%) than the placebo plus chemotherapy groups (74.8%) and higher with FOLFOX-4 regimens than XELOX regimens (although FOLFOX-4 was associated with different adverse events than XELOX). The manufacturer stated that most adverse events were associated with cytotoxic chemotherapy, and the higher incidence in the bevacizumab groups was likely to be a consequence of a longer duration of chemotherapy for patients receiving bevacizumab. No health-related quality-of-life data were collected in the NO16966 study.
The E3200 study was a phase III, multicentre, three-arm, randomised, open-label study. It compared B-FOLFOX-4 (n = 293), FOLFOX-4 (n = 292), and bevacizumab alone (n = 244) in adult patients with advanced or metastatic colorectal cancer previously treated with a fluoropyrimidine and irinotecan, either separately or in combination. Following a data monitoring review 18 months after the start of the trial, the bevacizumab-alone arm was terminated because of poorer efficacy. Patients were stratified by ECOG performance status (0 versus 1 or more) and prior radiation therapy (yes versus no). The dosage of bevacizumab was 10 mg/kg every 2 weeks. Median overall survival was 10.8 months in the FOLFOX 4 group and 13 months in the B-FOLFOX-4 group (intention-to-treat analysis, HR 0.751; 95% CI 0.332 to 0.893, p = 0.0012). Median progression-free survival increased from 4.5 months with FOLFOX-4 to 7.5 months with B-FOLFOX-4 (HR 0.518; 97.5% CI 0.416 to 0.646, p < 0.0001).
The manufacturer produced a Markov model to estimate the cost effectiveness of bevacizumab plus FOLFOX and XELOX compared with FOLFOX and XELOX alone. The model had four distinct health states: first-line treatment, after first-line treatment without progression, progressed disease and death. It was assumed that all patients start in the first health state (first-line treatment) in accordance with the NO16966 study. The model had a cycle length of 1 month and the time horizon was 8 years (equivalent to life expectancy in the population of interest). A half-cycle correction was applied to the model. An NHS and personal social services (PSS) perspective was taken.
Costs were mainly derived from 2007–2008 national reference costs, BNF 57 and PSSRU (Personal Social Services Research Unit) 2008. FOLFOX-4 was used in the pivotal trial of bevacizumab but the manufacturer stated that FOLFOX-6 (that is, the FOLFOX regimen delivered over 2 weeks but with only one long infusion in the first 48 hours) is more commonly used in UK clinical practice. Therefore, the economic model was adjusted to include FOLFOX-6 by assuming similar efficacy to FOLFOX-4 but with reduced costs.
Treatment duration and dose intensity were based on the NO16966 study. Mean and median treatment durations (6 and 7 months respectively) were shorter in the NO16966 study than progression-free survival. Duration of treatment varied between treatment arms and was longer with the addition of bevacizumab and longer in the FOLFOX than in the XELOX arms. Treatment duration was estimated and applied in the model for each arm of the NO16966 study. However, for simplicity it was assumed that oxaliplatin treatment duration was the same as bevacizumab treatment duration in the B-FOLFOX and B-XELOX arms. It was also assumed that treatment was given continuously, as in the NO16966 study, rather than intermittently. Kaplan–Meier estimates from the NO16966 study were used for progression-free and overall survival up to a median survival of 28 months. After this point, a Weibull probability distribution for overall survival and an exponential probability distribution of progression-free survival (based on average hazard for months 13–28) were used to model the tails. For overall survival, treatment effect was assumed to continue after the median follow-up period and this was further explored in the sensitivity analysis.
The manufacturer used utility values from 'Cetuximab for the first-line treatment of metastatic colorectal cancer' (NICE technology appraisal guidance 176). These utility values were taken from a randomised controlled trial comparing cetuximab plus FOLFIRI with FOLFIRI alone in first-line treatment of metastatic colorectal cancer and represented mean utility values from 42 patients using the EQ 5D questionnaire; however, only 37 patients fully completed the questionnaire. A utility value of 0.77 was assigned to the first-line treatment health state, the average of all the EQ-5D completed responses over the study period (this assumption was used in NICE technology appraisal guidance 176). A utility value of 0.79 was assigned to the health state after first-line treatment (that is, without disease progression). This was based on expert opinion that patients in this state will experience a higher quality of life than patients receiving first-line treatment, because of fewer adverse events, and their utility value will be similar to a person aged 55–64 years in the UK general population. A utility value of 0.68 was assigned to the progressed disease state, taken from a trial of cetuximab for the third-line treatment of metastatic colorectal cancer and using the Health Utility Index questionnaire (this assumption was used in NICE technology appraisal guidance 176).
The manufacturer's original submission included details of a proposed patient access scheme for the first-line use of bevacizumab. The scheme involved supplying bevacizumab at a fixed price per cycle of treatment (£800 for 2-weekly cycles and £1200 for 3-weekly cycles), with bevacizumab being provided free after 12 months of treatment and with oxaliplatin being provided free of charge throughout. The manufacturer stated that it would take approximately 5 minutes per cycle for the pharmacist to update the scheme's registry system. This equated to £4 per cycle. The Department of Health stated that it has concerns around the complexity of the patient access scheme and believes that the administration costs of the scheme would probably be greater than those set out by the manufacturer.
The manufacturer stated that the incremental cost-effectiveness ratios (ICERs) most relevant to the decision problem were B XELOX compared with XELOX and B-FOLFOX-6 compared with FOLFOX-6. In response to a request for clarification from the ERG, the manufacturer provided a revised base-case analysis. The ERG noted that 19.7% (n = 256) and 13.7% (n = 96) of patients were alive after median follow-up in the XELOX/FOLFOX-6 and B XELOX/B-FOLFOX-6 arms respectively. The ERG asked the manufacturer to use untruncated data to calculate the estimates of the parameters of the Weibull distribution. The manufacturer used Kaplan–Meier estimates of survival up to month 6 and then a Weibull distribution fitted to untruncated data after month 6 for progression-free survival and a Weibull distribution fitted to untruncated data for overall survival. The model also accounted for oxaliplatin wastage (that is, no vial sharing was assumed). In the manufacturer's base-case analysis (that is, pooling of the initial two-arm part of the study and the 2 x 2 factorial part of the study), B-XELOX produced an ICER of £35,912 per QALY gained when compared with XELOX (£84,553 per QALY gained without the patient access scheme), and B-FOLFOX-6 produced an ICER of £36,569 per QALY gained when compared with FOLFOX-6 (£92,634 per QALY gained without the patient access scheme). In the one-way sensitivity analyses, which were only provided with the patient access scheme, the ICERs were not greatly influenced by variations in any of the parameters. In the probabilistic sensitivity analysis, the mean ICER for the comparison of B-FOLFOX-6 with FOLFOX-6 was £36,907 per QALY gained and for the comparison of B-XELOX with XELOX the mean ICER was £36,205 per QALY gained (95% intervals not provided).
The manufacturer stated that currently only a minority (12%) of patients in the UK receive FOLFIRI as a first-line treatment for metastatic colorectal cancer and that in most of these patients treatment with oxaliplatin is contraindicated. For completeness, the manufacturer provided a cost-effectiveness analysis comparing bevacizumab in combination regimens containing oxaliplatin with FOLFIRI. The efficacy of FOLFIRI was derived from a mixed-treatment comparison. A constant hazard ratio was applied to the extrapolated progression-free survival and overall survival curves of FOLFOX-4 to derive the survival curves for FOLFIRI. The treatment duration and the drug administration and adverse event costs for FOLFIRI were assumed to be equivalent to those for FOLFOX-4. B-XELOX compared with FOLFIRI was associated with an ICER of £9192 per QALY gained, B-FOLFOX-6 compared with FOLFIRI was associated with an ICER of £38,835 per QALY gained, and B FOLFOX-4 compared with FOLFIRI was associated with an ICER of £58,575 per QALY gained.
The manufacturer provided a cost-effectiveness analysis of bevacizumab plus regimens including oxaliplatin in the second-line setting. Drug acquisition, administration and pharmacy costs per cycle were taken from the first-line analysis and multiplied by the mean number of cycles reported in the E3200 study. Costs associated with adverse events, third-line treatment and central venous access devices were not included in the second-line analysis and no discounting was applied. As a second-line treatment, B-FOLFOX-4 compared with FOLFOX-4 resulted in an ICER of £102,644 per QALY gained. The manufacturer stated that the larger ICERs reported in the second-line setting were mainly because of the higher doses of bevacizumab used and that bevacizumab could not be considered cost effective for second-line treatment.
The ERG stated that the manufacturer's submission generally followed the NICE reference case. It also highlighted that adequate methods of randomisation and allocation concealment were reported in the NO16966 and E3200 studies. However, the ERG noted that the manufacturer focused on a comparison of oxaliplatin chemotherapy regimens with or without bevacizumab as first-line treatment. This differed from the scope, which included irinotecan chemotherapy regimens without bevacizumab as comparators and bevacizumab plus oxaliplatin regimens as second-line treatment.
The ERG expressed concerns about pooling data from the initial two-arm part and the 2 x 2 factorial part of the NO16966 study. It stated that this was inappropriate because of the different designs of the two parts of the study. The European Medicines Agency (EMA) in their assessment report for bevacizumab also expressed concerns about the appropriateness of this method of pooling and it noted that this pooled analysis was specified in the protocol in case of borderline significance in progression-free survival in the 2 x 2 study. The EMA therefore questioned the validity of the results derived from the pooled analysis. The ERG also noted that the number of patients reported as Caucasian and the number of patients with ECOG performance status of 0 were 10% greater in the 2 x 2 factorial part of the study than the initial two-arm part and that both are associated with better prognosis. The ERG further highlighted that there was a difference in terms of the overall survival benefit associated with bevacizumab in the primary pooled analysis (overall survival significantly improved) and in the pooled analysis based on the 2 x 2 factorial design only (overall survival not significantly improved). The ERG suggested that this difference might be because of the imbalance of patients in the 2 x 2 part of the study who had a slower rate of disease progression (that is, patients whose disease took longer to relapse after prior adjuvant therapy) and the lack of statistical power to assess overall survival.
Additional analyses were provided by the manufacturer using only the 2 x 2 factorial design. For the comparison of B-XELOX with XELOX, using the 2 x 2 factorial part of the NO16966 study only (that is, the efficacies of B-XELOX and B-FOLFOX-4 combined compared with P-XELOX and P-FOLFOX-4 combined), B-XELOX produced an ICER of £48,111 per QALY gained (£129,911 per QALY gained without the patient access scheme). Removing the patients who had received prior adjuvant therapy reduced the ICER to £36,006 per QALY gained (£92,698 per QALY gained without the patient access scheme). If the XELOX and FOLFOX arms were not pooled then the ICER was £35,662 per QALY gained (£90,779 per QALY gained without the patient access scheme). For the comparison of B-FOLFOX-6 with FOLFOX-6, using the 2 x 2 factorial part of the NO16966 study (that is, the efficacies of B XELOX and B-FOLFOX-4 combined compared with P-XELOX and P-FOLFOX-4 combined), B-FOLFOX-6 produced an ICER of £39,771 per QALY gained (£134,309 per QALY gained without the patient access scheme). Removing patients who had received prior adjuvant therapy was associated with an ICER of £31,174 per QALY gained (£96,687 per QALY gained without the patient access scheme). When the XELOX and the FOLFOX arms were not pooled, then the ICER was £62,714 per QALY gained (£240,324 per QALY gained without the patient access scheme). The manufacturer did not provide any analysis using the 2 x 2 factorial part of the study with patients who had received prior adjuvant therapy excluded and the XELOX and FOLFOX arms not pooled.
The ERG reviewed the additional analyses submitted by the manufacturer (as outlined in section 3.22) and suggested that the most appropriate analysis was one using the 2 x 2 factorial design of the NO16966 study with XELOX and FOLFOX not pooled and patients who had received prior adjuvant therapy excluded. However, this analysis was not provided by the manufacturer despite requests by the ERG to do so. The ERG therefore suggested that the next most appropriate analysis was the one using data from the 2 x 2 factorial design of the NO16966 study with the XELOX and FOLFOX arms pooled and patients who had received prior adjuvant therapy excluded. This analysis gave Kaplan–Meier estimates up to month 6 and then the Weibull distribution was used for extrapolating progression-free survival, and Kaplan–Meier estimates up to month 28 with the Weibull distribution then used for extrapolating overall survival. With this analysis the ERG produced an ICER for B-XELOX of £36,354 per QALY gained compared with XELOX and £31,452 per QALY gained for B-FOLFOX-6 compared with FOLFOX-6 (ICERs without the patient access scheme were not provided). The results of the one-way sensitivity analyses showed that the ICERs were not greatly influenced by any of the parameter changes.
The ERG noted that the duration of chemotherapy treatment was relatively short (median approximately 6 months) despite the protocol allowing treatment until disease progression or unacceptable adverse events. The protocol also allowed bevacizumab/placebo treatment to continue until disease progression or unacceptable toxicity (as in the bevacizumab SPC) but the duration of therapy with bevacizumab was also relatively short (median 6.5 months). Although the ERG agreed that the manufacturer's economic model was an accurate replication of the NO16966 study, the ERG suggested that in clinical practice treatment with drugs other than oxaliplatin (fluorouracil, capecitabine, bevacizumab) might continue after oxaliplatin regimens stopped. The ERG conducted an exploratory analysis (using the 2 x 2 factorial design of the NO16966 study with the XELOX and FOLFOX arms pooled and patients who had received prior adjuvant therapy excluded) that examined the impact on ICERs of stopping oxaliplatin 1 month before the other treatment components. Under this scenario, costs in the XELOX and FOLFOX-6 arms were reduced. In the B-XELOX and B-FOLFOX arms, the cost of oxaliplatin remained the same because oxaliplatin is free for these groups. It was also assumed that no change in incremental survival occurred. In this analysis, the ICERs were increased from £36,354 to £43,511 per QALY gained when B XELOX was compared with XELOX and from £31,452 to £39,478 per QALY gained when B-FOLFOX-6 was compared with FOLFOX-6 (ICERs without the patient access scheme were not provided). The ERG also examined the impact of increasing the duration of bevacizumab treatment by 1 month on the ICERs. It was assumed that no change in survival occurred and the treatment duration of the other components remained the same. In this analysis, the ICERs increased from £36,354 to £47,312 per QALY gained when B-XELOX was compared with XELOX and from £31,452 to £41,692 per QALY gained when B-FOLFOX-6 was compared with FOLFOX-6 (ICERs without the patient access scheme were not provided).
The ERG stated that it was not possible to adequately check the sources considered for determining the utility values because the references were incomplete. The ERG suggested that the utility values from the guidance on 'Cetuximab for the first-line treatment of metastatic colorectal cancer' (NICE technology appraisal guidance 176) could be relevant to patients receiving bevacizumab. However, the ERG also commented that the assumption that the utility value of the health state after first-line treatment (that is, off treatment but not yet progressed) is similar to that of people aged 55–64 years in the UK general population is unrealistic. This is because after 6 months of chemotherapy, people are often less mentally and physically fit than those of the same age in the general population. In addition, the ERG noted that the utility value for the health state first-line treatment (that is, 0.77) might be an overestimate. This is because the utility value in the UK general population of the same age group is 0.79. The ERG further noted that the model did not take into account the fact that XELOX regimens might be associated with higher health-related quality of life than FOLFOX regimens because the former are considered more convenient. The ERG performed an exploratory analysis that investigated the impact of decreasing the utility values by 20%. This decrease in utility values had a large impact on the ICERs. Using the 2 x 2 factorial part of the study with patients with prior adjuvant therapy excluded, the ICER for B-XELOX increased from £36,354 to £45,433 per QALY gained when compared with XELOX and the ICER for B-FOLFOX-6 increased from £31,452 to £39,315 per QALY gained when compared with FOLFOX-6 (ICERs without the patient access scheme were not provided).
In response to consultation, the manufacturer provided revised cost-effectiveness estimates. These were based on the ICERs calculated by the ERG of £36,354 per QALY gained for B-XELOX compared with XELOX and £31,452 per QALY gained for B FOLFOX-6 compared with FOLFOX-6 as detailed in section 3.23 (ICERs without the patient access scheme were not provided). The manufacturer revised the time of operating the patient access scheme, based on the number of patients expected to enrol within the first 3 years of the scheme, to 131 minutes and 152 minutes per patient for the XELOX and FOLFOX regimens respectively, based on research within the NHS. This equated to an average cost per patient over years 1 to 3 of £57 and £67 for B-XELOX and B FOLFOX respectively. This increased the ICER for B-XELOX compared with XELOX by £164 per QALY gained and the ICER for B-FOLFOX-6 compared with FOLFOX-6 by £113 per QALY gained. The manufacturer also used a utility value of 0.77 in the health state after first-line treatment (that is, without disease progression) as opposed to a value of 0.79. This increased the ICER for B XELOX compared with XELOX by £647 per QALY gained and the ICER for B-FOLFOX-6 compared with FOLFOX-6 by £560 per QALY gained. The manufacturer also conducted a time-and-motion study of the preparation and administration of bevacizumab infusions at a private hospital. The manufacturer stated that preparation time was divided between the pharmacist and the pharmacy technician. This resulted in a reduction in the bevacizumab administration costs of £42 (as used in the original submission) to £31 per infusion. The ICER for B-XELOX compared with XELOX was reduced by £677 per QALY gained and the ICER for B-FOLFOX-6 compared with FOLFOX-6 was reduced by £1012 per QALY gained. The cumulative effect of these changes increased the ICER for B-XELOX compared with XELOX from £36,354 to £36,494 per QALY gained and decreased the ICER for B-FOLFOX-6 compared with FOLFOX-6 from £31,452 to £31,122 per QALY gained.
The manufacturer also confirmed that the patient access scheme would apply to bevacizumab given intermittently; that is, bevacizumab would be provided free of charge after 12 months of cumulative treatment had been given. The manufacturer did not state whether this would affect the ICERs. The manufacturer did not provide ICERs from the 2 x 2 factorial part of the study with patients who had received prior adjuvant therapy excluded and with the XELOX and FOLFOX arms not pooled.
The manufacturer submitted an amended patient access scheme that included all the elements of the original scheme and an additional upfront payment (designated by the manufacturer to be commercial in confidence) to the NHS for each person starting first-line treatment with bevacizumab. When the revised patient access scheme was included, the ICER for B-XELOX compared with XELOX was reduced from £36,494 to £29,975 per QALY gained and the ICER for B-FOLFOX-6 compared with FOLFOX-6 was reduced from £31,122 to £24,604 per QALY gained. Without the patient access scheme, the ICER for B-XELOX compared with XELOX was £104,870 per QALY gained and the ICER for B FOLFOX-6 compared with FOLFOX-6 was £108,267 per QALY gained.
The manufacturer provided an exploration of the effect of the individual components of the revised patient access scheme on the ICERs for B-XELOX compared with XELOX and for B-FOLFOX-6 compared with FOLFOX-6. Providing bevacizumab free after 12 months slightly reduced the ICERs. Providing oxaliplatin free of charge when given with bevacizumab led to a substantial reduction of the ICERs and was the major driver of the impact of the patient access scheme on cost effectiveness. Fixing the price of bevacizumab to £800 per 2-weekly cycle and £1200 per 3-weekly cycle and the upfront payment resulted in further but less marked reductions in the ICERs. The precise details of the effect of the individual components of the revised patient access scheme were designated by the manufacturer to be commercial in confidence.
The ERG commented on the revised ICERs and patient access scheme submitted by the manufacturer. The ERG noted that the time-and-motion study conducted by the manufacturer to ascertain the administration costs of bevacizumab was based on information from one small private hospital and may not fully reflect the true costs to the NHS. The ERG conducted the same analyses as the manufacturer and noted slight differences in the resulting ICERs. The ICER for B-XELOX compared with XELOX was £29,956 per QALY gained and the ICER for B-FOLFOX-6 compared with FOLFOX-6 was £24,577 per QALY gained when the revised patient access scheme was incorporated. The ERG stated that the reasons for the differences between their calculations and those of the manufacturer were unclear but recognised that the differences were small. The ERG further noted that when the manufacturer used higher operating costs of the patient access scheme then the ICERs were slightly increased. The ERG conducted the same analysis as the manufacturer but it set the cost per patient of operating the patient access scheme to £100. Under this scenario analysis the ICERs were slightly increased; £30,684 per QALY gained when B-XELOX was compared with XELOX and £25,312 per QALY gained when B FOLFOX-6 was compared with FOLFOX-6.
The ERG performed exploratory analyses incorporating discounts on the list price of oxaliplatin. The ICER with the patient access scheme for B XELOX compared with XELOX increased from £29,975 per QALY gained to £68,140 per QALY gained assuming a 90% discount and £70,260 per QALY gained assuming a 95% discount. The ICER with the patient access scheme for B-FOLFOX-6 compared with FOLFOX-6 increased from £24,604 per QALY gained to £70,470 per QALY gained assuming a 90% discount and £73,018 per QALY gained assuming a 95% discount. The ICERs without the patient access scheme applied were reduced slightly (by approximately 5%) when 90% and 95% discounts on the price of oxaliplatin were incorporated to all treatment arms in the model.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab, having considered evidence on the nature of metastatic colorectal cancer and the value placed on the benefits of bevacizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee discussed possible comparators used in the UK for the first-line treatment of metastatic colorectal cancer in clinical practice. It noted that the manufacturer, based on a market research analysis, and the ERG considered that the standard comparators were combination chemotherapy regimens including oxaliplatin because these are most commonly used in the UK. However, the ERG commented that FOLFIRI could also be considered a relevant comparator because there is previous NICE guidance (NICE technology appraisal guidance 93 ) recommending its use. However, the Committee heard from clinical specialists that the use of FOLFIRI as a first-line treatment is decreasing in the UK. The clinical specialists highlighted that most patients with metastatic colorectal cancer who are being treated with combination chemotherapy will receive oxaliplatin-containing regimens because these regimens are associated with less marrow suppression and less diarrhoea than FOLFIRI, although there is an increased risk of significant sensory neuropathy. The clinical specialists and patient experts also stated that oxaliplatin-containing regimens are used for patients with liver metastases that are potentially resectable. In addition, they highlighted that oral capecitabine is often preferred by patients to intravenous fluorouracil. However, the risk of diarrhoea increases when irinotecan is given in combination with capecitabine; therefore if capecitabine is given, it is combined with oxaliplatin (that is, XELOX) rather than with irinotecan. The Committee understood that most of the patients who receive first-line FOLFIRI do so because of contraindications to oxaliplatin, such as a pre-existing neuropathy, or a short period elapsing between the end of adjuvant chemotherapy with oxaliplatin and the development of recurrent disease. The Committee therefore concluded that FOLFIRI should be excluded as a comparator to bevacizumab given in combination with oxaliplatin-containing regimens.
# Clinical effectiveness
The Committee considered the data presented by the manufacturer for the clinical effectiveness of bevacizumab as a first-line treatment for metastatic colorectal cancer. It noted that the data came from a study that included an initial two-arm part and a later 2 x 2 factorial part (six arms in total). Data from the initial two-arm part of the study and the later 2 x 2 factorial part of the study were combined in the primary analysis. The Committee noted that in the primary analysis (that is, pooling of all bevacizumab arms compared with pooling of all placebo arms) statistically significant improvements in progression-free survival of 1.7 months and in overall survival of 2.3 months were reported for bevacizumab. However, the Committee noted an imbalance in prognostic factors between the initial two-arm part of the study and the 2 x 2 factorial part of the study that could bias the results in favour of bevacizumab: the number of patients reported as Caucasian and the proportion of patients with ECOG performance status of 0 were both 10% higher in the 2 x 2 factorial part of the study. Therefore, the Committee considered that the validity of the results from the pooled analysis was not acceptable. The Committee considered the secondary analysis (of the 2 x 2 factorial part of the study only) showing a statistically significant improvement in progression-free survival of 1.4 months, but no statistically significant increase in overall survival, to be more methodologically appropriate. However, the Committee agreed with the ERG that the most appropriate method of analysis would be with the XELOX and FOLFOX arms not pooled and patients with prior adjuvant therapy excluded and noted that this was not provided. The Committee concluded that bevacizumab provided a modest increase in progression-free and overall survival when compared with regimens without bevacizumab but was mindful that there was a significant degree of uncertainty in the clinical evidence.
The Committee discussed the equivalence of FOLFOX-4 and XELOX regimens. It heard from clinical specialists that FOLFOX-4 regimens are considered to offer equivalent clinical benefits to XELOX regimens. It also heard from patient experts that FOLFOX 4 regimens are associated with fewer and less serious adverse events than XELOX regimens, but XELOX regimens can be more convenient for patients. The Committee agreed that FOLFOX-4 and XELOX could be considered equivalent. The Committee discussed the imbalance observed in the study whereby the improvement in progression-free survival was only significant for the B-XELOX group and not the B-FOLFOX-4 group. The Committee understood that the P-FOLFOX-4 group (placebo and FOLFOX-4) had a greater time between adjuvant treatment and relapse than the other treatment groups and that this represented an important prognostic factor. The Committee noted that exclusion of the 25% of patients who had received prior adjuvant treatment resulted in significant improvement in progression-free survival for the B-FOLFOX-4 group. The Committee concluded that this indicated that there was an imbalance of prognostic factors within the study, but noted that at the time of the study the importance of this prognostic factor was not known.
The Committee discussed the use of bevacizumab in combination with oxaliplatin-containing regimens as a second-line treatment for metastatic colorectal cancer. The Committee considered the data presented by the manufacturer. It noted that the evidence suggested that both overall survival and progression-free survival were statistically significantly improved by 2 to 3 months (as detailed in section 3.11) in the second-line setting. The Committee concluded that bevacizumab was clinically effective as a second-line treatment. The Committee also noted that the manufacturer did not present any evidence of bevacizumab compared with FOLFIRI as a second-line treatment. It further noted that the manufacturer did not submit any evidence of bevacizumab in lines beyond second-line treatment.
The Committee noted that a significant percentage of patients withdrew early from the NO16966 study because of adverse events. It heard from clinical specialists that, in general, withdrawals often occur at an early stage for all chemotherapy regimens (including those containing bevacizumab). They further stated that if a patient is tolerant of bevacizumab at the beginning of the treatment, withdrawal is less likely at a later stage because of intolerance. For the chemotherapy agents, however, increased adverse events were likely because of increased time on treatment. The patient experts agreed that although the adverse events experienced with bevacizumab were unpredictable and affected health-related quality of life, they could be tolerated because of the trade-off with the benefits in terms of extension to life.
In summary, based on the clinical-effectiveness evidence and the opinions of the clinical specialists and patient experts, the Committee concluded that, for the first-line treatment of metastatic colorectal cancer, bevacizumab in combination with oxaliplatin-containing regimens gave a modest clinical benefit compared with regimens without bevacizumab. The Committee concluded that bevacizumab was clinically effective as part of second-line treatment. Benefits from bevacizumab were achieved at the expense of small but definite increases in adverse events.
# Cost effectiveness
The Committee reviewed the results of the economic analyses submitted by the manufacturer. The Committee noted that the manufacturer had assumed that FOLFOX-6 had similar efficacy to FOLFOX-4 but with reduced costs. The Committee heard from clinical specialists that FOLFOX-6 offers similar clinical outcomes to FOLFOX-4. In addition, it heard that FOLFOX-6 is more commonly used in UK clinical practice because it involves only one visit to hospital per therapy cycle rather than the two visits per treatment cycle on consecutive days for FOLFOX-4. The Committee agreed that the assumptions made by the manufacturer with regards to FOLFOX-6 in the economic analysis were appropriate.
The Committee noted that in the economic model and in the NO16966 study, treatment was continuous. It heard from clinical specialists that current practice in the UK is often intermittent treatment, with treatment restarting when there are signs of disease progression. Although intermittent chemotherapy may be associated with a small survival deficit, it involves shorter durations of treatment and this reduces adverse events such as neuropathy and other side effects of therapy. Intermittent treatment may therefore be associated with better health-related quality of life. However, the Committee noted responses from consultation that, although intermittent treatment is commonly used in the UK, the sole evidence base for the addition of bevacizumab to first-line combination chemotherapy was reflective of a continuous treatment strategy. Therefore, the Committee concluded that the economic model reflected the clinical evidence that was available.
The Committee discussed the base-case cost-effectiveness estimates originally provided by the manufacturer. It noted that a revised base case was submitted after the ERG suggested that untruncated data should be used to fit alternative distributions when extrapolating the trial data. The Committee noted that the manufacturer's revised base case involved pooling of the initial two-arm part of the study and the 2 x 2 factorial part of the study. As previously noted, the Committee considered that this analysis was inappropriate because of the different designs of the study and the imbalance of demographics between the two parts of the study. Therefore, the Committee concluded that only the 2 x 2 factorial part of the study with the revised modelling of survival should be used in the cost-effectiveness analysis.
The Committee considered that the most plausible model assumption(s) for cost effectiveness would be to use the 2 x 2 factorial design of the NO16966 study with XELOX and FOLFOX arms not pooled and patients who had received prior adjuvant therapy excluded and noted that this had not been provided by the manufacturer. The Committee heard from the ERG that because no estimates of the effect of treatment in this scenario had been provided it was not possible to demonstrate how the ICERs would be affected. The Committee heard the manufacturer's opinion that removing patients who had received prior adjuvant treatment resulted in similar survival outcomes for XELOX and FOLFOX, and for B-XELOX and B-FOLFOX. The manufacturer stated that the basis of this view was informed by the overall results of the NO16966 study, which showed that XELOX was not inferior to FOLFOX and that there was no interaction between bevacizumab and the chemotherapy regimens used. However, the Committee noted that the analysis that used the 2 x 2 factorial part of the study, with the XELOX and FOLFOX arms pooled and patients who had received prior therapy excluded, resulted in markedly different ICERs than when the XELOX and FOLFOX arms were not pooled and patients who had received prior therapy were included. The ICERs provided by the manufacturer without the patient access scheme for B-XELOX compared with XELOX decreased slightly from £92,700 to £90,800 per QALY gained, and the ICER for B-FOLFOX-6 compared with FOLFOX-6 increased markedly from £96,700 to £240,300 per QALY gained (as detailed in section 3.22). The Committee considered that the analysis that did not pool the XELOX and FOLFOX arms and excluded patients who had received prior adjuvant treatment should have been provided and that the effect of pooling the XELOX and FOLFOX arms was unclear. Additionally, the Committee considered that it was counter-intuitive for the analysis to pool the effects of treatment, but not to pool the duration of treatment in the XELOX and FOLFOX arms. Therefore the Committee concluded that the ICERs were associated with substantial uncertainty.
The Committee noted that the ICERs presented by the manufacturer represented the treatment durations observed in the trial (that is, bevacizumab was stopped at the same time as FOLFOX and XELOX and before disease progression). The Committee noted that the trial protocol and the SPC allowed bevacizumab treatment until disease progression, even if oxaliplatin was stopped early because of adverse events. The ERG and the clinical specialists stated that, if a continuous chemotherapy policy was being practised, treatment with non-oxaliplatin components (such as bevacizumab) would be likely to continue after oxaliplatin treatment had stopped. The Committee noted that stopping oxaliplatin treatment 1 month before the other treatment agents or receiving bevacizumab for 1 month after oxaliplatin treatment had stopped, increased the ICERs. It noted that both analyses assumed no increase in progression-free or overall survival. However, the Committee considered that if such increases in progression-free and overall survival were accounted for, the extra bevacizumab costs would be likely to outweigh any additional survival benefits of bevacizumab, given the previously noted modest impact on progression-free and overall survival. The Committee concluded that, although the economic model was an accurate replication of the study (in terms of treatment duration), in practice bevacizumab treatment would be expected to continue until disease progression in patients treated with a continuous therapy policy. This could potentially increase the ICERs.
The Committee noted the manufacturer's comments in response to consultation that it was plausible that with an increase in the treatment duration the ICERs might increase but that they might also decrease. The Committee heard from the manufacturer that this could be because patients who do not progress and continue to receive treatment are those that may receive the greatest benefit. The manufacturer thought it was possible that the additional benefits would not be outweighed by the additional costs of treatment. However, the ERG commented that ICERs were more likely to increase because the incremental cost of taking bevacizumab for 1 month after stopping oxaliplatin (that is, bevacizumab costs versus no oxaliplatin costs) is higher than the incremental cost of treatment with bevacizumab and oxaliplatin (that is, bevacizumab and oxaliplatin costs versus oxaliplatin costs). Therefore, the additional costs would outweigh any additional benefits and the ICERs would be likely to increase. The Committee agreed that there was uncertainty as to how the ICERs would be affected if bevacizumab was given until progression because of the lack of clinical evidence but noted the ERG's view that the ICERs were likely to increase. Therefore, the Committee concluded that the ICERs may not reflect the way in which bevacizumab would be used in UK clinical practice, and were therefore associated with additional uncertainty but were more likely to increase.
The Committee considered the utility values used in the economic model. The Committee noted that no health-related quality-of-life data were collected in the study and that the utility values were taken from 'Cetuximab for the first-line treatment of metastatic colorectal cancer' (NICE technology appraisal guidance 176). The ERG stated that the reporting of utility values in metastatic colorectal cancer was inconsistent and there is a paucity of data. The Committee noted that the manufacturer had adjusted the utility value associated with the health state after first-line treatment (that is, without disease progression) to 0.77 in the revised analyses. However, the Committee agreed that the utility value of 0.77 was still high because it was similar to the utility values of people in the UK general population rather than people with metastatic colorectal cancer. The Committee also noted that the utility values were obtained from a small study of patients with metastatic colorectal cancer receiving cetuximab and chemotherapy using the EQ-5D. In addition, the utility values in the economic model were not regimen-specific. It further noted that decreasing the utility values by 20% increased the ICERs substantially. The Committee concluded that these issues also increased the uncertainty associated with the base-case ICERs.
The Committee noted that disutility due to adverse events was not included in the economic model. The manufacturer stated that because the utility values were obtained using the EQ-5D, then disutility due to adverse events would be included implicitly within this measure. The Committee noted that a higher incidence of grade 3 and 4 adverse events associated with bevacizumab had been reported in the trial. It considered that there would be disutility (that is, the quality-of-life estimates were likely to have been overestimated) and additional costs associated with the toxicity of bevacizumab. The Committee heard from the manufacturer that the majority of grade 3 and 4 adverse events are due to hypertension, which in most cases is readily treatable and likely to have a small impact on the health state utility of the patient. However, the Committee considered that, in some cases, the adverse effects of bevacizumab could be serious and that the disutility due to adverse events specific to bevacizumab treatment should have been incorporated into the model. The Committee further noted that the utility values used by the manufacturer could not have accounted for the adverse effects of bevacizumab because they were obtained from a study that examined cetuximab. The Committee therefore concluded that the ICERs would increase if the disutility due to adverse events related to bevacizumab treatment was included.
The Committee noted that in the revised analyses provided by the manufacturer in response to consultation, the treatment administration costs of B-FOLFOX and B-XELOX were stated to have been overestimated in the original submission. The Committee noted the ERG's concerns about the time-and-motion study conducted by the manufacturer; in particular, the sources of the unit costs were unclear and the study was based on data from one small private hospital. The Committee considered that the addition of a bevacizumab infusion to either XELOX or FOLFOX could incur greater additional treatment administration costs than those stated by the manufacturer. The Committee concluded that if these higher administration costs were included, then this would result in an increase in the ICER estimates.
The Committee discussed the details of the patient access scheme and the impact of the patient access scheme on the ICERs. It noted that when the amended patient access scheme was applied the ICERs decreased from £105,000 to £30,000 per QALY gained for B-XELOX compared with XELOX, and from £108,000 to £24,600 per QALY gained for B-FOLFOX-6 compared with FOLFOX-6. The Committee noted that there was uncertainty expressed by the Department of Health around the operating costs of implementing the scheme. The Committee had concerns about the complexity of the scheme and considered that hospital trusts were likely to involve clinical staff and finance departments as well as pharmacists in its implementation. It noted the revised analyses presented by the manufacturer that incorporated higher operating costs of the patient access scheme. However, the Committee considered that the scheme was complex, with requirements for a number of financial transactions between the manufacturer, healthcare providers and commissioners. Therefore, the operating costs of the scheme were still likely to be greater than those presented by the manufacturer. The Committee noted the ERG's exploratory analysis showing that when the administration costs of the patient access scheme were increased to £100 the ICERs increased slightly. In addition, the Committee noted its earlier conclusions that all of the ICERs with and without the patient access scheme were associated with substantial uncertainty and could be underestimated.
The Committee considered how the four components of the patient access scheme contributed to the reduction in the ICERs. It noted that the provision of free oxaliplatin was the key component in reducing the ICERs. The Committee noted that the price of oxaliplatin in the economic model was based on the BNF 57 non-proprietary price of £313.50 per 100 mg. The Committee heard from the manufacturer that the list price of oxaliplatin had been used in accordance with the NICE methods guide. However, the Committee noted that the methods guide also states that when the acquisition price paid for a resource differs from the public list price then a sensitivity analysis should be conducted to assess the implications of variations from this price. The Committee acknowledged that generic versions of oxaliplatin have recently become available and that the list price was decreasing, with the list price in BNF 60 reduced to £299.50 per 100 mg. The Committee also noted information provided by the Commercial Medicines Unit of the Department of Health which stated that oxaliplatin is widely available in the NHS through procurement contracts at a discount of more than 90% off the list price. The Committee noted the ERG's exploratory analyses, which showed that when the oxaliplatin list price was discounted by 90% the ICERs with the patient access scheme were greatly increased to £68,100 per QALY gained for B-XELOX compared with XELOX, and to £70,500 per QALY gained for B-FOLFOX compared with FOLFOX-6. The Committee considered that it was more appropriate to use the discounted cost of oxaliplatin when assessing the impact of the patient access scheme on cost effectiveness and therefore did not accept the manufacturer's estimates that ICERs of £105,000 and £108,000 per QALY gained were reduced to £30,000 and £24,600 respectively with the amended patient access scheme.
The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations. In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.
The Committee discussed whether bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee noted that life expectancy with XELOX or FOLFOX was unlikely to be greater than 24 months and was potentially as low as 20 months and 11 months in the first-line and second-line settings respectively. In the first-line setting, the Committee noted from the 2 x 2 analysis of the clinical trial that bevacizumab increased overall survival by 1.4 months compared with XELOX and FOLFOX-4. However, the Committee considered the design of the trial was complex and that the most appropriate method of analysis (that is, with the XELOX and FOLFOX arms not pooled and patients with prior adjuvant therapy excluded) was not provided and therefore the Committee had concerns about the robustness of the evidence. The Committee further noted that bevacizumab as a second-line therapy (E3200 study) statistically significantly increased overall survival by 2.2 months compared with FOLFOX-4. The Committee was aware that the total number of patients currently presenting with metastatic colorectal cancer in England and Wales is approximately 16,000. In addition, the Committee understood that it should take into account the cumulative population for each product in considering the strength of any case, for justifying decisions which employ, in whole or part, the supplementary criteria for appraising life-extending, end-of-life treatments. It noted that bevacizumab was licensed for a number of other indications also involving large patient groups. In summary, the Committee concluded that bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer did not meet all of the criteria for a life-extending, end-of-life treatment.
The Committee concluded (on the basis of the submitted evidence) that the most appropriate cost-effectiveness estimates of bevacizumab as a first-line treatment for metastatic colorectal cancer available were those using the 2 x 2 factorial part of the study, with the XELOX and FOLFOX arms pooled and with patients who had received prior therapy excluded, giving ICERs of £105,000 per QALY gained for B-XELOX and £108,000 per QALY gained for B-FOLFOX-6 (without the patient access scheme) and £68,100 per QALY gained for B-XELOX and £70,500 per QALY gained for B-FOLFOX-6 (with the patient access scheme applied and the discounted price of oxaliplatin used). However, the Committee agreed that these ICERs (both without and with the patient access scheme) were associated with substantial uncertainty and that plausible adjustments to the key model inputs could increase these ICERs. The Committee recognised the novel mode of action of bevacizumab but did not consider it to be a substantially innovative technology in the treatment of metastatic colorectal cancer. The Committee concluded that bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine could not be recommended as a cost-effective use of NHS resources for the first-line treatment of metastatic colorectal cancer.
The Committee reviewed the cost-effectiveness analysis of bevacizumab in combination with oxaliplatin-containing regimens as a second-line treatment for metastatic colorectal cancer. The Committee noted that the base-case ICER presented by the manufacturer was £103,000 per QALY gained. The Committee noted that this ICER was substantially higher than those normally considered an acceptable use of NHS resources. In addition, the manufacturer stated that a cost-effective case for bevacizumab as a second-line treatment could not be made. The Committee further noted that no evidence of bevacizumab given after second-line treatment was submitted by the manufacturer. Therefore, the Committee concluded that bevacizumab in combination with oxaliplatin-containing regimens could not be recommended as a cost-effective use of NHS resources for second-line or later treatment of metastatic colorectal cancer.
The Committee considered whether there were issues related to equality to be taken into account in its considerations. It noted that no equality issues had been raised during the scoping, evidence submissions or consultation stages. Therefore, it concluded that there were no specific issues relating to equality that needed to be taken into account.# Related NICE guidance
Cetuximab for the first-line treatment of metastatic colorectal cancer. NICE technology appraisal guidance 176 (2009).
Cetuximab for the treatment of metastatic colorectal cancer following failure of oxaliplatin-containing chemotherapy (terminated appraisal). NICE technology appraisal guidance 150 (2008).
Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. NICE technology appraisal guidance 118 (2007).
Capecitabine and oxaliplatin in the adjuvant treatment of stage III (Dukes' C) colon cancer. NICE technology appraisal guidance 100 (2006).
Irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer (review of technology appraisal 33). NICE technology appraisal guidance 93 (2005).
Improving outcomes in colorectal cancers – manual update. NICE cancer service guidance (2004).
Guidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer. NICE technology appraisal guidance 61 (2003).# Review of guidance
The guidance on this technology will be considered for review in May 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveDecember 2010# Changes after publication
February 2014: minor maintenance
March 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
The recommendations from this guideline have been incorporated into a NICE Pathway. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine is not recommended for the treatment of metastatic colorectal cancer.\n\nPeople currently receiving bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer should have the option to continue treatment until they and their clinicians consider it appropriate to stop.', 'The technology ': "Bevacizumab (Avastin, Roche Products) is a recombinant humanised monoclonal IgG1 antibody that inhibits the formation of blood vessels (angiogenesis inhibitor). It targets the biological activity of human vascular endothelial growth factor (VEGF), which stimulates new blood vessel formation in the tumour. Bevacizumab in combination with fluoropyrimidine-based chemotherapy has a UK marketing authorisation for the treatment of patients with metastatic carcinoma of the colon or the rectum.\n\nThe summary of product characteristics (SPC) lists the following conditions that may be associated with bevacizumab treatment: gastrointestinal perforations, fistulae, wound healing complications, hypertension, proteinuria, arterial and venous thromboembolism, haemorrhage, pulmonary haemorrhage/haemoptysis, congestive heart failure, reversible posterior leucoencephalopathy and neutropenia. For full details of side effects and contraindications, see the SPC.\n\nBevacizumab is administered as an intravenous infusion. Bevacizumab treatment is given in combination with chemotherapy and is licensed for use until progression of the underlying disease. The recommended dosage for metastatic carcinoma of the colon or rectum is 5 mg/kg or 10 mg/kg of body weight once every 2 weeks when given with oxaliplatin and fluorouracil plus folinic acid (FOLFOX) or 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks when given with oxaliplatin and capecitabine (XELOX). Bevacizumab is available in 100-mg and 400-mg vials at net prices of £242.66 and £924.40 respectively (excluding VAT; 'British national formulary' [BNF] edition 58). For first-line treatment with bevacizumab, the manufacturer's economic model assumed a dosage of 5 mg/kg of body weight once every 2 weeks when given with FOLFOX and 7.5 mg/kg of body weight given once every 3 weeks XELOX, in line with the NO16966 trial. The acquisition cost of bevacizumab (excluding VAT and assuming wastage) for a patient weighing 70 kg is £924.40 at a dosage of 5 mg/kg every 2 weeks and £1409.72 at a dosage of 7.5 mg/kg every 3 weeks. The manufacturer of bevacizumab (Roche Products) proposed a patient access scheme to the Department of Health for the use of bevacizumab in metastatic colorectal cancer. The Department of Health was content for NICE to consider the patient access scheme proposed by Roche. However, it had concerns about the scheme's complexity and believed that the administrative burden of the scheme was greater than that originally set out by the manufacturer.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of bevacizumab and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer's approach to the decision problem compared bevacizumab plus FOLFOX (B-FOLFOX) or bevacizumab plus XELOX (B-XELOX) with FOLFOX and XELOX without bevacizumab as a first-line treatment. The manufacturer stated that the use of irinotecan in combination with folinic acid and fluorouracil (FOLFIRI) is decreasing and that it is mainly used in the small minority of patients in whom oxaliplatin is contraindicated or who cannot tolerate oxaliplatin. This was based on market research analysis, which indicated that combination chemotherapy regimens including oxaliplatin are the most commonly used in UK clinical practice. However, for completeness, the manufacturer performed an economic evaluation comparing B-FOLFOX or B-XELOX with FOLFIRI. The manufacturer stated that the cost effectiveness of bevacizumab as a second-line treatment could not be demonstrated.\n\nThe manufacturer undertook a systematic review of the literature and identified two randomised controlled trials: one assessed bevacizumab as a first-line therapy (NO16966) and one assessed bevacizumab as a second-line therapy (E3200). No evidence of bevacizumab used in lines of treatment beyond second-line therapy was provided by the manufacturer.\n\nThe NO16966 study started as a phase III, multinational, two-arm, randomised, open-label study. This study was originally designed to demonstrate the non-inferiority of XELOX compared with FOLFOX-4 (that is, the FOLFOX regimen given every 2 weeks, with two long infusions in the first 48 hours) in adult patients with histologically confirmed metastatic colorectal cancer who had not been treated before with chemotherapy. After randomisation of 634 patients to XELOX or FOLFOX-4, the original protocol design was amended to include a 2 x 2 factorial randomised study in which patients were subsequently randomised to either XELOX or FOLFOX plus either bevacizumab or placebo. A further 1401 patients were then recruited (blinded to the allocation of bevacizumab or placebo), and a final total of 2035 patients were randomised in the NO16966 study. The study amendment included an additional objective of demonstrating superiority of bevacizumab in combination with chemotherapy (B-XELOX or B-FOLFOX-4) over placebo in combination with chemotherapy (P-XELOX or P FOLFOX-4). The dosage of bevacizumab was 5 mg/kg every 2 weeks (B-FOLFOX-4) or 7.5 mg/kg every 3 weeks (B-XELOX). Treatment was planned to continue until disease progression, unacceptable toxicity, resection of metastatic disease or for 48 weeks, whichever came first (this being at the discretion of the investigator). Patients who completed the 48-week study treatment phase without progressive disease were eligible to enter the post-study treatment phase and continue their allocated treatment until their disease progressed. Patients whose disease became operable, and underwent resection, were eligible to enter the post-study treatment phase. The NO16966 protocol also allowed continuation of allocated treatment (bevacizumab or placebo) until disease progression (in line with the bevacizumab SPC, which was produced after the NO16966 study) if oxaliplatin treatment was terminated because of adverse events.\n\nAll patients in the study had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The study was stratified to ensure that study arms were balanced with regards to ECOG performance status (0 versus 1), number of organs with metastases at baseline (one versus more than one), alkaline phosphatase level at baseline (within normal range versus above normal range), liver as a site of metastasis (yes versus no) and geographic region. The median follow-up was 28 months. The manufacturer acknowledged that patients in the study were slightly younger and fitter than patients with metastatic colorectal cancer in the UK who are, on average, over 60 years of age.\n\nThe primary pooled analysis of non-inferiority of the NO16966 study (that is, pooling of all XELOX arms compared with pooling of all FOLFOX-4 arms) showed that the XELOX and FOLFOX-4 regimens were equivalent for overall and progression-free survival. The primary pooled analysis of superiority for the NO16966 study (that is, pooling of the initial two-arm study and the 2 x 2 factorial part of the study) showed that the addition of bevacizumab to chemotherapy (B-XELOX and B-FOLFOX-4) significantly improved progression-free survival compared with chemotherapy alone (P XELOX and P-FOLFOX-4 and XELOX and FOLFOX-4 combined). The median progression-free survival was 7.7 months in the placebo plus chemotherapy group and 9.4 months in the bevacizumab plus chemotherapy group (intention-to-treat analysis, hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.72 to 0.87, p = 0.0001). The median overall survival was 18.9 months in the placebo plus chemotherapy group compared with 21.2 months in the bevacizumab plus chemotherapy group (HR 0.83; 95% CI 0.74 to 0.93, p = 0.0019).\n\nThe manufacturer provided a secondary pooled analysis of superiority based only on the 2 x 2 factorial design (according to the original statistical plan, that is B-XELOX and B-FOLFOX-4 combined compared with P-XELOX and P-FOLFOX-4 combined). The median progression-free survival was 8.0 months in the placebo plus chemotherapy group and 9.4 months in the bevacizumab plus chemotherapy group (HR 0.83; 95% CI 0.72 to 0.95, p = 0.0023). The median overall survival was 19.9 months in the placebo plus chemotherapy group and 21.3 months in the bevacizumab plus chemotherapy group (HR 0.89; 95% CI 0.76 to 1.03, p = 0.0769).\n\nThe manufacturer reported that the difference in progression-free survival was statistically significant for bevacizumab versus placebo in the XELOX subgroup (HR 0.80; 97.5% CI 0.66 to 0.96, p = 0.0059) but not in the FOLFOX-4 subgroup (HR 0.89; 97.5% CI 0.74 to 1.06, p = 0.1312). An exploratory analysis submitted by the manufacturer suggested that bevacizumab did not deliver a benefit to patients in the FOLFOX-4 group who had received prior adjuvant treatment (HR 1.75; 97.5% CI 1.15 to 2.65, p value not reported), whereas it did give a benefit to patients in the FOLFOX-4 group who had not had adjuvant therapy (HR 0.72; 97.5% CI 0.58 to 0.90, p value not reported). The manufacturer stated that this difference could be because the patients in the P-FOLFOX-4 group had a greater time between adjuvant treatment and development of metastatic disease than all of the other groups. This suggested that there was an imbalance in the data due to the better prognosis in the P-FOLFOX-4 group because the cancers in this group were growing more slowly than in the other groups. Additional exploratory analyses showed that when the data for all patients who had received adjuvant treatment were removed from all treatment groups (and thereby including the removal of the subgroup of patients that may have had slower tumour progression), the hazard ratios for overall survival and for progression-free survival ranged from 0.83 to 0.85 (all p values < 0.03) and from 0.74 to 0.77 (all p values < 0.0001).\n\nThe manufacturer also conducted a post-hoc subgroup analysis of the impact of bevacizumab treatment on liver resection rates. This analysis suggested that bevacizumab improved liver resection rates, although this was not statistically significant. No analyses of KRAS or other mutations were submitted.\n\nThe rates of discontinuation in the NO16966 study were higher in the bevacizumab plus chemotherapy groups than in the placebo plus chemotherapy groups. In the 2 x 2 factorial part of the study, 29% (203/699) of patients receiving bevacizumab plus chemotherapy and 47% (329/701) of patients receiving chemotherapy alone were treated until progression (despite the protocol allowing treatment to be continued until disease progression, in line with the SPC of bevacizumab).\n\nIn the NO16966 study, the most common adverse events of bevacizumab treatment were thromboembolic (7.8% venous thromboembolic events compared with 5.1% in the placebo plus chemotherapy groups and 1.7% arterial thromboembolic events compared with 0.9% in the placebo plus chemotherapy groups). Grade 3 or 4 hypertension, proteinuria and bleeding were more common in the bevacizumab groups than in the placebo plus chemotherapy groups (4% versus 0.8%, 3.5% versus 0.9% and 1.9% versus 1.5% respectively). The incidence of serious and life-threatening (grade 3 and 4) adverse events was higher in the bevacizumab plus chemotherapy groups (79.9%) than the placebo plus chemotherapy groups (74.8%) and higher with FOLFOX-4 regimens than XELOX regimens (although FOLFOX-4 was associated with different adverse events than XELOX). The manufacturer stated that most adverse events were associated with cytotoxic chemotherapy, and the higher incidence in the bevacizumab groups was likely to be a consequence of a longer duration of chemotherapy for patients receiving bevacizumab. No health-related quality-of-life data were collected in the NO16966 study.\n\nThe E3200 study was a phase III, multicentre, three-arm, randomised, open-label study. It compared B-FOLFOX-4 (n = 293), FOLFOX-4 (n = 292), and bevacizumab alone (n = 244) in adult patients with advanced or metastatic colorectal cancer previously treated with a fluoropyrimidine and irinotecan, either separately or in combination. Following a data monitoring review 18 months after the start of the trial, the bevacizumab-alone arm was terminated because of poorer efficacy. Patients were stratified by ECOG performance status (0 versus 1 or more) and prior radiation therapy (yes versus no). The dosage of bevacizumab was 10 mg/kg every 2 weeks. Median overall survival was 10.8 months in the FOLFOX 4 group and 13 months in the B-FOLFOX-4 group (intention-to-treat analysis, HR 0.751; 95% CI 0.332 to 0.893, p = 0.0012). Median progression-free survival increased from 4.5 months with FOLFOX-4 to 7.5 months with B-FOLFOX-4 (HR 0.518; 97.5% CI 0.416 to 0.646, p < 0.0001).\n\nThe manufacturer produced a Markov model to estimate the cost effectiveness of bevacizumab plus FOLFOX and XELOX compared with FOLFOX and XELOX alone. The model had four distinct health states: first-line treatment, after first-line treatment without progression, progressed disease and death. It was assumed that all patients start in the first health state (first-line treatment) in accordance with the NO16966 study. The model had a cycle length of 1 month and the time horizon was 8 years (equivalent to life expectancy in the population of interest). A half-cycle correction was applied to the model. An NHS and personal social services (PSS) perspective was taken.\n\nCosts were mainly derived from 2007–2008 national reference costs, BNF 57 and PSSRU (Personal Social Services Research Unit) 2008. FOLFOX-4 was used in the pivotal trial of bevacizumab but the manufacturer stated that FOLFOX-6 (that is, the FOLFOX regimen delivered over 2 weeks but with only one long infusion in the first 48 hours) is more commonly used in UK clinical practice. Therefore, the economic model was adjusted to include FOLFOX-6 by assuming similar efficacy to FOLFOX-4 but with reduced costs.\n\nTreatment duration and dose intensity were based on the NO16966 study. Mean and median treatment durations (6 and 7 months respectively) were shorter in the NO16966 study than progression-free survival. Duration of treatment varied between treatment arms and was longer with the addition of bevacizumab and longer in the FOLFOX than in the XELOX arms. Treatment duration was estimated and applied in the model for each arm of the NO16966 study. However, for simplicity it was assumed that oxaliplatin treatment duration was the same as bevacizumab treatment duration in the B-FOLFOX and B-XELOX arms. It was also assumed that treatment was given continuously, as in the NO16966 study, rather than intermittently. Kaplan–Meier estimates from the NO16966 study were used for progression-free and overall survival up to a median survival of 28 months. After this point, a Weibull probability distribution for overall survival and an exponential probability distribution of progression-free survival (based on average hazard for months 13–28) were used to model the tails. For overall survival, treatment effect was assumed to continue after the median follow-up period and this was further explored in the sensitivity analysis.\n\nThe manufacturer used utility values from 'Cetuximab for the first-line treatment of metastatic colorectal cancer' (NICE technology appraisal guidance 176). These utility values were taken from a randomised controlled trial comparing cetuximab plus FOLFIRI with FOLFIRI alone in first-line treatment of metastatic colorectal cancer and represented mean utility values from 42 patients using the EQ 5D questionnaire; however, only 37 patients fully completed the questionnaire. A utility value of 0.77 was assigned to the first-line treatment health state, the average of all the EQ-5D completed responses over the study period (this assumption was used in NICE technology appraisal guidance 176). A utility value of 0.79 was assigned to the health state after first-line treatment (that is, without disease progression). This was based on expert opinion that patients in this state will experience a higher quality of life than patients receiving first-line treatment, because of fewer adverse events, and their utility value will be similar to a person aged 55–64 years in the UK general population. A utility value of 0.68 was assigned to the progressed disease state, taken from a trial of cetuximab for the third-line treatment of metastatic colorectal cancer and using the Health Utility Index questionnaire (this assumption was used in NICE technology appraisal guidance 176).\n\nThe manufacturer's original submission included details of a proposed patient access scheme for the first-line use of bevacizumab. The scheme involved supplying bevacizumab at a fixed price per cycle of treatment (£800 for 2-weekly cycles and £1200 for 3-weekly cycles), with bevacizumab being provided free after 12 months of treatment and with oxaliplatin being provided free of charge throughout. The manufacturer stated that it would take approximately 5 minutes per cycle for the pharmacist to update the scheme's registry system. This equated to £4 per cycle. The Department of Health stated that it has concerns around the complexity of the patient access scheme and believes that the administration costs of the scheme would probably be greater than those set out by the manufacturer.\n\nThe manufacturer stated that the incremental cost-effectiveness ratios (ICERs) most relevant to the decision problem were B XELOX compared with XELOX and B-FOLFOX-6 compared with FOLFOX-6. In response to a request for clarification from the ERG, the manufacturer provided a revised base-case analysis. The ERG noted that 19.7% (n = 256) and 13.7% (n = 96) of patients were alive after median follow-up in the XELOX/FOLFOX-6 and B XELOX/B-FOLFOX-6 arms respectively. The ERG asked the manufacturer to use untruncated data to calculate the estimates of the parameters of the Weibull distribution. The manufacturer used Kaplan–Meier estimates of survival up to month 6 and then a Weibull distribution fitted to untruncated data after month 6 for progression-free survival and a Weibull distribution fitted to untruncated data for overall survival. The model also accounted for oxaliplatin wastage (that is, no vial sharing was assumed). In the manufacturer's base-case analysis (that is, pooling of the initial two-arm part of the study and the 2 x 2 factorial part of the study), B-XELOX produced an ICER of £35,912 per QALY gained when compared with XELOX (£84,553 per QALY gained without the patient access scheme), and B-FOLFOX-6 produced an ICER of £36,569 per QALY gained when compared with FOLFOX-6 (£92,634 per QALY gained without the patient access scheme). In the one-way sensitivity analyses, which were only provided with the patient access scheme, the ICERs were not greatly influenced by variations in any of the parameters. In the probabilistic sensitivity analysis, the mean ICER for the comparison of B-FOLFOX-6 with FOLFOX-6 was £36,907 per QALY gained and for the comparison of B-XELOX with XELOX the mean ICER was £36,205 per QALY gained (95% intervals not provided).\n\nThe manufacturer stated that currently only a minority (12%) of patients in the UK receive FOLFIRI as a first-line treatment for metastatic colorectal cancer and that in most of these patients treatment with oxaliplatin is contraindicated. For completeness, the manufacturer provided a cost-effectiveness analysis comparing bevacizumab in combination regimens containing oxaliplatin with FOLFIRI. The efficacy of FOLFIRI was derived from a mixed-treatment comparison. A constant hazard ratio was applied to the extrapolated progression-free survival and overall survival curves of FOLFOX-4 to derive the survival curves for FOLFIRI. The treatment duration and the drug administration and adverse event costs for FOLFIRI were assumed to be equivalent to those for FOLFOX-4. B-XELOX compared with FOLFIRI was associated with an ICER of £9192 per QALY gained, B-FOLFOX-6 compared with FOLFIRI was associated with an ICER of £38,835 per QALY gained, and B FOLFOX-4 compared with FOLFIRI was associated with an ICER of £58,575 per QALY gained.\n\nThe manufacturer provided a cost-effectiveness analysis of bevacizumab plus regimens including oxaliplatin in the second-line setting. Drug acquisition, administration and pharmacy costs per cycle were taken from the first-line analysis and multiplied by the mean number of cycles reported in the E3200 study. Costs associated with adverse events, third-line treatment and central venous access devices were not included in the second-line analysis and no discounting was applied. As a second-line treatment, B-FOLFOX-4 compared with FOLFOX-4 resulted in an ICER of £102,644 per QALY gained. The manufacturer stated that the larger ICERs reported in the second-line setting were mainly because of the higher doses of bevacizumab used and that bevacizumab could not be considered cost effective for second-line treatment.\n\nThe ERG stated that the manufacturer's submission generally followed the NICE reference case. It also highlighted that adequate methods of randomisation and allocation concealment were reported in the NO16966 and E3200 studies. However, the ERG noted that the manufacturer focused on a comparison of oxaliplatin chemotherapy regimens with or without bevacizumab as first-line treatment. This differed from the scope, which included irinotecan chemotherapy regimens without bevacizumab as comparators and bevacizumab plus oxaliplatin regimens as second-line treatment.\n\nThe ERG expressed concerns about pooling data from the initial two-arm part and the 2 x 2 factorial part of the NO16966 study. It stated that this was inappropriate because of the different designs of the two parts of the study. The European Medicines Agency (EMA) in their assessment report for bevacizumab also expressed concerns about the appropriateness of this method of pooling and it noted that this pooled analysis was specified in the protocol in case of borderline significance in progression-free survival in the 2 x 2 study. The EMA therefore questioned the validity of the results derived from the pooled analysis. The ERG also noted that the number of patients reported as Caucasian and the number of patients with ECOG performance status of 0 were 10% greater in the 2 x 2 factorial part of the study than the initial two-arm part and that both are associated with better prognosis. The ERG further highlighted that there was a difference in terms of the overall survival benefit associated with bevacizumab in the primary pooled analysis (overall survival significantly improved) and in the pooled analysis based on the 2 x 2 factorial design only (overall survival not significantly improved). The ERG suggested that this difference might be because of the imbalance of patients in the 2 x 2 part of the study who had a slower rate of disease progression (that is, patients whose disease took longer to relapse after prior adjuvant therapy) and the lack of statistical power to assess overall survival.\n\nAdditional analyses were provided by the manufacturer using only the 2 x 2 factorial design. For the comparison of B-XELOX with XELOX, using the 2 x 2 factorial part of the NO16966 study only (that is, the efficacies of B-XELOX and B-FOLFOX-4 combined compared with P-XELOX and P-FOLFOX-4 combined), B-XELOX produced an ICER of £48,111 per QALY gained (£129,911 per QALY gained without the patient access scheme). Removing the patients who had received prior adjuvant therapy reduced the ICER to £36,006 per QALY gained (£92,698 per QALY gained without the patient access scheme). If the XELOX and FOLFOX arms were not pooled then the ICER was £35,662 per QALY gained (£90,779 per QALY gained without the patient access scheme). For the comparison of B-FOLFOX-6 with FOLFOX-6, using the 2 x 2 factorial part of the NO16966 study (that is, the efficacies of B XELOX and B-FOLFOX-4 combined compared with P-XELOX and P-FOLFOX-4 combined), B-FOLFOX-6 produced an ICER of £39,771 per QALY gained (£134,309 per QALY gained without the patient access scheme). Removing patients who had received prior adjuvant therapy was associated with an ICER of £31,174 per QALY gained (£96,687 per QALY gained without the patient access scheme). When the XELOX and the FOLFOX arms were not pooled, then the ICER was £62,714 per QALY gained (£240,324 per QALY gained without the patient access scheme). The manufacturer did not provide any analysis using the 2 x 2 factorial part of the study with patients who had received prior adjuvant therapy excluded and the XELOX and FOLFOX arms not pooled.\n\nThe ERG reviewed the additional analyses submitted by the manufacturer (as outlined in section 3.22) and suggested that the most appropriate analysis was one using the 2 x 2 factorial design of the NO16966 study with XELOX and FOLFOX not pooled and patients who had received prior adjuvant therapy excluded. However, this analysis was not provided by the manufacturer despite requests by the ERG to do so. The ERG therefore suggested that the next most appropriate analysis was the one using data from the 2 x 2 factorial design of the NO16966 study with the XELOX and FOLFOX arms pooled and patients who had received prior adjuvant therapy excluded. This analysis gave Kaplan–Meier estimates up to month 6 and then the Weibull distribution was used for extrapolating progression-free survival, and Kaplan–Meier estimates up to month 28 with the Weibull distribution then used for extrapolating overall survival. With this analysis the ERG produced an ICER for B-XELOX of £36,354 per QALY gained compared with XELOX and £31,452 per QALY gained for B-FOLFOX-6 compared with FOLFOX-6 (ICERs without the patient access scheme were not provided). The results of the one-way sensitivity analyses showed that the ICERs were not greatly influenced by any of the parameter changes.\n\nThe ERG noted that the duration of chemotherapy treatment was relatively short (median approximately 6 months) despite the protocol allowing treatment until disease progression or unacceptable adverse events. The protocol also allowed bevacizumab/placebo treatment to continue until disease progression or unacceptable toxicity (as in the bevacizumab SPC) but the duration of therapy with bevacizumab was also relatively short (median 6.5 months). Although the ERG agreed that the manufacturer's economic model was an accurate replication of the NO16966 study, the ERG suggested that in clinical practice treatment with drugs other than oxaliplatin (fluorouracil, capecitabine, bevacizumab) might continue after oxaliplatin regimens stopped. The ERG conducted an exploratory analysis (using the 2 x 2 factorial design of the NO16966 study with the XELOX and FOLFOX arms pooled and patients who had received prior adjuvant therapy excluded) that examined the impact on ICERs of stopping oxaliplatin 1 month before the other treatment components. Under this scenario, costs in the XELOX and FOLFOX-6 arms were reduced. In the B-XELOX and B-FOLFOX arms, the cost of oxaliplatin remained the same because oxaliplatin is free for these groups. It was also assumed that no change in incremental survival occurred. In this analysis, the ICERs were increased from £36,354 to £43,511 per QALY gained when B XELOX was compared with XELOX and from £31,452 to £39,478 per QALY gained when B-FOLFOX-6 was compared with FOLFOX-6 (ICERs without the patient access scheme were not provided). The ERG also examined the impact of increasing the duration of bevacizumab treatment by 1 month on the ICERs. It was assumed that no change in survival occurred and the treatment duration of the other components remained the same. In this analysis, the ICERs increased from £36,354 to £47,312 per QALY gained when B-XELOX was compared with XELOX and from £31,452 to £41,692 per QALY gained when B-FOLFOX-6 was compared with FOLFOX-6 (ICERs without the patient access scheme were not provided).\n\nThe ERG stated that it was not possible to adequately check the sources considered for determining the utility values because the references were incomplete. The ERG suggested that the utility values from the guidance on 'Cetuximab for the first-line treatment of metastatic colorectal cancer' (NICE technology appraisal guidance 176) could be relevant to patients receiving bevacizumab. However, the ERG also commented that the assumption that the utility value of the health state after first-line treatment (that is, off treatment but not yet progressed) is similar to that of people aged 55–64 years in the UK general population is unrealistic. This is because after 6 months of chemotherapy, people are often less mentally and physically fit than those of the same age in the general population. In addition, the ERG noted that the utility value for the health state first-line treatment (that is, 0.77) might be an overestimate. This is because the utility value in the UK general population of the same age group is 0.79. The ERG further noted that the model did not take into account the fact that XELOX regimens might be associated with higher health-related quality of life than FOLFOX regimens because the former are considered more convenient. The ERG performed an exploratory analysis that investigated the impact of decreasing the utility values by 20%. This decrease in utility values had a large impact on the ICERs. Using the 2 x 2 factorial part of the study with patients with prior adjuvant therapy excluded, the ICER for B-XELOX increased from £36,354 to £45,433 per QALY gained when compared with XELOX and the ICER for B-FOLFOX-6 increased from £31,452 to £39,315 per QALY gained when compared with FOLFOX-6 (ICERs without the patient access scheme were not provided).\n\nIn response to consultation, the manufacturer provided revised cost-effectiveness estimates. These were based on the ICERs calculated by the ERG of £36,354 per QALY gained for B-XELOX compared with XELOX and £31,452 per QALY gained for B FOLFOX-6 compared with FOLFOX-6 as detailed in section 3.23 (ICERs without the patient access scheme were not provided). The manufacturer revised the time of operating the patient access scheme, based on the number of patients expected to enrol within the first 3 years of the scheme, to 131 minutes and 152 minutes per patient for the XELOX and FOLFOX regimens respectively, based on research within the NHS. This equated to an average cost per patient over years 1 to 3 of £57 and £67 for B-XELOX and B FOLFOX respectively. This increased the ICER for B-XELOX compared with XELOX by £164 per QALY gained and the ICER for B-FOLFOX-6 compared with FOLFOX-6 by £113 per QALY gained. The manufacturer also used a utility value of 0.77 in the health state after first-line treatment (that is, without disease progression) as opposed to a value of 0.79. This increased the ICER for B XELOX compared with XELOX by £647 per QALY gained and the ICER for B-FOLFOX-6 compared with FOLFOX-6 by £560 per QALY gained. The manufacturer also conducted a time-and-motion study of the preparation and administration of bevacizumab infusions at a private hospital. The manufacturer stated that preparation time was divided between the pharmacist and the pharmacy technician. This resulted in a reduction in the bevacizumab administration costs of £42 (as used in the original submission) to £31 per infusion. The ICER for B-XELOX compared with XELOX was reduced by £677 per QALY gained and the ICER for B-FOLFOX-6 compared with FOLFOX-6 was reduced by £1012 per QALY gained. The cumulative effect of these changes increased the ICER for B-XELOX compared with XELOX from £36,354 to £36,494 per QALY gained and decreased the ICER for B-FOLFOX-6 compared with FOLFOX-6 from £31,452 to £31,122 per QALY gained.\n\nThe manufacturer also confirmed that the patient access scheme would apply to bevacizumab given intermittently; that is, bevacizumab would be provided free of charge after 12 months of cumulative treatment had been given. The manufacturer did not state whether this would affect the ICERs. The manufacturer did not provide ICERs from the 2 x 2 factorial part of the study with patients who had received prior adjuvant therapy excluded and with the XELOX and FOLFOX arms not pooled.\n\nThe manufacturer submitted an amended patient access scheme that included all the elements of the original scheme and an additional upfront payment (designated by the manufacturer to be commercial in confidence) to the NHS for each person starting first-line treatment with bevacizumab. When the revised patient access scheme was included, the ICER for B-XELOX compared with XELOX was reduced from £36,494 to £29,975 per QALY gained and the ICER for B-FOLFOX-6 compared with FOLFOX-6 was reduced from £31,122 to £24,604 per QALY gained. Without the patient access scheme, the ICER for B-XELOX compared with XELOX was £104,870 per QALY gained and the ICER for B FOLFOX-6 compared with FOLFOX-6 was £108,267 per QALY gained.\n\nThe manufacturer provided an exploration of the effect of the individual components of the revised patient access scheme on the ICERs for B-XELOX compared with XELOX and for B-FOLFOX-6 compared with FOLFOX-6. Providing bevacizumab free after 12 months slightly reduced the ICERs. Providing oxaliplatin free of charge when given with bevacizumab led to a substantial reduction of the ICERs and was the major driver of the impact of the patient access scheme on cost effectiveness. Fixing the price of bevacizumab to £800 per 2-weekly cycle and £1200 per 3-weekly cycle and the upfront payment resulted in further but less marked reductions in the ICERs. The precise details of the effect of the individual components of the revised patient access scheme were designated by the manufacturer to be commercial in confidence.\n\nThe ERG commented on the revised ICERs and patient access scheme submitted by the manufacturer. The ERG noted that the time-and-motion study conducted by the manufacturer to ascertain the administration costs of bevacizumab was based on information from one small private hospital and may not fully reflect the true costs to the NHS. The ERG conducted the same analyses as the manufacturer and noted slight differences in the resulting ICERs. The ICER for B-XELOX compared with XELOX was £29,956 per QALY gained and the ICER for B-FOLFOX-6 compared with FOLFOX-6 was £24,577 per QALY gained when the revised patient access scheme was incorporated. The ERG stated that the reasons for the differences between their calculations and those of the manufacturer were unclear but recognised that the differences were small. The ERG further noted that when the manufacturer used higher operating costs of the patient access scheme then the ICERs were slightly increased. The ERG conducted the same analysis as the manufacturer but it set the cost per patient of operating the patient access scheme to £100. Under this scenario analysis the ICERs were slightly increased; £30,684 per QALY gained when B-XELOX was compared with XELOX and £25,312 per QALY gained when B FOLFOX-6 was compared with FOLFOX-6.\n\nThe ERG performed exploratory analyses incorporating discounts on the list price of oxaliplatin. The ICER with the patient access scheme for B XELOX compared with XELOX increased from £29,975 per QALY gained to £68,140 per QALY gained assuming a 90% discount and £70,260 per QALY gained assuming a 95% discount. The ICER with the patient access scheme for B-FOLFOX-6 compared with FOLFOX-6 increased from £24,604 per QALY gained to £70,470 per QALY gained assuming a 90% discount and £73,018 per QALY gained assuming a 95% discount. The ICERs without the patient access scheme applied were reduced slightly (by approximately 5%) when 90% and 95% discounts on the price of oxaliplatin were incorporated to all treatment arms in the model.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab, having considered evidence on the nature of metastatic colorectal cancer and the value placed on the benefits of bevacizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed possible comparators used in the UK for the first-line treatment of metastatic colorectal cancer in clinical practice. It noted that the manufacturer, based on a market research analysis, and the ERG considered that the standard comparators were combination chemotherapy regimens including oxaliplatin because these are most commonly used in the UK. However, the ERG commented that FOLFIRI could also be considered a relevant comparator because there is previous NICE guidance (NICE technology appraisal guidance 93 [replaced by NICE clinical guideline 131]) recommending its use. However, the Committee heard from clinical specialists that the use of FOLFIRI as a first-line treatment is decreasing in the UK. The clinical specialists highlighted that most patients with metastatic colorectal cancer who are being treated with combination chemotherapy will receive oxaliplatin-containing regimens because these regimens are associated with less marrow suppression and less diarrhoea than FOLFIRI, although there is an increased risk of significant sensory neuropathy. The clinical specialists and patient experts also stated that oxaliplatin-containing regimens are used for patients with liver metastases that are potentially resectable. In addition, they highlighted that oral capecitabine is often preferred by patients to intravenous fluorouracil. However, the risk of diarrhoea increases when irinotecan is given in combination with capecitabine; therefore if capecitabine is given, it is combined with oxaliplatin (that is, XELOX) rather than with irinotecan. The Committee understood that most of the patients who receive first-line FOLFIRI do so because of contraindications to oxaliplatin, such as a pre-existing neuropathy, or a short period elapsing between the end of adjuvant chemotherapy with oxaliplatin and the development of recurrent disease. The Committee therefore concluded that FOLFIRI should be excluded as a comparator to bevacizumab given in combination with oxaliplatin-containing regimens.\n\n# Clinical effectiveness\n\nThe Committee considered the data presented by the manufacturer for the clinical effectiveness of bevacizumab as a first-line treatment for metastatic colorectal cancer. It noted that the data came from a study that included an initial two-arm part and a later 2 x 2 factorial part (six arms in total). Data from the initial two-arm part of the study and the later 2 x 2 factorial part of the study were combined in the primary analysis. The Committee noted that in the primary analysis (that is, pooling of all bevacizumab arms compared with pooling of all placebo arms) statistically significant improvements in progression-free survival of 1.7 months and in overall survival of 2.3 months were reported for bevacizumab. However, the Committee noted an imbalance in prognostic factors between the initial two-arm part of the study and the 2 x 2 factorial part of the study that could bias the results in favour of bevacizumab: the number of patients reported as Caucasian and the proportion of patients with ECOG performance status of 0 were both 10% higher in the 2 x 2 factorial part of the study. Therefore, the Committee considered that the validity of the results from the pooled analysis was not acceptable. The Committee considered the secondary analysis (of the 2 x 2 factorial part of the study only) showing a statistically significant improvement in progression-free survival of 1.4 months, but no statistically significant increase in overall survival, to be more methodologically appropriate. However, the Committee agreed with the ERG that the most appropriate method of analysis would be with the XELOX and FOLFOX arms not pooled and patients with prior adjuvant therapy excluded and noted that this was not provided. The Committee concluded that bevacizumab provided a modest increase in progression-free and overall survival when compared with regimens without bevacizumab but was mindful that there was a significant degree of uncertainty in the clinical evidence.\n\nThe Committee discussed the equivalence of FOLFOX-4 and XELOX regimens. It heard from clinical specialists that FOLFOX-4 regimens are considered to offer equivalent clinical benefits to XELOX regimens. It also heard from patient experts that FOLFOX 4 regimens are associated with fewer and less serious adverse events than XELOX regimens, but XELOX regimens can be more convenient for patients. The Committee agreed that FOLFOX-4 and XELOX could be considered equivalent. The Committee discussed the imbalance observed in the study whereby the improvement in progression-free survival was only significant for the B-XELOX group and not the B-FOLFOX-4 group. The Committee understood that the P-FOLFOX-4 group (placebo and FOLFOX-4) had a greater time between adjuvant treatment and relapse than the other treatment groups and that this represented an important prognostic factor. The Committee noted that exclusion of the 25% of patients who had received prior adjuvant treatment resulted in significant improvement in progression-free survival for the B-FOLFOX-4 group. The Committee concluded that this indicated that there was an imbalance of prognostic factors within the study, but noted that at the time of the study the importance of this prognostic factor was not known.\n\nThe Committee discussed the use of bevacizumab in combination with oxaliplatin-containing regimens as a second-line treatment for metastatic colorectal cancer. The Committee considered the data presented by the manufacturer. It noted that the evidence suggested that both overall survival and progression-free survival were statistically significantly improved by 2 to 3 months (as detailed in section 3.11) in the second-line setting. The Committee concluded that bevacizumab was clinically effective as a second-line treatment. The Committee also noted that the manufacturer did not present any evidence of bevacizumab compared with FOLFIRI as a second-line treatment. It further noted that the manufacturer did not submit any evidence of bevacizumab in lines beyond second-line treatment.\n\nThe Committee noted that a significant percentage of patients withdrew early from the NO16966 study because of adverse events. It heard from clinical specialists that, in general, withdrawals often occur at an early stage for all chemotherapy regimens (including those containing bevacizumab). They further stated that if a patient is tolerant of bevacizumab at the beginning of the treatment, withdrawal is less likely at a later stage because of intolerance. For the chemotherapy agents, however, increased adverse events were likely because of increased time on treatment. The patient experts agreed that although the adverse events experienced with bevacizumab were unpredictable and affected health-related quality of life, they could be tolerated because of the trade-off with the benefits in terms of extension to life.\n\nIn summary, based on the clinical-effectiveness evidence and the opinions of the clinical specialists and patient experts, the Committee concluded that, for the first-line treatment of metastatic colorectal cancer, bevacizumab in combination with oxaliplatin-containing regimens gave a modest clinical benefit compared with regimens without bevacizumab. The Committee concluded that bevacizumab was clinically effective as part of second-line treatment. Benefits from bevacizumab were achieved at the expense of small but definite increases in adverse events.\n\n# Cost effectiveness\n\nThe Committee reviewed the results of the economic analyses submitted by the manufacturer. The Committee noted that the manufacturer had assumed that FOLFOX-6 had similar efficacy to FOLFOX-4 but with reduced costs. The Committee heard from clinical specialists that FOLFOX-6 offers similar clinical outcomes to FOLFOX-4. In addition, it heard that FOLFOX-6 is more commonly used in UK clinical practice because it involves only one visit to hospital per therapy cycle rather than the two visits per treatment cycle on consecutive days for FOLFOX-4. The Committee agreed that the assumptions made by the manufacturer with regards to FOLFOX-6 in the economic analysis were appropriate.\n\nThe Committee noted that in the economic model and in the NO16966 study, treatment was continuous. It heard from clinical specialists that current practice in the UK is often intermittent treatment, with treatment restarting when there are signs of disease progression. Although intermittent chemotherapy may be associated with a small survival deficit, it involves shorter durations of treatment and this reduces adverse events such as neuropathy and other side effects of therapy. Intermittent treatment may therefore be associated with better health-related quality of life. However, the Committee noted responses from consultation that, although intermittent treatment is commonly used in the UK, the sole evidence base for the addition of bevacizumab to first-line combination chemotherapy was reflective of a continuous treatment strategy. Therefore, the Committee concluded that the economic model reflected the clinical evidence that was available.\n\nThe Committee discussed the base-case cost-effectiveness estimates originally provided by the manufacturer. It noted that a revised base case was submitted after the ERG suggested that untruncated data should be used to fit alternative distributions when extrapolating the trial data. The Committee noted that the manufacturer's revised base case involved pooling of the initial two-arm part of the study and the 2 x 2 factorial part of the study. As previously noted, the Committee considered that this analysis was inappropriate because of the different designs of the study and the imbalance of demographics between the two parts of the study. Therefore, the Committee concluded that only the 2 x 2 factorial part of the study with the revised modelling of survival should be used in the cost-effectiveness analysis.\n\nThe Committee considered that the most plausible model assumption(s) for cost effectiveness would be to use the 2 x 2 factorial design of the NO16966 study with XELOX and FOLFOX arms not pooled and patients who had received prior adjuvant therapy excluded and noted that this had not been provided by the manufacturer. The Committee heard from the ERG that because no estimates of the effect of treatment in this scenario had been provided it was not possible to demonstrate how the ICERs would be affected. The Committee heard the manufacturer's opinion that removing patients who had received prior adjuvant treatment resulted in similar survival outcomes for XELOX and FOLFOX, and for B-XELOX and B-FOLFOX. The manufacturer stated that the basis of this view was informed by the overall results of the NO16966 study, which showed that XELOX was not inferior to FOLFOX and that there was no interaction between bevacizumab and the chemotherapy regimens used. However, the Committee noted that the analysis that used the 2 x 2 factorial part of the study, with the XELOX and FOLFOX arms pooled and patients who had received prior therapy excluded, resulted in markedly different ICERs than when the XELOX and FOLFOX arms were not pooled and patients who had received prior therapy were included. The ICERs provided by the manufacturer without the patient access scheme for B-XELOX compared with XELOX decreased slightly from £92,700 to £90,800 per QALY gained, and the ICER for B-FOLFOX-6 compared with FOLFOX-6 increased markedly from £96,700 to £240,300 per QALY gained (as detailed in section 3.22). The Committee considered that the analysis that did not pool the XELOX and FOLFOX arms and excluded patients who had received prior adjuvant treatment should have been provided and that the effect of pooling the XELOX and FOLFOX arms was unclear. Additionally, the Committee considered that it was counter-intuitive for the analysis to pool the effects of treatment, but not to pool the duration of treatment in the XELOX and FOLFOX arms. Therefore the Committee concluded that the ICERs were associated with substantial uncertainty.\n\nThe Committee noted that the ICERs presented by the manufacturer represented the treatment durations observed in the trial (that is, bevacizumab was stopped at the same time as FOLFOX and XELOX and before disease progression). The Committee noted that the trial protocol and the SPC allowed bevacizumab treatment until disease progression, even if oxaliplatin was stopped early because of adverse events. The ERG and the clinical specialists stated that, if a continuous chemotherapy policy was being practised, treatment with non-oxaliplatin components (such as bevacizumab) would be likely to continue after oxaliplatin treatment had stopped. The Committee noted that stopping oxaliplatin treatment 1 month before the other treatment agents or receiving bevacizumab for 1 month after oxaliplatin treatment had stopped, increased the ICERs. It noted that both analyses assumed no increase in progression-free or overall survival. However, the Committee considered that if such increases in progression-free and overall survival were accounted for, the extra bevacizumab costs would be likely to outweigh any additional survival benefits of bevacizumab, given the previously noted modest impact on progression-free and overall survival. The Committee concluded that, although the economic model was an accurate replication of the study (in terms of treatment duration), in practice bevacizumab treatment would be expected to continue until disease progression in patients treated with a continuous therapy policy. This could potentially increase the ICERs.\n\nThe Committee noted the manufacturer's comments in response to consultation that it was plausible that with an increase in the treatment duration the ICERs might increase but that they might also decrease. The Committee heard from the manufacturer that this could be because patients who do not progress and continue to receive treatment are those that may receive the greatest benefit. The manufacturer thought it was possible that the additional benefits would not be outweighed by the additional costs of treatment. However, the ERG commented that ICERs were more likely to increase because the incremental cost of taking bevacizumab for 1 month after stopping oxaliplatin (that is, bevacizumab costs versus no oxaliplatin costs) is higher than the incremental cost of treatment with bevacizumab and oxaliplatin (that is, bevacizumab and oxaliplatin costs versus oxaliplatin costs). Therefore, the additional costs would outweigh any additional benefits and the ICERs would be likely to increase. The Committee agreed that there was uncertainty as to how the ICERs would be affected if bevacizumab was given until progression because of the lack of clinical evidence but noted the ERG's view that the ICERs were likely to increase. Therefore, the Committee concluded that the ICERs may not reflect the way in which bevacizumab would be used in UK clinical practice, and were therefore associated with additional uncertainty but were more likely to increase.\n\nThe Committee considered the utility values used in the economic model. The Committee noted that no health-related quality-of-life data were collected in the study and that the utility values were taken from 'Cetuximab for the first-line treatment of metastatic colorectal cancer' (NICE technology appraisal guidance 176). The ERG stated that the reporting of utility values in metastatic colorectal cancer was inconsistent and there is a paucity of data. The Committee noted that the manufacturer had adjusted the utility value associated with the health state after first-line treatment (that is, without disease progression) to 0.77 in the revised analyses. However, the Committee agreed that the utility value of 0.77 was still high because it was similar to the utility values of people in the UK general population rather than people with metastatic colorectal cancer. The Committee also noted that the utility values were obtained from a small study of patients with metastatic colorectal cancer receiving cetuximab and chemotherapy using the EQ-5D. In addition, the utility values in the economic model were not regimen-specific. It further noted that decreasing the utility values by 20% increased the ICERs substantially. The Committee concluded that these issues also increased the uncertainty associated with the base-case ICERs.\n\nThe Committee noted that disutility due to adverse events was not included in the economic model. The manufacturer stated that because the utility values were obtained using the EQ-5D, then disutility due to adverse events would be included implicitly within this measure. The Committee noted that a higher incidence of grade 3 and 4 adverse events associated with bevacizumab had been reported in the trial. It considered that there would be disutility (that is, the quality-of-life estimates were likely to have been overestimated) and additional costs associated with the toxicity of bevacizumab. The Committee heard from the manufacturer that the majority of grade 3 and 4 adverse events are due to hypertension, which in most cases is readily treatable and likely to have a small impact on the health state utility of the patient. However, the Committee considered that, in some cases, the adverse effects of bevacizumab could be serious and that the disutility due to adverse events specific to bevacizumab treatment should have been incorporated into the model. The Committee further noted that the utility values used by the manufacturer could not have accounted for the adverse effects of bevacizumab because they were obtained from a study that examined cetuximab. The Committee therefore concluded that the ICERs would increase if the disutility due to adverse events related to bevacizumab treatment was included.\n\nThe Committee noted that in the revised analyses provided by the manufacturer in response to consultation, the treatment administration costs of B-FOLFOX and B-XELOX were stated to have been overestimated in the original submission. The Committee noted the ERG's concerns about the time-and-motion study conducted by the manufacturer; in particular, the sources of the unit costs were unclear and the study was based on data from one small private hospital. The Committee considered that the addition of a bevacizumab infusion to either XELOX or FOLFOX could incur greater additional treatment administration costs than those stated by the manufacturer. The Committee concluded that if these higher administration costs were included, then this would result in an increase in the ICER estimates.\n\nThe Committee discussed the details of the patient access scheme and the impact of the patient access scheme on the ICERs. It noted that when the amended patient access scheme was applied the ICERs decreased from £105,000 to £30,000 per QALY gained for B-XELOX compared with XELOX, and from £108,000 to £24,600 per QALY gained for B-FOLFOX-6 compared with FOLFOX-6. The Committee noted that there was uncertainty expressed by the Department of Health around the operating costs of implementing the scheme. The Committee had concerns about the complexity of the scheme and considered that hospital trusts were likely to involve clinical staff and finance departments as well as pharmacists in its implementation. It noted the revised analyses presented by the manufacturer that incorporated higher operating costs of the patient access scheme. However, the Committee considered that the scheme was complex, with requirements for a number of financial transactions between the manufacturer, healthcare providers and commissioners. Therefore, the operating costs of the scheme were still likely to be greater than those presented by the manufacturer. The Committee noted the ERG's exploratory analysis showing that when the administration costs of the patient access scheme were increased to £100 the ICERs increased slightly. In addition, the Committee noted its earlier conclusions that all of the ICERs with and without the patient access scheme were associated with substantial uncertainty and could be underestimated.\n\nThe Committee considered how the four components of the patient access scheme contributed to the reduction in the ICERs. It noted that the provision of free oxaliplatin was the key component in reducing the ICERs. The Committee noted that the price of oxaliplatin in the economic model was based on the BNF 57 non-proprietary price of £313.50 per 100 mg. The Committee heard from the manufacturer that the list price of oxaliplatin had been used in accordance with the NICE methods guide. However, the Committee noted that the methods guide also states that when the acquisition price paid for a resource differs from the public list price then a sensitivity analysis should be conducted to assess the implications of variations from this price. The Committee acknowledged that generic versions of oxaliplatin have recently become available and that the list price was decreasing, with the list price in BNF 60 reduced to £299.50 per 100 mg. The Committee also noted information provided by the Commercial Medicines Unit of the Department of Health which stated that oxaliplatin is widely available in the NHS through procurement contracts at a discount of more than 90% off the list price. The Committee noted the ERG's exploratory analyses, which showed that when the oxaliplatin list price was discounted by 90% the ICERs with the patient access scheme were greatly increased to £68,100 per QALY gained for B-XELOX compared with XELOX, and to £70,500 per QALY gained for B-FOLFOX compared with FOLFOX-6. The Committee considered that it was more appropriate to use the discounted cost of oxaliplatin when assessing the impact of the patient access scheme on cost effectiveness and therefore did not accept the manufacturer's estimates that ICERs of £105,000 and £108,000 per QALY gained were reduced to £30,000 and £24,600 respectively with the amended patient access scheme.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24 months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations. In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe Committee discussed whether bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee noted that life expectancy with XELOX or FOLFOX was unlikely to be greater than 24 months and was potentially as low as 20 months and 11 months in the first-line and second-line settings respectively. In the first-line setting, the Committee noted from the 2 x 2 analysis of the clinical trial that bevacizumab increased overall survival by 1.4 months compared with XELOX and FOLFOX-4. However, the Committee considered the design of the trial was complex and that the most appropriate method of analysis (that is, with the XELOX and FOLFOX arms not pooled and patients with prior adjuvant therapy excluded) was not provided and therefore the Committee had concerns about the robustness of the evidence. The Committee further noted that bevacizumab as a second-line therapy (E3200 study) statistically significantly increased overall survival by 2.2 months compared with FOLFOX-4. The Committee was aware that the total number of patients currently presenting with metastatic colorectal cancer in England and Wales is approximately 16,000. In addition, the Committee understood that it should take into account the cumulative population for each product in considering the strength of any case, for justifying decisions which employ, in whole or part, the supplementary criteria for appraising life-extending, end-of-life treatments. It noted that bevacizumab was licensed for a number of other indications also involving large patient groups. In summary, the Committee concluded that bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer did not meet all of the criteria for a life-extending, end-of-life treatment.\n\nThe Committee concluded (on the basis of the submitted evidence) that the most appropriate cost-effectiveness estimates of bevacizumab as a first-line treatment for metastatic colorectal cancer available were those using the 2 x 2 factorial part of the study, with the XELOX and FOLFOX arms pooled and with patients who had received prior therapy excluded, giving ICERs of £105,000 per QALY gained for B-XELOX and £108,000 per QALY gained for B-FOLFOX-6 (without the patient access scheme) and £68,100 per QALY gained for B-XELOX and £70,500 per QALY gained for B-FOLFOX-6 (with the patient access scheme applied and the discounted price of oxaliplatin used). However, the Committee agreed that these ICERs (both without and with the patient access scheme) were associated with substantial uncertainty and that plausible adjustments to the key model inputs could increase these ICERs. The Committee recognised the novel mode of action of bevacizumab but did not consider it to be a substantially innovative technology in the treatment of metastatic colorectal cancer. The Committee concluded that bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine could not be recommended as a cost-effective use of NHS resources for the first-line treatment of metastatic colorectal cancer.\n\nThe Committee reviewed the cost-effectiveness analysis of bevacizumab in combination with oxaliplatin-containing regimens as a second-line treatment for metastatic colorectal cancer. The Committee noted that the base-case ICER presented by the manufacturer was £103,000 per QALY gained. The Committee noted that this ICER was substantially higher than those normally considered an acceptable use of NHS resources. In addition, the manufacturer stated that a cost-effective case for bevacizumab as a second-line treatment could not be made. The Committee further noted that no evidence of bevacizumab given after second-line treatment was submitted by the manufacturer. Therefore, the Committee concluded that bevacizumab in combination with oxaliplatin-containing regimens could not be recommended as a cost-effective use of NHS resources for second-line or later treatment of metastatic colorectal cancer.\n\nThe Committee considered whether there were issues related to equality to be taken into account in its considerations. It noted that no equality issues had been raised during the scoping, evidence submissions or consultation stages. Therefore, it concluded that there were no specific issues relating to equality that needed to be taken into account.", 'Related NICE guidance': "Cetuximab for the first-line treatment of metastatic colorectal cancer. NICE technology appraisal guidance 176 (2009).\n\nCetuximab for the treatment of metastatic colorectal cancer following failure of oxaliplatin-containing chemotherapy (terminated appraisal). NICE technology appraisal guidance 150 (2008). [replaced by NICE technology appraisal guidance 242]\n\nBevacizumab and cetuximab for the treatment of metastatic colorectal cancer. NICE technology appraisal guidance 118 (2007). [partially updated by NICE technology appraisal guidance 242]\n\nCapecitabine and oxaliplatin in the adjuvant treatment of stage III (Dukes' C) colon cancer. NICE technology appraisal guidance 100 (2006).\n\nIrinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer (review of technology appraisal 33). NICE technology appraisal guidance 93 (2005). [replaced by NICE clinical guideline 131]\n\nImproving outcomes in colorectal cancers – manual update. NICE cancer service guidance (2004).\n\nGuidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer. NICE technology appraisal guidance 61 (2003).", 'Review of guidance': 'The guidance on this technology will be considered for review in May 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveDecember 2010', 'Changes after publication': 'February 2014: minor maintenance\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nThe recommendations from this guideline have been incorporated into a NICE Pathway. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta212
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Evidence-based recommendations on bevacizumab (Avastin), with other drugs, for treating metastatic colorectal cancer in adults.
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fa65958f613cea35683c941bc49cbbf767745b48
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Sedation in under 19s: using sedation for diagnostic and therapeutic procedures
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Sedation in under 19s: using sedation for diagnostic and therapeutic procedures
This guideline covers the assessment, preparation, training and monitoring needed when using sedation in people aged under 19. It aims to help healthcare professionals decide when sedation is the most clinically and cost effective option for reducing pain and anxiety during operations for children and young people.
# Introduction
Advances in the treatment of paediatric diseases has led to an increase in the number of painful or distressing diagnostic or therapeutic procedures for which many children will need effective sedation or anaesthesia. The choice between sedation and anaesthesia will depend on the type of procedure. Some procedures are very common and healthcare providers and practitioners need to understand under which circumstances either sedation or anaesthesia is most cost effective.
In adults, many procedures can be undertaken with local anaesthesia and reassurance. In children and young people this is often not possible because the procedures are too frightening, too painful or need to be carried out in children who may be ill, in pain or have behavioural problems.
The aims of sedation during diagnostic or therapeutic procedures include reducing fear and anxiety, augmenting pain control and minimising movement. The importance of each of these aims will vary depending on the nature of the procedure and the characteristics of the patient.
There are many sedation techniques available but there is insufficient guidance on which techniques are effective and what resources, including staff training, are required to deliver them safely.
Sedation is not always effective enough and so occasionally the procedure has to be delayed until the child or young person can be anaesthetised. This may need to take place in a different healthcare setting or on another day. Consequently, sedation failure is distressing for the child or young person and also has major NHS cost implications.
Excessive sedation can cause unintended loss of consciousness and dangerous hypoxia. Planned anaesthesia, in comparison, is effective but might have resource implications.
# Definitions
## Age ranges
This guideline covers infants, children and young people under 19 years.
Infants: children from birth to 1 year.
Neonates: infants aged up to 1 month.
## Levels of sedation
The definitions of minimal, moderate, conscious and deep sedation used in this guideline are based on those of the American Society of Anesthesiologists (ASA).
Minimal sedation: A drug‑induced state during which patients are awake and calm, and respond normally to verbal commands. Although cognitive function and coordination may be impaired, ventilatory and cardiovascular functions are unaffected.
Moderate sedation: Drug‑induced depression of consciousness during which patients are sleepy but respond purposefully to verbal commands (known as conscious sedation in dentistry, see below) or light tactile stimulation (reflex withdrawal from a painful stimulus is not a purposeful response). No interventions are required to maintain a patent airway. Spontaneous ventilation is adequate. Cardiovascular function is usually maintained.
Conscious sedation: Drug‑induced depression of consciousness, similar to moderate sedation, except that verbal contact is always maintained with the patient. This term is used commonly in dentistry.
Deep sedation: Drug‑induced depression of consciousness during which patients are asleep and cannot be easily roused but do respond purposefully to repeated or painful stimulation. The ability to maintain ventilatory function independently may be impaired. Patients may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.
## Specialist sedation techniques
Sedation techniques that have a reduced margin of safety and increased risk of unintended deep sedation or anaesthesia, accompanied by airway obstruction and/or inadequate spontaneous ventilation. Healthcare professionals using specialist sedation techniques need to be trained to administer sedation drugs safely, to monitor the effects of the drug and to use equipment to maintain a patent airway and adequate respiration.
# Drug recommendations
In October 2018, no drugs had a UK marketing authorisation specifically for sedation in all ages of infants, children and young people under 19. See NICE's information on prescribing medicines. This is particularly relevant to recommendations 1.4.4, 1.6.1, 1.6.2, 1.6.3, 1.8.1, 1.8.3, 1.8.4, 1.9.1, 1.10.1 and 1.10.2.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
In October 2018, no drugs had a UK marketing authorisation specifically for sedation in all ages of infants, children and young people under 19. See NICE's information on prescribing medicines. This is particularly relevant to recommendations 1.4.4, 1.6.1, 1.6.2, 1.6.3, 1.8.1, 1.8.3, 1.8.4, 1.9.1, 1.10.1 and 1.10.2.
The following guidance is based on the best available evidence and consensus of the Guideline Development Group (GDG) members. The full guideline gives details of the methods and evidence used to develop the guidance.
# Pre‑sedation assessment, communication, patient information and consent
Ensure that trained healthcare professionals (see section 1.4) carry out pre‑sedation assessments and document the results in the healthcare record.
Establish suitability for sedation by assessing all of the following:
current medical condition and any surgical problems
weight (growth assessment)
past medical problems (including any associated with previous sedation or anaesthesia)
current and previous medication (including any allergies)
physical status (including the airway)
psychological and developmental status.
Seek advice from a specialist before delivering sedation:
if there is concern about a potential airway or breathing problem
if the child or young person is assessed as American Society of Anesthesiologists (ASA) grade 3 or greater (the ASA physical status classification system is a system to classify and grade a patient's physical status before anaesthesia).
for infants, including neonates.
Ensure that both the following will be available during sedation:
a healthcare professional and assistant trained (see section 1.4) in delivering and monitoring sedation in children and young people
immediate access to resuscitation and monitoring equipment (see section 1.5).
Choose the most suitable sedation technique based on all the following factors:
what the procedure involves
target level of sedation
contraindications
side effects
patient (or parent or carer) preference.
To enable the child or young person and their parents or carers to make an informed decision, offer them verbal and written information on all of the following:
proposed sedation technique
the alternatives to sedation
associated risks and benefits.
Obtain and document informed consent for sedation.
# Fasting
Before starting sedation, confirm and record the time of last food and fluid intake in the healthcare record.
Fasting is not needed for:
minimal sedation
sedation with nitrous oxide (in oxygen)
moderate sedation during which the child or young person will maintain verbal contact with the healthcare professional.
Refer to professional guidance for fasting for elective procedures using any sedation technique other than those in recommendation 1.2.2 (that is, for deep sedation and moderate sedation during which the child or young person might not maintain verbal contact with the healthcare professional).Note that in 2018 a change to the 2-4-6 fasting rule (fasting times should be as for general anaesthesia: 2 hours for clear fluids; 4 hours for breast milk; 6 hours for solids) was endorsed by the relevant professional bodies, supporting a reduction in the fasting period for clear fluids to 1 hour (see for example the Association of Paediatric Anaesthetists of Great Britain and Ireland consensus statement on clear fluids fasting for elective pediatric general anesthesia).
For an emergency procedure in a child or young person who has not fasted, base the decision to proceed with sedation on the urgency of the procedure and the target depth of sedation.
# Psychological preparation
Ensure that the child or young person is prepared psychologically for sedation by offering information about:
the procedure
what the child or young person should do and what the healthcare professional will do
the sensations associated with the procedure (for example, a sharp scratch or numbness)
how to cope with the procedure.
Ensure that the information is appropriate for the developmental stage of the child or young person and check that the child or young person has understood the information.
Offer parents and carers the opportunity to be present during sedation if appropriate. If a parent or carer decides to be present, offer them advice about their role during the procedure.
For an elective procedure, consider referring to a mental health specialist children or young people who are severely anxious or who have a learning disability.
# Personnel and training
Healthcare professionals delivering sedation should have knowledge and understanding of and competency in:
sedation drug pharmacology and applied physiology
assessment of children and young people
monitoring
recovery care
complications and their immediate management, including paediatric life support.
Healthcare professionals delivering sedation should have practical experience of:
effectively delivering the chosen sedation technique and managing complications
-bserving clinical signs (for example, airway patency, breathing rate and depth, pulse, pallor and cyanosis, and depth of sedation)
using monitoring equipment.
Ensure that all members of the sedation team have basic life support skills for minimal, moderate and deep sedation. At least 1 team member should have intermediate life support skills for moderate sedation and advanced life support skills for deep sedation. Minimal sedation includes sedation with nitrous oxide alone (in oxygen) and conscious sedation in dentistry.
Ensure that a healthcare professional trained in delivering anaesthetic agents is available to administer:
sevoflurane
propofol
-pioids combined with ketamine.
Healthcare professionals delivering sedation should have documented up‑to‑date evidence of competency including:
satisfactory completion of a theoretical training course covering the principles of sedation practice
a comprehensive record of practical experience of sedation techniques, including details of:
sedation in children and young people performed under supervision
successful completion of work‑based assessments.
Each healthcare professional and their team delivering sedation should ensure they update their knowledge and skills through programmes designed for continuing professional development.
Consider referring to an anaesthesia specialist a child or young person who is not able to tolerate the procedure under sedation.
# Discharge criteria
Ensure that all of the following criteria are met before the child or young person is discharged:
vital signs (usually body temperature, heart rate, blood pressure and respiratory rate) have returned to normal levels
the child or young person is awake (or returned to baseline level of consciousness) and there is no risk of further reduced level of consciousness
nausea, vomiting and pain have been adequately managed.
# Painless imaging
Do not routinely use ketamine or opioids for painless imaging procedures.
For children and young people who are unable to tolerate a painless procedure (for example, during diagnostic imaging) consider one of the following drugs, which have a wide margin of safety:
chloral hydrate for children under 15 kg
midazolam.
For children and young people who are unable to tolerate painless imaging with the above drugs, consider one of the following, used in specialist techniques, which have a narrow margin of safety (see section 1.4):
propofol
sevoflurane.
# Clinical environment and monitoring
For moderate sedation excluding with nitrous oxide alone (in oxygen) continuously monitor, interpret and respond to changes in all of the following:
depth of sedation
respiration
-xygen saturation
heart rate
pain
coping
distress.
For deep sedation continuously monitor, interpret and respond to changes in all of the following:
depth of sedation
respiration
-xygen saturation
heart rate
three‑lead electrocardiogram
pain
coping
distress. Also continuously monitor, interpret and respond to the following, provided that monitoring does not cause the patient to awaken and so prevent completion of the procedure:
end tidal CO2 (capnography)
blood pressure (monitor every 5 minutes)The healthcare professional administering sedation should be involved only in continuously monitoring, interpreting and responding to all of the above.
Ensure that data from continuous monitoring during sedation are clearly documented in the healthcare record.
After the procedure, continue monitoring until the child or young person:
has a patent airway
shows protective airway and breathing reflexes
is haemodynamically stable
is easily roused.
# Painful procedures
For children and young people undergoing a painful procedure (for example suture laceration or orthopaedic manipulation), when the target level of sedation is minimal or moderate, consider:
nitrous oxide (in oxygen) and/or
midazolam (oral or intranasal).
For all children and young people undergoing a painful procedure, consider using a local anaesthetic, as well as a sedative.
For children and young people undergoing a painful procedure (for example, suture laceration or orthopaedic manipulation) in whom nitrous oxide (in oxygen) and/or midazolam (oral or intranasal) are unsuitable consider:
ketamine (intravenous or intramuscular), or
intravenous midazolam with or without fentanyl (to achieve moderate sedation).
For children and young people undergoing a painful procedure (for example suture laceration or orthopaedic manipulation) in whom ketamine (intravenous or intramuscular) or intravenous midazolam with or without fentanyl (to achieve moderate sedation) are unsuitable, consider a specialist sedation technique such as propofol with or without fentanyl.
# Dental procedures
For a child or young person who cannot tolerate a dental procedure with local anaesthesia alone, to achieve conscious sedation consider:
nitrous oxide (in oxygen) or
midazolam.If these sedation techniques are not suitable or sufficient, refer to a specialist team for an alternative sedation technique.
# Endoscopy
Consider intravenous midazolam to achieve minimal or moderate sedation for upper gastrointestinal endoscopy.
Consider fentanyl (or equivalent opioid) in combination with intravenous midazolam to achieve moderate sedation for lower gastrointestinal endoscopy.# Recommendations for research
The Guideline Development Group (GDG) has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The GDG's full set of recommendations for research is detailed in the full guideline.
# Pre‑sedation assessment
For children and young people under the age of 19 having diagnostic and therapeutic procedures under sedation, what factors should be assessed to establish the need for sedation and reduce the risk of adverse events?
## Why this is important
Some children need sedation, some need anaesthesia, and some need behavioural management alone. There is wide variation in how this choice is made. A recommended standard method of assessment could reduce variation and improve both success and safety when sedation is chosen. Furthermore, an assessment tool could help prevent unsuitable choices and improve the overall management of procedures in children. The Guideline Development Group suggests an observational study to determine the important factors, followed by a consensus study to develop a tool. The assessment tool should be tested by a randomised comparison of children and young people who have been assessed routinely with those who have been assessed using the tool. The aim is for the assessment tool to improve sedation success and quality, and reduce any complications.
# Training for personnel involved in sedation
For personnel involved in delivering sedation to children and young people under the age of 19 having diagnostic and therapeutic procedures, what training is required to achieve and maintain essential skills?
## Why this is important
Potent drugs can cause unintended airway obstruction. Anaesthetists are skilled at managing airway obstruction because they practise the skills regularly. However, anaesthetists are a scarce resource so non‑anaesthetists need to learn how to manage airway obstruction. The skills that are needed have been identified but can these skills be attained and maintained by professionals who need them only occasionally? The Guideline Development Group suggests that a standard teaching method and assessment tool are developed. This would involve an observational study of a cohort of trainees, who can be assessed, trained and then reassessed at intervals to determine whether the training is successful and how often it is necessary.
# Drugs combination
For children and young people under the age of 19 having minor painful procedures, what potent analgesic drugs can be combined with midazolam to provide safe moderate sedation?
## Why this is important
Midazolam has a strong safety profile in inducing either minimal or moderate sedation. For painful procedures midazolam should be combined with analgesia. Ideally, analgesia is achieved by local anaesthesia. Sometimes local analgesia is insufficient and potent opioid analgesia is necessary. The combination of potent opioid and midazolam can cause deep sedation and airway obstruction. These effects can be managed safely but involve extra resources. If would be safer if a technique could be developed that was both reliable and had a wide margin of safety. Prospective and retrospective audit data are available to help guide the choice of opioid and the doses. A randomised controlled trial is needed to test the efficacy and safety of these combinations.
# Development of a national registry of sedation
What are the safety and efficacy profiles of sedation techniques in current practice?
## Why this is important
There are no data on the safety of sedation in the UK. A large prospective database of sedation cases, that includes data on drugs, procedures, the depth of sedation and complications, would help to define the safety of sedation and actively promote safe practice. The Guideline Development Group suggests that a national registry for paediatric sedation is established to help create a database with sufficient data.
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{'Introduction': "Advances in the treatment of paediatric diseases has led to an increase in the number of painful or distressing diagnostic or therapeutic procedures for which many children will need effective sedation or anaesthesia. The choice between sedation and anaesthesia will depend on the type of procedure. Some procedures are very common and healthcare providers and practitioners need to understand under which circumstances either sedation or anaesthesia is most cost effective.\n\nIn adults, many procedures can be undertaken with local anaesthesia and reassurance. In children and young people this is often not possible because the procedures are too frightening, too painful or need to be carried out in children who may be ill, in pain or have behavioural problems.\n\nThe aims of sedation during diagnostic or therapeutic procedures include reducing fear and anxiety, augmenting pain control and minimising movement. The importance of each of these aims will vary depending on the nature of the procedure and the characteristics of the patient.\n\nThere are many sedation techniques available but there is insufficient guidance on which techniques are effective and what resources, including staff training, are required to deliver them safely.\n\nSedation is not always effective enough and so occasionally the procedure has to be delayed until the child or young person can be anaesthetised. This may need to take place in a different healthcare setting or on another day. Consequently, sedation failure is distressing for the child or young person and also has major NHS cost implications.\n\nExcessive sedation can cause unintended loss of consciousness and dangerous hypoxia. Planned anaesthesia, in comparison, is effective but might have resource implications.\n\n# Definitions\n\n## Age ranges\n\nThis guideline covers infants, children and young people under 19 years.\n\nInfants: children from birth to 1\xa0year.\n\nNeonates: infants aged up to 1\xa0month.\n\n## Levels of sedation\n\nThe definitions of minimal, moderate, conscious and deep sedation used in this guideline are based on those of the American Society of Anesthesiologists (ASA).\n\nMinimal sedation: A drug‑induced state during which patients are awake and calm, and respond normally to verbal commands. Although cognitive function and coordination may be impaired, ventilatory and cardiovascular functions are unaffected.\n\nModerate sedation: Drug‑induced depression of consciousness during which patients are sleepy but respond purposefully to verbal commands (known as conscious sedation in dentistry, see below) or light tactile stimulation (reflex withdrawal from a painful stimulus is not a purposeful response). No interventions are required to maintain a patent airway. Spontaneous ventilation is adequate. Cardiovascular function is usually maintained.\n\nConscious sedation: Drug‑induced depression of consciousness, similar to moderate sedation, except that verbal contact is always maintained with the patient. This term is used commonly in dentistry.\n\nDeep sedation: Drug‑induced depression of consciousness during which patients are asleep and cannot be easily roused but do respond purposefully to repeated or painful stimulation. The ability to maintain ventilatory function independently may be impaired. Patients may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.\n\n## Specialist sedation techniques\n\nSedation techniques that have a reduced margin of safety and increased risk of unintended deep sedation or anaesthesia, accompanied by airway obstruction and/or inadequate spontaneous ventilation. Healthcare professionals using specialist sedation techniques need to be trained to administer sedation drugs safely, to monitor the effects of the drug and to use equipment to maintain a patent airway and adequate respiration.\n\n# Drug recommendations\n\nIn October 2018, no drugs had a UK marketing authorisation specifically for sedation in all ages of infants, children and young people under\xa019. See NICE's information on prescribing medicines. This is particularly relevant to recommendations 1.4.4, 1.6.1, 1.6.2, 1.6.3, 1.8.1, 1.8.3, 1.8.4, 1.9.1, 1.10.1 and 1.10.2.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nIn October 2018, no drugs had a UK marketing authorisation specifically for sedation in all ages of infants, children and young people under\xa019. See NICE's information on prescribing medicines. This is particularly relevant to recommendations 1.4.4, 1.6.1, 1.6.2, 1.6.3, 1.8.1, 1.8.3, 1.8.4, 1.9.1, 1.10.1 and 1.10.2.\n\nThe following guidance is based on the best available evidence and consensus of the Guideline Development Group (GDG) members. The full guideline gives details of the methods and evidence used to develop the guidance.\n\n# Pre‑sedation assessment, communication, patient information and consent\n\nEnsure that trained healthcare professionals (see section\xa01.4) carry out pre‑sedation assessments and document the results in the healthcare record.\n\nEstablish suitability for sedation by assessing all of the following:\n\ncurrent medical condition and any surgical problems\n\nweight (growth assessment)\n\npast medical problems (including any associated with previous sedation or anaesthesia)\n\ncurrent and previous medication (including any allergies)\n\nphysical status (including the airway)\n\npsychological and developmental status.\n\nSeek advice from a specialist before delivering sedation:\n\nif there is concern about a potential airway or breathing problem\n\nif the child or young person is assessed as American Society of Anesthesiologists (ASA) grade\xa03 or greater (the ASA physical status classification system [grades\xa01\xa0to\xa06] is a system to classify and grade a patient's physical status before anaesthesia).\n\nfor infants, including neonates.\n\nEnsure that both the following will be available during sedation:\n\na healthcare professional and assistant trained (see section\xa01.4) in delivering and monitoring sedation in children and young people\n\nimmediate access to resuscitation and monitoring equipment (see section\xa01.5).\n\nChoose the most suitable sedation technique based on all the following factors:\n\nwhat the procedure involves\n\ntarget level of sedation\n\ncontraindications\n\nside effects\n\npatient (or parent or carer) preference.\n\nTo enable the child or young person and their parents or carers to make an informed decision, offer them verbal and written information on all of the following:\n\nproposed sedation technique\n\nthe alternatives to sedation\n\nassociated risks and benefits.\n\nObtain and document informed consent for sedation.\n\n# Fasting\n\nBefore starting sedation, confirm and record the time of last food and fluid intake in the healthcare record.\n\nFasting is not needed for:\n\nminimal sedation\n\nsedation with nitrous oxide (in oxygen)\n\nmoderate sedation during which the child or young person will maintain verbal contact with the healthcare professional.\n\nRefer to professional guidance for fasting for elective procedures using any sedation technique other than those in recommendation 1.2.2 (that is, for deep sedation and moderate sedation during which the child or young person might not maintain verbal contact with the healthcare professional).Note that in 2018 a change to the 2-4-6 fasting rule (fasting times should be as for general anaesthesia: 2\xa0hours for clear fluids; 4\xa0hours for breast milk; 6\xa0hours for solids) was endorsed by the relevant professional bodies, supporting a reduction in the fasting period for clear fluids to 1\xa0hour (see for example the Association of Paediatric Anaesthetists of Great Britain and Ireland consensus statement on clear fluids fasting for elective pediatric general anesthesia).\n\nFor an emergency procedure in a child or young person who has not fasted, base the decision to proceed with sedation on the urgency of the procedure and the target depth of sedation.\n\n# Psychological preparation\n\nEnsure that the child or young person is prepared psychologically for sedation by offering information about:\n\nthe procedure\n\nwhat the child or young person should do and what the healthcare professional will do\n\nthe sensations associated with the procedure (for example, a sharp scratch or numbness)\n\nhow to cope with the procedure.\n\nEnsure that the information is appropriate for the developmental stage of the child or young person and check that the child or young person has understood the information.\n\nOffer parents and carers the opportunity to be present during sedation if appropriate. If a parent or carer decides to be present, offer them advice about their role during the procedure.\n\nFor an elective procedure, consider referring to a mental health specialist children or young people who are severely anxious or who have a learning disability.\n\n# Personnel and training\n\nHealthcare professionals delivering sedation should have knowledge and understanding of and competency in:\n\nsedation drug pharmacology and applied physiology\n\nassessment of children and young people\n\nmonitoring\n\nrecovery care\n\ncomplications and their immediate management, including paediatric life support.\n\nHealthcare professionals delivering sedation should have practical experience of:\n\neffectively delivering the chosen sedation technique and managing complications\n\nobserving clinical signs (for example, airway patency, breathing rate and depth, pulse, pallor and cyanosis, and depth of sedation)\n\nusing monitoring equipment.\n\nEnsure that all members of the sedation team have basic life support skills for minimal, moderate and deep sedation. At least 1 team member should have intermediate life support skills for moderate sedation and advanced life support skills for deep sedation. Minimal sedation includes sedation with nitrous oxide alone (in oxygen) and conscious sedation in dentistry.\n\nEnsure that a healthcare professional trained in delivering anaesthetic agents is available to administer:\n\nsevoflurane\n\npropofol\n\nopioids combined with ketamine.\n\nHealthcare professionals delivering sedation should have documented up‑to‑date evidence of competency including:\n\nsatisfactory completion of a theoretical training course covering the principles of sedation practice\n\na comprehensive record of practical experience of sedation techniques, including details of:\n\n\n\nsedation in children and young people performed under supervision\n\nsuccessful completion of work‑based assessments.\n\n\n\nEach healthcare professional and their team delivering sedation should ensure they update their knowledge and skills through programmes designed for continuing professional development.\n\nConsider referring to an anaesthesia specialist a child or young person who is not able to tolerate the procedure under sedation.\n\n# Discharge criteria\n\nEnsure that all of the following criteria are met before the child or young person is discharged:\n\nvital signs (usually body temperature, heart rate, blood pressure and respiratory rate) have returned to normal levels\n\nthe child or young person is awake (or returned to baseline level of consciousness) and there is no risk of further reduced level of consciousness\n\nnausea, vomiting and pain have been adequately managed.\n\n# Painless imaging\n\nDo not routinely use ketamine or opioids for painless imaging procedures.\n\nFor children and young people who are unable to tolerate a painless procedure (for example, during diagnostic imaging) consider one of the following drugs, which have a wide margin of safety:\n\nchloral hydrate for children under 15\xa0kg\n\nmidazolam.\n\nFor children and young people who are unable to tolerate painless imaging with the above drugs, consider one of the following, used in specialist techniques, which have a narrow margin of safety (see section\xa01.4):\n\npropofol\n\nsevoflurane.\n\n# Clinical environment and monitoring\n\nFor moderate sedation excluding with nitrous oxide alone (in oxygen) continuously monitor, interpret and respond to changes in all of the following:\n\ndepth of sedation\n\nrespiration\n\noxygen saturation\n\nheart rate\n\npain\n\ncoping\n\ndistress.\n\nFor deep sedation continuously monitor, interpret and respond to changes in all of the following:\n\ndepth of sedation\n\nrespiration\n\noxygen saturation\n\nheart rate\n\nthree‑lead electrocardiogram\n\npain\n\ncoping\n\ndistress. Also continuously monitor, interpret and respond to the following, provided that monitoring does not cause the patient to awaken and so prevent completion of the procedure:\n\nend tidal CO2 (capnography)\n\nblood pressure (monitor every 5\xa0minutes)The healthcare professional administering sedation should be involved only in continuously monitoring, interpreting and responding to all of the above.\n\nEnsure that data from continuous monitoring during sedation are clearly documented in the healthcare record.\n\nAfter the procedure, continue monitoring until the child or young person:\n\nhas a patent airway\n\nshows protective airway and breathing reflexes\n\nis haemodynamically stable\n\nis easily roused.\n\n# Painful procedures\n\nFor children and young people undergoing a painful procedure (for example suture laceration or orthopaedic manipulation), when the target level of sedation is minimal or moderate, consider:\n\nnitrous oxide (in oxygen) and/or\n\nmidazolam (oral or intranasal).\n\nFor all children and young people undergoing a painful procedure, consider using a local anaesthetic, as well as a sedative.\n\nFor children and young people undergoing a painful procedure (for example, suture laceration or orthopaedic manipulation) in whom nitrous oxide (in oxygen) and/or midazolam (oral or intranasal) are unsuitable consider:\n\nketamine (intravenous or intramuscular), or\n\nintravenous midazolam with or without fentanyl (to achieve moderate sedation).\n\nFor children and young people undergoing a painful procedure (for example suture laceration or orthopaedic manipulation) in whom ketamine (intravenous or intramuscular) or intravenous midazolam with or without fentanyl (to achieve moderate sedation) are unsuitable, consider a specialist sedation technique such as propofol with or without fentanyl.\n\n# Dental procedures\n\nFor a child or young person who cannot tolerate a dental procedure with local anaesthesia alone, to achieve conscious sedation consider:\n\nnitrous oxide (in oxygen) or\n\nmidazolam.If these sedation techniques are not suitable or sufficient, refer to a specialist team for an alternative sedation technique.\n\n# Endoscopy\n\nConsider intravenous midazolam to achieve minimal or moderate sedation for upper gastrointestinal endoscopy.\n\nConsider fentanyl (or equivalent opioid) in combination with intravenous midazolam to achieve moderate sedation for lower gastrointestinal endoscopy.", 'Recommendations for research': "The Guideline Development Group (GDG) has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The GDG's full set of recommendations for research is detailed in the full guideline.\n\n# Pre‑sedation assessment\n\nFor children and young people under the age of 19 having diagnostic and therapeutic procedures under sedation, what factors should be assessed to establish the need for sedation and reduce the risk of adverse events?\n\n## Why this is important\n\nSome children need sedation, some need anaesthesia, and some need behavioural management alone. There is wide variation in how this choice is made. A recommended standard method of assessment could reduce variation and improve both success and safety when sedation is chosen. Furthermore, an assessment tool could help prevent unsuitable choices and improve the overall management of procedures in children. The Guideline Development Group suggests an observational study to determine the important factors, followed by a consensus study to develop a tool. The assessment tool should be tested by a randomised comparison of children and young people who have been assessed routinely with those who have been assessed using the tool. The aim is for the assessment tool to improve sedation success and quality, and reduce any complications.\n\n# Training for personnel involved in sedation\n\nFor personnel involved in delivering sedation to children and young people under the age of 19 having diagnostic and therapeutic procedures, what training is required to achieve and maintain essential skills?\n\n## Why this is important\n\nPotent drugs can cause unintended airway obstruction. Anaesthetists are skilled at managing airway obstruction because they practise the skills regularly. However, anaesthetists are a scarce resource so non‑anaesthetists need to learn how to manage airway obstruction. The skills that are needed have been identified but can these skills be attained and maintained by professionals who need them only occasionally? The Guideline Development Group suggests that a standard teaching method and assessment tool are developed. This would involve an observational study of a cohort of trainees, who can be assessed, trained and then reassessed at intervals to determine whether the training is successful and how often it is necessary.\n\n# Drugs combination\n\nFor children and young people under the age of 19 having minor painful procedures, what potent analgesic drugs can be combined with midazolam to provide safe moderate sedation?\n\n## Why this is important\n\nMidazolam has a strong safety profile in inducing either minimal or moderate sedation. For painful procedures midazolam should be combined with analgesia. Ideally, analgesia is achieved by local anaesthesia. Sometimes local analgesia is insufficient and potent opioid analgesia is necessary. The combination of potent opioid and midazolam can cause deep sedation and airway obstruction. These effects can be managed safely but involve extra resources. If would be safer if a technique could be developed that was both reliable and had a wide margin of safety. Prospective and retrospective audit data are available to help guide the choice of opioid and the doses. A randomised controlled trial is needed to test the efficacy and safety of these combinations.\n\n# Development of a national registry of sedation\n\nWhat are the safety and efficacy profiles of sedation techniques in current practice?\n\n## Why this is important\n\nThere are no data on the safety of sedation in the UK. A large prospective database of sedation cases, that includes data on drugs, procedures, the depth of sedation and complications, would help to define the safety of sedation and actively promote safe practice. The Guideline Development Group suggests that a national registry for paediatric sedation is established to help create a database with sufficient data."}
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https://www.nice.org.uk/guidance/cg112
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This guideline covers the assessment, preparation, training and monitoring needed when using sedation in people aged under 19. It aims to help healthcare professionals decide when sedation is the most clinically and cost effective option for reducing pain and anxiety during operations for children and young people.
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d32bf5211b4bf2cbffbf9983933ff90aea867697
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nice
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Cryotherapy for the treatment of liver metastases
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Cryotherapy for the treatment of liver metastases
# Guidance
Current evidence on the safety of cryotherapy for the treatment of liver metastases appears adequate in the context of treating patients whose condition has such a poor prognosis, but the evidence on efficacy is inadequate in quality. Therefore cryotherapy for the treatment of liver metastases should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake cryotherapy for the treatment of liver metastases should take the following actions.
Inform the clinical governance leads in their Trusts.
Ensure that patients and their carers understand that other ablative treatments are available and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.
Audit and review clinical outcomes of all patients having cryotherapy for liver metastases (see section 3.1).
Patient selection and treatment should be carried out by a hepatobiliary multidisciplinary team with expertise in the use of ablative techniques.# The procedure
# Indications and current treatments
Liver metastases are commonly caused by colorectal cancer or other primary malignancies, such as lung and gastric cancer.
For a minority of patients, surgical resection of liver metastases with curative intent may be possible. For most patients however, treatment is palliative and options include systemic chemotherapy, external beam radiotherapy, other thermal ablation techniques, and selective internal radiation therapy. Multiple treatment modalities may be used for individual patients.
# Outline of the procedure
Thermal ablation procedures including cryotherapy may be used as the primary treatment for liver metastases in patients who are not considered suitable for surgery, or to treat post-resection recurrence. They may also be used as an adjunct to hepatic resection. Cryotherapy can be delivered as part of an open resection procedure (requiring general anaesthesia and intraoperative ultrasound), or percutaneously (under local or general anaesthesia, with ultrasound, computed tomography or magnetic resonance imaging guidance).
Cryotherapy probes (single or multiple, depending on the size of the tumour) deliver coolant at subzero temperatures directly to the tumour in freeze-thaw cycles with the aim of destroying tumour cells.
The maximum recommended hepatic tumour size for cryotherapy is 4 cm. Cryotherapy for larger tumours requires multiple probes and is associated with increased morbidity.
Various devices can be used for this procedure.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A randomised controlled trial (RCT) of 123 patients treated by cryotherapy and chemotherapy or by surgical resection and chemotherapy reported disease-free survival in 14% (9/63) and 5% (3/60) of patients respectively at 10-year follow-up (significance not stated).
A non-randomised controlled trial of 415 patients treated by surgical resection and cryotherapy (for remnant lesions) or resection alone reported median survival of 29 and 34 months respectively (p = 0.206).
A case series of 326 patients reported median overall survival of 29 months after cryotherapy of colorectal liver metastases, with tumour recurrence in 42% (136/326) of patients at a median of 32 months. In a subset of 280 patients who had CT imaging at baseline and during follow-up, complete response was reported in 15% (41/280), partial response in 41% (115/280), stable disease in 24% (68/280), and progressive disease in 20% (56/280) (follow-up not stated).
The Specialist Advisers listed key efficacy outcomes as tumour destruction with small margins of additional tissue destruction, and survival.
# Safety
A non-randomised controlled study of 223 patients reported no significant difference in perioperative mortality between the cryotherapy group (2% ) and the surgical resection group (5% ) (p = 0.30). However overall perioperative morbidity was significantly lower in the cryotherapy group (11% than in the resection group (26% ) (p = 0.01).
A case series of 326 patients reported mortality in 2% (7/326) of patients (follow-up period and details of causes were not reported, but 1 patient died from 'cryoshock' syndrome and 1 from liver failure).
A case report described death of a patient from hepatic failure related to portal vein thrombosis and intra-hepatic MRSA sepsis, 2 months after a second cryotherapy course via an open approach.
Infections directly related to cryotherapy were reported after 8% (12/158) of procedures in the case series of 150 patients (most occurred within 3 weeks of treatment). Fever over 38°C was reported in 33% (108/326) of patients in the case series of 326 patients (timing of events not stated).
Haemorrhage was reported in 4% (2/55) and 1% (2/168) of patients treated with cryotherapy and surgical resection respectively in the non randomised controlled trial of 223 patients (timing of event not stated).
The Specialist Advisers listed anecdotal adverse events as damage to bile ducts and structures outside the liver. The Specialist Advisers also cited reports of major haemorrhage, the rare but fatal complication of cryoshock syndrome, and a high local recurrence rate; they stated that cryotherapy is therefore no longer widely used.
# Other comments
The Committee noted possible differences in the safety of this procedure when used intraoperatively, compared with the percutaneous approach that uses narrower probes. Evidence on the percutaneous approach is limited in quantity.# Further information
This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
For related NICE guidance see our website.
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
It has been incorporated into the NICE pathway on colorectal cancer, along with other related guidance and products.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Changes since publication
January 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
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{'Guidance': "Current evidence on the safety of cryotherapy for the treatment of liver metastases appears adequate in the context of treating patients whose condition has such a poor prognosis, but the evidence on efficacy is inadequate in quality. Therefore cryotherapy for the treatment of liver metastases should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake cryotherapy for the treatment of liver metastases should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand that other ablative treatments are available and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having cryotherapy for liver metastases (see section 3.1).\n\nPatient selection and treatment should be carried out by a hepatobiliary multidisciplinary team with expertise in the use of ablative techniques.", 'The procedure': "# Indications and current treatments\n\nLiver metastases are commonly caused by colorectal cancer or other primary malignancies, such as lung and gastric cancer.\n\nFor a minority of patients, surgical resection of liver metastases with curative intent may be possible. For most patients however, treatment is palliative and options include systemic chemotherapy, external beam radiotherapy, other thermal ablation techniques, and selective internal radiation therapy. Multiple treatment modalities may be used for individual patients.\n\n# Outline of the procedure\n\nThermal ablation procedures including cryotherapy may be used as the primary treatment for liver metastases in patients who are not considered suitable for surgery, or to treat post-resection recurrence. They may also be used as an adjunct to hepatic resection. Cryotherapy can be delivered as part of an open resection procedure (requiring general anaesthesia and intraoperative ultrasound), or percutaneously (under local or general anaesthesia, with ultrasound, computed tomography [CT] or magnetic resonance imaging guidance).\n\nCryotherapy probes (single or multiple, depending on the size of the tumour) deliver coolant at subzero temperatures directly to the tumour in freeze-thaw cycles with the aim of destroying tumour cells.\n\nThe maximum recommended hepatic tumour size for cryotherapy is 4 cm. Cryotherapy for larger tumours requires multiple probes and is associated with increased morbidity.\n\nVarious devices can be used for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 123 patients treated by cryotherapy and chemotherapy or by surgical resection and chemotherapy reported disease-free survival in 14% (9/63) and 5% (3/60) of patients respectively at 10-year follow-up (significance not stated).\n\nA non-randomised controlled trial of 415 patients treated by surgical resection and cryotherapy (for remnant lesions) or resection alone reported median survival of 29 and 34 months respectively (p = 0.206).\n\nA case series of 326 patients reported median overall survival of 29 months after cryotherapy of colorectal liver metastases, with tumour recurrence in 42% (136/326) of patients at a median of 32 months. In a subset of 280 patients who had CT imaging at baseline and during follow-up, complete response was reported in 15% (41/280), partial response in 41% (115/280), stable disease in 24% (68/280), and progressive disease in 20% (56/280) (follow-up not stated).\n\nThe Specialist Advisers listed key efficacy outcomes as tumour destruction with small margins of additional tissue destruction, and survival.\n\n# Safety\n\nA non-randomised controlled study of 223 patients reported no significant difference in perioperative mortality between the cryotherapy group (2% [1/55]) and the surgical resection group (5% [8/168]) (p = 0.30). However overall perioperative morbidity was significantly lower in the cryotherapy group (11% [6/55] than in the resection group (26% [44/168]) (p = 0.01).\n\nA case series of 326 patients reported mortality in 2% (7/326) of patients (follow-up period and details of causes were not reported, but 1 patient died from 'cryoshock' syndrome and 1 from liver failure).\n\nA case report described death of a patient from hepatic failure related to portal vein thrombosis and intra-hepatic MRSA sepsis, 2 months after a second cryotherapy course via an open approach.\n\nInfections directly related to cryotherapy were reported after 8% (12/158) of procedures in the case series of 150 patients (most occurred within 3 weeks of treatment). Fever over 38°C was reported in 33% (108/326) of patients in the case series of 326 patients (timing of events not stated).\n\nHaemorrhage was reported in 4% (2/55) and 1% (2/168) of patients treated with cryotherapy and surgical resection respectively in the non randomised controlled trial of 223 patients (timing of event not stated).\n\nThe Specialist Advisers listed anecdotal adverse events as damage to bile ducts and structures outside the liver. The Specialist Advisers also cited reports of major haemorrhage, the rare but fatal complication of cryoshock syndrome, and a high local recurrence rate; they stated that cryotherapy is therefore no longer widely used.\n\n# Other comments\n\nThe Committee noted possible differences in the safety of this procedure when used intraoperatively, compared with the percutaneous approach that uses narrower probes. Evidence on the percutaneous approach is limited in quantity.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt has been incorporated into the NICE pathway on colorectal cancer, along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg369
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3a6649145157a0ba8ef358ccb709dab71191f6e0
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nice
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Percutaneous closure of patent foramen ovale for recurrent migraine
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Percutaneous closure of patent foramen ovale for recurrent migraine
# Guidance
Current evidence on the efficacy of percutaneous closure of patent foramen ovale (PFO) for recurrent migraine is inadequate in quality and quantity. The evidence on safety shows a small incidence of well-recognised but sometimes serious adverse events, including device embolisation and device prolapse (each reported in less than 1% of patients). Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake percutaneous closure of PFO for recurrent migraine should take the following actions.
Inform the clinical governance leads in their Trusts.
Ensure that patients and their carers understand the uncertainty about the procedure's efficacy and the possibility of serious complications. Clinicians should provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.
Patient selection for percutaneous closure of PFO for recurrent migraine should be carried out by a neurologist or other specialist in headache followed by an interventional cardiologist. Use of this procedure should be restricted to patients who are severely affected by recurrent, refractory migraine.
The procedure should be done by an interventional cardiologist and supporting team with specific training in the procedure.
The procedure should only be carried out in units where there are arrangements for emergency cardiac surgical support in the event of complications.
Data on all patients having this procedure should be submitted to the UK Central Cardiac Audit Database.
NICE encourages further research into this procedure, which should investigate the uncertainty surrounding the aetiology and natural history of migraine in patients with PFO. NICE may review this procedure on publication of further evidence.# The procedure
# Indications and current treatments
A PFO is the persistence of an opening (the foramen ovale) in the septum between the right atrium and left atrium of the heart. In the fetus, the foramen ovale allows blood to bypass the lungs, directly from the venous to the arterial side of the circulation. After birth the foramen ovale normally closes but in approximately 25% of people it remains either fully or partially patent throughout life. Studies evaluating PFO closure to prevent paradoxical thromboembolism noted a change in the incidence of migraine amongst patients. Any physiological effect of PFO closure in migraine treatment is not understood.
Current treatment for patients with recurrent migraine is aimed at either preventing or aborting episodes through medical management. Invasive treatments such as nerve blocks or physical therapies such as acupuncture are sometimes used if medical therapy has failed.
# Outline of the procedure
Percutaneous closure of PFO for recurrent migraine is carried out with the patient under local anaesthesia and intravenous sedation, or general anaesthesia. A guidewire and delivery sheath are introduced via a small incision in the femoral vein into the heart and across the PFO. A closure device is then inserted through the opening via the delivery sheath and released, closing the PFO.
A range of different devices are available for this procedure.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the migraine- and embolism-related overviews.
# Efficacy
Immediate closure of the PFO (confirmed with echocardiography) was reported in 99% (148/150), 89% (42/47), 97% (179/185), 100% (76/76) and 99.8% (823/825) of patients in studies across a range of indications.
A randomised controlled trial (RCT) of 147 patients treated either by the procedure (n = 74) or a sham procedure (n = 73) reported that 3 patients in each group had experienced no further migraines at 6-month follow-up. The study reported no significant difference in the reduction in median MIDAS score (a measure of migraine-related disability on a scale of 0–21+; higher score indicates more severe disability) between the procedure and sham groups (from 36 to 17 vs 34 to 18 respectively), or mean migraine headache days (from 26 to 19 vs 30 to 21 days respectively) over 6 months.
A non-randomised comparative study of 86 patients reported a significant reduction in mean MIDAS score in the 40 patients treated by the procedure and the 46 patients treated by medical therapy at a mean follow-up of 29.2 months (from 35.8 to 8.3, p < 0.003 vs 22.6 to 19.1, p = 0.059 respectively; significance of between-group difference not stated).
The Specialist Advisers listed key efficacy outcomes as evidence of complete closure, and frequency and severity of migraine.
# Safety
The following safety data were obtained from studies of PFO closure for a range of indications because:
safety data are likely to be similar for the various indications
the larger numbers of patients provide more robust evidence on safety than those from studies specifically relating to migraine.
Cardiac tamponade requiring surgery was reported in 2 patients in a non randomised comparative study of 280 patients: 1 occurred 5 weeks after the procedure because of left atrial laceration.
Late perforation of the aortic root by the device requiring pericardiocentesis and emergency cardiothoracic surgery occurred in 1 patient in a case report.
Device embolisation was reported in 0.6% (5/825) and 1% (2/167) of patients treated by the procedure in a case series of 825 patients and a non randomised comparative study of 280 patients respectively (device removed percutaneously in the first study but no further details given for the second).
Post- or peri-procedural arrhythmia was reported in 17% (8/47) and 10% (5/48) of patients in non-randomised comparative studies of 121 and 92 patients respectively.
The Specialist Advisers considered an additional theoretical adverse event to be valve dysfunction.# Further information
For related NICE guidance see our website.
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.
NICE has also written guidance on this procedure for:
IPG371 Percutaneous closure of patent foramen ovale for the secondary prevention of recurrent paradoxical embolism in divers
IPG109 Percutaneous closure of the patent foramen ovale for the prevention of cerebral embolic stroke
Changes since publication
May 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': "Current evidence on the efficacy of percutaneous closure of patent foramen ovale (PFO) for recurrent migraine is inadequate in quality and quantity. The evidence on safety shows a small incidence of well-recognised but sometimes serious adverse events, including device embolisation and device prolapse (each reported in less than 1% of patients). Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake percutaneous closure of PFO for recurrent migraine should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's efficacy and the possibility of serious complications. Clinicians should provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nPatient selection for percutaneous closure of PFO for recurrent migraine should be carried out by a neurologist or other specialist in headache followed by an interventional cardiologist. Use of this procedure should be restricted to patients who are severely affected by recurrent, refractory migraine.\n\nThe procedure should be done by an interventional cardiologist and supporting team with specific training in the procedure.\n\nThe procedure should only be carried out in units where there are arrangements for emergency cardiac surgical support in the event of complications.\n\nData on all patients having this procedure should be submitted to the UK Central Cardiac Audit Database.\n\nNICE encourages further research into this procedure, which should investigate the uncertainty surrounding the aetiology and natural history of migraine in patients with PFO. NICE may review this procedure on publication of further evidence.", 'The procedure': '# Indications and current treatments\n\nA PFO is the persistence of an opening (the foramen ovale) in the septum between the right atrium and left atrium of the heart. In the fetus, the foramen ovale allows blood to bypass the lungs, directly from the venous to the arterial side of the circulation. After birth the foramen ovale normally closes but in approximately 25% of people it remains either fully or partially patent throughout life. Studies evaluating PFO closure to prevent paradoxical thromboembolism noted a change in the incidence of migraine amongst patients. Any physiological effect of PFO closure in migraine treatment is not understood.\n\nCurrent treatment for patients with recurrent migraine is aimed at either preventing or aborting episodes through medical management. Invasive treatments such as nerve blocks or physical therapies such as acupuncture are sometimes used if medical therapy has failed.\n\n# Outline of the procedure\n\nPercutaneous closure of PFO for recurrent migraine is carried out with the patient under local anaesthesia and intravenous sedation, or general anaesthesia. A guidewire and delivery sheath are introduced via a small incision in the femoral vein into the heart and across the PFO. A closure device is then inserted through the opening via the delivery sheath and released, closing the PFO.\n\nA range of different devices are available for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the migraine- and embolism-related overviews.\n\n\n\n# Efficacy\n\nImmediate closure of the PFO (confirmed with echocardiography) was reported in 99% (148/150), 89% (42/47), 97% (179/185), 100% (76/76) and 99.8% (823/825) of patients in studies across a range of indications.\n\nA randomised controlled trial (RCT) of 147 patients treated either by the procedure (n = 74) or a sham procedure (n = 73) reported that 3 patients in each group had experienced no further migraines at 6-month follow-up. The study reported no significant difference in the reduction in median MIDAS score (a measure of migraine-related disability on a scale of 0–21+; higher score indicates more severe disability) between the procedure and sham groups (from 36 to 17 vs 34 to 18 respectively), or mean migraine headache days (from 26 to 19 vs 30 to 21 days respectively) over 6 months.\n\nA non-randomised comparative study of 86 patients reported a significant reduction in mean MIDAS score in the 40 patients treated by the procedure and the 46 patients treated by medical therapy at a mean follow-up of 29.2 months (from 35.8 to 8.3, p < 0.003 vs 22.6 to 19.1, p = 0.059 respectively; significance of between-group difference not stated).\n\nThe Specialist Advisers listed key efficacy outcomes as evidence of complete closure, and frequency and severity of migraine.\n\n# Safety\n\nThe following safety data were obtained from studies of PFO closure for a range of indications because:\n\nsafety data are likely to be similar for the various indications\n\nthe larger numbers of patients provide more robust evidence on safety than those from studies specifically relating to migraine.\n\nCardiac tamponade requiring surgery was reported in 2 patients in a non randomised comparative study of 280 patients: 1 occurred 5 weeks after the procedure because of left atrial laceration.\n\nLate perforation of the aortic root by the device requiring pericardiocentesis and emergency cardiothoracic surgery occurred in 1 patient in a case report.\n\nDevice embolisation was reported in 0.6% (5/825) and 1% (2/167) of patients treated by the procedure in a case series of 825 patients and a non randomised comparative study of 280 patients respectively (device removed percutaneously in the first study but no further details given for the second).\n\nPost- or peri-procedural arrhythmia was reported in 17% (8/47) and 10% (5/48) of patients in non-randomised comparative studies of 121 and 92 patients respectively.\n\nThe Specialist Advisers considered an additional theoretical adverse event to be valve dysfunction.', 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nNICE has also written guidance on this procedure for:\n\nIPG371 Percutaneous closure of patent foramen ovale for the secondary prevention of recurrent paradoxical embolism in divers\n\nIPG109 Percutaneous closure of the patent foramen ovale for the prevention of cerebral embolic stroke\n\nChanges since publication\n\nMay 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg370
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7550ec8f4f9b672cb76c15422e603b8d3bf8bd39
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nice
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Percutaneous closure of patent foramen ovale for the secondary prevention of recurrent paradoxical embolism in divers
|
Percutaneous closure of patent foramen ovale for the secondary prevention of recurrent paradoxical embolism in divers
# Guidance
Current evidence on the efficacy of percutaneous closure of patent foramen ovale (PFO) for the secondary prevention of recurrent paradoxical embolism in divers is inadequate in quality and quantity, and the evidence on safety shows that there is a possibility of serious complications. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to undertake percutaneous closure of PFO for the secondary prevention of recurrent paradoxical embolism in divers should take the following actions.
Inform the clinical governance leads in their Trusts.
Ensure that patients understand the uncertainty about the procedure's efficacy and the possibility of complications, and that they understand alternative options which may include modifying their diving practice to reduce the risk of gas bubble formation. Clinicians should provide patients with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.
Patient selection for this procedure should only be carried out by clinicians with specific expertise in decompression sickness, in liaison with an interventional cardiologist.
The procedure should only be carried out in units where there are arrangements for emergency cardiac surgical support in the event of complications.
Data on all patients having this procedure should be submitted to the UK Central Cardiac Audit Database.
NICE encourages further research into this procedure. Studies should document the recurrence of neurological decompression sickness in patients treated by this procedure compared with recurrence among those in whom the PFO is not closed. Outcomes should include details of the depth and duration profile of dives undertaken.# The procedure
# Indications and current treatments
A PFO is the persistence of an opening (the foramen ovale) in the septum between the right atrium and left atrium of the heart. In the fetus, the foramen ovale allows blood to bypass the lungs, directly from the venous to the arterial side of the circulation. After birth the foramen ovale normally closes but in approximately 25% of people it remains either fully or partially patent throughout life. Usually a PFO causes no symptoms, although a 'shunt' or movement of blood from the right to left side of the heart may be demonstrable using specialist tests.
During a dive, inert gas (usually nitrogen or helium) accumulates within blood and tissues. On ascent, provided that appropriate decompression schedules are followed, excess gas is excreted via the lungs. However, during deep or long duration dives, venous gas emboli (VGE) often form, and in the presence of a PFO, VGE may become arterialised, resulting in neurological symptoms that may resemble a stroke (termed 'neurological decompression illness').
There is currently no consensus on the optimal management of divers with a PFO and a history of neurological decompression sickness.
# Outline of the procedure
Percutaneous closure of PFO for the secondary prevention of recurrent paradoxical embolism in divers is carried out with the patient under local anaesthesia and intravenous sedation, or general anaesthesia. A guidewire and delivery sheath are introduced via a small incision in the femoral vein into the heart and across the PFO. A closure device is then inserted through the opening via the delivery sheath and released, closing the PFO.
A range of different devices are available for this procedure.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the embolism- and migraine-related overviews.
# Efficacy
Immediate closure of the PFO (confirmed with echocardiography) was reported in 99% (148/150), 89% (42/47), 97% (179/185), 100% (76/76) and 99.8% (823/825) of patients in studies across a range of indications.
A case series of 29 divers treated by percutaneous closure of PFO for neurological decompression sickness reported that 79% (23/29) had returned to diving (3 had only recently had closure and 3 had not returned to diving for other unrelated reasons). In the 23 who returned to diving, no recurrences of decompression sickness were reported.
The Specialist Advisers stated that a key efficacy outcome is adequate closure of the PFO assessed by a suitable technique (such as bubble contrast echocardiography).
# Safety
The following safety data were obtained from studies of PFO closure for a range of indications because:
safety data are likely to be similar for the various indications
the larger numbers of patients provide more robust evidence on safety than those from studies specifically relating to divers.
Cardiac tamponade requiring surgery was reported in 2 patients in a non randomised comparative study of 280 patients: 1 occurred 5 weeks after the procedure because of left atrial laceration.
Late perforation of the aortic root by the device requiring pericardiocentesis and emergency cardiothoracic surgery occurred in 1 patient in a case report.
Device embolisation was reported in 0.6% (5/825) and 1% (2/167) of patients treated by the procedure in a case series of 825 patients and a non randomised comparative study of 280 patients respectively (device removed percutaneously in the first study but no further details given for the second).
Post- or peri-procedural arrhythmia was reported in 17% (8/47) and 10% (5/48) of patients in non-randomised comparative studies of 121 and 92 patients respectively.
The Specialist Advisers considered an additional theoretical adverse event to be valve dysfunction.
# Other comments
The Committee noted that an episode of neurological decompression sickness might influence subsequent diving activity whether a PFO is present or not. This could confound evaluation of the effect of PFO closure.# Further information
For related NICE guidance see our website.
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.
NICE has also written guidance on this procedure for:
IPG370 Percutaneous closure of patent foramen ovale for recurrent migraine
IPG109 Percutaneous closure of the patent foramen ovale for the prevention of cerebral embolic stroke
Changes since publication
May 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': "Current evidence on the efficacy of percutaneous closure of patent foramen ovale (PFO) for the secondary prevention of recurrent paradoxical embolism in divers is inadequate in quality and quantity, and the evidence on safety shows that there is a possibility of serious complications. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake percutaneous closure of PFO for the secondary prevention of recurrent paradoxical embolism in divers should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy and the possibility of complications, and that they understand alternative options which may include modifying their diving practice to reduce the risk of gas bubble formation. Clinicians should provide patients with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nPatient selection for this procedure should only be carried out by clinicians with specific expertise in decompression sickness, in liaison with an interventional cardiologist.\n\nThe procedure should only be carried out in units where there are arrangements for emergency cardiac surgical support in the event of complications.\n\nData on all patients having this procedure should be submitted to the UK Central Cardiac Audit Database.\n\nNICE encourages further research into this procedure. Studies should document the recurrence of neurological decompression sickness in patients treated by this procedure compared with recurrence among those in whom the PFO is not closed. Outcomes should include details of the depth and duration profile of dives undertaken.", 'The procedure': "# Indications and current treatments\n\nA PFO is the persistence of an opening (the foramen ovale) in the septum between the right atrium and left atrium of the heart. In the fetus, the foramen ovale allows blood to bypass the lungs, directly from the venous to the arterial side of the circulation. After birth the foramen ovale normally closes but in approximately 25% of people it remains either fully or partially patent throughout life. Usually a PFO causes no symptoms, although a 'shunt' or movement of blood from the right to left side of the heart may be demonstrable using specialist tests.\n\nDuring a dive, inert gas (usually nitrogen or helium) accumulates within blood and tissues. On ascent, provided that appropriate decompression schedules are followed, excess gas is excreted via the lungs. However, during deep or long duration dives, venous gas emboli (VGE) often form, and in the presence of a PFO, VGE may become arterialised, resulting in neurological symptoms that may resemble a stroke (termed 'neurological decompression illness').\n\nThere is currently no consensus on the optimal management of divers with a PFO and a history of neurological decompression sickness.\n\n# Outline of the procedure\n\nPercutaneous closure of PFO for the secondary prevention of recurrent paradoxical embolism in divers is carried out with the patient under local anaesthesia and intravenous sedation, or general anaesthesia. A guidewire and delivery sheath are introduced via a small incision in the femoral vein into the heart and across the PFO. A closure device is then inserted through the opening via the delivery sheath and released, closing the PFO.\n\nA range of different devices are available for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the embolism- and migraine-related overviews.\n\n\n\n\n\n# Efficacy\n\nImmediate closure of the PFO (confirmed with echocardiography) was reported in 99% (148/150), 89% (42/47), 97% (179/185), 100% (76/76) and 99.8% (823/825) of patients in studies across a range of indications.\n\nA case series of 29 divers treated by percutaneous closure of PFO for neurological decompression sickness reported that 79% (23/29) had returned to diving (3 had only recently had closure and 3 had not returned to diving for other unrelated reasons). In the 23 who returned to diving, no recurrences of decompression sickness were reported.\n\nThe Specialist Advisers stated that a key efficacy outcome is adequate closure of the PFO assessed by a suitable technique (such as bubble contrast echocardiography).\n\n# Safety\n\nThe following safety data were obtained from studies of PFO closure for a range of indications because:\n\nsafety data are likely to be similar for the various indications\n\nthe larger numbers of patients provide more robust evidence on safety than those from studies specifically relating to divers.\n\nCardiac tamponade requiring surgery was reported in 2 patients in a non randomised comparative study of 280 patients: 1 occurred 5 weeks after the procedure because of left atrial laceration.\n\nLate perforation of the aortic root by the device requiring pericardiocentesis and emergency cardiothoracic surgery occurred in 1 patient in a case report.\n\nDevice embolisation was reported in 0.6% (5/825) and 1% (2/167) of patients treated by the procedure in a case series of 825 patients and a non randomised comparative study of 280 patients respectively (device removed percutaneously in the first study but no further details given for the second).\n\nPost- or peri-procedural arrhythmia was reported in 17% (8/47) and 10% (5/48) of patients in non-randomised comparative studies of 121 and 92 patients respectively.\n\nThe Specialist Advisers considered an additional theoretical adverse event to be valve dysfunction.\n\n# Other comments\n\nThe Committee noted that an episode of neurological decompression sickness might influence subsequent diving activity whether a PFO is present or not. This could confound evaluation of the effect of PFO closure.", 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nNICE has also written guidance on this procedure for:\n\nIPG370 Percutaneous closure of patent foramen ovale for recurrent migraine\n\nIPG109 Percutaneous closure of the patent foramen ovale for the prevention of cerebral embolic stroke\n\nChanges since publication\n\nMay 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg371
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3d02327f755b25529fef353fc4bbffbface54054
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nice
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Percutaneous radiofrequency ablation for primary or secondary lung cancers
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Percutaneous radiofrequency ablation for primary or secondary lung cancers
# Guidance
This document replaces previous guidance on percutaneous radiofrequency ablation for primary and secondary lung cancers (interventional procedure guidance 185).
Current evidence on the efficacy of percutaneous radiofrequency ablation (RFA) for primary or secondary lung cancers is adequate in terms of tumour control. There is a small incidence of complications, specifically pneumothorax, which may have serious implications for these patients with already compromised respiratory reserve. This procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.
Patient selection for percutaneous RFA for primary or secondary lung cancers should be carried out by a multidisciplinary team, which will usually include a thoracic surgeon, an oncologist and a radiologist.
This procedure should only be carried out by radiologists who regularly undertake image-guided interventional procedures.
NICE encourages further research into this procedure. Research studies should include a clear description of case mix and lesion size, and report long-term survival.# The procedure
# Indications and current treatments
Both primary and metastatic lung cancer are common, and the prognosis for most patients is poor.
Treatment depends mainly on tumour histology and stage, and may include surgical resection (open or thoracoscopic), external beam radiotherapy, chemotherapy or a combination of these treatments. If the tumour protrudes into major airways, bronchoscopic treatments including diathermy, laser therapy, cryotherapy, brachytherapy and photodynamic therapy may be used.
# Outline of the procedure
Percutaneous RFA may be used in patients with small, early-stage lung cancers or small numbers of lung metastases who are unsuitable for, or prefer not to undergo, surgery. It may also have a place in multi-modality treatment of more advanced primary lung cancers.
The procedure is usually carried out with the patient under local anaesthesia with conscious sedation, but general anaesthesia may be required. The procedure involves inserting a small needle electrode percutaneously directly into the tumour, normally under computed tomography (CT) guidance. Radiofrequency energy is passed through the electrode causing heating of the tissues around the tip of the needle. The tumour tissue in the target area is coagulated. A small margin of normal tissue around the tumour is also destroyed to reduce local recurrence risk.
The procedure can be applied to more than one tumour during one or more treatment sessions, and can be used alone or in combination with surgery, radiotherapy or chemotherapy.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A case series of 100 patients with inoperable colorectal lung metastases reported median overall survival and overall 5-year survival after RFA treatment of 36 months and 30% respectively. A systematic review of 46 studies including a total of 1584 patients reported a mean overall survival rate of 59% over a mean follow-up period of 18 months.
Another case series of 100 patients reported median overall survival of 27 months for patients with primary lung cancer, 33 months for patients with recurrent lung cancer and 18 months for patients with metastatic disease.
A case series of 153 patients reported that the median time to progression (assessed by follow-up CT scans and also positron-emission tomography scans in selected patients) for tumours of 3 cm or smaller was 45 months, with 1-, 3- and 5-year local tumour progression-free rates of 83%, 57% and 47% respectively. Median time to progression for larger tumours was 12 months, with 1-, 3- and 5-year progression-free rates of 45%, 25% and 25% respectively. A case series of 78 patients with colorectal lung metastases reported 1-, 3- and 5-year overall progression rates (assessed by CT) of 10%, 21% and 21% respectively.
In a case series of 106 patients, there was no significant difference between quality of life at baseline and at 12 months after RFA, using the Functional Assessment of Cancer Therapy – Lung and Short-Form 12 questionnaires.
The Specialist Advisers listed key efficacy outcomes as symptomatic improvement, quality of life, local tumour control, progression-free survival, overall survival, respiratory morbidity and the need for repeat interventions.
# Safety
Four procedure-related deaths within 30 days were reported in the case series of 153 patients, 2 of which were in single-lung patients. The causes of death were haemorrhage into the pleural space; exacerbation of underlying pulmonary fibrosis; congestive heart failure; and respiratory arrest while undergoing conscious sedation. Two deaths were reported in a case series of 137 patients: 1 from intractable pneumothorax and pneumonia at 53 days, the other from massive haemoptysis 28 days after RFA. Two deaths resulting from interstitial pneumonia were reported in a case series of 130 patients (timing of events not stated). One case series of 100 patients reported no treatment-related mortality.
Pneumothorax requiring chest tube insertion was reported in less than 10% of patients in 4 centres and in 10–30% of patients in 3 centres in a case series of 493 RFA procedures performed. In 5 further case series, rates of pneumothorax requiring chest tube drainage ranged from 10% (18/183) to 20% (27/137).
Pleural effusion requiring drainage was reported in less than 10% of patients in 6 centres and more than 30% in 1 centre in the case series of 493 RFA procedures. In 3 further case series, rates of pleural effusion requiring drainage were 2% (4/211), 3% (4/137) and 3% (3/100).
The Specialist Advisers considered theoretical adverse events to include abscess, infection, pulmonary embolism, pain, damage to other intrathoracic structures, postprocedure mortality and death from interstitial pneumonitis.# Further information
For related NICE guidance see our website.
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
It updates and replaces NICE interventional procedure guidance 185.
It has been incorporated into the NICE pathway on colorectal cancer, along with other related guidance and products.
We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.
Changes since publication
January 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': 'This document replaces previous guidance on percutaneous radiofrequency ablation for primary and secondary lung cancers (interventional procedure guidance 185).\n\nCurrent evidence on the efficacy of percutaneous radiofrequency ablation (RFA) for primary or secondary lung cancers is adequate in terms of tumour control. There is a small incidence of complications, specifically pneumothorax, which may have serious implications for these patients with already compromised respiratory reserve. This procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatient selection for percutaneous RFA for primary or secondary lung cancers should be carried out by a multidisciplinary team, which will usually include a thoracic surgeon, an oncologist and a radiologist.\n\nThis procedure should only be carried out by radiologists who regularly undertake image-guided interventional procedures.\n\nNICE encourages further research into this procedure. Research studies should include a clear description of case mix and lesion size, and report long-term survival.', 'The procedure': '# Indications and current treatments\n\nBoth primary and metastatic lung cancer are common, and the prognosis for most patients is poor.\n\nTreatment depends mainly on tumour histology and stage, and may include surgical resection (open or thoracoscopic), external beam radiotherapy, chemotherapy or a combination of these treatments. If the tumour protrudes into major airways, bronchoscopic treatments including diathermy, laser therapy, cryotherapy, brachytherapy and photodynamic therapy may be used.\n\n# Outline of the procedure\n\nPercutaneous RFA may be used in patients with small, early-stage lung cancers or small numbers of lung metastases who are unsuitable for, or prefer not to undergo, surgery. It may also have a place in multi-modality treatment of more advanced primary lung cancers.\n\nThe procedure is usually carried out with the patient under local anaesthesia with conscious sedation, but general anaesthesia may be required. The procedure involves inserting a small needle electrode percutaneously directly into the tumour, normally under computed tomography (CT) guidance. Radiofrequency energy is passed through the electrode causing heating of the tissues around the tip of the needle. The tumour tissue in the target area is coagulated. A small margin of normal tissue around the tumour is also destroyed to reduce local recurrence risk.\n\nThe procedure can be applied to more than one tumour during one or more treatment sessions, and can be used alone or in combination with surgery, radiotherapy or chemotherapy.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 100 patients with inoperable colorectal lung metastases reported median overall survival and overall 5-year survival after RFA treatment of 36 months and 30% respectively. A systematic review of 46 studies including a total of 1584 patients reported a mean overall survival rate of 59% over a mean follow-up period of 18 months.\n\nAnother case series of 100 patients reported median overall survival of 27 months for patients with primary lung cancer, 33 months for patients with recurrent lung cancer and 18 months for patients with metastatic disease.\n\nA case series of 153 patients reported that the median time to progression (assessed by follow-up CT scans and also positron-emission tomography scans in selected patients) for tumours of 3 cm or smaller was 45 months, with 1-, 3- and 5-year local tumour progression-free rates of 83%, 57% and 47% respectively. Median time to progression for larger tumours was 12 months, with 1-, 3- and 5-year progression-free rates of 45%, 25% and 25% respectively. A case series of 78 patients with colorectal lung metastases reported 1-, 3- and 5-year overall progression rates (assessed by CT) of 10%, 21% and 21% respectively.\n\nIn a case series of 106 patients, there was no significant difference between quality of life at baseline and at 12 months after RFA, using the Functional Assessment of Cancer Therapy – Lung and Short-Form 12 questionnaires.\n\nThe Specialist Advisers listed key efficacy outcomes as symptomatic improvement, quality of life, local tumour control, progression-free survival, overall survival, respiratory morbidity and the need for repeat interventions.\n\n# Safety\n\nFour procedure-related deaths within 30 days were reported in the case series of 153 patients, 2 of which were in single-lung patients. The causes of death were haemorrhage into the pleural space; exacerbation of underlying pulmonary fibrosis; congestive heart failure; and respiratory arrest while undergoing conscious sedation. Two deaths were reported in a case series of 137 patients: 1 from intractable pneumothorax and pneumonia at 53 days, the other from massive haemoptysis 28 days after RFA. Two deaths resulting from interstitial pneumonia were reported in a case series of 130 patients (timing of events not stated). One case series of 100 patients reported no treatment-related mortality.\n\nPneumothorax requiring chest tube insertion was reported in less than 10% of patients in 4 centres and in 10–30% of patients in 3 centres in a case series of 493 RFA procedures performed. In 5 further case series, rates of pneumothorax requiring chest tube drainage ranged from 10% (18/183) to 20% (27/137).\n\nPleural effusion requiring drainage was reported in less than 10% of patients in 6 centres and more than 30% in 1 centre in the case series of 493 RFA procedures. In 3 further case series, rates of pleural effusion requiring drainage were 2% (4/211), 3% (4/137) and 3% (3/100).\n\nThe Specialist Advisers considered theoretical adverse events to include abscess, infection, pulmonary embolism, pain, damage to other intrathoracic structures, postprocedure mortality and death from interstitial pneumonitis.', 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 185.\n\nIt has been incorporated into the NICE pathway on colorectal cancer, along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg372
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811813c4b65e79c51cee9f515e6da21505dff948
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nice
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Selective dorsal rhizotomy for spasticity in cerebral palsy
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Selective dorsal rhizotomy for spasticity in cerebral palsy
# Guidance
This document replaces previous guidance on selective dorsal rhizotomy for spasticity in cerebral palsy (interventional procedure guidance 195).
Current evidence on selective dorsal rhizotomy for spasticity in cerebral palsy shows that there is a risk of serious but well-recognised complications. The evidence on efficacy is adequate. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance and audit.
During the consent process parents or carers should be informed that selective dorsal rhizotomy for spasticity in cerebral palsy is irreversible, and that patients may experience deterioration in walking ability or bladder function, and later complications including spinal deformity. They should understand that prolonged physiotherapy and aftercare will be required and that additional surgery may be necessary.
Patient selection and treatment should be carried out by a multidisciplinary team with specialist training and expertise in the care of spasticity in patients with cerebral palsy, and with access to the full range of treatment options. This team would normally include a physiotherapist, a paediatrician and surgeons, all with specific training and expertise.
NICE encourages further research into this procedure. Long-term outcomes are encouraged. Outcome measures should include: the incidence of neurological impairment and spinal deformity; the need for additional operations; and assessments of disability, social inclusion, and quality of life.# The procedure
# Indications and current treatments
Cerebral palsy encompasses different brain disorders originating during fetal development, birth or early childhood. It is associated with abnormalities of movement, balance and posture, language and vision. Lower limb spasticity affects 80% of people with cerebral palsy. This can impair walking and sitting, and can cause discomfort, cramps and spasms.
Current treatments include oral muscle relaxant medication, orthotic devices, physiotherapy, and repeated intramuscular injections of botulinum toxin. Surgical procedures include tendonotomy, tendon lengthening, peripheral neurotomy, osteotomy, electrical stimulation of the muscles or dorsal spinal cord, and continuous intrathecal baclofen infusion.
# Outline of the procedure
The aim of selective dorsal rhizotomy is to achieve a long-term reduction in sensory input to the sensory–motor reflex arcs responsible for increased muscle tone, by dividing some of the lumbar sensory nerve roots.
With the patient under general anaesthesia, a laminectomy of one or more vertebrae is performed to expose the dural sac, which is opened to display the spinal conus with or without the cauda equina. Intraoperative neurophysiological assessment is commonly used to identify the sensory nerve rootlets judged to be most responsible for the excess motor tone. Selected sensory rootlets are divided, preserving some sensory supply and the motor roots responsible for voluntary movements.
Intensive physiotherapy and aftercare is usually given for several months after the procedure. Patients who were previously able to walk may have to learn different walking skills.
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.
# Efficacy
A non-randomised comparative study of 142 patients treated by the procedure (n = 71) or intrathecal baclofen pump (ITBP) (n = 71) reported improvements in Modified Ashworth Scale scores (measures muscle tone on a scale from 0 to 5; lower score indicates lower muscle tone) of −2.52 and −1.23 points respectively at 1-year follow-up (p < 0.0001).
A non-randomised comparative study of 108 patients treated by the procedure plus physiotherapy or physiotherapy alone reported mean improvements in Gross Motor Function Measure (GMFM) score (higher score indicates better gross motor functioning) from baseline of 87 to 92 and 89 to 91 respectively at 20-month follow-up (p < 0.05 for both groups from baseline).
The non-randomised comparative study of 142 patients treated by the procedure or ITBP reported that 94% and 96% of parents respectively were satisfied at 1-year follow-up (absolute figures not stated) (p = 0.71).
The Specialist Advisers listed key efficacy outcomes as reduction in lower limb spasticity, reduction in number of subsequent orthopaedic procedures, improved gross motor function, improved gait and walking, improved level of independence and quality of life.
# Safety
Radiologically observed scoliosis was reported in 9% (5/58) of patients who had laminectomy and 1% (2/150) of patients who had laminoplasty in the case series of 208 patients at a mean follow-up of 4.2 years. The percentage of patients with scoliosis pre-operatively was not stated. Case series of 105, 98 and 30 patients reported scoliosis of 10° or more in 55% at 4.3 years, in 43% at 5.8 years, and scoliosis of less than 35° in 50% at 21.4 years respectively.
In a case series of 61 patients, 4 patients developed spondylolysis and grade-I spondylolisthesis between 3 and 5 years after the procedure.
Urinary retention due to decreased bladder tone and hyporeflexia was reported in 10% (20/208) of patients in the case series of 208 patients. This resolved spontaneously within 4 weeks in 18 patients but 2 patients had long term urinary incontinence because of atonic bladder.
The Specialist Advisers considered theoretical adverse events to include death, worsening motor function and/or paraplegia, wound infection, meningitis, cerebrospinal fluid leakage, dislocation of the hip(s), back pain, constipation, weakness, chronic pain, and late arachnoiditis and/or syringomyelia.
# Other comments
The Committee noted that most of the evidence for this procedure relates to children aged 4–10 years. The Committee also noted that this procedure and patient selection for it are still evolving. Several commentators recommend limited laminectomy to reduce the risk of late spinal deformity, and others question the need for intraoperative neurophysiology.# Further information
For related NICE guidance see our website.
# Information for patients
NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance
NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.
This guidance was developed using the NICE interventional procedure guidance process.
It updates and replaces NICE interventional procedure guidance 195.
We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.
Changes since publication
January 2012: minor maintenance.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
Contact NICE
National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT
www.nice.org.uk
nice@nice.org.uk
|
{'Guidance': 'This document replaces previous guidance on selective dorsal rhizotomy for spasticity in cerebral palsy (interventional procedure guidance 195).\n\nCurrent evidence on selective dorsal rhizotomy for spasticity in cerebral palsy shows that there is a risk of serious but well-recognised complications. The evidence on efficacy is adequate. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance and audit.\n\nDuring the consent process parents or carers should be informed that selective dorsal rhizotomy for spasticity in cerebral palsy is irreversible, and that patients may experience deterioration in walking ability or bladder function, and later complications including spinal deformity. They should understand that prolonged physiotherapy and aftercare will be required and that additional surgery may be necessary.\n\nPatient selection and treatment should be carried out by a multidisciplinary team with specialist training and expertise in the care of spasticity in patients with cerebral palsy, and with access to the full range of treatment options. This team would normally include a physiotherapist, a paediatrician and surgeons, all with specific training and expertise.\n\nNICE encourages further research into this procedure. Long-term outcomes are encouraged. Outcome measures should include: the incidence of neurological impairment and spinal deformity; the need for additional operations; and assessments of disability, social inclusion, and quality of life.', 'The procedure': '# Indications and current treatments\n\nCerebral palsy encompasses different brain disorders originating during fetal development, birth or early childhood. It is associated with abnormalities of movement, balance and posture, language and vision. Lower limb spasticity affects 80% of people with cerebral palsy. This can impair walking and sitting, and can cause discomfort, cramps and spasms.\n\nCurrent treatments include oral muscle relaxant medication, orthotic devices, physiotherapy, and repeated intramuscular injections of botulinum toxin. Surgical procedures include tendonotomy, tendon lengthening, peripheral neurotomy, osteotomy, electrical stimulation of the muscles or dorsal spinal cord, and continuous intrathecal baclofen infusion.\n\n# Outline of the procedure\n\nThe aim of selective dorsal rhizotomy is to achieve a long-term reduction in sensory input to the sensory–motor reflex arcs responsible for increased muscle tone, by dividing some of the lumbar sensory nerve roots.\n\nWith the patient under general anaesthesia, a laminectomy of one or more vertebrae is performed to expose the dural sac, which is opened to display the spinal conus with or without the cauda equina. Intraoperative neurophysiological assessment is commonly used to identify the sensory nerve rootlets judged to be most responsible for the excess motor tone. Selected sensory rootlets are divided, preserving some sensory supply and the motor roots responsible for voluntary movements.\n\nIntensive physiotherapy and aftercare is usually given for several months after the procedure. Patients who were previously able to walk may have to learn different walking skills.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA non-randomised comparative study of 142 patients treated by the procedure (n = 71) or intrathecal baclofen pump (ITBP) (n = 71) reported improvements in Modified Ashworth Scale scores (measures muscle tone on a scale from 0 to 5; lower score indicates lower muscle tone) of −2.52 and −1.23 points respectively at 1-year follow-up (p < 0.0001).\n\nA non-randomised comparative study of 108 patients treated by the procedure plus physiotherapy or physiotherapy alone reported mean improvements in Gross Motor Function Measure (GMFM) score (higher score indicates better gross motor functioning) from baseline of 87 to 92 and 89 to 91 respectively at 20-month follow-up (p < 0.05 for both groups from baseline).\n\nThe non-randomised comparative study of 142 patients treated by the procedure or ITBP reported that 94% and 96% of parents respectively were satisfied at 1-year follow-up (absolute figures not stated) (p = 0.71).\n\nThe Specialist Advisers listed key efficacy outcomes as reduction in lower limb spasticity, reduction in number of subsequent orthopaedic procedures, improved gross motor function, improved gait and walking, improved level of independence and quality of life.\n\n# Safety\n\nRadiologically observed scoliosis was reported in 9% (5/58) of patients who had laminectomy and 1% (2/150) of patients who had laminoplasty in the case series of 208 patients at a mean follow-up of 4.2 years. The percentage of patients with scoliosis pre-operatively was not stated. Case series of 105, 98 and 30 patients reported scoliosis of 10° or more in 55% at 4.3 years, in 43% at 5.8 years, and scoliosis of less than 35° in 50% at 21.4 years respectively.\n\nIn a case series of 61 patients, 4 patients developed spondylolysis and grade-I spondylolisthesis between 3 and 5 years after the procedure.\n\nUrinary retention due to decreased bladder tone and hyporeflexia was reported in 10% (20/208) of patients in the case series of 208 patients. This resolved spontaneously within 4 weeks in 18 patients but 2 patients had long term urinary incontinence because of atonic bladder.\n\nThe Specialist Advisers considered theoretical adverse events to include death, worsening motor function and/or paraplegia, wound infection, meningitis, cerebrospinal fluid leakage, dislocation of the hip(s), back pain, constipation, weakness, chronic pain, and late arachnoiditis and/or syringomyelia.\n\n# Other comments\n\nThe Committee noted that most of the evidence for this procedure relates to children aged 4–10 years. The Committee also noted that this procedure and patient selection for it are still evolving. Several commentators recommend limited laminectomy to reduce the risk of late spinal deformity, and others question the need for intraoperative neurophysiology.', 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 195.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}
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https://www.nice.org.uk/guidance/ipg373
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05f7f4d85d0e4f28ddb80e235e2174fb2139330b
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nice
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Unintentional injuries: prevention strategies for under 15s
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Unintentional injuries: prevention strategies for under 15s
This guideline covers strategies, regulation, enforcement, surveillance and workforce development in relation to preventing unintentional injuries in the home, on the road and during outdoor play and leisure.
# Introduction
This is one of three pieces of NICE guidance published in November 2010 on how to prevent unintentional injuries among under-15s. A second publication covers the provision of home safety equipment and home risk assessments and a third covers unintentional injuries on the road.
The Department of Health (DH) asked the National Institute for Health and Care Excellence (NICE) to produce public health guidance on the prevention of unintentional injuries among children and young people aged under 15. This guidance focuses on strategies, regulation, enforcement, surveillance and workforce development in relation to preventing unintentional injuries in the home, on the road and during outdoor play and leisure.
The guidance is for commissioners and providers of health services, local authority children's services, local authorities and their strategic partnerships, local highway authorities, local safeguarding children boards, police, fire and rescue services, policy makers, professional bodies, providers of play and leisure facilities, and schools.
It is also for other public, private, voluntary and community organisations and services which have a direct or indirect role in preventing unintentional injuries among children and young people aged under 15.
The guidance may also be of interest to children, young people, parents, carers and other members of the public.
This is one of three pieces of NICE guidance published in November 2010 on how to prevent unintentional injuries among children and young people aged under 15. It should be read in conjunction with the two other publications. These focus on: the provision of home safety equipment and home risk assessments and road design and modification. (For further details, see section 7.)
The Programme Development Group (PDG) developed these recommendations on the basis of reviews of the evidence, economic modelling, expert testimony, stakeholder comments and fieldwork.
Members of the PDG are listed in appendix A. The methods used to develop the guidance are summarised in appendix B.
Supporting documents used to prepare this document are listed in appendix E.
Full details of the evidence collated, including fieldwork data and stakeholder comments, are available on the NICE website, along with a list of the stakeholders involved and NICE's supporting process and methods manuals.# Recommendations
This is NICE's formal guidance on strategies to prevent unintentional injuries among children and young people aged under 15. When writing the recommendations, the Programme Development Group (PDG) (see appendix A) considered the evidence of effectiveness (including cost effectiveness), expert testimony, fieldwork data and comments from stakeholders. Full details are available online.
The evidence statements underpinning the recommendations are listed in appendix C.
The evidence reviews, supporting evidence statements and economic analysis are available online.
Please note: the absence of recommendations on any particular measures to prevent unintentional injuries is a result of a lack of evidence that met the inclusion criteria for the evidence reviews. It should not be taken as a judgement on whether or not any such measures are effective and cost effective.
# Definitions
The guidance uses the term 'unintentional injuries' rather than 'accidents' as: "most injuries and their precipitating events are predictable and preventable". The term 'accident' implies an unpredictable and therefore unavoidable event.
The term 'vulnerable' is used to refer to children and young people who are at greater than average risk of an unintentional injury due to one or more factors. As an example, they may be more vulnerable if they:
are under the age of 5 years (generally, under-5s are more vulnerable to unintentional injuries in the home)
are over the age of 11 (generally, over-11s are more vulnerable to unintentional injuries on the road)
have a disability or impairment (physical or learning)
are from some minority ethnic groups
live with a family on a low income
live in accommodation which potentially puts them more at risk (this could include multiple-occupied housing and social and privately rented housing).
# Topics
The recommendations are divided into six categories: general, workforce training and capacity building, injury surveillance, home safety, outdoor play and leisure, and road safety.
# National recommendations
The guidance includes some national recommendations to assist local action (see recommendations 1, 5, 7, 10 and 21).
The decision on whether these recommendations are taken forward – and how they are prioritised – will be determined by government and subject to statutory regulatory and cost impact assessments.
# General recommendations
## Context
The prevention of unintentional injuries among children and young people may not be a priority among local organisations. To ensure prevention activities are accorded the importance they deserve, they need to be incorporated into national objectives aiming to improve the population's health. Local injury prevention coordinators could promote a strategic framework for action and encourage local agencies to work together.
Children and young people aged under 15, their parents and carers (some of the recommendations may also benefit the wider population).
## Recommendation 1 Incorporating unintentional injury prevention within local and national plans and strategies for children and young people's health and wellbeing
Local authority children's services and their partnerships, in consultation with local safeguarding children boards.
Government departments with a responsibility for preparing policy and plans relating to children and young people's health and wellbeing.
Ensure local and national plans and strategies for children and young people's health and wellbeing include a commitment to preventing unintentional injuries among them. In particular, the plans and strategies should aim to prevent unintentional injuries among the most vulnerable groups to reduce inequalities in health. This commitment should be part of a wider objective to keep children and young people safe.
Ensure plans and strategies include the following to prevent unintentional injuries among children and young people:
support for cross-departmental and cross-agency working to achieve national and local commitments
support for local partnerships, including those with the voluntary sector, and a requirement that they work together to ensure children and young people can lead healthy, active lives
information about how partners will collaborate on injury prevention
support for data collection on the incidence, severity, type, cause and place of injury (for example, see recommendations 7–8 on injury surveillance)
support for monitoring the outcomes of injury prevention initiatives
support for the development of workforce capacity in this area, including the provision of suitably trained staff and opportunities for initial and ongoing multi-agency training and development (see recommendations 4–6).
Local authorities should report to the local strategic partnership on progress made to meet the commitments set out in the plans and strategies. This should include details on the experiences of children, young people, their parents and carers.
## Recommendation 2 Coordinating unintentional injury prevention activities
Local authority children's services and their partnerships, in consultation with local safeguarding children boards.
Local highway authorities and their road safety partnerships.
Other local authority services that may have a remit for preventing unintentional injuries such as education, environmental health and trading standards.
Ensure there is a child and young person injury prevention coordinator. The aim is to help achieve the commitments set out in local plans and strategies for children and young people's health and wellbeing. The coordinator could be someone in the local authority, an NHS organisation or another local partner organisation (such as the fire and rescue service or a housing association). Alternatively, the coordinating role could be jointly funded by several local partners.
Ensure the coordinator:
works with local partnerships that include organisations involved with children, young people, their parents and carers
develops a 2 to 3-year injury prevention strategy with these partners which is integrated into all relevant local plans and strategies for children and young people's health and wellbeing
networks at regional and national level with other child and young person injury prevention coordinators
raises local awareness about the need for prevention activities. This includes sitting on the local safeguarding children board. It also includes acting as a local source of information and advice on prevention
monitors progress made on the injury prevention commitments set out in local plans and strategies for children and young people's health and wellbeing. They should report progress to the director of children's services.
Ensure the coordinator understands the range of preventive measures available and is trained – and has the skills – to carry out the above activities. Provide them with both informal and formal learning opportunities. (The former could include using peer support and 'cascade learning' within placements. The latter could include the acquisition of qualifications at different stages of a formal career pathway.)
Ensure specialist learning and training is monitored and evaluated to see what effect it has on the coordinator's performance. Revise approaches that are found to be ineffective.
## Recommendation 3 Identifying and responding to attendances at emergency departments and minor injuries units
Staff in emergency departments and minor injuries units, including triage nurses.
Local child and young person injury prevention coordinators.
Local safeguarding children boards.
Liaison health visitors.
Staff offering out-of-hours health services for children and young people (for example, in walk-in centres).
Ensure health visitors, school nurses and GPs are aware of families which might benefit from injury prevention advice and a home safety assessment. Do this by using local protocols to alert them when a child or young person repeatedly needs treatment for unintentional injuries at an emergency department or minor injuries unit. Do the same when a single attendance raises concerns.
# Recommendations for workforce training and capacity building
## Context
Professional standards are needed to set out the knowledge and skills (or 'competencies') for a range of injury prevention roles within and outside the NHS. Funding to develop these standards and curricula – and the provision of accessible training – is also required.
Children and young people aged under 15, their parents and carers (some of the recommendations may also benefit the wider population).
## Recommendation 4 Developing professional standards for injury prevention
Faculty of Public Health.
Royal colleges and professional bodies (for example, the Nursing and Midwifery Council).
Health and Care Professions Council.
Sector skills councils.
Relevant voluntary sector organisations.
Universities.
Develop professional standards for unintentional injury prevention. These should take into account the different roles and responsibilities of professionals working within and outside the NHS. They should also take practitioners' views into account.
Ensure all relevant organisations incorporate these standards into their professional skills development programmes.
## Recommendation 5 Funding the development of injury prevention standards and curricula
Department of Health and Social Care.
Department for Education.
Encourage funding for educational establishments and organisations to help them develop standards for competencies in – and courses and modules on – the prevention of unintentional injuries among children and young people. The establishments and organisations involved could include: the Faculty of Public Health, the Children's Workforce Development Council, universities, royal colleges and organisations in the voluntary sector.
## Recommendation 6 Providing the wider childcare workforce with access to injury prevention training
Local authority children's services and their partnerships, including local safeguarding children boards.
Local injury prevention coordinators.
Commissioners, managers and practitioners working in health, social care and education services.
Relevant organisations in the voluntary and private sector.
Provide access to appropriate education and training in how to prevent unintentional injuries for everyone who works with (or cares for and supports) children, young people and their families. Prioritise those who work directly with children, young people and their families.
Ensure the education and training:
supports the wider child health remit (for example, the promotion of children and young people's development)
helps develop an understanding of the importance of preventing unintentional injuries and their consequences and the preventive measures available.
Ensure specialist education and training is monitored and evaluated to see what effect it has on practitioner performance. Revise approaches that are found to be ineffective.
# Recommendations for injury surveillance
## Context
Injury 'surveillance' is needed to monitor unintentional injuries among children and young people locally, regionally and nationwide. The data gathered could be used as the basis to plan preventive initiatives. Such initiatives may need to take a particular type of injury into account locally or regionally – even though it may not be a major problem nationwide.
Children and young people aged under 15, their parents and carers (some of the recommendations may also benefit the wider population).
## Recommendation 7 Establishing a national injuries surveillance resource
College of Emergency Medicine.
Government departments including Department of Health and Social Care and Public Health England, Department for Education, Department for Transport, Ministry for Housing, Communities and Local Government and the Home Office.
Office for National Statistics.
The Information Centre for Health and Social Care.
Establish a national injuries surveillance resource covering all populations and injuries to help monitor injury risks and the effects of preventive measures. It could be provided by a network of agencies but there should be a single point of contact or a coordinating agency. The resource could be part of the proposed 'Information revolution'.
Ensure the resource includes local, regional and national injury datasets and data sources. For example, it should include data gathered from: emergency departments, walk-in centres, minor injury units, Reporting of Injuries, Diseases and Dangerous Occurrences Regulations (RIDDOR), Hospital Episode Statistics (HES), coroner reports, ambulance call-out reports, fire and rescue service reports, reported road casualty statistics (STATS19) and the child death review process (as data become available).
The coordinating agency or network of agencies should:
ensure datasets can be integrated to provide accurate, anonymised and aggregated statistics on local injuries and their causes
collate, manage, analyse and interpret injury-related data (using experienced injury researchers to advise on analysis and interpretation)
provide a secure and reliable information system for recording and interrogating data (compliant with the Data Protection Act 2018)
monitor the quality of data submissions and datasets
report relevant findings to support the monitoring of emergency department service contracts
provide government departments with advice on developing standardised injury data collection and coding across datasets (for example, for data collected by fire and rescue services and emergency departments)
identify and develop new data sources for example, data collected by non-governmental agencies and the voluntary sector
disseminate information locally and regionally and provide a readily available, searchable database for authorised users
support the European Commission's work on injury surveillance.
Ensure national guidance on data-sharing protocols is adopted by all agencies that collect local injury data. This includes: ambulance services, child death overview panels, coroners, emergency departments, fire and rescue services, the Health and Safety Executive and police forces.
Promote the development of an enhanced national emergency department dataset based on submissions from a representative sample of hospitals. Ensure it includes additional data on events and activities leading to an injury.
## Recommendation 8 Gathering high quality injury data from emergency departments
Commissioners of health services.
Ensure all hospital trusts are made aware of the data collection requirements for the universal and mandatory A&E (minimum) commissioning dataset.
Ensure commissioning contracts for emergency departments (including minor injury units and walk-in centres) stipulate that all required data are collected – and to the required A&E (minimum) commissioning dataset standard. Contracts should also stipulate which data collection and submission methods should be used.
Ensure contracts include financial penalties for failure to meet the requirements of the A&E (minimum) commissioning dataset.
Ensure all hospital trust injury data are submitted to the NHS Information Centre for Health and Social Care.
# Recommendations for home safety
## Definitions and context
For the purposes of this guidance, 'home' refers to the home, garden and boundaries of a property. A home safety assessment is the process of systematically identifying potential hazards in these areas, evaluating the risks and providing information or advice on how to reduce them. Other terms commonly used to describe the same process include 'home risk assessment' and 'home safety check'. It may be carried out by a trained assessor or by parents, carers and other householders using an appropriate checklist.
Permanent home safety equipment is defined here as any device that needs to be fitted and cannot easily be modified or removed by the householder. Examples include smoke and carbon monoxide alarms, thermostatic mixing valves and window restrictors.
Ensuring permanent safety equipment is fitted in homes and the provision of home safety assessments should help prevent unintentional injuries among all under-15s. However, groups facing a higher than average risk of an unintentional injury need to be prioritised. Particularly vulnerable groups in relation to home safety are children aged under 5 and those living in temporary, rented and social housing with families on a low income (for other vulnerable groups see definitions at the beginning of section 1).
(See also recommendations made in NICE's guideline on unintentional injuries in the home: interventions for under 15s.)
Children and young people aged under 15 and their families (some of the recommendations may also benefit the wider population).
## Recommendation 9 Installation and maintenance of permanent safety equipment in social and rented dwellings
Local authorities.
Consider developing local agreements with housing associations and landlords to ensure permanent home safety equipment is installed and maintained in all social and rented dwellings. Priority should be given to accommodation where children aged under 5 are living. Use the Housing Health and Safety Rating System (HHSRS). Permanent safety equipment includes:
thermostatic mixer valves for baths
window restrictors.For duties about installing and maintaining smoke and carbon monoxide alarms, refer to the Smoke and Carbon Monoxide Alarm (England) Regulations 2015.
Publicise any local agreements to install and maintain permanent safety equipment. Provide information about these agreements to the following groups and evaluate their awareness:
those responsible for social and rented dwellings, such as landlords and social housing providers
practitioners with an injury prevention remit or who have an opportunity to help prevent injuries among children and young people
practitioners with a role in assessing health and safety in residential properties
residents in rented and social dwellings.
## Recommendation 10 Incorporating guidance on home safety assessments within relevant national initiatives
Department of Health.
Department for Education.
Ensure national initiatives to improve child health include guidance on delivering home safety assessments and providing safety education to families with a child under 5 or with other children who may be particularly vulnerable to unintentional injuries. (Relevant national initiatives include the Healthy Child Programme.)
## Recommendation 11 Incorporating home safety assessments and equipment provision within local plans and strategies for children and young people's health and wellbeing
Local authority children's services and their partnerships, in consultation with local safeguarding children boards.
Ensure home safety assessments and education are incorporated in local plans and strategies for children and young people's health and wellbeing. They should be aimed at families with a child under 5 or with other children who may be particularly vulnerable to unintentional injuries.
Commission local agencies to offer home safety assessments and, where appropriate, supply and install suitable, high quality home safety equipment (whenever possible, adhering to British or equivalent European standards.)
Ensure commissions specify that the assessment and the supply and installation of equipment needs to be tailored to meet the household's specific needs and circumstances. Factors to take into account include the developmental age of the children and whether or not a child or family member has a disability. Cultural and religious beliefs, whether or not English is the first language and levels of literacy within the household also need to be noted. In addition, the level of control people have over their home environment and the household's perception of, and degree of trust in, authority should be taken into account.
Ensure commissions specify that the assessment needs to help parents, carers, older children and young people identify and address the potential risks from water in the home (this includes baths and garden ponds.
Ensure commissions specify that education, advice and information is needed both during a home safety assessment and during the supply and installation of home safety equipment. This should emphasise the need to be vigilant about home safety and explain how to maintain and check home safety equipment. It should also explain why safety equipment has been installed – and the danger of disabling it. In addition, commissions should specify that useful links and contacts need to be given to householders as part of this provision, in case of a home safety problem.
# Recommendations for outdoor play and leisure
## Context
Children and young people learn, develop and mature when playing and taking part in activities that challenge them. Their participation in regular physical activity and outdoor play and leisure is important for their growth, development and general health and wellbeing – in both the short and long term. (For example, it can help reduce the risk of obesity and cardiovascular disease.)
The type of hazards encountered during outdoor activities will vary for different age groups and according to where they take place. Likewise, the factors to be considered when addressing and balancing risks and benefits will also differ. For example, where children and young people go off-road cycling will vary, depending on their age and experience: younger children are most likely to cycle in gardens and parks, while older children and young people may get involved in activities such as BMX racing or mountain biking.
These recommendations cover preventive activities at the strategic level (for example, the need to monitor compliance with safety standards). This does not imply that they are the only actions that could be taken to prevent unintentional injuries outdoors and during play and leisure.
Children and young people aged under 15, their parents and carers (some of the recommendations may also benefit the wider population).
## Recommendation 12 Developing policies for public outdoor play and leisure
Head teachers and school governors.
Local strategic partnerships.
Play and leisure providers in the public, private, voluntary and community sector. This includes representatives of the leisure industry, parish and town councils and early years services. It also includes private providers of outdoor play facilities that are open to the public, such as pubs and hotels.
Public, private, voluntary and community sector managers and decision makers responsible for play and leisure policies.
Ensure a policy is in place which:
takes a balanced approach to assessing the risks and benefits of play and leisure environments and activities (see NICE's guideline on physical activity for children and young people)
counters excessive risk aversion
promotes the need for children and young people to develop skills to assess and manage risks, according to their age and ability
takes into account children and young people's preferences about the types of outdoor play and leisure activities they want to participate in
is inclusive, taking into account the needs of all children and young people, including those from lower socioeconomic groups, those from minority ethnic groups with specific cultural requirements and those who have a disability.
Use local information and data on environments, equipment and behaviour that pose a risk of serious unintentional injury to help plan prevention initiatives. Include information and data provided by practitioners, play and leisure providers, children, young people, their parents and carers.
Focus prevention initiatives on groups most at risk of an unintentional injury. Initiatives could include modification of equipment and the environment, and the provision of information, education and safety equipment.
Take into account the principles of British and European standards covering equipment and the environment (where they exist) as part of a risk-benefit assessment of outdoor play and leisure environments. This includes standards covering playgrounds, fairgrounds, toy safety and swimming pools, as well as those for inspection and maintenance.
Where equipment and the environment cannot be modified, provide information, advice and education about risk management and the use of any appropriate safety equipment.
## Recommendation 13 Providing education and advice on water safety
Injury prevention coordinators and health practitioners (for example, health visitors and school nurses).
Lifeguards.
Outdoor activity and holiday centre managers.
Schools.
Swimming instructors.
Swimming pool managers.
Know which groups of children and young people are at high risk of drowning – and when that risk is increased. For example, children with certain medical conditions may be more at risk and boys are more likely to be at risk than girls. In addition, older children are more likely to drown outside the home.
Provide children, young people, their parents and carers with information and education on water safety in play and leisure environments. This should be appropriate to the age, developmental stage and experience of the child or young person and meet the household's particular needs and circumstances. It should be readily available in a suitable format. It should also be factually correct and consistent.
Ensure the information and education:
helps parents, carers, older children and young people identify and address the potential risks from water in the wider environment (this includes lakes, canals, rivers and on the coast)
stresses the importance of proper supervision, particularly for younger children, and describes in detail what this means.
Provide timely information and advice, for example, during the holiday season and for dealing with conditions such as heatwaves and extreme cold. (Ice might form on ponds, rivers and lakes during extreme cold spells.) This could include clearly displayed information at appropriate locations.
Encourage children, young people, their parents and carers to become competent swimmers and to learn other water safety skills (for example, so that they know how to effect a rescue).
Ensure swimming lessons include general and specific water safety information. Specific information could include detail on the meaning of different coastal warning flags. It should also raise children and young people's awareness of how difficult it is to assess and manage the hazards posed by water in a range of different outdoor environments.
## Recommendation 14 Water safety advice for leisure providers
Leisure facility providers such as leisure centre and pool operators, boat hire companies, hoteliers, holiday companies and tour operators.
Use risk analysis and management procedures to identify where there may be a risk of drowning. Minimise that risk, wherever possible, without discouraging swimming.
Provide water safety information in a range of languages and formats. This could include clearly displayed information at appropriate locations. Ensure provision is timely. For example, ensure it is provided during the holiday season and in extreme weather conditions such as heatwaves and extreme cold. (Ice might form on ponds, rivers and lakes during extreme cold spells.)
## Recommendation 15 Advising on off-road cycle safety
NHS and other health organisations.
Local authorities.
Schools and school travel advisers.
Injury prevention coordinators.
Police.
Retail outlets and cycle hire centres.
NHS, other health organisations and local authorities should use local information campaigns and ongoing education to encourage cycle training and promote the use of correctly fitted and fastened cycle helmets while cycling off the road. Campaigns could focus on younger children learning to cycle, for example in gardens and parks, and on older children and young people who go BMX racing or mountain biking. The campaigns could suggest that adults set an example by wearing helmets whenever they cycle.
Schools, school travel advisers, injury prevention coordinators, local authorities and the police should ensure travel plans cover off-road routes. They should also encourage children and young people to undertake cycle training and to wear cycle helmets.
Retailers should provide point-of-sale advice on the correct fitting of cycle helmets (this includes online sales). They should also consider setting up a certified retailer scheme like that run by the British Equestrian Trade Association.
Cycle hire centres should advise about the advantages of children and young people wearing correctly fitted and fastened cycle helmets. They should provide them if requested.
## Recommendation 16 Conducting local firework safety campaigns
Environmental health officers.
Fire service.
Clinical commissioning groups and hospital trusts.
Injury prevention coordinators.
Local authority children's services and their partnerships.
Police.
Schools.
Trading standards officers.
Use emergency department surveillance data to inform local firework injury prevention campaigns.
Conduct local firework injury prevention campaigns during the lead up to all celebrations and festivals where fireworks are used. This includes Bonfire Night, New Year and Diwali. Use the principles of behaviour change to inform campaign planning, delivery and evaluation. Evaluate the effectiveness of campaigns.
Trading standards officers should ensure adults are given the firework safety code when they buy fireworks, as a condition of the licence to store and sell fireworks. The code should be available in a range of languages and formats.
# Recommendations for road safety
## Context
These recommendations propose that those responsible for road safety should focus on the needs of local children and young people. This includes helping drivers to reduce their speed in areas where children and young people are present. They should be read in conjunction with recommendations made in NICE's guideline on unintentional injuries on the road: interventions for under 15s.
Children and young people aged under 15, their parents and carers (some of the recommendations may also benefit the wider population).
## Recommendation 17 Maintaining and managing road safety partnerships
Local highway authorities.
Maintain the existing road safety partnership (or establish one where none exists) to help plan, coordinate and manage road safety activities. It should include the road safety team, fire and rescue services, the injury prevention coordinator, the NHS, police, local education authorities and local safeguarding children boards.
Ensure the health sector plays an active role in the partnership (see NICE's guideline on unintentional injuries on the road: interventions for under 15s).
Nominate a member of staff who is responsible for road safety partnership work.
Work with the partners listed in the first action point above, children and young people's services, relevant voluntary sector organisations and others to identify and manage road environments that pose a high risk to children and young people.
Secure funding streams for local road safety initiatives and support these partnerships by promoting good practice.
Ensure the road safety partnership develops policies, strategies and programmes which are based on an understanding of how children and young people use (and wish to use) their environment. This involves consulting parents and carers about their children's road use and safety. It also involves gaining local information from other professional partnerships, children's councils and neighbourhood forums.
Ensure the road safety partnership draws on all available information (such as demographics and risk-exposure data) to plan road injury reduction programmes, as part of the local community safety strategy. The programmes should take into account how injury risk differs according to age and road type. They should also reflect the increased risks facing children and young people from disadvantaged areas and communities.
Evaluate programmes using a range of outcome measures, including road injury data. A variety of evaluation methods should be used, such as controlled trials, 'stepped-wedge' trials (sequential rollout to all participants) and process evaluations.
## Recommendation 18 Carrying out local child road safety reviews and consultations
Local highway authorities and their road safety partnerships (see recommendation 17).
Ensure local child road safety reviews are carried out at least every 3 years. To ensure consistency within regions, ensure they include the following:
all road injury data collected by road safety partners
data which can identify whether some social groups experience more injuries than others (inequalities data)
risks to local children and young people
information about all types of journey, not just those to and from school.
Ensure local children and young people, particularly those from disadvantaged communities, are consulted about their road use and their opinions about the risks involved. In addition, consult parents and carers about their children's road use and safety.
Use the reviews and consultation findings to inform local initiatives to reduce road injuries among children and young people.
Evaluate the impact of initiatives on local policies (including health inequalities policy), practice and injuries.
## Recommendation 19 Aligning local child road safety policies
Local authority children's services and their partnerships, in consultation with local safeguarding children boards.
Local highway authorities and their road safety partnerships.
Review local partners' priorities and strategies to ensure they are coordinated.
Involve the local injury prevention coordinator in the development of the child road safety review and liaise with them about consultations with the local community.
Ensure consistency between the road injury prevention priorities and strategies within child safety policies, local plans and strategies for children and young people's health and wellbeing, the road safety strategy and local authority community safety plans. (This includes ensuring consistency at all levels within non-unitary organisations.)
## Recommendation 20 Promoting and enforcing speed reduction
Local highway authorities and their road safety partnerships.
Use signage, road design and engineering measures to reduce vehicle speeds on roads where children and young people are likely to be, such as those passing playgrounds or schools (see NICE's guideline on unintentional injuries on the road: interventions for under 15s).
Use signage to warn drivers of the likely presence of children and young people in areas that they frequent (such as schools and playgrounds) and the need to comply with safety measures.
Use national and local education and media campaigns to promote the benefits of safety initiatives – including 20 mph speed limits and zones – in areas frequented by children and young people.
Evaluate compliance with speed limits.
Where evaluation shows that compliance is poor, work with the police to improve it through education and, where necessary, enforcement activities.
## Recommendation 21 Involving the police in driver education initiatives and activities to reduce traffic speed
Her Majesty's Inspectorate of Constabulary.
The Home Office.
Include road safety and enforcement in Her Majesty's Inspectorate of Constabulary (HMIC) evaluation tools (report cards) to ensure both are considered when police priorities are set.
Encourage the police to work with other local partners (see recommendations 17–20) on road safety issues in relation to children and young people aged under 15. In particular, encourage the police to contribute to driver education initiatives on the need for compliance with speed limits.
Encourage the police to work with the existing road safety partnership (or with relevant agencies if there is no such partnership) to determine areas where vehicle speeds need to be reduced. Draw upon the knowledge of safer neighbourhood teams and the demographic and consultation data within community safety plans to understand local children and young people's use of the road environment.
Davis R, Pless B (2001) BMJ bans 'accidents'. Accidents are not unpredictable. BMJ 322: 1320–21.
Surveillance of any health issue is defined as the: 'systematic, ongoing collection, collation and analysis of health-related information that is communicated in a timely manner to all who need to know which health problems require action in their community'. Last JM (2007) A dictionary of public health. Oxford: Oxford University Press.
See Department of Health (2010) An information revolution: a consultation on proposals. London: Department of Health.
See the NHS Information Governance Toolkit website and Department of Health (2007) NHS information governance guidance on legal and professional obligations. London: Department of Health. Also see HM Government (2015) Information sharing advice for safeguarding practitioners. London: Department for Education.
Such a dataset is being piloted by the Department of Health and the College of Emergency Medicine. It contains similar detail to that previously collected for the Home and Leisure Accident Surveillance Systems and the results are presented as anonymised, aggregated data.
Home safety assessment tools are available from: The Royal Society for the Prevention of Accidents and SafeHome.
The HHSRS is a method for assessing potential risks to the health and safety of occupants in residential properties. It is used by local authorities to assess social and rented dwellings, and to require landlords to carry out remedial action to address any serious hazards.
See the three Healthy Child Programme core documents.
This is an edited extract from a recommendation that appears in NICE's guideline on unintentional injuries in the home: interventions for under 15s. In that guidance, home safety equipment includes door guards and cupboard locks, safety gates and barriers, smoke and carbon monoxide alarms, thermostatic mixing valves and window restrictors.
Many people may not have the authority to agree to an installation, for example, tenants of social and private landlords and those who are unable to make household or financial decisions.
For example, advice from the National Water Safety Forum and leaflets and booklets from the Child Accident Prevention Trust (CAPT).
For example, advice from the National Water Safety Forum, the RoSPA water safety code for children and the Child Accident Prevention Trust leaflets and booklets.
See Department for Business, Energy and Industrial Strategy (2010) Firework safety: be media wise!
See NICE's guideline on behaviour change.# Public health need and practice
# Background
Unintentional injury is a leading cause of death among children and young people aged 1–14 (Audit Commission and Healthcare Commission 2007). In England and Wales in 2008, 208 children and young people aged 0–14 died from such injuries. Around 44% of those deaths were transport-related (Office for National Statistics 2009).
In 2009, 65 under-15s were killed and 18,307 were injured on the roads in Great Britain, 2267 of them seriously. Of those killed or seriously injured, 1507 (65%) were pedestrians. Cyclists (381) and car passengers (380) made up the bulk of the remainder (that is, cyclists and car passengers each accounted for around 16% of the total) (Department for Transport 2010).
A substantial number of children also die from unintentional injuries at home or in leisure environments. For example, in England and Wales in 2008, 55 children died from choking, suffocation or strangling, 17 from drowning and 10 from smoke, fire and flames (Office for National Statistics 2009).
Death rates from unintentional injuries are falling (Edwards et al. 2006). However, in England alone, around 100,000 children and young people aged under 15 were admitted to hospital in 2009/10 as a result of such injuries (The Information Centre for Health and Social Care 2010).
In 2002, nearly 900,000 children and young people in the UK aged under 15 attended hospital following an unintentional injury in the home (Department of Trade and Industry 2002). Over a million children and young people aged under 15 were taken to hospital following an unintentional injury outside their home; 360,000 were injured while at school, 180,000 while playing sport and 33,000 while in a public playground (Department of Trade and Industry 2002).
Unintentional injury can affect a child or young person's social and emotional wellbeing. For example, those who survive a serious unintentional injury can experience severe pain and may need lengthy treatment (including numerous stays in hospital). They could also be permanently disabled or disfigured (Eurosafe 2006).
Minor unintentional injuries are part of growing up and help children and young people to learn their boundaries and manage risks for themselves. The need to balance encouraging them to explore and develop, and managing the risks to prevent serious injury, was recognised in a government review published in 2009 (Department for Children, Schools and Families 2009a).
# Risk factors
Children and young people from lower socioeconomic groups are more likely to be affected by unintentional injuries (Towner et al. 2005). Children whose parents have never worked (or are long-term unemployed) are 13 times more likely to die from an unintentional injury compared to children whose parents are in higher managerial or professional occupations. The social gradient is particularly steep in relation to deaths caused by household fires, cycling and walking (Edwards et al. 2006).
A range of other factors also influence the likelihood of an unintentional injury. These include: personal attributes (such as age, physical ability and medical conditions), behaviour (such as risk-taking), the environment (for example, living in a house that opens onto a road or living in poor quality housing) (Audit Commission and Healthcare Commission 2007; Towner et al. 2005; Millward et al. 2003).
While combinations of these factors create the conditions in which unintentional injuries occur, many are preventable (Audit Commission and Healthcare Commission 2007).
# Preventing unintentional injuries
Approaches to preventing unintentional injuries range from education (providing information and training) to product or environmental modifications and enforcement (regulations and legislation). The World Health Organization argues that legislation is a powerful tool that has helped reduce unintentional injuries on the road, in the home and in leisure environments (Peden et al. 2008).
It has been suggested that the most effective strategies use a combination of approaches (British Medical Association 2001). Experience from European countries with the best safety records show that positive leadership, together with concerted efforts to provide safer physical and social environments, can reduce unintentional injuries (Sethi et al. 2008).
# Costs
There are six million visits to A&E departments in the UK each year as a result of unintentional injuries. Around two million involve children and young people – at a cost to the NHS of approximately £146 million a year (Audit Commission and Healthcare Commission 2007). Further treatment costs are significant. For example, £250,000 may be needed to treat one severe bath water scald (Child Accident Prevention Trust 2008).
The cost of unintentional injury is also borne by other public sector services such as transport, the police, fire and rescue services and the criminal justice system (Mallender et al. 2002). The long-term health needs and indirect 'human costs' for the family (Mallender et al. 2002) could include the repercussions of enforced absence from school, including the need for children and young people to be supervised. This, in turn, could involve family and carers having to take time off from work (Audit Commission and Healthcare Commission 2007).
# Current policy and practice
The 'Children's plan' carried forward the 'Every child matters' objective to keep children and young people safe (Department for Children, Schools and Families 2003; 2007; 2008a; 2009b.) The 'Staying safe: action plan' set out a cross-government strategy (Department for Children, Schools and Families 2008b).
Strategic partnerships and local safeguarding children boards have a duty to promote children and young people's safety as part of the action plan.
In addition, the national indicator set for local authorities and local authority partnerships addressed the prevention of injuries among children and young people (Department for Communities and Local Government 2007).
Other relevant government initiatives have included:
the housing health and safety rating system (Office of the Deputy Prime Minister 2006)
the child road safety strategy (Department for Transport 2007)
responsibility for safety in workforce settings (Health and Safety Executive 2009).
The Treasury has also set out guidance on the value of preventing unintended fatalities and injuries (HM Treasury 2003).
Local area agreements have provided an opportunity for local authorities, in partnership with the NHS and other organisations, to focus on preventing unintentional injuries. Practice is variable, however some areas are adopting an innovative approach.
National indicators NI70: Hospital admissions caused by unintentional and deliberate injuries to children and young people and NI48: Children killed or seriously injured in road traffic accidents.# Considerations
The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations.
# General
This is one of three pieces of NICE guidance on how to prevent unintentional injuries among children and young people aged under 15. Several PDG members (including the chair) were co-opted as members of NICE's Public Health Interventions Advisory Committee (PHIAC) to advise on two pieces of guidance developed using NICE's public health intervention process. These covered unintentional injuries on the road and in the home and were published at the same time as this guidance. (For details see section 7.)
The extent of participation in any activity (that is, someone's exposure to risk of injury) correlates with injury rates. However, multiple risk factors may also correlate with the number and type of injuries in any given situation. Therefore, the determinants of injury (such as exposure and context) need to be understood. Details such as the nature and duration of the activity – and number of people undertaking it – could be used to supplement injury data and develop this understanding. Care is required when interpreting children and young people's self-reported data, as they may be reluctant to report where they have been and what they have done. In addition, younger children do not have a well-developed sense of time, making their exposure difficult to estimate.
Many areas of the home, road and play and leisure environments have hazards which increase the risk of injury. Supervision, safety equipment and education are important to help keep children and young people safe. Equipment has to be maintained to be effective.
Some families may not be receptive to advice on how to prevent unintentional injury because of 'fatigue' from repeated contact about other health problems, such as cardiovascular disease (CVD) and cancer.
Injury prevention interventions can be passive or active. Passive interventions do not require an active change in behaviour (as an example, they could include the presence of fire resistant materials or air bags in cars).
Children are not just small adults. Their physical, psychological and behavioural characteristics make them more vulnerable to injuries than adults. For example, the small stature of young children increases their risk on the road, where they may be masked by parked cars. Similarly, a given amount of a poisonous substance is likely to be more toxic for a child who has a much smaller body mass than an adult (Peden et al. 2008).
Targeting specific groups may help reduce health inequalities. However, it will have a limited impact on overall injury rates. Targeted and universal approaches are required to reduce both the overall injury rate and health inequalities.
Preventing serious injury is important. For every death, there are many more serious injuries which result in hospitalisation and most of these are avoidable.
# Legislation, regulation and enforcement
Caution should be exercised when considering evidence from other countries as different contexts often apply. For example, the drafting and introduction of UK legislation is often preceded by extensive consultation, which is not the case in all countries.
Legislation can cover everyone, not just children and young people. For example, home safety regulation that requires gas inspections generally benefits everyone in the home.
Numerous mechanisms are available to encourage compliance with safety procedures (for example, enforcement, insurance, health and safety legislation and the use of penalty points for drivers). However, enforcement activities may be more acceptable in public spaces such as on roads than in private spaces such as the home.
Levels of compliance with legislation and regulation are dependent upon having a structured and comprehensive inspection process. For example, Australian studies on swimming pools have found that compliance with safety regulations is more likely if: there is a register of households with swimming pools, there is an annual inspection programme, and penalties are enforced for any breach of the regulations.
# Injury surveillance
In 2002, the Home Accident Surveillance System (HASS) and the Leisure Accident Surveillance System (LASS) both came to an end. Since then, there has been a lack of standardised data collection of unintentional injuries in the home and in leisure settings. 'An information revolution' (DH 2010) proposes that health data should be collected from multiple sources and disseminated by a single agency. It highlights the central role that high quality information can play in improving outcomes and narrowing inequalities.
The Programme Development Group (PDG) acknowledged a number of factors that may confound injury data. This includes the following:
Road traffic collisions not reported to the police are unlikely to be included in the STATS19 statistics. The actual number of road injuries is thought to be more than three times that in 'Reported road casualties in Great Britain 2009' (Department for Transport 2010).
The number of injuries and fatalities may fall because an initiative intended to reduce injuries could also lead to a reduction in the number of people taking part in a given activity. Likewise, an initiative to promote physical activity might lead to an increase in the number of injuries due to an increase in the number of participants.
A dataset may not include all injuries which occur in localities that lack emergency departments (for example, rural areas where the distance from hospital is a barrier to attendance).
Sharing injury data between organisations (for example, the ambulance service, hospitals and the police) is necessary to overcome gaps in knowledge and inconsistencies in recording such injuries. However, the PDG was aware that organisations can find it difficult to share data. Barriers can be institutional or relate to the confidentiality and security of personal information.
Injury rates may vary according to the time of year. For example, children and young people's activity patterns may be different during the school term compared with the school holidays.
Shortcomings in injury data collection may result from a lack of awareness of the benefits of monitoring and surveillance. For example, emergency department staff may consider data collection an unnecessary burden. Greater awareness of the use and benefits of this information may lead to a greater commitment to data collection among these staff.
# Home safety
The recommendations on home safety assessments and the supply and installation of home safety equipment are aimed at preventing unintentional injuries among all children and young people aged under 15. However, they prioritise households where children and young people are at greater than average risk of unintentional injuries due to one or more factors. For example, those aged under 5 and those living in social, rented or temporary accommodation with families on a low income are particularly vulnerable.
Extensive evidence suggests that socioeconomic disadvantage increases the risk of childhood injury. Forty-four per cent of lone parents with dependent children are social tenants (Communities and Local Government 2009). Social tenants and often, tenants of private landlords have less income than owner-occupiers.
Given the extent of unintentional injuries among children under 5 in the home – and the increased risk of injuries among disadvantaged families, the PDG has made specific recommendations for these groups.
The physical environment may have an influence on the rate and type of injuries that occur. For example, high-rise flats often have potential hazards such as balconies, communal stairs and unsecured windows (Child Accident Prevention Trust 2010). In such situations, tenants may not have permission or the resources to make alterations.
The evidence available focused on items that need to be fitted to use at home, such as smoke alarms, window restrictors and thermostatic mixing valves (although there was no evidence about some equipment, including carbon monoxide alarms). It does not cover safety devices that do not need installing (for example, those already fitted onto lighters).
When interpreting the evidence it should be noted that:
housing type and density differs between non-UK and UK studies, so research findings from other countries should be applied with caution
an economic downturn can lead to a decline in the rate of construction of new buildings, so the potential to reduce unintentional injuries through recommendations for new-build homes is also lessened
in studies reporting the effectiveness of thermostatic mixing valves:
some may have included scalds from other hot liquids such as drinks (that is, not just scalds caused by bath or shower water)
surveillance of their use may itself have contributed to their reported effectiveness, as the people being observed may have been inclined to take more care
some suggested that the occupant could reset the device, but it was not reported how often this occurred; the ability to override them could mean the degree of effectiveness demonstrated in studies could change
installation of thermostatic mixing valves may change other safety practices, such as reducing the number of times parents check the water temperature before bathing a child. However, this will not increase the risk of scalds if the device is functional and set to an appropriate temperature.
It became compulsory to fit thermostatic mixing valves to bath taps in all new homes in England and Wales from 6 April 2010. Thermostatic mixing valves are usually fitted near to the tap, so that most stored hot water remains at a high enough temperature to kill the bacterium that causes Legionnaires' disease.
With the exception of window restrictors, all age groups would benefit from home safety equipment (smoke and carbon monoxide alarms and thermostatic mixing valves). Window restrictors should benefit children aged over 2 as they are capable of climbing and falling from an unguarded window. The age at which window restrictors become ineffective is not clear. However, it is likely that most children can overcome child-resistant mechanisms by the time they reach the age of 5. Key-operated locks (where the key is inaccessible to a child) tend to be effective for longer. It is important to note the need to open windows in a fire emergency.
As more smoke alarms are installed than any other type of safety equipment, there is less potential to use them to reduce health inequalities.
Gaining access to people's homes needs sensitive consideration. The PDG acknowledge that the home is a private space and access will involve discussion and negotiation with residents.
# Outdoor play and leisure
The PDG agreed with the Royal Society for the Prevention of Accidents (RoSPA) that children should be "as safe as necessary, not as safe as possible". Children and young people learn, develop and mature when playing and taking part in activities that challenge them and that sometimes involves taking risks. Play and leisure activities help children and young people to learn about the complex relationship between themselves and the world in which they live. Exposure to a degree of challenge may be beneficial during these activities. However, a distinction should be made between manageable and unmanageable situations:
Some challenging situations are manageable and help a child to develop physically and emotionally. For example, undertaking a familiar activity without adult supervision is likely to be manageable.
In other situations, the risks may be too difficult for a child to assess and manage, or are unlikely to lead to any obvious benefits. They may even expose the child to danger. Examples would be swimming in a disused quarry, or playing on poorly designed and maintained equipment in a play area.
Parents' and carers' and their child's perception of safety can influence the amount of time children and young people spend on outdoor play and leisure activities. These perceptions can be influenced by the media. In addition, fear of litigation can influence the nature and extent of activities provided by educational and play organisations.
It is difficult to regulate activities such as canyoning and wild swimming and the settings in which they take place. It is also difficult to regulate inland waterways not currently used for supervised recreation.
The classification of a leisure activity is not always clear. For example, when a child is cycling it's not always clear whether cycling is a leisure activity or is being used as a form of transport. Similarly, it's not always clear whether a child or young person is playing in water or swimming, playing with a ball or participating in sport.
Media campaigns to promote injury prevention activities may increase health inequalities, as uptake is likely to vary among different groups. For example, disadvantaged families are less likely to respond to health information than families who are more advantaged.
The PDG acknowledged that dividing on- and off-road cycling into two separate activities was an artificial division, particularly in relation to older children. The scope of the guidance did not include equipment used to prevent against unintentional injuries on the road. However, it did cover outdoor play and leisure, so the use of helmets in parks, on bridleways and in other environments was reviewed. (Children often fall off their bikes, especially when they are learning to ride a bicycle and when they are learning BMX and mountain bike skills, so there is a need to protect them from unnecessary injury.)
Recommendations have been made about promoting cycle helmets but not about making them compulsory. The PDG was aware of the debate on cycle helmets.
The PDG considered a number of issues in relation to the use of helmets including the:
need to purchase one when buying a bike
need to include helmets as part of rent-a-bike schemes
need to introduce them into the informal secondhand bike market (which includes passing bikes down and between families)
design and fitting
fact that some adults are poor role models when it comes to helmet wearing
need to wear them for other activities such as skateboarding and some high-risk water sports
potential for injury if they are worn when using equipment not designed for their use (such as playground equipment) or are used in other inappropriate ways.
Current playground standards aiming to reduce the incidence of traumatic brain injury are important, as it is a potentially serious injury. Protection against broken arms and legs is also needed, as these are common and can result in disability and deformity.
Interventions that have been shown to reduce firework injuries in other countries may not, necessarily, have the same effect in England. For example, in countries with drier weather conditions, the danger from unexploded fireworks is greater and so measures to clear them up are likely to have a greater impact. Enforcing firework regulations in England is also different because they are only on sale here for short periods of time. For example, retailers and display organisers are granted temporary licences to sell them in advance of Bonfire Night and other festivals.
# Road safety
The PDG noted several demographic differences in child pedestrian injuries. For example, more boys than girls are injured. In addition, children aged 10 and under are more likely to be injured on minor urban roads, while those aged 11 and over are more likely to be harmed on main roads. It also noted that children living in deprived areas (and those from some minority ethnic groups) are more likely than the general population to make journeys alone or only supervised by an older sibling.
Most studies on traffic speed are conducted on the main road network. Fewer are conducted on minor residential roads where children and young people are more likely to be present.
The PDG acknowledged that injury prevention activities should take into account the importance of public transport and sustainable travel modes, such as walking and cycling, which have known health benefits. Reducing traffic speed should help to encourage physically active modes of travel.
Most studies focus on the evaluation of legislation which is enforced by imposing sanctions on those who break the rules. This is because data on the effect of such interventions are more readily available than for less punitive measures. Although the latter may be equally effective, they have not been recommended due to a lack of evidence.
Transport studies tend to use a 'before-and-after' design. They estimate the relationship between two or more factors using data collected at a number of specified intervals over a period of time. They require an adequate control to demonstrate causality.
Children and young people cannot influence the speed or general manner in which vehicles are driven or whether seatbelts are available. In addition, they often have little or no choice about their mode of travel.
The evidence review on the effectiveness of safety cameras which informed evidence statement 3.1 only included systematic reviews. One of these has since been updated (Wilson et al. 2010) and evidence statement 3.1 has been amended in appendix C of this guidance to include its findings. The systematic reviews in the original report to NICE did not capture evidence from relevant primary sources that report differential effectiveness. However, the PDG noted that the National Safety Camera Programme (Gains et al. 2005) reports differential effects on children, for urban and rural environments and for fixed and mobile cameras. The cost effectiveness review which informed evidence statement 6.5 used primary sources, including the National Safety Camera Programme.
# Limitations of the evidence
The recommendations reflect the evidence identified and the PDG's discussions. The absence of recommendations on any particular measures to prevent unintentional injuries is a result of a lack of evidence that met the inclusion criteria for the evidence reviews. It should not be taken as a judgement on whether or not any such measures are effective and cost effective.
Repeated testing of outcome measures can affect the validity of an evaluation. For example, a variable that is extreme when first measured will tend to be closer to the mean when measured later. If this statistical effect is not taken into account, caution will need to be exercised when interpreting any conclusions about an intervention's effectiveness.
Many injury prevention programmes do not lend themselves to the use of 'blinding' (whereby participants are not aware which research study group they have been allocated to). However, it is often possible to have evaluators who are 'blind' to group allocation.
Although interventions often include adults, children and young people, the outcomes for children and young people are not reported separately.
Studies of the effectiveness of strategic approaches to injury prevention (such as legislation and enforcement) did not provide a strong evidence base for economic modelling. As a result, most of the assumptions or variables used in the modelling are based on very limited or estimated data and the conclusions should be treated with caution.# Recommendations for research
The Programme Development Group (PDG) recommends that the following research questions should be addressed to fill the most important gaps in the evidence in relation to this and the other two pieces of NICE guidance that were published in November 2010. These form part of a 'suite' of NICE advice on preventing unintentional injuries:
Unintentional injuries in the home: interventions for under 15s (NICE guideline PH30).
Unintentional injuries on the road: interventions for under 15s (NICE guideline PH31).
The PDG notes that 'effectiveness' in these contexts relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects.
Studies of effectiveness and cost effectiveness should investigate and report on the differential effectiveness for children and young people who are more at risk of unintentional injury. They should collect data on the factors listed in research recommendation 1 and also on the:
short and long-term effects (physical, psychological and financial) on children, young people, their parents and carers (for example, time away from school for children and work for parents and extent of residual disability)
long-term quality-of-life and public sector cost impacts of non-fatal injuries.
# Epidemiology and behaviour
What are the recent epidemiological and aetiological trends in types, causes and impact of unintentional injuries among under-15s? Use data collected by the recommended surveillance systems (see recommendations 7–8) to identify findings for specific groups and activities in the home, on the road and during outdoor play and leisure. Factors to consider are:
cause, nature, location and factors involved in the incident and type, site and severity of injury
numbers of children and young people involved, time spent undertaking the activity and the extent of supervision
demographic details with data presented for subgroups of children and young people (for example, grouped according to age, gender, ethnicity, socioeconomic status, disability and place of residence).
How do parents, carers, children and young people perceive risk in the home, on the road and during outdoor play and leisure – and how do they perceive the risks and benefits inherent in specific activities? How do these perceptions vary between populations and subgroups based on gender, age, race/ethnicity, socioeconomic status, disability, or other characteristics of the participants or their environment? How strongly associated is children and young people's exposure to risk with their behaviour, the causes, incidence and severity of unintentional injury?
Does exposure to risk and the opportunity to experience risk-taking have a beneficial effect on children and young people? Does the effect vary according to age and other socio-demographic factors or according to the quality and nature of the risk?
To what extent – and how – does children and young people's behaviour alter when their environment is made safer? How does children and young people's (and their parents' and carers') perception of risk impact on the amount and type of physical activity undertaken by children and young people?
# Effectiveness studies
What is the differential effectiveness and cost effectiveness of legislation, regulation, policies and standards to prevent unintentional injuries in the UK? Studies should consider the process and cost of development, promotion, implementation and enforcement. They should collect baseline data prior to any change and for a meaningful length of time afterwards on:
home safety assessments, thermostatic mixing valves (TMVs), smoke alarms (hard-wired and 10-year battery-operated), carbon monoxide alarms and window restrictors
water safety initiatives, sports rules and regulations, cycling skills training for children and young people and cycle helmet use
road safety knowledge and skills, road user behaviour, different types of road signage, differential effectiveness of speed enforcement (networked, targeted or mixed approaches) in rural and residential areas.
How effective and cost effective are social marketing and mass-media campaigns in support of legislation, regulation, policy and standards to reduce unintentional injuries among children and young people in the home, on the road and during outdoor play and leisure?
What is the impact of injury prevention training and development initiatives on those involved in preventing injuries in terms of their level of knowledge and degree of competency? What impact do such initiatives have on the scope and quality of preventive activities? Examples of training and developmental initiatives include: training people to undertake home risk assessments and educating representatives of community partnerships and private landlords about the Housing Health and Safety Rating System (HHSRS).
What prevents and what encourages children and young people to comply with legislation, regulation and standards to prevent unintentional injuries in the home, on the road and during outdoor play and leisure?
What prevents and what encourages delivery and implementation of policies/strategies to prevent unintentional injuries among children and young people in the home, on the road and during outdoor play and leisure? (These are outlined, for example, in white and green papers and policy briefings.)
# Interventions: all settings
How do the following factors influence the effectiveness and cost effectiveness of interventions to prevent unintentional injury in the home, on the road and during outdoor play and leisure:
method of delivery (for example, session format, learning materials)
content
frequency and duration of follow-ups
deliverer
parental/carer involvement
demographic characteristics of the participants (for example, gender, age, race/ethnicity, socioeconomic status and disability)?
What are the most effective and cost-effective ways of providing under-15s, their parents and carers with information, advice and education about safety and hazards in the home, on the road and in outdoor play and leisure environments?
To what extent do interventions to prevent unintentional injuries among under-15s in the home, on the road and during outdoor play and leisure impact on the household's safety knowledge and behaviour? What role do family members and carers (fathers, mothers, grandparents and extended family units) play in preventing unintentional injuries?
# Interventions: road safety
To what extent do interventions to reduce speed and prevent unintentional injuries on the road among under-15s influence people's attitude, knowledge and behaviour towards road safety (both drivers and the general public)? How can interventions be designed to maximise this effect?
How can systematic methods, combining health and engineering research, be developed to:
assess the effectiveness and cost effectiveness of injury prevention interventions outside the health sector (for example, within education and employment)
identify wider public health outcomes as a standard part of research into engineering measures to reduce speed and unintentional injuries (including co-benefits and unintended consequences, such as the impact on physical activity and air quality)?
# Interventions: home safety
How effective and cost effective are home safety interventions (including combined interventions) in preventing unintentional injuries among different population groups? For example, how effective are they in relation to participants' gender, age, race/ethnicity, socioeconomic status, disability, or other characteristics? To what extent does effectiveness and cost effectiveness vary according to the type of injury being prevented?
To what extent does the provision of safety information, advice and education during a home safety intervention contribute to its effectiveness and cost effectiveness? (For example, does it reduce the number – and severity – of unintentional injuries in the home among under-15s?)
How effective and cost effective are the different methods used to deliver safety information, advice and education? To what extent do effectiveness and cost effectiveness vary with different types of injury prevention activity?
# Interventions: play and leisure
To what extent does exposure to risk during outdoor play and leisure affect children and young people's risk-management skills in the setting where the hazard was encountered, other designated play areas, non-designated play areas and non-play settings?More detail on the gaps in the evidence identified during development of this guidance is provided in appendix D.# Updating the recommendations
This guidance will be reviewed 3 years after publication to determine whether all or part of it should be updated. Information on the progress of any update will be posted on our website.# Related NICE guidance
Community engagement: improving health and wellbeing and reducing health inequalities (2016) NICE guideline NG44.
Unintentional injuries on the road: interventions for under 15s (2010) NICE guideline PH31.
Unintentional injuries in the home: interventions for under 15s (2010) NICE guideline PH30.
Child maltreatment: when to suspect maltreatment in under 18s (2009) NICE guideline CG89.
Behaviour change: general approaches (2007) NICE guideline PH6.
Postnatal care up to 8 weeks after birth (2006) NICE guideline CG37.# References
Audit Commission/Healthcare Commission (2007) Better safe than sorry: preventing unintentional injury to children. London: Audit Commission
British Medical Association (2001) Injury prevention. London: British Medical Association Board of Science and Education
Child Accident Prevention Trust (2008) Child Accident Prevention Trust factsheet: preventing bath water scalds using thermostatic mixing valves. London: Child Accident Prevention Trust
Child Accident Prevention Trust (2010) Children and their accidents. Factsheet. London: Child Accident Prevention Trust
Communities and Local Government (2009) Housing and planning statistics. London: Communities and Local Government
Department for Children, Schools and Families (2003) Every child matters. London: The Stationery Office
Department for Children, Schools and Families (2007) The children's plan: building brighter futures. London: Department for Children, Schools and Families
Department for Children, Schools and Families (2008a) The children's plan. One year on. London: Department for Children, Schools and Families
Department for Children, Schools and Families (2008b) Staying safe: action plan. London: Department for Children, Schools and Families
Department for Children, Schools and Families (2009a) Accident prevention among children and young people. A priority review. London: Department for Children, Schools and Families
Department for Children, Schools and Families (2009b) The children's plan. Two years on. London: Department for Children, Schools and Families
Department for Communities and Local Government (2007) The new performance framework for local authorities & local authority partnerships. London: Department for Communities and Local Government
Department for Transport (2007) The child road safety strategy. London: Department for Transport
Department for Transport (2010) Reported road casualties Great Britain 2009: annual report. London: Department for Transport
Department of Health (2010) An information revolution: a consultation on proposals. London: Department of Health
Department of Trade and Industry (2002) Home accidents surveillance system (HASS)
Edwards P, Roberts I, Green J et al. (2006) Deaths from injury in children and employment status in family: analysis of trends in class specific death rates. BMJ 333: 119–21
Eurosafe (2006) Childhood burns and scalds: facts. Netherlands: Eurosafe
Gains A, Norstrom M, Heydecker BG et al. (2005) The national safety camera programme: four-year evaluation report. London: Department for Transport
Health and Safety Executive (2009) The health and safety of Great Britain
HM Treasury (2003) The green book. Appraisal and evaluation in central government. London: The Stationery Office
Mallender J, O'Leary C, Lowdell C (2002) Costs of injuries to London. In Lowdell C, Fitzpatrick J, Wallis R et al. editors. Too high a price: injuries and accidents in London. London: London Health Observatory
Millward LM, Morgan A, Kelly MP (2003) Prevention and reduction of accidental injury in children and older people. London: Health Development Agency
Office for National Statistics (2009) Mortality statistics: deaths registered in 2008. Table 5.19 ICD10 codes V01–X59. Review of the Registrar General on deaths in England and Wales
Office of the Deputy Prime Minister (2006) The housing health and safety rating system (HHSRS) operating guidance. Housing Act 2004: Guidance about inspections and assessment of hazards given under Section 9. London: Office of the Deputy Prime Minister
Peden M, Oyegbite K, Ozanne-Smith J et al. editors (2008) World report on child injury prevention. Geneva: World Health Organization
Sethi D, Towner E, Vincenten J et al. editors (2008) European report on child injury prevention. Copenhagen: World Health Organization Regional Office for Europe
The Information Centre for Health and Social Care (2010) Hospital episode statistics (HES)
Towner E, Dowswell T, Errington G et al. (2005) Injuries in children aged 0–14 years and inequalities. London: Health Development Agency
Wilson C, Willis C, Hendrikz JK et al. (2010) Speed cameras for the prevention of road traffic injuries and deaths (review). Cochrane Library: 10# Appendix B: Summary of the methods used to develop this guidance
# Introduction
The reviews, primary research, commissioned reports and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.
The minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations.
All supporting documents are listed in appendix E and are available online.
# Guidance development
The stages involved in developing public health programme guidance are outlined in the box below.
. Draft scope released for consultation
. Stakeholder meeting about the draft scope
. Stakeholder comments used to revise the scope
. Final scope and responses to comments published on website
. Evidence reviews and economic analysis undertaken
. Evidence released for consultation
. Comments and any additional material submitted by stakeholders
. Review of any additional material submitted by stakeholders (screened against inclusion criteria used in reviews)
. Evidence and economic analysis submitted to PDG
. PDG produces draft recommendations
. Draft guidance released for consultation and for field testing
. PDG amends recommendations
. Final guidance published on website
. Responses to comments published on website
# Key questions
The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching questions were:
Which approaches are effective and cost effective in preventing or reducing unintentional injuries among children and young people aged under 15?
Which approaches are effective and cost effective in preventing or reducing unintentional injuries among children and young people aged under 15 from disadvantaged families?
Which types of approach effectively (and cost effectively) support and help develop the skills of professionals and others involved in childhood injury prevention?
What type of monitoring systems are effective and cost effective in recording and detecting changes in the type, incidence and prevalence of unintentional injuries among children and young people aged under 15?
What are the barriers and facilitators to implementing initiatives to prevent unintentional injuries among children and young people aged under 15?
These questions were made more specific for each review (see reviews for further details).
# Reviewing the evidence
## Effectiveness reviews
Five reviews of effectiveness were conducted. One compared international practice (review 1), one covered quantitative correlates (review 2) and three were reviews of effectiveness (reviews 3–5).
## Identifying the evidence
The following databases were searched for the effectiveness reviews (from 1990 to January 2009 , 1990 to February 2009 , 1990 to April 2009 , 1990 to June 2009 and 1990 to July 2009 ):
Cochrane Database of Systematic Reviews
Database of Abstracts of Reviews of Effectiveness (DARE)
EPPI Centre databases (Bibliomap, DoPHER, TRoPHI)
Health Management Information Consortium (HMIC)
Kings Fund catalogue and Department of Health data
Health Technology Assessment (HTA)
MEDLINE
NHS Economic Evaluation Database (NHS EED)
SafetyLit
Social Science Citation Index
The Campbell Collaboration
In addition, the following databases were searched, as appropriate, for individual reviews (from 1990 to January 2009 , 1990 to February 2009 , 1990 to April 2009 , 1990 to June 2009 and 1990 to July 2009 ):
Assia
Cinahl
Cochrane Injuries Group Register
EconLit
Embase
ISI Web of Science
International Transport Research Documentation (ITRD)1
PsycINFO
SPORTDiscus
Transport Research Information Service (via the TRIS)
Transport Research Laboratory
Website searches included:
Child accident prevention trust (CAPT)
Eurosafe
Injury Observatory for Britain and Ireland (IOBI)
Institute of Highway Incorporated Engineers
Institute of Home Safety
Royal Society for the Prevention of Accidents (RoSPA)
Royal Town Planning Institute
Safe routes to school
South West Public Health Observatory
UK Department for Transport (DfT)
For review 1, searches were primarily conducted by snowball sampling of key organisations and individual contacts, supplemented by Internet searches, including the web pages of international and national organisations. For reviews 2–5, electronic searches of relevant bibliographic databases and selected websites were supplemented by communication with experts and organisations involved in the relevant research or policy areas.
Further details of the databases, search terms and strategies are included in the review reports.
## Selection criteria
Studies were included in reviews 1 and 2 if they were published between 1997 and 2009 in English. In addition:
Review 1 included studies which reported separately for children in at least two countries (or 'country-sized' regions).
Review 2 focused on observational research and intervention studies which quantified the association or relationship between unintentional injuries among children and two or more variables such as exposure to a particular environment or socioeconomic status.
Studies were included in reviews 3–5 if they:
were published between January 1990 and February 2009 in English
used comparative studies to compare groups of people, places or activities
More detailed inclusion and exclusion criteria for individual reviews can be found on our website.
## Quality appraisal
For reviews 1 and 3 to 5, the included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.
++ All or most of the checklist criteria have been fulfilled, where they have not been fulfilled the conclusions are very unlikely to alter.
- Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.
– Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.
The main reasons for studies being assessed as (–) were:
lack of control or comparison group
lack of baseline equivalence/data
inadequately described interventions
inadequate analysis and reporting of data.
For reviews 2 to 5, the studies were also assessed for their applicability to the area under investigation and the evidence statements were graded as follows:
Directly applicable.
Partially applicable.
Not applicable.
## Summarising the evidence and making evidence statements
The review data was summarised in evidence tables (see full reviews).
The findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the public health collaborating centres (see appendix A). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.
# Cost effectiveness
There was a review of economic evaluations and an economic modelling exercise.
## Review of economic evaluations
This sought to identify and review economic evaluations published since 1990 of relevant legislation, regulation or other strategic approaches of interest. The search was undertaken in two stages.
First the RefMan database was searched for 'hits' from the five reviews and two related pieces of NICE public health guidance (preventing unintentional injuries to children on the road and in the home).
Second, a new search was carried out in EconLit and NHSEED (NHS Economic Evaluation Database) using text words and thesaurus terms covering all types of injuries among children.
## Economic modelling
An economic model was constructed to explore the cost-effectiveness of jurisdiction-wide strategic approaches to prevent unintentional injuries among children aged under 15 years. The exploratory analyses were conducted from a UK public sector perspective.
Two different strategic policies were explored: to reduce unintentional injuries among children and adults on the road and at home. The former focused on legislation or regulations, supported by other activities, introducing mandatory 20mph zones in high casualty residential areas. The latter focused on legislation or regulations, supported by other activities, to promote installation of thermostatic mixer valves in family social housing where children are aged less than 5 years.
Due to a paucity of data, the model explored which factors might be important in determining cost effectiveness.
The results are reported in: Economic modelling of legislation/regulations and related national strategies to promote the wider use of: 20 mph zones in residential areas, and TMVs in social housing for families.
# Fieldwork
Fieldwork was carried out to evaluate how relevant and useful NICE's recommendations would be for practitioners and how feasible it would be to put them into practice.
It was conducted with practitioners and commissioners who are involved in preventing unintentional injuries among children and young people. This included those working in primary care trusts (PCTs), local safeguarding children boards and accident prevention and road safety teams. It also included health visitors, nurses and policy leads, within the NHS, those working in the fire and police services, leisure and play services, and environmental health and housing.
The fieldwork comprised:
Seven discussion groups conducted in Lancashire, South East London and Sussex by Word of Mouth research consultancy.
Forty-nine face-to-face and telephone interviews conducted by Word of Mouth with staff from Lancashire, South East London and Sussex. In addition to the groups listed above, participants also included: an assistant school head, a cycle events organiser and a cycle retailer, further education college curriculum managers, healthy schools managers, paediatricians, staff from children's centres, a safer communities manager, a school governor, social workers and voluntary sector children's services managers.
The main issues arising are set out in appendix C under 'Fieldwork findings'. The full fieldwork report Strategies to prevent unintentional injury among under-15s is available online.
# How the PDG formulated the recommendations
At its meetings between February 2009 and July 2010, the Programme Development Group (PDG) considered the evidence, expert testimony and cost effectiveness to determine:
whether there was sufficient evidence (in terms of strength and applicability) to form a judgement
where relevant, whether (on balance) the evidence demonstrates that the intervention or programme can be effective or is inconclusive
where relevant, the typical size of effect (where there is one)
whether the evidence is applicable to the target groups and context covered by the guidance.
The PDG developed draft recommendations through informal consensus, based on the following criteria:
Strength (type, quality, quantity and consistency) of the evidence.
The applicability of the evidence to the populations and settings referred to in the scope.
Effect size and potential impact on the target population's health.
Impact on inequalities in health between different groups of the population.
Equality and diversity legislation.
Ethical issues and social value judgements.
Cost effectiveness (for the NHS and other public sector organisations).
Balance of harms and benefits.
Ease of implementation and any anticipated changes in practice.
Where possible, recommendations were linked to an evidence statement(s) (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).
The draft guidance, including the recommendations, was released for consultation in May 2010. At its meeting in July 2010, the PDG amended the guidance in light of comments from stakeholders and experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in October 2010.# Appendix C: The evidence
This appendix lists the evidence statements from six reviews provided by the public health collaborating centre (see appendix A) and links them to the relevant recommendations. (See appendix B for the key to quality assessments.) The evidence statements are presented here without references – these can be found in the full reviews (see appendix E for details).
The appendix also lists six expert testimonies and their links to the recommendations and sets out a brief summary of findings from the economic analysis.
The six evidence reviews are:
Review 1: 'Current practice and innovative approaches to prevent childhood unintentional injuries: An overview and synthesis of international comparative analyses and surveys of injury prevention policies, legislation and other activities'.
Review 2: 'A systematic review of risk factors for unintentional injuries among children and young people aged under 15 years'.
Review 3: 'An overview and synthesis of evidence relating to strategies and frameworks for planning, implementing, enforcing or promoting activities to prevent unintentional injury to children and young people on the road: legislation, regulation, standards and related strategies focusing on the design and modification of highways, roads or streets'.
Review 4: 'Strategic and regulatory frameworks for guiding, enforcing or promoting activities to prevent unintentional injury in children and young people in the home environment'.
Review 5: 'Strategies, policies and regulatory or legal frameworks and/or mass media campaigns to prevent unintentional injury to children during play and leisure in the external environment'.
Review 6: 'Preventing unintentional injuries in children. Systematic review to provide an overview of published economic evaluations of relevant legislation, regulations, standards, and/or their enforcement and promotion by mass media'.
Evidence statement number 1.1 indicates that the linked statement is numbered 1 in review 1. Evidence statement number 2.1 indicates that the linked statement is numbered 1 in review 2. Evidence statement number 3.1 indicates that the linked statement is numbered 1 in review 3. ET1 indicates that expert testimony number 1 is linked to the recommendation.
The reviews, expert testimony and economic analysis are available online.
Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).
Recommendation 1: evidence statements 2.2, 2.3, 2.4, 2.5, 2.7, 2.8, 2.9, 2.10, 2.11, 2.12, 2.14a, 2.14b, 2.14c, 2.14f, 2.14i; ET3
Recommendation 2: IDE
Recommendation 3: IDE
Recommendation 4: IDE
Recommendation 5: IDE
Recommendation 6: IDE
Recommendation 7: evidence statement 1.1; ET6
Recommendation 8: evidence statement 1.1; ET6
Recommendation 9: evidence statements 4.1, 4.2, 4.3, 4.4; ET3
Recommendation 10: evidence statements 2.2, 2.3, 2.4, 2.5, 2.7, 2.8, 2.9, 2.10, 2.11, 2.12, 2.14a, 2.14b, 2.14c, 2.14f, 2.14i, 4.1, 4.2, 4.3; ET3
Recommendation 11: evidence statements 2.2, 2.3, 2.4, 2.5, 2.7, 2.8, 2.9, 2.10, 2.11, 2.12, 2.14a, 2.14b, 2.14c, 2.14f, 2.14i, 4.1, 4.2, 4.3; ET3
Recommendation 12: evidence statement 5.4
Recommendation 13: IDE
Recommendation 14: IDE
Recommendation 15: evidence statement 5.3; IDE
Recommendation 16: evidence statement 5.5
Recommendation 17: IDE
Recommendation 18: evidence statements 1.3, 2.14f; ET1
Recommendation 19: evidence statement 2.14f; ET1
Recommendation 20: IDE
Recommendation 21: evidence statements 1.2, 3.1, 3.2, 6.5
# Evidence statements
Please note that the wording of some evidence statements has been altered slightly from those in the review team's report to make them more consistent with each other and NICE's standard house style.
## Evidence statement 1.1
Three (+) international comparison studies show a lack of comparable in-depth information on exposure to risk to help in analysis of the relative impact of different legislative, regulatory, enforcement and compliance interventions.
## Evidence Statement 1.2
Two ecological studies (one and one ) in high income countries were unable to associate variations in child morbidity and/or mortality rates across countries to differences in legislation, regulation, enforcement and compliance for road environment modification, road design, home and leisure environment interventions. However for road safety, evidence from two ecological studies (one and one ), suggest a weak trend towards better performing countries (in terms of child fatality rates) having more road environment modification and road design measures in place.
## Evidence Statement 1.3
Evidence from one (++) ecological study indicates that differences in the distribution of exposure in the road environment for child pedestrians (in particular relating to time spent near busy main roads) can explain some of the difference in severe child injury and fatality rates between Great Britain and two other northern European countries, France and the Netherlands.
## Evidence statement 2.2
There is evidence from 10 studies (one UK). There is evidence of a strong association (that is, relative risk equivalent of greater than 2.0) of injuries being associated with travelling in a car driven by a non-sibling teenager. There is evidence of weak to moderate association (that is, relative risk equivalent of greater than 1.0 to less than 2.0) of injuries with lower parental income, employment status, educational status, socioeconomic status, and with travelling in a car with a female driver (when the injured child was appropriately restrained). The increased risk in females may well reflect their longer periods of time in the presence of children. There is mixed evidence regarding the association of injuries with ethnicity.
## Evidence statement 2.3
There is evidence from 18 studies (five UK). There is evidence of a strong association between the lowest socioeconomic quintiles, being of Native American descent (for pedestrians), having parents who were migrants, hyperactivity, behavioural difficulties, or bicycle riding (riding slowly or only on the pavement) and injuries. There is evidence of weak to moderate association of injuries with membership of the second socioeconomic quintile, social deprivation, non-professional parental occupation, rural and mixed-urban environments, being male, or behavioural disorders. There was no statistical evidence of injuries being associated with social fragmentation or ethnicity (for cyclists).
## Evidence statement 2.4
There is evidence from seven studies (one UK). There is evidence of weak to moderate association of injuries with socioeconomic deprivation and being African-American. There is mixed evidence regarding the association of socioeconomic status (measured by parental occupation) with injuries. There was no statistical evidence of injuries being associated with autism.
## Evidence statement 2.5
There is evidence from six studies (one UK) on burns and fire in the home of a strong association between child's age (less than 1 year), low mother education and age, and areas of concentrated poverty (and high numbers of African-American population) and injuries. There is evidence of weak to moderate association of burn injuries with children being male, from an ethnic minority, having behavioural problems and a poor reading score, low parental education, lower home income, a larger number of children in the home, and rural location. There was no statistical evidence of burn injuries being associated with type of home ownership.
## Evidence statement 2.7
There is evidence from three studies (none UK) on falls in the home of a strong association between greater child's age (older than 1 year) and injuries. There is evidence of weak to moderate association of injuries with: being male, of African-American descent, families being in receipt of social welfare benefits, lower educational status of parents, lower income, single parent households, lower mother's age at childbirth, non-owner housing occupancy, living in a flat or farmhouse, older housing and being a migrant. Being lone parent status, neighbourhood poverty and living in cities were not statistically associated with falls.
## Evidence statement 2.8
There is evidence from seven studies (one UK) on poisoning in the home of a strong association between child's age (from 1 to 4 years), behavioural problems, and autism and injuries. There is evidence of weak to moderate association of injuries being associated with: being male, having a lower reading score, lower educational status of parents, lower income, larger families, being in receipt of social welfare benefits, younger age of mother at childbirth, being of Native American descent, living in the country, and the birth of a sibling within 12 months (for iron tablet poisoning). There was no statistical evidence of injuries beingassociated with single parent households, family size, overcrowding, or house type.
## Evidence statement 2.9
There is evidence from two studies (one UK) on undefined causes of injury in the home of weak to moderate association of injuries with lower educational status of parents and lower family income. There was no statistical evidence of injuries being associated with parental marital status or of being in receipt of social welfare benefits.
## Evidence statement 2.10
There is evidence from four studies (none UK). There is evidence of a strong association between the use of public playgrounds or being of African-American descent and injuries. There is evidence of weak to moderate association of injuries being with being of Latin American descent, location of a school within an urban area, schools with larger numbers of classes (greater than or equal to 24), longer school hours, and the levels of physical activity engaged in outside of school. There was no statistical evidence of injuries being associated with the levels of physical activity engaged in within school.
## Evidence statement 2.11
There is evidence from six studies (one UK) on burns and fire in all environments of a strong association between the most socioeconomically deprived families, living in a house with one to three or more bedrooms, attention deficit hyperactivity disorder (ADHD), and being of Native American descent and injuries. There was no statistical evidence of injuries being associated with autism, having previously endured an unintentional burn/fire injury, parental employment status, entitlement to Medicaid, or order of sibling birth.
## Evidence statement 2.12
There is evidence from three studies (none UK). There is evidence of weak to moderate association of injuries with entitlement to Medicaid (in children aged 5 to 14 years) and with non-entitlement to Medicaid (in infants aged 0 to 4 years). There was no statistical evidence of injuries being associated with being of Native-American descent or the presence of behavioural disorders.
## Evidence statement 2.14a
There is evidence from 12 studies (four UK) on all injury types in all environments of a strong association (compared with newborns aged up to 6 weeks) between children aged 7–24 months and injuries. There is evidence of weak to moderate association of injuries with increasing age (4 years or older versus younger than 4 years), children aged 15–54 months (versus younger than 6 months), and increasing age among children with a disability. There was no statistical evidence of injuries being associated with increasing age in the case of head injuries.
## Evidence statement 2.14b
There is evidence from 16 studies (four UK). There is evidence of weak to moderate association of injuries (of all severities, including fatalities) with being male.
## Evidence statement 2.14c
There is mixed evidence from eight studies (one UK) on ethnicity in all injury types in all environments regarding the association of child ethnicity with injuries. There is evidence of weak to moderate association of injuries with being of black or Native American descent. There was no statistical evidence of injuries being associated with being of Asian descent or a wide range of other ethnicities.
## Evidence statement 2.14f
There is evidence from 27 studies (six UK) on family's socioeconomic status in all injury types in all environments of weak to moderate association of injuries with socioeconomic deprivation. There is no statistical evidence of injuries (reported in some studies) being associated with socioeconomic deprivation within certain age categories. There is mixed evidence regarding the association of parental educational attainment and household income with injuries.
## Evidence statement 2.14i
There is evidence from eight studies (four UK). There is evidence of weak to moderate association of injuries with socioeconomic deprivation, but no evidence of association between other indicators of neighbourhood disadvantage and the occurrence of unintentional injuries.
## Evidence Statement 3.1
There is moderate evidence from three recent systematic reviews (one and two ) that road speed enforcement devices (cameras, lasers or radar) reduce road injuries, and serious/fatal injury crashes/collisions in the vicinity of the devices. One systematic review (+) also concluded that similar size of speed reduction effects were observed over wider geographical areas around the enforcement device sites. The size of the observed reductions in different studies, and in different localities within studies, varies considerably. Similarly, one systematic review (++) found that in those studies where enforcement devices were temporarily placed at certain locations, the duration of speed reductions after removal of the devices (the 'time halo') varied from 1 day to 8 weeks. However, only one of the systematic reviews (++) was able to identify any factor which was consistently associated with higher injury or crash reductions – this was that the effect on urban roads was greater than that on rural roads. There was insufficient consistency between studies to enable the detection of the effects of other factors (such as different roads user groups, automated versus non-automated detection, mobile versus fixed, covert versus overt, or other roads versus motorway.). The greater effect on urban roads where children are more likely to be pedestrians is relevant. Included studies did not consistently state what the penalties or fines would be for detected speeding, although one systematic review (++) implied there was a relationship between size of pre- and post-reduction in speeding vehicles and the speed threshold set.
This evidence is judged as directly applicable to the UK as the results from the UK studies were generally consistent with the studies from other developed countries.
## Evidence Statement 3.2
There is weak evidence from three controlled before-and-after studies (in Australia, Israel and California) that increased or rationalised police enforcement of traffic speeds reduces injury crashes (two and one ). There is also weak evidence from three multivariate analyses of longitudinal road accident/injury data (in New Zealand, California and Greece) that increased levels of police enforcement of traffic speeds reduces injury crashes and all injuries (two and one ). There is also moderate evidence from one (+) controlled before-and-after study, on motorways in the Netherlands, that increasing the intensity of enforcement – from apprehending 1 in 100 speeding offenders, to 1 in 25, to 1 in 6 – produces statistically significant (p less than 0.05) reductions in mean speed (1 km per hour for 1:25 versus 1:100; and 3.5 km per hour for 1:6 versus 1:25).
This evidence is judged as partially applicable to road safety policy in the UK. This is because in the included studies there are a number of differences in the way police forces are organised and contribute to speed enforcement. Also, in the role of the police in enforcing speed limits through speed traps and mobile cameras/radar needs to be considered in the context of the widespread use of fixed site automated cameras around the UK road network.
## Evidence statement 4.1
There is evidence from one controlled before-and-after study (+) in the USA that law requiring the installation of smoke detectors, increases the number of houses which have at least one functioning smoke detector and that this may reduce fatalities related to fires in targeted properties.
Knowledge of the law and the penalty for non-compliance may be associated with greater smoke detector installation than knowledge of the law only.
The law assessed required smoke detectors in all bedroom areas of one-, two- and multi-family dwellings, applied retrospectively to homes built prior to the law, and can be enforced by a fine or jail time. In addition, sale of a property is contingent on appropriate smoke detectors being present.
Given the differences in legal systems, responsibilities and enforcement between the USA and the UK, and the high socioeconomic status of the studies communities, the applicability of this finding has been assessed as poor. However, the observations that systems of enforcement which involve regular inspection, with a system of warnings prior to prosecution are effective; that laws which reflect societal laws are effective and that media campaigns to support the introduction of new laws may be important, may be applicable across other settings.
## Evidence statement 4.2
There is evidence from one comparative study in the USA (+) that window guard legislation in New York City reduces child injury related to falls from buildings by about half, despite greater numbers at risk as residents of multiple-family dwellings (1.5 per 100,000 children aged 0–18 years compared with an average of 2.81 per 100,000 in 27 other US states without legislation, and 3 per 100,000 in Massachusetts which introduced interventions without legislation). The law required owners of multiple-family dwellings to provide window guards in apartments where children aged 10 or under lived (half the injuries recorded in NYC were in those aged 11–18). Compliance was subject to annual enforcement. The introduction of the law was accompanied by a coordinated education and advertising programme ('Children can't fly') which involved outreach, dissemination of literature, a media campaign and the distribution of free window guards.
Given the differences in legal systems, responsibilities and enforcement between the USA and the UK, and the differences in housing stock and management, the applicability of this finding has been assessed as poor. However, the observation that effective enforcement is a key element of legislative success may be applicable across a range of settings.
## Evidence statement 4.3
There is mixed evidence from four uncontrolled before-and-after studies (all , two from the US and two from Australia) about hot water tap temperature legislation. Two studies (one US and one Australia) reported that the annual incidence of burn injuries in children aged 4–13 years increased after the introduction of legislation, and a US study found that injury rates were raised compared to the period immediately prior to legislation being introduced but fell in relation to an earlier comparator time-period. Only one Australian study (+) reported p-values, but this was a significant increase (p = 0.01).
One study (Australia) suggested there may be a decrease in the number of scald injuries in children aged 0–4 years, however, the reported differences were non-significant (p = 0.57).
Given the differences in legal systems, responsibilities and enforcement between the USA and Australia and the UK, and the differences in housing stock and management, the applicability of these findings have been assessed as poor. However, the observation that legislation aimed at safety in the home may be limited in its effectiveness where it is implemented only in that housing stock where access and enforcement is easier (such as in rented or newly built accommodation only), may be applicable across a range of settings.
## Evidence statement 4.4
There is mixed evidence from four studies (two case control, and two comparative) about swimming pool fencing legislation (two one from USA and one from Australia and two one from New Zealand and one from Australia).
Two studies (both , one USA and one Australia) suggest that legislation is ineffective where it only requires three-sided fencing. The US study suggests no impact of such legislation on drowning in children aged younger than 10 years compared to no legislation (odds ratio 1.27, 95% confidence interval 0.72 to 2.25). The Australian study found the incident rate ratio of drowning in children aged younger than 5 years living in houses with three-sided rather than four-sided pool fencing was 1.78 (95% CI 1.14 to 1.79).
Three studies, two (-) and one (+) (two Australia, one New Zealand) report on outcomes related to legislative management and compliance.
The New South Wales study (-) found that a more structured and comprehensive approach to inspection (including a register of owners, annual inspections, and enforcement of the act including fines) resulted in twice the level of compliance as those with less structured or detailed approaches. Key informant interviews also suggest that lack of clarity in the Fencing Act, and failure to detail how councils should ensure compliance, including how it should be funded, hampered effective implementation.
The Western Australia study (+) suggests that compliance is highest immediately after legislation is introduced, and falls off thereafter, although regular inspection enhances compliance. The New Zealand study (-) found no association with compliance rates and: local authorities having written policies about locating and inspecting pools; a re-inspection programme; or advertising of pool owners' obligations under the relevant act.
Given the differences in legal systems, responsibilities and enforcement between the USA, Australia, New Zealand and the UK, and the low level of private swimming pool ownership in the UK, the applicability of these findings have been assessed as poor. However, some key lessons from these studies may be applicable across a range of settings, such as: the importance of adequate legal requirements in order to glean maximum benefit (as illustrated by three- versus four-sided fencing here); the need for regular inspection regimes which are consistently enforced, and the related need for clear lines of responsibility and sufficient funding for these; the need for concurrent education to help owners comply with the spirit as well as the letter of the law (for example, the need for maintenance of equipment, and the valuing of safety over convenience) and finally the need for legislation which does not contradict or confuse other existing rulings.
## Evidence statement 5.3
There is moderate-to-weak evidence from two controlled before-and-after studies (one and one ) to show that mass-media campaigns, employed as part of a broader non-legislative strategy (that involved educational programmes and purchase subsidies) were effective in increasing compliance with bicycle helmet use. There was also moderate evidence from uncontrolled before-and-after data from one of the studies (-) that the programmes helped to reduce the rates of bicycle-related head injuries in the intervention area.
In the US study (+), the sales of one brand of a youth helmet in the Seattle area (intervention area) rose from 1,500 to 22,000 over a 3-year period (no figures stated for the control area) while observed helmet usage rate among school-age children increased from 5% to 16% compared with a rise of only 1% to 3% in a control community, Portland, Oregon, over the same period.
In the UK study (-) self-reported helmet use among young people aged 11–15 years living in the campaign area increased from 11% at the start of the campaign to 31% after 5 years (p < 0.001), with no significant change in the control group. Hospital casualty figures in the campaign area (Reading) for cycle-related head injuries in the under 16 years age group, fell from 112.5 per 100,000 to 60.8 per 100,000 (from 21.6% of all cycle injuries to 11.7%; p < 0.005). No injury data were provided for Basingstoke, the control. Applicability: The evidence is judged to be directly applicable to the UK – one of the studies was carried out in the UK and although the other was carried out in the US, it was embarked upon and completed before the introduction of a bicycle helmet legislation, so in a sense the settings reflected what is currently obtainable in the UK, a country without mandatory helmet wearing legislation. Furthermore, both countries are similar in terms of living standards and economic development.
## Evidence statement 5.4
There is mixed evidence from two controlled before-and-after studies (both , one from Canada and one from the UK) that removal and replacement of unsafe equipment to comply with regulatory standards is an effective strategy for preventing playground injuries. The Canadian study demonstrated statistically non-significant reduction in equipment-related injury rate in the intervention schools after replacement of equipment using the new Canadian Standards Association standards (relative risk = 0.82 to 0.66 to 1.03). This translated into 177 equipment-related injuries avoided during the study period. The comparable equipment-related injury rate in the non-intervention schools increased by about 15% after the study period, although not statistically significant (RR = 1.15; 95% CI 0.96 to 1.37). The overall injury rate reduced in the intervention schools (RR = 0.70; 95% CI 0.62 to 0.78) and increased in the non-intervention schools (RR = 1.40; 95% CI 1.07 to 2.53) after the study period. However, in the UK study, injury rate per observed child was significantly reduced in the five playgrounds where changes (use of greater depth of bark and replacement of overhead horizontal ladders with rope climbing frame) had been made compared to the control playgrounds without changes.
Applicability: The non‐UK study is only partially applicable to the current UK context due to similarities in level of economic development, nature of the playgrounds, as well as targeted populations. The UK study findings are directly applicable.
## Evidence statement 5.5
There is weak evidence from two before-and-after studies (one and one , from UK and Italy) and one retrospective time series (one from UK) on the effect of fireworks legislation and enforcement activities on firework-related injuries.
One study in Italy (+) reported that a comprehensive, multifaceted programme, comprising the combination of enforcement of fireworks law, media campaign and education, reduced the rate of fireworks-related injury from 10 per 100,000 before the intervention programme to 6.1 per 100,000 after it was implemented, and a time-series based study found that amendments to restrictive fireworks legislation led to a reduction of firework-related injury in children.
The study from Northern Ireland (-) did not find a significant increase in fireworks-related injuries requiring hospital admission following liberalisation of the law on fireworks sale (incidence of admissions before: 0.38 per 100,000; after: 0.43 per 100,000). However, the annual number of injuries in this study was already very small relative to annual variations.
Applicability: The Italian study is partially applicable to current UK context while the UK findings are directly applicable. However, the Northern Ireland study may not be directly applicable to the rest of UK because of the civil unrest reported in that part of the kingdom.
## Evidence statement 6.5
There were two cost-benefit analyses which assessed the impact of speed enforcement programmes. The photo radar programme in British Columbia was estimated to produce net benefits to society of about C$114 million (in 2001), and still produced substantial net savings of C$38 million if only considered from the provincial insurance corporation's perspective.
Similarly, the 420 automated speed camera sites in the UK in 1995/6 were estimated to have a positive net present value of over £26 million, even after 1 year, rising to £241 million after 10 years. This is because annualised fixed costs of £5.3 million plus annual recurrent costs of £3.6 million, would be offset not just by the £6.7 million in fine income, but also the over £30 million in the estimated annual value to society of accidents avoided. In all ten police force areas there was a positive net present value (that is, benefits exceeded costs) within a year of the programme starting.
These older findings should be seen as having been superseded by the more recent study for the Department for Transport, which evaluated the national safety camera programme. (This study was added to the review after the original report was submitted to NICE.) In this study, it was estimated that there would be 4230 fewer personal injury collisions (any road collision which results in at least one casualty, whether fatal, serious or slight) annually as a result of the safety cameras across all 38 safety camera partnerships. At an estimated value of £61,120 per collision avoided (using Department for Transport standard estimates for 2004) this means an annual estimated economic benefit of £258 million. This compares with the total annual cost of the programme of £96 million. Comparing only the revenue costs per collision prevented (£61,120) with the corresponding economic benefit per collision due to injuries prevented (£22,653), over the four years, gives a cost–benefit ratio of approximately 2.7:1. They also use data from both speed and red light camera sites, although at speed camera sites the reductions in personal injury collisions were associated with reductions in speeds.
# Additional evidence
## Expert testimony
Expert testimony 1: 'Child road safety' (including 'Child casualties in road accidents: 2007. Road accidents factsheet number 5 ' )
Expert testimony 3: 'Inequities in child injuries'
Expert testimony 6: 'Monitoring and surveillance issues – A&E pilot'.
# Cost-effectiveness evidence
The modelling (see appendix B) explored the potential cost effectiveness of a selection of strategic approaches to encouraging the uptake of interventions to prevent unintentional injuries among children.
The cost and effectiveness of implementation was the most important factor in relation to legislation or regulations promoting 20 mph zones. The cost of introducing that legislation or regulation – or of enforcing and monitoring compliance – was much less significant.
Several factors determined the cost effectiveness of legislation, regulations and other strategies to promote the earlier and wider installation of thermostatic mixing valves in social housing used by families with young children. These were:
expected level of uptake and installation following the introduction of regulations
number of years before all social housing has one fitted, given the expected uptake after regulations are introduced
cost of enforcing and monitoring compliance
number of social housing households that would be eligible for a thermostatic mixing valve under the regulations.
# Fieldwork findings
Fieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations. For details, go to the fieldwork section in appendix B and 'Strategies to prevent unintentional injury among under-15s'.
The fieldwork took place between the formation of a new government in May 2010 and the budget of June 2010. In this context, the issue of financial uncertainty was raised by many participants. They also found it difficult to comment on the 'who should take action' part of the recommendations as the new government departmental structures were unclear.
The general recommendations were seen as a positive way to increase the profile of unintentional injury prevention, although the issue of funding and concerns about the technological infrastructure needed were raised. The injury surveillance recommendations were positively received, as participants pointed to the lack of authoritative evidence as a key problem. There were, however, concerns about the resource implications of carrying out additional data collection and data coordination activities.
The introduction of a regulatory framework for home safety equipment was strongly welcomed. However, participants did point to the potential impact on the private sector market – as well as the difficulty of getting private sector landlords to comply. Home safety assessments are offered by a range of different services and some participants welcomed the prospect of a standard, common approach. It was noted that some of these recommendations referred to 'all families with children under 5' and that more clarity was required.
Although welcomed in principle, there were concerns about the feasibility of putting the water safety recommendations into practice. For example, lifeguards do not have enough time, hospitality and leisure businesses do not have the skills, and those offering swimming lessons struggle to attract those most in need – even when lessons are free of charge. There was, however, support for a social marketing campaign on water safety.
The recommendations on cycle helmet usage were met with some scepticism and there was no consensus on the safety benefits.
The recommendations on play were welcomed. In particular, all participants liked the acknowledgement that any risks involved should be balanced with the benefits. However, they felt that it would not be easy to communicate these recommendations to the diverse range of organisations involved.
Participants liked the prospect of a national fireworks campaign and the emphasis on evaluation. However, some doubted whether the recommendations would prevent further injuries.
The road safety recommendations were generally welcomed as reflecting best practice. Some participants felt that a number of them could be combined. Some welcomed the fact that they could help to get the NHS involved with road safety partnerships.
This evidence statement differs from the one in the report submitted to NICE. It has been amended to include findings from one (++) systematic review that was included in the original report and has since been updated. The updated review is: Wilson C, Willis C, Hendrikz JK et al. (2010). Speed cameras for the prevention of road traffic injuries and deaths (review). Cochrane Library: 10.# Appendix D: Gaps in the evidence
The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination based on an assessment of the evidence. These gaps are set out below.
There is a lack of UK studies evaluating the effectiveness and cost-effectiveness of legislation, regulation and standards and their enforcement on related outcomes such as compliance, safety, risk taking behaviours and injury. Cost-effectiveness data rarely considers the cost of developing and promoting legislation.
Most studies rely on self-reporting to record morbidity outcomes, protective factors and unintended consequences before and after legislation. In addition, baseline data is rarely collected prior to legislative or regulatory change.
There is a lack of studies that report specific outcomes for children.
There is a lack of UK studies which record and take into account confounding factors that could impact on the effectiveness of legislation, regulation and standards. This includes children and young people's exposure to risk, environmental characteristics and changes in design standards.
There is a lack of studies comparing the effectiveness of legislation, regulation and standards across high-, middle- and low-income countries.
There is a lack of studies evaluating the impact of mass-media campaigns to support legislation, regulation and standards.
There is a lack of good quality qualitative research on the barriers preventing – and facilitators aiding – compliance with legislation, regulation and standards.
There is a lack of qualitative and quantitative research on injury prevention in the home.
There is a lack of information on the effectiveness of legislation relating to home safety assessments, thermal mixing valves, smoke alarms and window restrictors. Evaluations do not tend to incorporate process and outcome factors.
There is a lack of information on how well rules and regulations for different sports are enforced.
There is a lack of studies addressing the quantitative correlates of drowning.
There is a lack of evaluation of the effectiveness of different types of road signage.
There is a lack of studies on the differential effectiveness of network-wide, targeted or mixed approaches to speed enforcement on the road. There is also a lack of studies identifying the factors consistently associated with a reduction in injuries from road crashes.
The Group made 18 recommendations for research. These are listed in section 5.# Appendix E: Supporting documents
Supporting documents are available online. These include the following:
Evidence reviews:
Review 1: 'Current practice and innovative approaches to prevent childhood unintentional injuries: An overview and synthesis of international comparative analyses and surveys of injury prevention policies, legislation and other activities'
Review 2: 'A systematic review of risk factors for unintentional injuries among children and young people aged under 15 years'
Review 3: 'An overview and synthesis of evidence relating to strategies and frameworks for planning, implementing, enforcing or promoting activities to prevent unintentional injury to children and young people on the road: legislation, regulation, standards and related strategies focusing on the design and modification of highways, roads or streets'
Review 4: 'Strategic and regulatory frameworks for guiding, enforcing or promoting activities to prevent unintentional injury in children and young people in the home environment'
Review 5: 'Strategies, policies and regulatory or legal frameworks and/or mass media campaigns to prevent unintentional injury to children during play and leisure in the external environment'.
Review 6: 'Systematic review to provide an overview of published economic evaluations of relevant legislation, regulations, standards, and/or their enforcement and promotion by mass media'.
Economic analysis: 'Economic modelling of legislation/regulations and related national strategies to promote the wider use of: 20mph zones in residential areas, and thermostatic mixing valves (TMVs) in social housing for families'.
Expert testimony:
Expert testimony 1: 'Child road safety' (including 'Child casualties in road accidents: 2007. Road accidents factsheet number 5 ' )
Expert testimony 2: 'Preventing unintentional injuries among under-15s'
Expert testimony 3: 'Inequities in child injuries'
Expert testimony 4: 'Legislating for Health'
Expert testimony 5: 'Cycle helmets – epidemiology and effectiveness'
Expert testimony 6: 'Monitoring and surveillance issues – A&E pilot'.
Fieldwork report: 'Strategies to prevent unintentional injury among under-15s'.
For information on how NICE public health guidance is developed see:
Methods for development of NICE public health guidance (second edition, 2009)'
The NICE public health guidance development process: An overview for stakeholders including public health practitioners, policy makers and the public (second edition, 2009).# About this guidance
NICE public health guidance makes recommendations on the promotion of good health and the prevention of ill health.
This guidance was developed using the NICE public health programme guidance process.
Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
This is one of three pieces of NICE guidance published in November 2010 on how to prevent unintentional injuries among under-15s. A second publication covers the provision of home safety equipment and home risk assessments and a third covers unintentional injuries on the road.
ISBN: 978-1-4731-3613-7
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{'Introduction': "This is one of three pieces of NICE guidance published in November 2010 on how to prevent unintentional injuries among under-15s. A second publication covers the provision of home safety equipment and home risk assessments and a third covers unintentional injuries on the road.\n\nThe Department of Health (DH) asked the National Institute for Health and Care Excellence (NICE) to produce public health guidance on the prevention of unintentional injuries among children and young people aged under 15. This guidance focuses on strategies, regulation, enforcement, surveillance and workforce development in relation to preventing unintentional injuries in the home, on the road and during outdoor play and leisure.\n\nThe guidance is for commissioners and providers of health services, local authority children's services, local authorities and their strategic partnerships, local highway authorities, local safeguarding children boards, police, fire and rescue services, policy makers, professional bodies, providers of play and leisure facilities, and schools.\n\nIt is also for other public, private, voluntary and community organisations and services which have a direct or indirect role in preventing unintentional injuries among children and young people aged under 15.\n\nThe guidance may also be of interest to children, young people, parents, carers and other members of the public.\n\nThis is one of three pieces of NICE guidance published in November 2010 on how to prevent unintentional injuries among children and young people aged under 15. It should be read in conjunction with the two other publications. These focus on: the provision of home safety equipment and home risk assessments and road design and modification. (For further details, see section 7.)\n\nThe Programme Development Group (PDG) developed these recommendations on the basis of reviews of the evidence, economic modelling, expert testimony, stakeholder comments and fieldwork.\n\nMembers of the PDG are listed in appendix A. The methods used to develop the guidance are summarised in appendix B.\n\nSupporting documents used to prepare this document are listed in appendix E.\n\nFull details of the evidence collated, including fieldwork data and stakeholder comments, are available on the NICE website, along with a list of the stakeholders involved and NICE's supporting process and methods manuals.", 'Recommendations ': 'This is NICE\'s formal guidance on strategies to prevent unintentional injuries among children and young people aged under 15. When writing the recommendations, the Programme Development Group (PDG) (see appendix A) considered the evidence of effectiveness (including cost effectiveness), expert testimony, fieldwork data and comments from stakeholders. Full details are available online.\n\nThe evidence statements underpinning the recommendations are listed in appendix C.\n\nThe evidence reviews, supporting evidence statements and economic analysis are available online.\n\nPlease note: the absence of recommendations on any particular measures to prevent unintentional injuries is a result of a lack of evidence that met the inclusion criteria for the evidence reviews. It should not be taken as a judgement on whether or not any such measures are effective and cost effective.\n\n# Definitions\n\nThe guidance uses the term \'unintentional injuries\' rather than \'accidents\' as: "most injuries and their precipitating events are predictable and preventable". The term \'accident\' implies an unpredictable and therefore unavoidable event.\n\nThe term \'vulnerable\' is used to refer to children and young people who are at greater than average risk of an unintentional injury due to one or more factors. As an example, they may be more vulnerable if they:\n\nare under the age of 5 years (generally, under-5s are more vulnerable to unintentional injuries in the home)\n\nare over the age of 11 (generally, over-11s are more vulnerable to unintentional injuries on the road)\n\nhave a disability or impairment (physical or learning)\n\nare from some minority ethnic groups\n\nlive with a family on a low income\n\nlive in accommodation which potentially puts them more at risk (this could include multiple-occupied housing and social and privately rented housing).\n\n# Topics\n\nThe recommendations are divided into six categories: general, workforce training and capacity building, injury surveillance, home safety, outdoor play and leisure, and road safety.\n\n# National recommendations\n\nThe guidance includes some national recommendations to assist local action (see recommendations 1, 5, 7, 10 and 21).\n\nThe decision on whether these recommendations are taken forward – and how they are prioritised – will be determined by government and subject to statutory regulatory and cost impact assessments.\n\n# General recommendations\n\n## Context\n\nThe prevention of unintentional injuries among children and young people may not be a priority among local organisations. To ensure prevention activities are accorded the importance they deserve, they need to be incorporated into national objectives aiming to improve the population\'s health. Local injury prevention coordinators could promote a strategic framework for action and encourage local agencies to work together.\n\nChildren and young people aged under 15, their parents and carers (some of the recommendations may also benefit the wider population).\n\n## Recommendation 1 Incorporating unintentional injury prevention within local and national plans and strategies for children and young people\'s health and wellbeing\n\nLocal authority children\'s services and their partnerships, in consultation with local safeguarding children boards.\n\nGovernment departments with a responsibility for preparing policy and plans relating to children and young people\'s health and wellbeing.\n\nEnsure local and national plans and strategies for children and young people\'s health and wellbeing include a commitment to preventing unintentional injuries among them. In particular, the plans and strategies should aim to prevent unintentional injuries among the most vulnerable groups to reduce inequalities in health. This commitment should be part of a wider objective to keep children and young people safe.\n\nEnsure plans and strategies include the following to prevent unintentional injuries among children and young people:\n\n\n\nsupport for cross-departmental and cross-agency working to achieve national and local commitments\n\nsupport for local partnerships, including those with the voluntary sector, and a requirement that they work together to ensure children and young people can lead healthy, active lives\n\ninformation about how partners will collaborate on injury prevention\n\nsupport for data collection on the incidence, severity, type, cause and place of injury (for example, see recommendations 7–8 on injury surveillance)\n\nsupport for monitoring the outcomes of injury prevention initiatives\n\nsupport for the development of workforce capacity in this area, including the provision of suitably trained staff and opportunities for initial and ongoing multi-agency training and development (see recommendations 4–6).\n\n\n\nLocal authorities should report to the local strategic partnership on progress made to meet the commitments set out in the plans and strategies. This should include details on the experiences of children, young people, their parents and carers.\n\n## Recommendation 2 Coordinating unintentional injury prevention activities\n\nLocal authority children\'s services and their partnerships, in consultation with local safeguarding children boards.\n\nLocal highway authorities and their road safety partnerships.\n\nOther local authority services that may have a remit for preventing unintentional injuries such as education, environmental health and trading standards.\n\nEnsure there is a child and young person injury prevention coordinator. The aim is to help achieve the commitments set out in local plans and strategies for children and young people\'s health and wellbeing. The coordinator could be someone in the local authority, an NHS organisation or another local partner organisation (such as the fire and rescue service or a housing association). Alternatively, the coordinating role could be jointly funded by several local partners.\n\nEnsure the coordinator:\n\n\n\nworks with local partnerships that include organisations involved with children, young people, their parents and carers\n\ndevelops a 2 to 3-year injury prevention strategy with these partners which is integrated into all relevant local plans and strategies for children and young people\'s health and wellbeing\n\nnetworks at regional and national level with other child and young person injury prevention coordinators\n\nraises local awareness about the need for prevention activities. This includes sitting on the local safeguarding children board. It also includes acting as a local source of information and advice on prevention\n\nmonitors progress made on the injury prevention commitments set out in local plans and strategies for children and young people\'s health and wellbeing. They should report progress to the director of children\'s services.\n\n\n\nEnsure the coordinator understands the range of preventive measures available and is trained – and has the skills – to carry out the above activities. Provide them with both informal and formal learning opportunities. (The former could include using peer support and \'cascade learning\' within placements. The latter could include the acquisition of qualifications at different stages of a formal career pathway.)\n\nEnsure specialist learning and training is monitored and evaluated to see what effect it has on the coordinator\'s performance. Revise approaches that are found to be ineffective.\n\n## Recommendation 3 Identifying and responding to attendances at emergency departments and minor injuries units\n\nStaff in emergency departments and minor injuries units, including triage nurses.\n\nLocal child and young person injury prevention coordinators.\n\nLocal safeguarding children boards.\n\nLiaison health visitors.\n\nStaff offering out-of-hours health services for children and young people (for example, in walk-in centres).\n\nEnsure health visitors, school nurses and GPs are aware of families which might benefit from injury prevention advice and a home safety assessment. Do this by using local protocols to alert them when a child or young person repeatedly needs treatment for unintentional injuries at an emergency department or minor injuries unit. Do the same when a single attendance raises concerns.\n\n# Recommendations for workforce training and capacity building\n\n## Context\n\nProfessional standards are needed to set out the knowledge and skills (or \'competencies\') for a range of injury prevention roles within and outside the NHS. Funding to develop these standards and curricula – and the provision of accessible training – is also required.\n\nChildren and young people aged under 15, their parents and carers (some of the recommendations may also benefit the wider population).\n\n## Recommendation 4 Developing professional standards for injury prevention\n\nFaculty of Public Health.\n\nRoyal colleges and professional bodies (for example, the Nursing and Midwifery Council).\n\nHealth and Care Professions Council.\n\nSector skills councils.\n\nRelevant voluntary sector organisations.\n\nUniversities.\n\nDevelop professional standards for unintentional injury prevention. These should take into account the different roles and responsibilities of professionals working within and outside the NHS. They should also take practitioners\' views into account.\n\nEnsure all relevant organisations incorporate these standards into their professional skills development programmes.\n\n## Recommendation 5 Funding the development of injury prevention standards and curricula\n\nDepartment of Health and Social Care.\n\nDepartment for Education.\n\nEncourage funding for educational establishments and organisations to help them develop standards for competencies in – and courses and modules on – the prevention of unintentional injuries among children and young people. The establishments and organisations involved could include: the Faculty of Public Health, the Children\'s Workforce Development Council, universities, royal colleges and organisations in the voluntary sector.\n\n## Recommendation 6 Providing the wider childcare workforce with access to injury prevention training\n\nLocal authority children\'s services and their partnerships, including local safeguarding children boards.\n\nLocal injury prevention coordinators.\n\nCommissioners, managers and practitioners working in health, social care and education services.\n\nRelevant organisations in the voluntary and private sector.\n\nProvide access to appropriate education and training in how to prevent unintentional injuries for everyone who works with (or cares for and supports) children, young people and their families. Prioritise those who work directly with children, young people and their families.\n\nEnsure the education and training:\n\n\n\nsupports the wider child health remit (for example, the promotion of children and young people\'s development)\n\nhelps develop an understanding of the importance of preventing unintentional injuries and their consequences and the preventive measures available.\n\n\n\nEnsure specialist education and training is monitored and evaluated to see what effect it has on practitioner performance. Revise approaches that are found to be ineffective.\n\n# Recommendations for injury surveillance\n\n## Context\n\nInjury \'surveillance\' is needed to monitor unintentional injuries among children and young people locally, regionally and nationwide. The data gathered could be used as the basis to plan preventive initiatives. Such initiatives may need to take a particular type of injury into account locally or regionally – even though it may not be a major problem nationwide.\n\nChildren and young people aged under 15, their parents and carers (some of the recommendations may also benefit the wider population).\n\n## Recommendation 7 Establishing a national injuries surveillance resource\n\nCollege of Emergency Medicine.\n\nGovernment departments including Department of Health and Social Care and Public Health England, Department for Education, Department for Transport, Ministry for Housing, Communities and Local Government and the Home Office.\n\nOffice for National Statistics.\n\nThe Information Centre for Health and Social Care.\n\nEstablish a national injuries surveillance resource covering all populations and injuries to help monitor injury risks and the effects of preventive measures. It could be provided by a network of agencies but there should be a single point of contact or a coordinating agency. The resource could be part of the proposed \'Information revolution\'.\n\nEnsure the resource includes local, regional and national injury datasets and data sources. For example, it should include data gathered from: emergency departments, walk-in centres, minor injury units, Reporting of Injuries, Diseases and Dangerous Occurrences Regulations (RIDDOR), Hospital Episode Statistics (HES), coroner reports, ambulance call-out reports, fire and rescue service reports, reported road casualty statistics (STATS19) and the child death review process (as data become available).\n\nThe coordinating agency or network of agencies should:\n\n\n\nensure datasets can be integrated to provide accurate, anonymised and aggregated statistics on local injuries and their causes\n\ncollate, manage, analyse and interpret injury-related data (using experienced injury researchers to advise on analysis and interpretation)\n\nprovide a secure and reliable information system for recording and interrogating data (compliant with the Data Protection Act 2018)\n\nmonitor the quality of data submissions and datasets\n\nreport relevant findings to support the monitoring of emergency department service contracts\n\nprovide government departments with advice on developing standardised injury data collection and coding across datasets (for example, for data collected by fire and rescue services and emergency departments)\n\nidentify and develop new data sources for example, data collected by non-governmental agencies and the voluntary sector\n\ndisseminate information locally and regionally and provide a readily available, searchable database for authorised users\n\nsupport the European Commission\'s work on injury surveillance.\n\n\n\nEnsure national guidance on data-sharing protocols is adopted by all agencies that collect local injury data. This includes: ambulance services, child death overview panels, coroners, emergency departments, fire and rescue services, the Health and Safety Executive and police forces.\n\nPromote the development of an enhanced national emergency department dataset based on submissions from a representative sample of hospitals. Ensure it includes additional data on events and activities leading to an injury.\n\n## Recommendation 8 Gathering high quality injury data from emergency departments\n\nCommissioners of health services.\n\nEnsure all hospital trusts are made aware of the data collection requirements for the universal and mandatory A&E (minimum) commissioning dataset.\n\nEnsure commissioning contracts for emergency departments (including minor injury units and walk-in centres) stipulate that all required data are collected – and to the required A&E (minimum) commissioning dataset standard. Contracts should also stipulate which data collection and submission methods should be used.\n\nEnsure contracts include financial penalties for failure to meet the requirements of the A&E (minimum) commissioning dataset.\n\nEnsure all hospital trust injury data are submitted to the NHS Information Centre for Health and Social Care.\n\n# Recommendations for home safety\n\n## Definitions and context\n\nFor the purposes of this guidance, \'home\' refers to the home, garden and boundaries of a property. A home safety assessment is the process of systematically identifying potential hazards in these areas, evaluating the risks and providing information or advice on how to reduce them. Other terms commonly used to describe the same process include \'home risk assessment\' and \'home safety check\'. It may be carried out by a trained assessor or by parents, carers and other householders using an appropriate checklist.\n\nPermanent home safety equipment is defined here as any device that needs to be fitted and cannot easily be modified or removed by the householder. Examples include smoke and carbon monoxide alarms, thermostatic mixing valves and window restrictors.\n\nEnsuring permanent safety equipment is fitted in homes and the provision of home safety assessments should help prevent unintentional injuries among all under-15s. However, groups facing a higher than average risk of an unintentional injury need to be prioritised. Particularly vulnerable groups in relation to home safety are children aged under 5 and those living in temporary, rented and social housing with families on a low income (for other vulnerable groups see definitions at the beginning of section 1).\n\n(See also recommendations made in NICE\'s guideline on unintentional injuries in the home: interventions for under 15s.)\n\nChildren and young people aged under 15 and their families (some of the recommendations may also benefit the wider population).\n\n## Recommendation 9 Installation and maintenance of permanent safety equipment in social and rented dwellings\n\nLocal authorities.\n\nConsider developing local agreements with housing associations and landlords to ensure permanent home safety equipment is installed and maintained in all social and rented dwellings. Priority should be given to accommodation where children aged under 5 are living. Use the Housing Health and Safety Rating System (HHSRS). Permanent safety equipment includes:\n\n\n\nthermostatic mixer valves for baths\n\nwindow restrictors.For duties about installing and maintaining smoke and carbon monoxide alarms, refer to the Smoke and Carbon Monoxide Alarm (England) Regulations 2015.\n\n\n\nPublicise any local agreements to install and maintain permanent safety equipment. Provide information about these agreements to the following groups and evaluate their awareness:\n\n\n\nthose responsible for social and rented dwellings, such as landlords and social housing providers\n\npractitioners with an injury prevention remit or who have an opportunity to help prevent injuries among children and young people\n\npractitioners with a role in assessing health and safety in residential properties\n\nresidents in rented and social dwellings.\n\n\n\n## Recommendation 10 Incorporating guidance on home safety assessments within relevant national initiatives\n\nDepartment of Health.\n\nDepartment for Education.\n\nEnsure national initiatives to improve child health include guidance on delivering home safety assessments and providing safety education to families with a child under 5 or with other children who may be particularly vulnerable to unintentional injuries. (Relevant national initiatives include the Healthy Child Programme.)\n\n## Recommendation 11 Incorporating home safety assessments and equipment provision within local plans and strategies for children and young people\'s health and wellbeing\n\nLocal authority children\'s services and their partnerships, in consultation with local safeguarding children boards.\n\nEnsure home safety assessments and education are incorporated in local plans and strategies for children and young people\'s health and wellbeing. They should be aimed at families with a child under 5 or with other children who may be particularly vulnerable to unintentional injuries.\n\nCommission local agencies to offer home safety assessments and, where appropriate, supply and install suitable, high quality home safety equipment (whenever possible, adhering to British or equivalent European standards.)\n\nEnsure commissions specify that the assessment and the supply and installation of equipment needs to be tailored to meet the household\'s specific needs and circumstances. Factors to take into account include the developmental age of the children and whether or not a child or family member has a disability. Cultural and religious beliefs, whether or not English is the first language and levels of literacy within the household also need to be noted. In addition, the level of control people have over their home environment and the household\'s perception of, and degree of trust in, authority should be taken into account.\n\nEnsure commissions specify that the assessment needs to help parents, carers, older children and young people identify and address the potential risks from water in the home (this includes baths and garden ponds.\n\nEnsure commissions specify that education, advice and information is needed both during a home safety assessment and during the supply and installation of home safety equipment. This should emphasise the need to be vigilant about home safety and explain how to maintain and check home safety equipment. It should also explain why safety equipment has been installed – and the danger of disabling it. In addition, commissions should specify that useful links and contacts need to be given to householders as part of this provision, in case of a home safety problem.\n\n# Recommendations for outdoor play and leisure\n\n## Context\n\nChildren and young people learn, develop and mature when playing and taking part in activities that challenge them. Their participation in regular physical activity and outdoor play and leisure is important for their growth, development and general health and wellbeing – in both the short and long term. (For example, it can help reduce the risk of obesity and cardiovascular disease.)\n\nThe type of hazards encountered during outdoor activities will vary for different age groups and according to where they take place. Likewise, the factors to be considered when addressing and balancing risks and benefits will also differ. For example, where children and young people go off-road cycling will vary, depending on their age and experience: younger children are most likely to cycle in gardens and parks, while older children and young people may get involved in activities such as BMX racing or mountain biking.\n\nThese recommendations cover preventive activities at the strategic level (for example, the need to monitor compliance with safety standards). This does not imply that they are the only actions that could be taken to prevent unintentional injuries outdoors and during play and leisure.\n\nChildren and young people aged under 15, their parents and carers (some of the recommendations may also benefit the wider population).\n\n## Recommendation 12 Developing policies for public outdoor play and leisure\n\nHead teachers and school governors.\n\nLocal strategic partnerships.\n\nPlay and leisure providers in the public, private, voluntary and community sector. This includes representatives of the leisure industry, parish and town councils and early years services. It also includes private providers of outdoor play facilities that are open to the public, such as pubs and hotels.\n\nPublic, private, voluntary and community sector managers and decision makers responsible for play and leisure policies.\n\nEnsure a policy is in place which:\n\n\n\ntakes a balanced approach to assessing the risks and benefits of play and leisure environments and activities (see NICE\'s guideline on physical activity for children and young people)\n\ncounters excessive risk aversion\n\npromotes the need for children and young people to develop skills to assess and manage risks, according to their age and ability\n\ntakes into account children and young people\'s preferences about the types of outdoor play and leisure activities they want to participate in\n\nis inclusive, taking into account the needs of all children and young people, including those from lower socioeconomic groups, those from minority ethnic groups with specific cultural requirements and those who have a disability.\n\n\n\nUse local information and data on environments, equipment and behaviour that pose a risk of serious unintentional injury to help plan prevention initiatives. Include information and data provided by practitioners, play and leisure providers, children, young people, their parents and carers.\n\nFocus prevention initiatives on groups most at risk of an unintentional injury. Initiatives could include modification of equipment and the environment, and the provision of information, education and safety equipment.\n\nTake into account the principles of British and European standards covering equipment and the environment (where they exist) as part of a risk-benefit assessment of outdoor play and leisure environments. This includes standards covering playgrounds, fairgrounds, toy safety and swimming pools, as well as those for inspection and maintenance.\n\nWhere equipment and the environment cannot be modified, provide information, advice and education about risk management and the use of any appropriate safety equipment.\n\n## Recommendation 13 Providing education and advice on water safety\n\nInjury prevention coordinators and health practitioners (for example, health visitors and school nurses).\n\nLifeguards.\n\nOutdoor activity and holiday centre managers.\n\nSchools.\n\nSwimming instructors.\n\nSwimming pool managers.\n\nKnow which groups of children and young people are at high risk of drowning – and when that risk is increased. For example, children with certain medical conditions may be more at risk and boys are more likely to be at risk than girls. In addition, older children are more likely to drown outside the home.\n\nProvide children, young people, their parents and carers with information and education on water safety in play and leisure environments. This should be appropriate to the age, developmental stage and experience of the child or young person and meet the household\'s particular needs and circumstances. It should be readily available in a suitable format. It should also be factually correct and consistent.\n\nEnsure the information and education:\n\n\n\nhelps parents, carers, older children and young people identify and address the potential risks from water in the wider environment (this includes lakes, canals, rivers and on the coast)\n\nstresses the importance of proper supervision, particularly for younger children, and describes in detail what this means.\n\n\n\nProvide timely information and advice, for example, during the holiday season and for dealing with conditions such as heatwaves and extreme cold. (Ice might form on ponds, rivers and lakes during extreme cold spells.) This could include clearly displayed information at appropriate locations.\n\nEncourage children, young people, their parents and carers to become competent swimmers and to learn other water safety skills (for example, so that they know how to effect a rescue).\n\nEnsure swimming lessons include general and specific water safety information. Specific information could include detail on the meaning of different coastal warning flags. It should also raise children and young people\'s awareness of how difficult it is to assess and manage the hazards posed by water in a range of different outdoor environments.\n\n## Recommendation 14 Water safety advice for leisure providers\n\nLeisure facility providers such as leisure centre and pool operators, boat hire companies, hoteliers, holiday companies and tour operators.\n\nUse risk analysis and management procedures to identify where there may be a risk of drowning. Minimise that risk, wherever possible, without discouraging swimming.\n\nProvide water safety information in a range of languages and formats. This could include clearly displayed information at appropriate locations. Ensure provision is timely. For example, ensure it is provided during the holiday season and in extreme weather conditions such as heatwaves and extreme cold. (Ice might form on ponds, rivers and lakes during extreme cold spells.)\n\n## Recommendation 15 Advising on off-road cycle safety\n\nNHS and other health organisations.\n\nLocal authorities.\n\nSchools and school travel advisers.\n\nInjury prevention coordinators.\n\nPolice.\n\nRetail outlets and cycle hire centres.\n\nNHS, other health organisations and local authorities should use local information campaigns and ongoing education to encourage cycle training and promote the use of correctly fitted and fastened cycle helmets while cycling off the road. Campaigns could focus on younger children learning to cycle, for example in gardens and parks, and on older children and young people who go BMX racing or mountain biking. The campaigns could suggest that adults set an example by wearing helmets whenever they cycle.\n\nSchools, school travel advisers, injury prevention coordinators, local authorities and the police should ensure travel plans cover off-road routes. They should also encourage children and young people to undertake cycle training and to wear cycle helmets.\n\nRetailers should provide point-of-sale advice on the correct fitting of cycle helmets (this includes online sales). They should also consider setting up a certified retailer scheme like that run by the British Equestrian Trade Association.\n\nCycle hire centres should advise about the advantages of children and young people wearing correctly fitted and fastened cycle helmets. They should provide them if requested.\n\n## Recommendation 16 Conducting local firework safety campaigns\n\nEnvironmental health officers.\n\nFire service.\n\nClinical commissioning groups and hospital trusts.\n\nInjury prevention coordinators.\n\nLocal authority children\'s services and their partnerships.\n\nPolice.\n\nSchools.\n\nTrading standards officers.\n\nUse emergency department surveillance data to inform local firework injury prevention campaigns.\n\nConduct local firework injury prevention campaigns during the lead up to all celebrations and festivals where fireworks are used. This includes Bonfire Night, New Year and Diwali. Use the principles of behaviour change to inform campaign planning, delivery and evaluation. Evaluate the effectiveness of campaigns.\n\nTrading standards officers should ensure adults are given the firework safety code when they buy fireworks, as a condition of the licence to store and sell fireworks. The code should be available in a range of languages and formats.\n\n# Recommendations for road safety\n\n## Context\n\nThese recommendations propose that those responsible for road safety should focus on the needs of local children and young people. This includes helping drivers to reduce their speed in areas where children and young people are present. They should be read in conjunction with recommendations made in NICE\'s guideline on unintentional injuries on the road: interventions for under 15s.\n\nChildren and young people aged under 15, their parents and carers (some of the recommendations may also benefit the wider population).\n\n## Recommendation 17 Maintaining and managing road safety partnerships\n\nLocal highway authorities.\n\nMaintain the existing road safety partnership (or establish one where none exists) to help plan, coordinate and manage road safety activities. It should include the road safety team, fire and rescue services, the injury prevention coordinator, the NHS, police, local education authorities and local safeguarding children boards.\n\nEnsure the health sector plays an active role in the partnership (see NICE\'s guideline on unintentional injuries on the road: interventions for under 15s).\n\nNominate a member of staff who is responsible for road safety partnership work.\n\nWork with the partners listed in the first action point above, children and young people\'s services, relevant voluntary sector organisations and others to identify and manage road environments that pose a high risk to children and young people.\n\nSecure funding streams for local road safety initiatives and support these partnerships by promoting good practice.\n\nEnsure the road safety partnership develops policies, strategies and programmes which are based on an understanding of how children and young people use (and wish to use) their environment. This involves consulting parents and carers about their children\'s road use and safety. It also involves gaining local information from other professional partnerships, children\'s councils and neighbourhood forums.\n\nEnsure the road safety partnership draws on all available information (such as demographics and risk-exposure data) to plan road injury reduction programmes, as part of the local community safety strategy. The programmes should take into account how injury risk differs according to age and road type. They should also reflect the increased risks facing children and young people from disadvantaged areas and communities.\n\nEvaluate programmes using a range of outcome measures, including road injury data. A variety of evaluation methods should be used, such as controlled trials, \'stepped-wedge\' trials (sequential rollout to all participants) and process evaluations.\n\n## Recommendation 18 Carrying out local child road safety reviews and consultations\n\nLocal highway authorities and their road safety partnerships (see recommendation 17).\n\nEnsure local child road safety reviews are carried out at least every 3 years. To ensure consistency within regions, ensure they include the following:\n\n\n\nall road injury data collected by road safety partners\n\ndata which can identify whether some social groups experience more injuries than others (inequalities data)\n\nrisks to local children and young people\n\ninformation about all types of journey, not just those to and from school.\n\n\n\nEnsure local children and young people, particularly those from disadvantaged communities, are consulted about their road use and their opinions about the risks involved. In addition, consult parents and carers about their children\'s road use and safety.\n\nUse the reviews and consultation findings to inform local initiatives to reduce road injuries among children and young people.\n\nEvaluate the impact of initiatives on local policies (including health inequalities policy), practice and injuries.\n\n## Recommendation 19 Aligning local child road safety policies\n\nLocal authority children\'s services and their partnerships, in consultation with local safeguarding children boards.\n\nLocal highway authorities and their road safety partnerships.\n\nReview local partners\' priorities and strategies to ensure they are coordinated.\n\nInvolve the local injury prevention coordinator in the development of the child road safety review and liaise with them about consultations with the local community.\n\nEnsure consistency between the road injury prevention priorities and strategies within child safety policies, local plans and strategies for children and young people\'s health and wellbeing, the road safety strategy and local authority community safety plans. (This includes ensuring consistency at all levels within non-unitary organisations.)\n\n## Recommendation 20 Promoting and enforcing speed reduction\n\nLocal highway authorities and their road safety partnerships.\n\nUse signage, road design and engineering measures to reduce vehicle speeds on roads where children and young people are likely to be, such as those passing playgrounds or schools (see NICE\'s guideline on unintentional injuries on the road: interventions for under 15s).\n\nUse signage to warn drivers of the likely presence of children and young people in areas that they frequent (such as schools and playgrounds) and the need to comply with safety measures.\n\nUse national and local education and media campaigns to promote the benefits of safety initiatives – including 20\xa0mph speed limits and zones – in areas frequented by children and young people.\n\nEvaluate compliance with speed limits.\n\nWhere evaluation shows that compliance is poor, work with the police to improve it through education and, where necessary, enforcement activities.\n\n## Recommendation 21 Involving the police in driver education initiatives and activities to reduce traffic speed\n\nHer Majesty\'s Inspectorate of Constabulary.\n\nThe Home Office.\n\nInclude road safety and enforcement in Her Majesty\'s Inspectorate of Constabulary (HMIC) evaluation tools (report cards) to ensure both are considered when police priorities are set.\n\nEncourage the police to work with other local partners (see recommendations 17–20) on road safety issues in relation to children and young people aged under 15. In particular, encourage the police to contribute to driver education initiatives on the need for compliance with speed limits.\n\nEncourage the police to work with the existing road safety partnership (or with relevant agencies if there is no such partnership) to determine areas where vehicle speeds need to be reduced. Draw upon the knowledge of safer neighbourhood teams and the demographic and consultation data within community safety plans to understand local children and young people\'s use of the road environment.\n\n Davis R, Pless B (2001) BMJ bans \'accidents\'. Accidents are not unpredictable. BMJ 322: 1320–21.\n\n Surveillance of any health issue is defined as the: \'systematic, ongoing collection, collation and analysis of health-related information that is communicated in a timely manner to all who need to know which health problems require action in their community\'. Last JM (2007) A dictionary of public health. Oxford: Oxford University Press.\n\n See Department of Health (2010) An information revolution: a consultation on proposals. London: Department of Health.\n\n See the NHS Information Governance Toolkit website and Department of Health (2007) NHS information governance guidance on legal and professional obligations. London: Department of Health. Also see HM Government (2015) Information sharing advice for safeguarding practitioners. London: Department for Education.\n\n Such a dataset is being piloted by the Department of Health and the College of Emergency Medicine. It contains similar detail to that previously collected for the Home and Leisure Accident Surveillance Systems [HASS/LASS] and the results are presented as anonymised, aggregated data.\n\n Home safety assessment tools are available from: The Royal Society for the Prevention of Accidents and SafeHome.\n\n The HHSRS is a method for assessing potential risks to the health and safety of occupants in residential properties. It is used by local authorities to assess social and rented dwellings, and to require landlords to carry out remedial action to address any serious hazards.\n\n See the three Healthy Child Programme core documents.\n\n This is an edited extract from a recommendation that appears in NICE\'s guideline on unintentional injuries in the home: interventions for under 15s. In that guidance, home safety equipment includes door guards and cupboard locks, safety gates and barriers, smoke and carbon monoxide alarms, thermostatic mixing valves and window restrictors.\n\n Many people may not have the authority to agree to an installation, for example, tenants of social and private landlords and those who are unable to make household or financial decisions.\n\n For example, advice from the National Water Safety Forum and leaflets and booklets from the Child Accident Prevention Trust (CAPT).\n\n For example, advice from the National Water Safety Forum, the RoSPA water safety code for children and the Child Accident Prevention Trust leaflets and booklets.\n\n See Department for Business, Energy and Industrial Strategy (2010) Firework safety: be media wise!\n\n See NICE\'s guideline on behaviour change.', 'Public health need and practice': "# Background\n\nUnintentional injury is a leading cause of death among children and young people aged 1–14 (Audit Commission and Healthcare Commission 2007). In England and Wales in 2008, 208 children and young people aged 0–14 died from such injuries. Around 44% of those deaths were transport-related (Office for National Statistics 2009).\n\nIn 2009, 65 under-15s were killed and 18,307 were injured on the roads in Great Britain, 2267 of them seriously. Of those killed or seriously injured, 1507 (65%) were pedestrians. Cyclists (381) and car passengers (380) made up the bulk of the remainder (that is, cyclists and car passengers each accounted for around 16% of the total) (Department for Transport 2010).\n\nA substantial number of children also die from unintentional injuries at home or in leisure environments. For example, in England and Wales in 2008, 55 children died from choking, suffocation or strangling, 17 from drowning and 10 from smoke, fire and flames (Office for National Statistics 2009).\n\nDeath rates from unintentional injuries are falling (Edwards et al. 2006). However, in England alone, around 100,000 children and young people aged under 15 were admitted to hospital in 2009/10 as a result of such injuries (The Information Centre for Health and Social Care 2010).\n\nIn 2002, nearly 900,000 children and young people in the UK aged under 15 attended hospital following an unintentional injury in the home (Department of Trade and Industry 2002). Over a million children and young people aged under 15 were taken to hospital following an unintentional injury outside their home; 360,000 were injured while at school, 180,000 while playing sport and 33,000 while in a public playground (Department of Trade and Industry 2002).\n\nUnintentional injury can affect a child or young person's social and emotional wellbeing. For example, those who survive a serious unintentional injury can experience severe pain and may need lengthy treatment (including numerous stays in hospital). They could also be permanently disabled or disfigured (Eurosafe 2006).\n\nMinor unintentional injuries are part of growing up and help children and young people to learn their boundaries and manage risks for themselves. The need to balance encouraging them to explore and develop, and managing the risks to prevent serious injury, was recognised in a government review published in 2009 (Department for Children, Schools and Families 2009a).\n\n# Risk factors\n\nChildren and young people from lower socioeconomic groups are more likely to be affected by unintentional injuries (Towner et al. 2005). Children whose parents have never worked (or are long-term unemployed) are 13 times more likely to die from an unintentional injury compared to children whose parents are in higher managerial or professional occupations. The social gradient is particularly steep in relation to deaths caused by household fires, cycling and walking (Edwards et al. 2006).\n\nA range of other factors also influence the likelihood of an unintentional injury. These include: personal attributes (such as age, physical ability and medical conditions), behaviour (such as risk-taking), the environment (for example, living in a house that opens onto a road or living in poor quality housing) (Audit Commission and Healthcare Commission 2007; Towner et al. 2005; Millward et al. 2003).\n\nWhile combinations of these factors create the conditions in which unintentional injuries occur, many are preventable (Audit Commission and Healthcare Commission 2007).\n\n# Preventing unintentional injuries\n\nApproaches to preventing unintentional injuries range from education (providing information and training) to product or environmental modifications and enforcement (regulations and legislation). The World Health Organization argues that legislation is a powerful tool that has helped reduce unintentional injuries on the road, in the home and in leisure environments (Peden et al. 2008).\n\nIt has been suggested that the most effective strategies use a combination of approaches (British Medical Association 2001). Experience from European countries with the best safety records show that positive leadership, together with concerted efforts to provide safer physical and social environments, can reduce unintentional injuries (Sethi et al. 2008).\n\n# Costs\n\nThere are six million visits to A&E departments in the UK each year as a result of unintentional injuries. Around two million involve children and young people – at a cost to the NHS of approximately £146 million a year (Audit Commission and Healthcare Commission 2007). Further treatment costs are significant. For example, £250,000 may be needed to treat one severe bath water scald (Child Accident Prevention Trust 2008).\n\nThe cost of unintentional injury is also borne by other public sector services such as transport, the police, fire and rescue services and the criminal justice system (Mallender et al. 2002). The long-term health needs and indirect 'human costs' for the family (Mallender et al. 2002) could include the repercussions of enforced absence from school, including the need for children and young people to be supervised. This, in turn, could involve family and carers having to take time off from work (Audit Commission and Healthcare Commission 2007).\n\n# Current policy and practice\n\nThe 'Children's plan' carried forward the 'Every child matters' objective to keep children and young people safe (Department for Children, Schools and Families 2003; 2007; 2008a; 2009b.) The 'Staying safe: action plan' set out a cross-government strategy (Department for Children, Schools and Families 2008b).\n\nStrategic partnerships and local safeguarding children boards have a duty to promote children and young people's safety as part of the action plan.\n\nIn addition, the national indicator set for local authorities and local authority partnerships addressed the prevention of injuries among children and young people (Department for Communities and Local Government 2007).\n\nOther relevant government initiatives have included:\n\nthe housing health and safety rating system (Office of the Deputy Prime Minister 2006)\n\nthe child road safety strategy (Department for Transport 2007)\n\nresponsibility for safety in workforce settings (Health and Safety Executive 2009).\n\nThe Treasury has also set out guidance on the value of preventing unintended fatalities and injuries (HM Treasury 2003).\n\nLocal area agreements have provided an opportunity for local authorities, in partnership with the NHS and other organisations, to focus on preventing unintentional injuries. Practice is variable, however some areas are adopting an innovative approach.\n\n National indicators NI70: Hospital admissions caused by unintentional and deliberate injuries to children and young people and NI48: Children killed or seriously injured in road traffic accidents.", 'Considerations': 'The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations.\n\n# General\n\nThis is one of three pieces of NICE guidance on how to prevent unintentional injuries among children and young people aged under 15. Several PDG members (including the chair) were co-opted as members of NICE\'s Public Health Interventions Advisory Committee (PHIAC) to advise on two pieces of guidance developed using NICE\'s public health intervention process. These covered unintentional injuries on the road and in the home and were published at the same time as this guidance. (For details see section 7.)\n\nThe extent of participation in any activity (that is, someone\'s exposure to risk of injury) correlates with injury rates. However, multiple risk factors may also correlate with the number and type of injuries in any given situation. Therefore, the determinants of injury (such as exposure and context) need to be understood. Details such as the nature and duration of the activity – and number of people undertaking it – could be used to supplement injury data and develop this understanding. Care is required when interpreting children and young people\'s self-reported data, as they may be reluctant to report where they have been and what they have done. In addition, younger children do not have a well-developed sense of time, making their exposure difficult to estimate.\n\nMany areas of the home, road and play and leisure environments have hazards which increase the risk of injury. Supervision, safety equipment and education are important to help keep children and young people safe. Equipment has to be maintained to be effective.\n\nSome families may not be receptive to advice on how to prevent unintentional injury because of \'fatigue\' from repeated contact about other health problems, such as cardiovascular disease (CVD) and cancer.\n\nInjury prevention interventions can be passive or active. Passive interventions do not require an active change in behaviour (as an example, they could include the presence of fire resistant materials or air bags in cars).\n\nChildren are not just small adults. Their physical, psychological and behavioural characteristics make them more vulnerable to injuries than adults. For example, the small stature of young children increases their risk on the road, where they may be masked by parked cars. Similarly, a given amount of a poisonous substance is likely to be more toxic for a child who has a much smaller body mass than an adult (Peden et al. 2008).\n\nTargeting specific groups may help reduce health inequalities. However, it will have a limited impact on overall injury rates. Targeted and universal approaches are required to reduce both the overall injury rate and health inequalities.\n\nPreventing serious injury is important. For every death, there are many more serious injuries which result in hospitalisation and most of these are avoidable.\n\n# Legislation, regulation and enforcement\n\nCaution should be exercised when considering evidence from other countries as different contexts often apply. For example, the drafting and introduction of UK legislation is often preceded by extensive consultation, which is not the case in all countries.\n\nLegislation can cover everyone, not just children and young people. For example, home safety regulation that requires gas inspections generally benefits everyone in the home.\n\nNumerous mechanisms are available to encourage compliance with safety procedures (for example, enforcement, insurance, health and safety legislation and the use of penalty points for drivers). However, enforcement activities may be more acceptable in public spaces such as on roads than in private spaces such as the home.\n\nLevels of compliance with legislation and regulation are dependent upon having a structured and comprehensive inspection process. For example, Australian studies on swimming pools have found that compliance with safety regulations is more likely if: there is a register of households with swimming pools, there is an annual inspection programme, and penalties are enforced for any breach of the regulations.\n\n# Injury surveillance\n\nIn 2002, the Home Accident Surveillance System (HASS) and the Leisure Accident Surveillance System (LASS) both came to an end. Since then, there has been a lack of standardised data collection of unintentional injuries in the home and in leisure settings. \'An information revolution\' (DH 2010) proposes that health data should be collected from multiple sources and disseminated by a single agency. It highlights the central role that high quality information can play in improving outcomes and narrowing inequalities.\n\nThe Programme Development Group (PDG) acknowledged a number of factors that may confound injury data. This includes the following:\n\nRoad traffic collisions not reported to the police are unlikely to be included in the STATS19 statistics. The actual number of road injuries is thought to be more than three times that in \'Reported road casualties in Great Britain 2009\' (Department for Transport 2010).\n\nThe number of injuries and fatalities may fall because an initiative intended to reduce injuries could also lead to a reduction in the number of people taking part in a given activity. Likewise, an initiative to promote physical activity might lead to an increase in the number of injuries due to an increase in the number of participants.\n\nA dataset may not include all injuries which occur in localities that lack emergency departments (for example, rural areas where the distance from hospital is a barrier to attendance).\n\nSharing injury data between organisations (for example, the ambulance service, hospitals and the police) is necessary to overcome gaps in knowledge and inconsistencies in recording such injuries. However, the PDG was aware that organisations can find it difficult to share data. Barriers can be institutional or relate to the confidentiality and security of personal information.\n\nInjury rates may vary according to the time of year. For example, children and young people\'s activity patterns may be different during the school term compared with the school holidays.\n\nShortcomings in injury data collection may result from a lack of awareness of the benefits of monitoring and surveillance. For example, emergency department staff may consider data collection an unnecessary burden. Greater awareness of the use and benefits of this information may lead to a greater commitment to data collection among these staff.\n\n# Home safety\n\nThe recommendations on home safety assessments and the supply and installation of home safety equipment are aimed at preventing unintentional injuries among all children and young people aged under 15. However, they prioritise households where children and young people are at greater than average risk of unintentional injuries due to one or more factors. For example, those aged under 5 and those living in social, rented or temporary accommodation with families on a low income are particularly vulnerable.\n\nExtensive evidence suggests that socioeconomic disadvantage increases the risk of childhood injury. Forty-four per cent of lone parents with dependent children are social tenants (Communities and Local Government 2009). Social tenants and often, tenants of private landlords have less income than owner-occupiers.\n\nGiven the extent of unintentional injuries among children under 5 in the home – and the increased risk of injuries among disadvantaged families, the PDG has made specific recommendations for these groups.\n\nThe physical environment may have an influence on the rate and type of injuries that occur. For example, high-rise flats often have potential hazards such as balconies, communal stairs and unsecured windows (Child Accident Prevention Trust 2010). In such situations, tenants may not have permission or the resources to make alterations.\n\nThe evidence available focused on items that need to be fitted to use at home, such as smoke alarms, window restrictors and thermostatic mixing valves (although there was no evidence about some equipment, including carbon monoxide alarms). It does not cover safety devices that do not need installing (for example, those already fitted onto lighters).\n\nWhen interpreting the evidence it should be noted that:\n\nhousing type and density differs between non-UK and UK studies, so research findings from other countries should be applied with caution\n\nan economic downturn can lead to a decline in the rate of construction of new buildings, so the potential to reduce unintentional injuries through recommendations for new-build homes is also lessened\n\nin studies reporting the effectiveness of thermostatic mixing valves:\n\n\n\nsome may have included scalds from other hot liquids such as drinks (that is, not just scalds caused by bath or shower water)\n\nsurveillance of their use may itself have contributed to their reported effectiveness, as the people being observed may have been inclined to take more care\n\nsome suggested that the occupant could reset the device, but it was not reported how often this occurred; the ability to override them could mean the degree of effectiveness demonstrated in studies could change\n\ninstallation of thermostatic mixing valves may change other safety practices, such as reducing the number of times parents check the water temperature before bathing a child. However, this will not increase the risk of scalds if the device is functional and set to an appropriate temperature.\n\n\n\nIt became compulsory to fit thermostatic mixing valves to bath taps in all new homes in England and Wales from 6 April 2010. Thermostatic mixing valves are usually fitted near to the tap, so that most stored hot water remains at a high enough temperature to kill the bacterium that causes Legionnaires\' disease.\n\nWith the exception of window restrictors, all age groups would benefit from home safety equipment (smoke and carbon monoxide alarms and thermostatic mixing valves). Window restrictors should benefit children aged over 2 as they are capable of climbing and falling from an unguarded window. The age at which window restrictors become ineffective is not clear. However, it is likely that most children can overcome child-resistant mechanisms by the time they reach the age of 5. Key-operated locks (where the key is inaccessible to a child) tend to be effective for longer. It is important to note the need to open windows in a fire emergency.\n\nAs more smoke alarms are installed than any other type of safety equipment, there is less potential to use them to reduce health inequalities.\n\nGaining access to people\'s homes needs sensitive consideration. The PDG acknowledge that the home is a private space and access will involve discussion and negotiation with residents.\n\n# Outdoor play and leisure\n\nThe PDG agreed with the Royal Society for the Prevention of Accidents (RoSPA) that children should be "as safe as necessary, not as safe as possible". Children and young people learn, develop and mature when playing and taking part in activities that challenge them and that sometimes involves taking risks. Play and leisure activities help children and young people to learn about the complex relationship between themselves and the world in which they live. Exposure to a degree of challenge may be beneficial during these activities. However, a distinction should be made between manageable and unmanageable situations:\n\nSome challenging situations are manageable and help a child to develop physically and emotionally. For example, undertaking a familiar activity without adult supervision is likely to be manageable.\n\nIn other situations, the risks may be too difficult for a child to assess and manage, or are unlikely to lead to any obvious benefits. They may even expose the child to danger. Examples would be swimming in a disused quarry, or playing on poorly designed and maintained equipment in a play area.\n\nParents\' and carers\' and their child\'s perception of safety can influence the amount of time children and young people spend on outdoor play and leisure activities. These perceptions can be influenced by the media. In addition, fear of litigation can influence the nature and extent of activities provided by educational and play organisations.\n\nIt is difficult to regulate activities such as canyoning and wild swimming and the settings in which they take place. It is also difficult to regulate inland waterways not currently used for supervised recreation.\n\nThe classification of a leisure activity is not always clear. For example, when a child is cycling it\'s not always clear whether cycling is a leisure activity or is being used as a form of transport. Similarly, it\'s not always clear whether a child or young person is playing in water or swimming, playing with a ball or participating in sport.\n\nMedia campaigns to promote injury prevention activities may increase health inequalities, as uptake is likely to vary among different groups. For example, disadvantaged families are less likely to respond to health information than families who are more advantaged.\n\nThe PDG acknowledged that dividing on- and off-road cycling into two separate activities was an artificial division, particularly in relation to older children. The scope of the guidance did not include equipment used to prevent against unintentional injuries on the road. However, it did cover outdoor play and leisure, so the use of helmets in parks, on bridleways and in other environments was reviewed. (Children often fall off their bikes, especially when they are learning to ride a bicycle and when they are learning BMX and mountain bike skills, so there is a need to protect them from unnecessary injury.)\n\nRecommendations have been made about promoting cycle helmets but not about making them compulsory. The PDG was aware of the debate on cycle helmets.\n\nThe PDG considered a number of issues in relation to the use of helmets including the:\n\nneed to purchase one when buying a bike\n\nneed to include helmets as part of rent-a-bike schemes\n\nneed to introduce them into the informal secondhand bike market (which includes passing bikes down and between families)\n\ndesign and fitting\n\nfact that some adults are poor role models when it comes to helmet wearing\n\nneed to wear them for other activities such as skateboarding and some high-risk water sports\n\npotential for injury if they are worn when using equipment not designed for their use (such as playground equipment) or are used in other inappropriate ways.\n\nCurrent playground standards aiming to reduce the incidence of traumatic brain injury are important, as it is a potentially serious injury. Protection against broken arms and legs is also needed, as these are common and can result in disability and deformity.\n\nInterventions that have been shown to reduce firework injuries in other countries may not, necessarily, have the same effect in England. For example, in countries with drier weather conditions, the danger from unexploded fireworks is greater and so measures to clear them up are likely to have a greater impact. Enforcing firework regulations in England is also different because they are only on sale here for short periods of time. For example, retailers and display organisers are granted temporary licences to sell them in advance of Bonfire Night and other festivals.\n\n# Road safety\n\nThe PDG noted several demographic differences in child pedestrian injuries. For example, more boys than girls are injured. In addition, children aged 10 and under are more likely to be injured on minor urban roads, while those aged 11 and over are more likely to be harmed on main roads. It also noted that children living in deprived areas (and those from some minority ethnic groups) are more likely than the general population to make journeys alone or only supervised by an older sibling.\n\nMost studies on traffic speed are conducted on the main road network. Fewer are conducted on minor residential roads where children and young people are more likely to be present.\n\nThe PDG acknowledged that injury prevention activities should take into account the importance of public transport and sustainable travel modes, such as walking and cycling, which have known health benefits. Reducing traffic speed should help to encourage physically active modes of travel.\n\nMost studies focus on the evaluation of legislation which is enforced by imposing sanctions on those who break the rules. This is because data on the effect of such interventions are more readily available than for less punitive measures. Although the latter may be equally effective, they have not been recommended due to a lack of evidence.\n\nTransport studies tend to use a \'before-and-after\' design. They estimate the relationship between two or more factors using data collected at a number of specified intervals over a period of time. They require an adequate control to demonstrate causality.\n\nChildren and young people cannot influence the speed or general manner in which vehicles are driven or whether seatbelts are available. In addition, they often have little or no choice about their mode of travel.\n\nThe evidence review on the effectiveness of safety cameras which informed evidence statement 3.1 only included systematic reviews. One of these has since been updated (Wilson et al. 2010) and evidence statement 3.1 has been amended in appendix C of this guidance to include its findings. The systematic reviews in the original report to NICE did not capture evidence from relevant primary sources that report differential effectiveness. However, the PDG noted that the National Safety Camera Programme (Gains et al. 2005) reports differential effects on children, for urban and rural environments and for fixed and mobile cameras. The cost effectiveness review which informed evidence statement 6.5 used primary sources, including the National Safety Camera Programme.\n\n# Limitations of the evidence\n\nThe recommendations reflect the evidence identified and the PDG\'s discussions. The absence of recommendations on any particular measures to prevent unintentional injuries is a result of a lack of evidence that met the inclusion criteria for the evidence reviews. It should not be taken as a judgement on whether or not any such measures are effective and cost effective.\n\nRepeated testing of outcome measures can affect the validity of an evaluation. For example, a variable that is extreme when first measured will tend to be closer to the mean when measured later. If this statistical effect is not taken into account, caution will need to be exercised when interpreting any conclusions about an intervention\'s effectiveness.\n\nMany injury prevention programmes do not lend themselves to the use of \'blinding\' (whereby participants are not aware which research study group they have been allocated to). However, it is often possible to have evaluators who are \'blind\' to group allocation.\n\nAlthough interventions often include adults, children and young people, the outcomes for children and young people are not reported separately.\n\nStudies of the effectiveness of strategic approaches to injury prevention (such as legislation and enforcement) did not provide a strong evidence base for economic modelling.\xa0 As a result, most of the assumptions or variables used in the modelling are based on very limited or estimated data and the conclusions should be treated with caution.', 'Recommendations for research': "The Programme Development Group (PDG) recommends that the following research questions should be addressed to fill the most important gaps in the evidence in relation to this and the other two pieces of NICE guidance that were published in November 2010. These form part of a 'suite' of NICE advice on preventing unintentional injuries:\n\nUnintentional injuries in the home: interventions for under 15s (NICE guideline PH30).\n\nUnintentional injuries on the road: interventions for under 15s (NICE guideline PH31).\n\nThe PDG notes that 'effectiveness' in these contexts relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects.\n\nStudies of effectiveness and cost effectiveness should investigate and report on the differential effectiveness for children and young people who are more at risk of unintentional injury. They should collect data on the factors listed in research recommendation 1 and also on the:\n\nshort and long-term effects (physical, psychological and financial) on children, young people, their parents and carers (for example, time away from school for children and work for parents and extent of residual disability)\n\nlong-term quality-of-life and public sector cost impacts of non-fatal injuries.\n\n# Epidemiology and behaviour\n\nWhat are the recent epidemiological and aetiological trends in types, causes and impact of unintentional injuries among under-15s? Use data collected by the recommended surveillance systems (see recommendations 7–8) to identify findings for specific groups and activities in the home, on the road and during outdoor play and leisure. Factors to consider are:\n\ncause, nature, location and factors involved in the incident and type, site and severity of injury\n\nnumbers of children and young people involved, time spent undertaking the activity and the extent of supervision\n\ndemographic details with data presented for subgroups of children and young people (for example, grouped according to age, gender, ethnicity, socioeconomic status, disability and place of residence).\n\nHow do parents, carers, children and young people perceive risk in the home, on the road and during outdoor play and leisure – and how do they perceive the risks and benefits inherent in specific activities? How do these perceptions vary between populations and subgroups based on gender, age, race/ethnicity, socioeconomic status, disability, or other characteristics of the participants or their environment? How strongly associated is children and young people's exposure to risk with their behaviour, the causes, incidence and severity of unintentional injury?\n\nDoes exposure to risk and the opportunity to experience risk-taking have a beneficial effect on children and young people? Does the effect vary according to age and other socio-demographic factors or according to the quality and nature of the risk?\n\nTo what extent – and how – does children and young people's behaviour alter when their environment is made safer? How does children and young people's (and their parents' and carers') perception of risk impact on the amount and type of physical activity undertaken by children and young people?\n\n# Effectiveness studies\n\nWhat is the differential effectiveness and cost effectiveness of legislation, regulation, policies and standards to prevent unintentional injuries in the UK? Studies should consider the process and cost of development, promotion, implementation and enforcement. They should collect baseline data prior to any change and for a meaningful length of time afterwards on:\n\nhome safety assessments, thermostatic mixing valves (TMVs), smoke alarms (hard-wired and 10-year battery-operated), carbon monoxide alarms and window restrictors\n\nwater safety initiatives, sports rules and regulations, cycling skills training for children and young people and cycle helmet use\n\nroad safety knowledge and skills, road user behaviour, different types of road signage, differential effectiveness of speed enforcement (networked, targeted or mixed approaches) in rural and residential areas.\n\nHow effective and cost effective are social marketing and mass-media campaigns in support of legislation, regulation, policy and standards to reduce unintentional injuries among children and young people in the home, on the road and during outdoor play and leisure?\n\nWhat is the impact of injury prevention training and development initiatives on those involved in preventing injuries in terms of their level of knowledge and degree of competency? What impact do such initiatives have on the scope and quality of preventive activities? Examples of training and developmental initiatives include: training people to undertake home risk assessments and educating representatives of community partnerships and private landlords about the Housing Health and Safety Rating System (HHSRS).\n\nWhat prevents and what encourages children and young people to comply with legislation, regulation and standards to prevent unintentional injuries in the home, on the road and during outdoor play and leisure?\n\nWhat prevents and what encourages delivery and implementation of policies/strategies to prevent unintentional injuries among children and young people in the home, on the road and during outdoor play and leisure? (These are outlined, for example, in white and green papers and policy briefings.)\n\n# Interventions: all settings\n\nHow do the following factors influence the effectiveness and cost effectiveness of interventions to prevent unintentional injury in the home, on the road and during outdoor play and leisure:\n\nmethod of delivery (for example, session format, learning materials)\n\ncontent\n\nfrequency and duration of follow-ups\n\ndeliverer\n\nparental/carer involvement\n\ndemographic characteristics of the participants (for example, gender, age, race/ethnicity, socioeconomic status and disability)?\n\nWhat are the most effective and cost-effective ways of providing under-15s, their parents and carers with information, advice and education about safety and hazards in the home, on the road and in outdoor play and leisure environments?\n\nTo what extent do interventions to prevent unintentional injuries among under-15s in the home, on the road and during outdoor play and leisure impact on the household's safety knowledge and behaviour? What role do family members and carers (fathers, mothers, grandparents and extended family units) play in preventing unintentional injuries?\n\n# Interventions: road safety\n\nTo what extent do interventions to reduce speed and prevent unintentional injuries on the road among under-15s influence people's attitude, knowledge and behaviour towards road safety (both drivers and the general public)? How can interventions be designed to maximise this effect?\n\nHow can systematic methods, combining health and engineering research, be developed to:\n\nassess the effectiveness and cost effectiveness of injury prevention interventions outside the health sector (for example, within education and employment)\n\nidentify wider public health outcomes as a standard part of research into engineering measures to reduce speed and unintentional injuries (including co-benefits and unintended consequences, such as the impact on physical activity and air quality)?\n\n# Interventions: home safety\n\nHow effective and cost effective are home safety interventions (including combined interventions) in preventing unintentional injuries among different population groups? For example, how effective are they in relation to participants' gender, age, race/ethnicity, socioeconomic status, disability, or other characteristics? To what extent does effectiveness and cost effectiveness vary according to the type of injury being prevented?\n\nTo what extent does the provision of safety information, advice and education during a home safety intervention contribute to its effectiveness and cost effectiveness? (For example, does it reduce the number – and severity – of unintentional injuries in the home among under-15s?)\n\nHow effective and cost effective are the different methods used to deliver safety information, advice and education? To what extent do effectiveness and cost effectiveness vary with different types of injury prevention activity?\n\n# Interventions: play and leisure\n\nTo what extent does exposure to risk during outdoor play and leisure affect children and young people's risk-management skills in the setting where the hazard was encountered, other designated play areas, non-designated play areas and non-play settings?More detail on the gaps in the evidence identified during development of this guidance is provided in appendix D.", 'Updating the recommendations ': 'This guidance will be reviewed 3 years after publication to determine whether all or part of it should be updated. Information on the progress of any update will be posted on our website.', 'Related NICE guidance': 'Community engagement: improving health and wellbeing and reducing health inequalities (2016) NICE guideline NG44.\n\nUnintentional injuries on the road: interventions for under 15s (2010) NICE guideline PH31.\n\nUnintentional injuries in the home: interventions for under 15s (2010) NICE guideline PH30.\n\nChild maltreatment: when to suspect maltreatment in under 18s (2009) NICE guideline CG89.\n\nBehaviour change: general approaches (2007) NICE guideline PH6.\n\nPostnatal care up to 8 weeks after birth (2006) NICE guideline CG37.', 'References': "Audit Commission/Healthcare Commission (2007) Better safe than sorry: preventing unintentional injury to children. London: Audit Commission\n\nBritish Medical Association (2001) Injury prevention. London: British Medical Association Board of Science and Education\n\nChild Accident Prevention Trust (2008) Child Accident Prevention Trust factsheet: preventing bath water scalds using thermostatic mixing valves. London: Child Accident Prevention Trust\n\nChild Accident Prevention Trust (2010) Children and their accidents. Factsheet. London: Child Accident Prevention Trust\n\nCommunities and Local Government (2009) Housing and planning statistics. London: Communities and Local Government\n\nDepartment for Children, Schools and Families (2003) Every child matters. London: The Stationery Office\n\nDepartment for Children, Schools and Families (2007) The children's plan: building brighter futures. London: Department for Children, Schools and Families\n\nDepartment for Children, Schools and Families (2008a) The children's plan. One year on. London: Department for Children, Schools and Families\n\nDepartment for Children, Schools and Families (2008b) Staying safe: action plan. London: Department for Children, Schools and Families\n\nDepartment for Children, Schools and Families (2009a) Accident prevention among children and young people. A priority review. London: Department for Children, Schools and Families\n\nDepartment for Children, Schools and Families (2009b) The children's plan. Two years on. London: Department for Children, Schools and Families\n\nDepartment for Communities and Local Government (2007) The new performance framework for local authorities & local authority partnerships. London: Department for Communities and Local Government\n\nDepartment for Transport (2007) The child road safety strategy. London: Department for Transport\n\nDepartment for Transport (2010) Reported road casualties Great Britain 2009: annual report. London: Department for Transport\n\nDepartment of Health (2010) An information revolution: a consultation on proposals. London: Department of Health\n\nDepartment of Trade and Industry (2002) Home accidents surveillance system (HASS)\n\nEdwards P, Roberts I, Green J et al. (2006) Deaths from injury in children and employment status in family: analysis of trends in class specific death rates. BMJ 333: 119–21\n\nEurosafe (2006) Childhood burns and scalds: facts. Netherlands: Eurosafe\n\nGains A, Norstrom M, Heydecker BG et al. (2005) The national safety camera programme: four-year evaluation report. London: Department for Transport\n\nHealth and Safety Executive (2009) The health and safety of Great Britain\n\nHM Treasury (2003) The green book. Appraisal and evaluation in central government. London: The Stationery Office\n\nMallender J, O'Leary C, Lowdell C (2002) Costs of injuries to London. In Lowdell C, Fitzpatrick J, Wallis R et al. editors. Too high a price: injuries and accidents in London. London: London Health Observatory\n\nMillward LM, Morgan A, Kelly MP (2003) Prevention and reduction of accidental injury in children and older people. London: Health Development Agency\n\nOffice for National Statistics (2009) Mortality statistics: deaths registered in 2008. Table 5.19 ICD10 codes V01–X59. Review of the Registrar General on deaths in England and Wales\n\nOffice of the Deputy Prime Minister (2006) The housing health and safety rating system (HHSRS) operating guidance. Housing Act 2004: Guidance about inspections and assessment of hazards given under Section 9. London: Office of the Deputy Prime Minister\n\nPeden M, Oyegbite K, Ozanne-Smith J et al. editors (2008) World report on child injury prevention. Geneva: World Health Organization\n\nSethi D, Towner E, Vincenten J et al. editors (2008) European report on child injury prevention. Copenhagen: World Health Organization Regional Office for Europe\n\nThe Information Centre for Health and Social Care (2010) Hospital episode statistics (HES) [accessed 5 December 2009]\n\nTowner E, Dowswell T, Errington G et al. (2005) Injuries in children aged 0–14 years and inequalities. London: Health Development Agency\n\nWilson C, Willis C, Hendrikz JK et al. (2010) Speed cameras for the prevention of road traffic injuries and deaths (review). Cochrane Library: 10", 'Appendix B: Summary of the methods used to develop this guidance': "# Introduction\n\nThe reviews, primary research, commissioned reports and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in appendix E and are available online.\n\n# Guidance development\n\nThe stages involved in developing public health programme guidance are outlined in the box below.\n\n. Draft scope released for consultation\n\n. Stakeholder meeting about the draft scope\n\n. Stakeholder comments used to revise the scope\n\n. Final scope and responses to comments published on website\n\n. Evidence reviews and economic analysis undertaken\n\n. Evidence released for consultation\n\n. Comments and any additional material submitted by stakeholders\n\n. Review of any additional material submitted by stakeholders (screened against inclusion criteria used in reviews)\n\n. Evidence and economic analysis submitted to PDG\n\n. PDG produces draft recommendations\n\n. Draft guidance released for consultation and for field testing\n\n. PDG amends recommendations\n\n. Final guidance published on website\n\n. Responses to comments published on website\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching questions were:\n\nWhich approaches are effective and cost effective in preventing or reducing unintentional injuries among children and young people aged under 15?\n\nWhich approaches are effective and cost effective in preventing or reducing unintentional injuries among children and young people aged under 15 from disadvantaged families?\n\nWhich types of approach effectively (and cost effectively) support and help develop the skills of professionals and others involved in childhood injury prevention?\n\nWhat type of monitoring systems are effective and cost effective in recording and detecting changes in the type, incidence and prevalence of unintentional injuries among children and young people aged under 15?\n\nWhat are the barriers and facilitators to implementing initiatives to prevent unintentional injuries among children and young people aged under 15?\n\nThese questions were made more specific for each review (see reviews for further details).\n\n# Reviewing the evidence\n\n## Effectiveness reviews\n\nFive reviews of effectiveness were conducted. One compared international practice (review 1), one covered quantitative correlates (review 2) and three were reviews of effectiveness (reviews 3–5).\n\n## Identifying the evidence\n\nThe following databases were searched for the effectiveness reviews (from 1990 to January 2009 [review 1], 1990 to February 2009 [review 2], 1990 to April 2009 [review 3], 1990 to June 2009 [review 4] and 1990 to July 2009 [review 5]):\n\nCochrane Database of Systematic Reviews\n\nDatabase of Abstracts of Reviews of Effectiveness (DARE)\n\nEPPI Centre databases (Bibliomap, DoPHER, TRoPHI)\n\nHealth Management Information Consortium (HMIC)\n\nKings Fund catalogue and Department of Health data\n\nHealth Technology Assessment (HTA)\n\nMEDLINE\n\nNHS Economic Evaluation Database (NHS EED)\n\nSafetyLit\n\nSocial Science Citation Index\n\nThe Campbell Collaboration\n\nIn addition, the following databases were searched, as appropriate, for individual reviews (from 1990 to January 2009 [review 1], 1990 to February 2009 [review 2], 1990 to April 2009 [review 3], 1990 to June 2009 [review 4] and 1990 to July 2009 [review 5]):\n\nAssia\n\nCinahl\n\nCochrane Injuries Group Register\n\nEconLit\n\nEmbase\n\nISI Web of Science\n\nInternational Transport Research Documentation (ITRD)1\n\nPsycINFO\n\nSPORTDiscus\n\nTransport Research Information Service (via the TRIS)\n\nTransport Research Laboratory\n\nWebsite searches included:\n\nChild accident prevention trust (CAPT)\n\nEurosafe\n\nInjury Observatory for Britain and Ireland (IOBI)\n\nInstitute of Highway Incorporated Engineers\n\nInstitute of Home Safety\n\nRoyal Society for the Prevention of Accidents (RoSPA)\n\nRoyal Town Planning Institute\n\nSafe routes to school\n\nSouth West Public Health Observatory\n\nUK Department for Transport (DfT)\n\nFor review 1, searches were primarily conducted by snowball sampling of key organisations and individual contacts, supplemented by Internet searches, including the web pages of international and national organisations. For reviews 2–5, electronic searches of relevant bibliographic databases and selected websites were supplemented by communication with experts and organisations involved in the relevant research or policy areas.\n\nFurther details of the databases, search terms and strategies are included in the review reports.\n\n## Selection criteria\n\nStudies were included in reviews 1 and 2 if they were published between 1997 and 2009 in English. In addition:\n\nReview 1 included studies which reported separately for children in at least two countries (or 'country-sized' regions).\n\nReview 2 focused on observational research and intervention studies which quantified the association or relationship between unintentional injuries among children and two or more variables such as exposure to a particular environment or socioeconomic status.\n\nStudies were included in reviews 3–5 if they:\n\nwere published between January 1990 and February 2009 in English\n\nused comparative studies to compare groups of people, places or activities\n\nMore detailed inclusion and exclusion criteria for individual reviews can be found on our website.\n\n## Quality appraisal\n\nFor reviews 1 and 3 to 5, the included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.\n\n++ All or most of the checklist criteria have been fulfilled, where they have not been fulfilled the conclusions are very unlikely to alter.\n\n+ Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.\n\n– Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\n\nThe main reasons for studies being assessed as (–) were:\n\nlack of control or comparison group\n\nlack of baseline equivalence/data\n\ninadequately described interventions\n\ninadequate analysis and reporting of data.\n\nFor reviews 2 to 5, the studies were also assessed for their applicability to the area under investigation and the evidence statements were graded as follows:\n\nDirectly applicable.\n\nPartially applicable.\n\nNot applicable.\n\n## Summarising the evidence and making evidence statements\n\nThe review data was summarised in evidence tables (see full reviews).\n\nThe findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the public health collaborating centres (see appendix A). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.\n\n# Cost effectiveness\n\nThere was a review of economic evaluations and an economic modelling exercise.\n\n## Review of economic evaluations\n\nThis sought to identify and review economic evaluations published since 1990 of relevant legislation, regulation or other strategic approaches of interest. The search was undertaken in two stages.\n\nFirst the RefMan database was searched for 'hits' from the five reviews and two related pieces of NICE public health guidance (preventing unintentional injuries to children on the road and in the home).\n\nSecond, a new search was carried out in EconLit and NHSEED (NHS Economic Evaluation Database) using text words and thesaurus terms covering all types of injuries among children.\n\n## Economic modelling\n\nAn economic model was constructed to explore the cost-effectiveness of jurisdiction-wide strategic approaches to prevent unintentional injuries among children aged under 15 years.\xa0 The exploratory analyses were conducted from a UK public sector perspective.\n\nTwo different strategic policies were explored: to reduce unintentional injuries among children and adults on the road and at home. The former focused on legislation or regulations, supported by other activities, introducing mandatory 20mph zones in high casualty residential areas. The latter focused on legislation or regulations, supported by other activities, to promote installation of thermostatic mixer valves in family social housing where children are aged less than 5 years.\n\nDue to a paucity of data, the model explored which factors might be important in determining cost effectiveness.\n\nThe results are reported in: Economic modelling of legislation/regulations and related national strategies to promote the wider use of: 20\xa0mph zones in residential areas, and TMVs in social housing for families.\n\n# Fieldwork\n\nFieldwork was carried out to evaluate how relevant and useful NICE's recommendations would be for practitioners and how feasible it would be to put them into practice.\n\nIt was conducted with practitioners and commissioners who are involved in preventing unintentional injuries among children and young people. This included those working in primary care trusts (PCTs), local safeguarding children boards and accident prevention and road safety teams. It also included health visitors, nurses and policy leads, within the NHS, those working in the fire and police services, leisure and play services, and environmental health and housing.\n\nThe fieldwork comprised:\n\nSeven discussion groups conducted in Lancashire, South East London and Sussex by Word of Mouth research consultancy.\n\nForty-nine face-to-face and telephone interviews conducted by Word of Mouth with staff from Lancashire, South East London and Sussex. In addition to the groups listed above, participants also included: an assistant school head, a cycle events organiser and a cycle retailer, further education college curriculum managers, healthy schools managers, paediatricians, staff from children's centres, a safer communities manager, a school governor, social workers and voluntary sector children's services managers.\n\nThe main issues arising are set out in appendix C under 'Fieldwork findings'. The full fieldwork report Strategies to prevent unintentional injury among under-15s is available online.\n\n# How the PDG formulated the recommendations\n\nAt its meetings between February 2009 and July 2010, the Programme Development Group (PDG) considered the evidence, expert testimony and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of strength and applicability) to form a judgement\n\nwhere relevant, whether (on balance) the evidence demonstrates that the intervention or programme can be effective or is inconclusive\n\nwhere relevant, the typical size of effect (where there is one)\n\nwhether the evidence is applicable to the target groups and context covered by the guidance.\n\nThe PDG developed draft recommendations through informal consensus, based on the following criteria:\n\nStrength (type, quality, quantity and consistency) of the evidence.\n\nThe applicability of the evidence to the populations and settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nEquality and diversity legislation.\n\nEthical issues and social value judgements.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of harms and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nWhere possible, recommendations were linked to an evidence statement(s) (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).\n\nThe draft guidance, including the recommendations, was released for consultation in May 2010. At its meeting in July 2010, the PDG amended the guidance in light of comments from stakeholders and experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in October 2010.", 'Appendix C: The evidence ': "This appendix lists the evidence statements from six reviews provided by the public health collaborating centre (see appendix A) and links them to the relevant recommendations. (See appendix B for the key to quality assessments.) The evidence statements are presented here without references – these can be found in the full reviews (see appendix E for details).\n\nThe appendix also lists six expert testimonies and their links to the recommendations and sets out a brief summary of findings from the economic analysis.\n\nThe six evidence reviews are:\n\nReview 1: 'Current practice and innovative approaches to prevent childhood unintentional injuries: An overview and synthesis of international comparative analyses and surveys of injury prevention policies, legislation and other activities'.\n\nReview 2: 'A systematic review of risk factors for unintentional injuries among children and young people aged under 15 years'.\n\nReview 3: 'An overview and synthesis of evidence relating to strategies and frameworks for planning, implementing, enforcing or promoting activities to prevent unintentional injury to children and young people on the road: legislation, regulation, standards and related strategies focusing on the design and modification of highways, roads or streets'.\n\nReview 4: 'Strategic and regulatory frameworks for guiding, enforcing or promoting activities to prevent unintentional injury in children and young people in the home environment'.\n\nReview 5: 'Strategies, policies and regulatory or legal frameworks and/or mass media campaigns to prevent unintentional injury to children during play and leisure in the external environment'.\n\nReview 6: 'Preventing unintentional injuries in children. Systematic review to provide an overview of published economic evaluations of relevant legislation, regulations, standards, and/or their enforcement and promotion by mass media'.\n\nEvidence statement number 1.1 indicates that the linked statement is numbered 1 in review 1. Evidence statement number 2.1 indicates that the linked statement is numbered 1 in review 2. Evidence statement number 3.1 indicates that the linked statement is numbered 1 in review 3. ET1 indicates that expert testimony number 1 is linked to the recommendation.\n\nThe reviews, expert testimony and economic analysis are available online.\n\nWhere a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nRecommendation 1: evidence statements 2.2, 2.3, 2.4, 2.5, 2.7, 2.8, 2.9, 2.10, 2.11, 2.12, 2.14a, 2.14b, 2.14c, 2.14f, 2.14i; ET3\n\nRecommendation 2: IDE\n\nRecommendation 3: IDE\n\nRecommendation 4: IDE\n\nRecommendation 5: IDE\n\nRecommendation 6: IDE\n\nRecommendation 7: evidence statement 1.1; ET6\n\nRecommendation 8: evidence statement 1.1; ET6\n\nRecommendation 9: evidence statements 4.1, 4.2, 4.3, 4.4; ET3\n\nRecommendation 10: evidence statements 2.2, 2.3, 2.4, 2.5, 2.7, 2.8, 2.9, 2.10, 2.11, 2.12, 2.14a, 2.14b, 2.14c, 2.14f, 2.14i, 4.1, 4.2, 4.3; ET3\n\nRecommendation 11: evidence statements 2.2, 2.3, 2.4, 2.5, 2.7, 2.8, 2.9, 2.10, 2.11, 2.12, 2.14a, 2.14b, 2.14c, 2.14f, 2.14i, 4.1, 4.2, 4.3; ET3\n\nRecommendation 12: evidence statement 5.4\n\nRecommendation 13: IDE\n\nRecommendation 14: IDE\n\nRecommendation 15: evidence statement 5.3; IDE\n\nRecommendation 16: evidence statement 5.5\n\nRecommendation 17: IDE\n\nRecommendation 18: evidence statements 1.3, 2.14f; ET1\n\nRecommendation 19: evidence statement 2.14f; ET1\n\nRecommendation 20: IDE\n\nRecommendation 21: evidence statements 1.2, 3.1, 3.2, 6.5\n\n# Evidence statements\n\nPlease note that the wording of some evidence statements has been altered slightly from those in the review team's report to make them more consistent with each other and NICE's standard house style.\n\n## Evidence statement 1.1\n\nThree (+) international comparison studies show a lack of comparable in-depth information on exposure to risk to help in analysis of the relative impact of different legislative, regulatory, enforcement and compliance interventions.\n\n## Evidence Statement 1.2\n\nTwo ecological studies (one [+] and one [-]) in high income countries were unable to associate variations in child morbidity and/or mortality rates across countries to differences in legislation, regulation, enforcement and compliance for road environment modification, road design, home and leisure environment interventions. However for road safety, evidence from two ecological studies (one [+] and one [++]), suggest a weak trend towards better performing countries (in terms of child fatality rates) having more road environment modification and road design measures in place.\n\n## Evidence Statement 1.3\n\nEvidence from one (++) ecological study indicates that differences in the distribution of exposure in the road environment for child pedestrians (in particular relating to time spent near busy main roads) can explain some of the difference in severe child injury and fatality rates between Great Britain and two other northern European countries, France and the Netherlands.\n\n## Evidence statement 2.2\n\nThere is evidence from 10 studies (one UK). There is evidence of a strong association (that is, relative risk equivalent of greater than 2.0) of injuries being associated with travelling in a car driven by a non-sibling teenager. There is evidence of weak to moderate association (that is, relative risk equivalent of greater than 1.0 to less than 2.0) of injuries with lower parental income, employment status, educational status, socioeconomic status, and with travelling in a car with a female driver (when the injured child was appropriately restrained). The increased risk in females may well reflect their longer periods of time in the presence of children. There is mixed evidence regarding the association of injuries with ethnicity.\n\n## Evidence statement 2.3\n\nThere is evidence from 18 studies (five UK). There is evidence of a strong association between the lowest socioeconomic quintiles, being of Native American descent (for pedestrians), having parents who were migrants, hyperactivity, behavioural difficulties, or bicycle riding (riding slowly or only on the pavement) and injuries. There is evidence of weak to moderate association of injuries with membership of the second socioeconomic quintile, social deprivation, non-professional parental occupation, rural and mixed-urban environments, being male, or behavioural disorders. There was no statistical evidence of injuries being associated with social fragmentation or ethnicity (for cyclists).\n\n## Evidence statement 2.4\n\nThere is evidence from seven studies (one UK). There is evidence of weak to moderate association of injuries with socioeconomic deprivation and being African-American. There is mixed evidence regarding the association of socioeconomic status (measured by parental occupation) with injuries. There was no statistical evidence of injuries being associated with autism.\n\n## Evidence statement 2.5\n\nThere is evidence from six studies (one UK) on burns and fire in the home of a strong association between child's age (less than 1 year), low mother education and age, and areas of concentrated poverty (and high numbers of African-American population) and injuries. There is evidence of weak to moderate association of burn injuries with children being male, from an ethnic minority, having behavioural problems and a poor reading score, low parental education, lower home income, a larger number of children in the home, and rural location. There was no statistical evidence of burn injuries being associated with type of home ownership.\n\n## Evidence statement 2.7\n\nThere is evidence from three studies (none UK) on falls in the home of a strong association between greater child's age (older than 1 year) and injuries. There is evidence of weak to moderate association of injuries with: being male, of African-American descent, families being in receipt of social welfare benefits, lower educational status of parents, lower income, single parent households, lower mother's age at childbirth, non-owner housing occupancy, living in a flat or farmhouse, older housing and being a migrant. Being lone parent status, neighbourhood poverty and living in cities were not statistically associated with falls.\n\n## Evidence statement 2.8\n\nThere is evidence from seven studies (one UK) on poisoning in the home of a strong association between child's age (from 1 to 4 years), behavioural problems, and autism and injuries. There is evidence of weak to moderate association of injuries being associated with: being male, having a lower reading score, lower educational status of parents, lower income, larger families, being in receipt of social welfare benefits, younger age of mother at childbirth, being of Native American descent, living in the country, and the birth of a sibling within 12 months (for iron tablet poisoning). There was no statistical evidence of injuries beingassociated with single parent households, family size, overcrowding, or house type.\n\n## Evidence statement 2.9\n\nThere is evidence from two studies (one UK) on undefined causes of injury in the home of weak to moderate association of injuries with lower educational status of parents and lower family income. There was no statistical evidence of injuries being associated with parental marital status or of being in receipt of social welfare benefits.\n\n## Evidence statement 2.10\n\nThere is evidence from four studies (none UK). There is evidence of a strong association between the use of public playgrounds or being of African-American descent and injuries. There is evidence of weak to moderate association of injuries being with being of Latin American descent, location of a school within an urban area, schools with larger numbers of classes (greater than or equal to 24), longer school hours, and the levels of physical activity engaged in outside of school. There was no statistical evidence of injuries being associated with the levels of physical activity engaged in within school.\n\n## Evidence statement 2.11\n\nThere is evidence from six studies (one UK) on burns and fire in all environments of a strong association between the most socioeconomically deprived families, living in a house with one to three or more bedrooms, attention deficit hyperactivity disorder (ADHD), and being of Native American descent and injuries. There was no statistical evidence of injuries being associated with autism, having previously endured an unintentional burn/fire injury, parental employment status, entitlement to Medicaid, or order of sibling birth.\n\n## Evidence statement 2.12\n\nThere is evidence from three studies (none UK). There is evidence of weak to moderate association of injuries with entitlement to Medicaid (in children aged 5 to 14 years) and with non-entitlement to Medicaid (in infants aged 0 to 4 years). There was no statistical evidence of injuries being associated with being of Native-American descent or the presence of behavioural disorders.\n\n## Evidence statement 2.14a\n\nThere is evidence from 12 studies (four UK) on all injury types in all environments of a strong association (compared with newborns aged up to 6 weeks) between children aged 7–24 months and injuries. There is evidence of weak to moderate association of injuries with increasing age (4 years or older versus younger than 4 years), children aged 15–54 months (versus younger than 6 months), and increasing age among children with a disability. There was no statistical evidence of injuries being associated with increasing age in the case of head injuries.\n\n## Evidence statement 2.14b\n\nThere is evidence from 16 studies (four UK). There is evidence of weak to moderate association of injuries (of all severities, including fatalities) with being male.\n\n## Evidence statement 2.14c\n\nThere is mixed evidence from eight studies (one UK) on ethnicity in all injury types in all environments regarding the association of child ethnicity with injuries. There is evidence of weak to moderate association of injuries with being of black or Native American descent. There was no statistical evidence of injuries being associated with being of Asian descent or a wide range of other ethnicities.\n\n## Evidence statement 2.14f\n\nThere is evidence from 27 studies (six UK) on family's socioeconomic status in all injury types in all environments of weak to moderate association of injuries with socioeconomic deprivation. There is no statistical evidence of injuries (reported in some studies) being associated with socioeconomic deprivation within certain age categories. There is mixed evidence regarding the association of parental educational attainment and household income with injuries.\n\n## Evidence statement 2.14i\n\nThere is evidence from eight studies (four UK). There is evidence of weak to moderate association of injuries with socioeconomic deprivation, but no evidence of association between other indicators of neighbourhood disadvantage and the occurrence of unintentional injuries.\n\n## Evidence Statement 3.1\n\nThere is moderate evidence from three recent systematic reviews (one [++] and two [+]) that road speed enforcement devices (cameras, lasers or radar) reduce road injuries, and serious/fatal injury crashes/collisions in the vicinity of the devices. One systematic review (+) also concluded that similar size of speed reduction effects were observed over wider geographical areas around the enforcement device sites. The size of the observed reductions in different studies, and in different localities within studies, varies considerably. Similarly, one systematic review (++) found that in those studies where enforcement devices were temporarily placed at certain locations, the duration of speed reductions after removal of the devices (the 'time halo') varied from 1 day to 8 weeks. However, only one of the systematic reviews (++) was able to identify any factor which was consistently associated with higher injury or crash reductions – this was that the effect on urban roads was greater than that on rural roads. There was insufficient consistency between studies to enable the detection of the effects of other factors (such as different roads user groups, automated versus non-automated detection, mobile versus fixed, covert versus overt, or other roads versus motorway.). The greater effect on urban roads where children are more likely to be pedestrians is relevant. Included studies did not consistently state what the penalties or fines would be for detected speeding, although one systematic review (++) implied there was a relationship between size of pre- and post-reduction in speeding vehicles and the speed threshold set.\n\nThis evidence is judged as directly applicable to the UK as the results from the UK studies were generally consistent with the studies from other developed countries.\n\n## Evidence Statement 3.2\n\nThere is weak evidence from three controlled before-and-after studies (in Australia, Israel and California) that increased or rationalised police enforcement of traffic speeds reduces injury crashes (two [+] and one [-]). There is also weak evidence from three multivariate analyses of longitudinal road accident/injury data (in New Zealand, California and Greece) that increased levels of police enforcement of traffic speeds reduces injury crashes and all injuries (two [+] and one [-]). There is also moderate evidence from one (+) controlled before-and-after study, on motorways in the Netherlands, that increasing the intensity of enforcement – from apprehending 1 in 100 speeding offenders, to 1 in 25, to 1 in 6 – produces statistically significant (p less than 0.05) reductions in mean speed (1\xa0km per hour for 1:25 versus 1:100; and 3.5\xa0km per hour for 1:6 versus 1:25).\n\nThis evidence is judged as partially applicable to road safety policy in the UK. This is because in the included studies there are a number of differences in the way police forces are organised and contribute to speed enforcement. Also, in the role of the police in enforcing speed limits through speed traps and mobile cameras/radar needs to be considered in the context of the widespread use of fixed site automated cameras around the UK road network.\n\n## Evidence statement 4.1\n\nThere is evidence from one controlled before-and-after study (+) in the USA that law requiring the installation of smoke detectors, increases the number of houses which have at least one functioning smoke detector and that this may reduce fatalities related to fires in targeted properties.\n\nKnowledge of the law and the penalty for non-compliance may be associated with greater smoke detector installation than knowledge of the law only.\n\nThe law assessed required smoke detectors in all bedroom areas of one-, two- and multi-family dwellings, applied retrospectively to homes built prior to the law, and can be enforced by a fine or jail time. In addition, sale of a property is contingent on appropriate smoke detectors being present.\n\nGiven the differences in legal systems, responsibilities and enforcement between the USA and the UK, and the high socioeconomic status of the studies communities, the applicability of this finding has been assessed as poor. However, the observations that systems of enforcement which involve regular inspection, with a system of warnings prior to prosecution are effective; that laws which reflect societal laws are effective and that media campaigns to support the introduction of new laws may be important, may be applicable across other settings.\n\n## Evidence statement 4.2\n\nThere is evidence from one comparative study in the USA (+) that window guard legislation in New York City reduces child injury related to falls from buildings by about half, despite greater numbers at risk as residents of multiple-family dwellings (1.5 per 100,000 children aged 0–18 years compared with an average of 2.81 per 100,000 in 27 other US states without legislation, and 3 per 100,000 in Massachusetts which introduced interventions without legislation). The law required owners of multiple-family dwellings to provide window guards in apartments where children aged 10 or under lived (half the injuries recorded in NYC were in those aged 11–18). Compliance was subject to annual enforcement. The introduction of the law was accompanied by a coordinated education and advertising programme ('Children can't fly') which involved outreach, dissemination of literature, a media campaign and the distribution of free window guards.\n\nGiven the differences in legal systems, responsibilities and enforcement between the USA and the UK, and the differences in housing stock and management, the applicability of this finding has been assessed as poor. However, the observation that effective enforcement is a key element of legislative success may be applicable across a range of settings.\n\n## Evidence statement 4.3\n\nThere is mixed evidence from four uncontrolled before-and-after studies (all [+], two from the US and two from Australia) about hot water tap temperature legislation. Two studies (one US and one Australia) reported that the annual incidence of burn injuries in children aged 4–13 years increased after the introduction of legislation, and a US study found that injury rates were raised compared to the period immediately prior to legislation being introduced but fell in relation to an earlier comparator time-period. Only one Australian study (+) reported p-values, but this was a significant increase (p = 0.01).\n\nOne study (Australia) suggested there may be a decrease in the number of scald injuries in children aged 0–4 years, however, the reported differences were non-significant (p = 0.57).\n\nGiven the differences in legal systems, responsibilities and enforcement between the USA and Australia and the UK, and the differences in housing stock and management, the applicability of these findings have been assessed as poor. However, the observation that legislation aimed at safety in the home may be limited in its effectiveness where it is implemented only in that housing stock where access and enforcement is easier (such as in rented or newly built accommodation only), may be applicable across a range of settings.\n\n## Evidence statement 4.4\n\nThere is mixed evidence from four studies (two case control, and two comparative) about swimming pool fencing legislation (two [+] one from USA and one from Australia and two [-] one from New Zealand and one from Australia).\n\nTwo studies (both [+], one USA and one Australia) suggest that legislation is ineffective where it only requires three-sided fencing. The US study suggests no impact of such legislation on drowning in children aged younger than 10 years compared to no legislation (odds ratio [OR] 1.27, 95% confidence interval [CI] 0.72 to 2.25). The Australian study found the incident rate ratio of drowning in children aged younger than 5 years living in houses with three-sided rather than four-sided pool fencing was 1.78 (95% CI 1.14 to 1.79).\n\nThree studies, two (-) and one (+) (two Australia, one New Zealand) report on outcomes related to legislative management and compliance.\n\nThe New South Wales study (-) found that a more structured and comprehensive approach to inspection (including a register of owners, annual inspections, and enforcement of the act including fines) resulted in twice the level of compliance as those with less structured or detailed approaches. Key informant interviews also suggest that lack of clarity in the Fencing Act, and failure to detail how councils should ensure compliance, including how it should be funded, hampered effective implementation.\n\nThe Western Australia study (+) suggests that compliance is highest immediately after legislation is introduced, and falls off thereafter, although regular inspection enhances compliance. The New Zealand study (-) found no association with compliance rates and: local authorities having written policies about locating and inspecting pools; a re-inspection programme; or advertising of pool owners' obligations under the relevant act.\n\nGiven the differences in legal systems, responsibilities and enforcement between the USA, Australia, New Zealand and the UK, and the low level of private swimming pool ownership in the UK, the applicability of these findings have been assessed as poor. However, some key lessons from these studies may be applicable across a range of settings, such as: the importance of adequate legal requirements in order to glean maximum benefit (as illustrated by three- versus four-sided fencing here); the need for regular inspection regimes which are consistently enforced, and the related need for clear lines of responsibility and sufficient funding for these; the need for concurrent education to help owners comply with the spirit as well as the letter of the law (for example, the need for maintenance of equipment, and the valuing of safety over convenience) and finally the need for legislation which does not contradict or confuse other existing rulings.\n\n## Evidence statement 5.3\n\nThere is moderate-to-weak evidence from two controlled before-and-after studies (one [+] and one [-]) to show that mass-media campaigns, employed as part of a broader non-legislative strategy (that involved educational programmes and purchase subsidies) were effective in increasing compliance with bicycle helmet use. There was also moderate evidence from uncontrolled before-and-after data from one of the studies (-) that the programmes helped to reduce the rates of bicycle-related head injuries in the intervention area.\n\nIn the US study (+), the sales of one brand of a youth helmet in the Seattle area (intervention area) rose from 1,500 to 22,000 over a 3-year period (no figures stated for the control area) while observed helmet usage rate among school-age children increased from 5% to 16% compared with a rise of only 1% to 3% in a control community, Portland, Oregon, over the same period.\n\nIn the UK study (-) self-reported helmet use among young people aged 11–15 years living in the campaign area increased from 11% at the start of the campaign to 31% after 5 years (p < 0.001), with no significant change in the control group. Hospital casualty figures in the campaign area (Reading) for cycle-related head injuries in the under 16 years age group, fell from 112.5 per 100,000 to 60.8 per 100,000 (from 21.6% of all cycle injuries to 11.7%; p < 0.005). No injury data were provided for Basingstoke, the control. Applicability: The evidence is judged to be directly applicable to the UK – one of the studies was carried out in the UK and although the other was carried out in the US, it was embarked upon and completed before the introduction of a bicycle helmet legislation, so in a sense the settings reflected what is currently obtainable in the UK, a country without mandatory helmet wearing legislation. Furthermore, both countries are similar in terms of living standards and economic development.\n\n## Evidence statement 5.4\n\nThere is mixed evidence from two controlled before-and-after studies (both [-], one from Canada and one from the UK) that removal and replacement of unsafe equipment to comply with regulatory standards is an effective strategy for preventing playground injuries. The Canadian study demonstrated statistically non-significant reduction in equipment-related injury rate in the intervention schools after replacement of equipment using the new Canadian Standards Association standards (relative risk [RR] = 0.82 to 0.66 to 1.03). This translated into 177 equipment-related injuries avoided during the study period. The comparable equipment-related injury rate in the non-intervention schools increased by about 15% after the study period, although not statistically significant (RR = 1.15; 95% CI 0.96 to 1.37). The overall injury rate reduced in the intervention schools (RR = 0.70; 95% CI 0.62 to 0.78) and increased in the non-intervention schools (RR = 1.40; 95% CI 1.07 to 2.53) after the study period. However, in the UK study, injury rate per observed child was significantly reduced in the five playgrounds where changes (use of greater depth of bark and replacement of overhead horizontal ladders with rope climbing frame) had been made compared to the control playgrounds without changes.\n\nApplicability: The non‐UK study is only partially applicable to the current UK context due to similarities in level of economic development, nature of the playgrounds, as well as targeted populations. The UK study findings are directly applicable.\n\n## Evidence statement 5.5\n\nThere is weak evidence from two before-and-after studies (one [-] and one [+], from UK and Italy) and one retrospective time series (one [+] from UK) on the effect of fireworks legislation and enforcement activities on firework-related injuries.\n\nOne study in Italy (+) reported that a comprehensive, multifaceted programme, comprising the combination of enforcement of fireworks law, media campaign and education, reduced the rate of fireworks-related injury from 10 per 100,000 before the intervention programme to 6.1 per 100,000 after it was implemented, and a time-series based study found that amendments to restrictive fireworks legislation led to a reduction of firework-related injury in children.\n\nThe study from Northern Ireland (-) did not find a significant increase in fireworks-related injuries requiring hospital admission following liberalisation of the law on fireworks sale (incidence of admissions before: 0.38 per 100,000; after: 0.43 per 100,000). However, the annual number of injuries in this study was already very small relative to annual variations.\n\nApplicability: The Italian study is partially applicable to current UK context while the UK findings are directly applicable. However, the Northern Ireland study may not be directly applicable to the rest of UK because of the civil unrest reported in that part of the kingdom.\n\n## Evidence statement 6.5\n\nThere were two cost-benefit analyses which assessed the impact of speed enforcement programmes. The photo radar programme in British Columbia was estimated to produce net benefits to society of about C$114 million (in 2001), and still produced substantial net savings of C$38 million if only considered from the provincial insurance corporation's perspective.\n\nSimilarly, the 420 automated speed camera sites in the UK in 1995/6 were estimated to have a positive net present value of over £26 million, even after 1 year, rising to £241 million after 10 years. This is because annualised fixed costs of £5.3 million plus annual recurrent costs of £3.6 million, would be offset not just by the £6.7 million in fine income, but also the over £30 million in the estimated annual value to society of accidents avoided. In all ten police force areas there was a positive net present value (that is, benefits exceeded costs) within a year of the programme starting.\n\nThese older findings should be seen as having been superseded by the more recent study for the Department for Transport, which evaluated the national safety camera programme.\xa0 (This study was added to the review after the original report was submitted to NICE.)\xa0 In this study, it was estimated that there would be 4230 fewer personal injury collisions (any road collision which results in at least one casualty, whether fatal, serious or slight) annually as a result of the safety cameras across all 38 safety camera partnerships. \xa0At an estimated value of £61,120 per collision avoided (using Department for Transport standard estimates for 2004) this means an annual estimated economic benefit of £258 million. This compares with the total annual cost of the programme of £96 million. Comparing only the revenue costs per collision prevented (£61,120) with the corresponding economic benefit per collision due to injuries prevented (£22,653), over the four years, gives a cost–benefit ratio of approximately 2.7:1. \xa0They also use data from both speed and red light camera sites, although at speed camera sites the reductions in personal injury collisions were associated with reductions in speeds.\n\n# Additional evidence\n\n## Expert testimony\n\nExpert testimony 1: 'Child road safety' (including 'Child casualties in road accidents: 2007. Road accidents factsheet number 5 ' [Department for Transport])\n\nExpert testimony 3: 'Inequities in child injuries'\n\nExpert testimony 6: 'Monitoring and surveillance issues – A&E pilot'.\n\n# Cost-effectiveness evidence\n\nThe modelling (see appendix B) explored the potential cost effectiveness of a selection of strategic approaches to encouraging the uptake of interventions to prevent unintentional injuries among children.\n\nThe cost and effectiveness of implementation was the most important factor in relation to legislation or regulations promoting 20\xa0mph zones. The cost of introducing that legislation or regulation – or of enforcing and monitoring compliance – was much less significant.\n\nSeveral factors determined the cost effectiveness of legislation, regulations and other strategies to promote the earlier and wider installation of thermostatic mixing valves in social housing used by families with young children. These were:\n\nexpected level of uptake and installation following the introduction of regulations\n\nnumber of years before all social housing has one fitted, given the expected uptake after regulations are introduced\n\ncost of enforcing and monitoring compliance\n\nnumber of social housing households that would be eligible for a thermostatic mixing valve under the regulations.\n\n# Fieldwork findings\n\nFieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations. For details, go to the fieldwork section in appendix B and 'Strategies to prevent unintentional injury among under-15s'.\n\nThe fieldwork took place between the formation of a new government in May 2010 and the budget of June 2010. In this context, the issue of financial uncertainty was raised by many participants. They also found it difficult to comment on the 'who should take action' part of the recommendations as the new government departmental structures were unclear.\n\nThe general recommendations were seen as a positive way to increase the profile of unintentional injury prevention, although the issue of funding and concerns about the technological infrastructure needed were raised. The injury surveillance recommendations were positively received, as participants pointed to the lack of authoritative evidence as a key problem. There were, however, concerns about the resource implications of carrying out additional data collection and data coordination activities.\n\nThe introduction of a regulatory framework for home safety equipment was strongly welcomed. However, participants did point to the potential impact on the private sector market – as well as the difficulty of getting private sector landlords to comply. Home safety assessments are offered by a range of different services and some participants welcomed the prospect of a standard, common approach. It was noted that some of these recommendations referred to 'all families with children under 5' and that more clarity was required.\n\nAlthough welcomed in principle, there were concerns about the feasibility of putting the water safety recommendations into practice. For example, lifeguards do not have enough time, hospitality and leisure businesses do not have the skills, and those offering swimming lessons struggle to attract those most in need – even when lessons are free of charge. There was, however, support for a social marketing campaign on water safety.\n\nThe recommendations on cycle helmet usage were met with some scepticism and there was no consensus on the safety benefits.\n\nThe recommendations on play were welcomed. In particular, all participants liked the acknowledgement that any risks involved should be balanced with the benefits. However, they felt that it would not be easy to communicate these recommendations to the diverse range of organisations involved.\n\nParticipants liked the prospect of a national fireworks campaign and the emphasis on evaluation. However, some doubted whether the recommendations would prevent further injuries.\n\nThe road safety recommendations were generally welcomed as reflecting best practice. Some participants felt that a number of them could be combined. Some welcomed the fact that they could help to get the NHS involved with road safety partnerships.\n\n This evidence statement differs from the one in the report submitted to NICE. It has been amended to include findings from one (++) systematic review that was included in the original report and has since been updated. The updated review is: Wilson C, Willis C, Hendrikz JK et al. (2010). Speed cameras for the prevention of road traffic injuries and deaths (review). Cochrane Library: 10.", 'Appendix D: Gaps in the evidence': "The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination based on an assessment of the evidence. These gaps are set out below.\n\nThere is a lack of UK studies evaluating the effectiveness and cost-effectiveness of legislation, regulation and standards and their enforcement on related outcomes such as compliance, safety, risk taking behaviours and injury. Cost-effectiveness data rarely considers the cost of developing and promoting legislation.\n\nMost studies rely on self-reporting to record morbidity outcomes, protective factors and unintended consequences before and after legislation. In addition, baseline data is rarely collected prior to legislative or regulatory change.\n\nThere is a lack of studies that report specific outcomes for children.\n\nThere is a lack of UK studies which record and take into account confounding factors that could impact on the effectiveness of legislation, regulation and standards. This includes children and young people's exposure to risk, environmental characteristics and changes in design standards.\n\nThere is a lack of studies comparing the effectiveness of legislation, regulation and standards across high-, middle- and low-income countries.\n\nThere is a lack of studies evaluating the impact of mass-media campaigns to support legislation, regulation and standards.\n\nThere is a lack of good quality qualitative research on the barriers preventing – and facilitators aiding – compliance with legislation, regulation and standards.\n\nThere is a lack of qualitative and quantitative research on injury prevention in the home.\n\nThere is a lack of information on the effectiveness of legislation relating to home safety assessments, thermal mixing valves, smoke alarms and window restrictors. Evaluations do not tend to incorporate process and outcome factors.\n\nThere is a lack of information on how well rules and regulations for different sports are enforced.\n\nThere is a lack of studies addressing the quantitative correlates of drowning.\n\nThere is a lack of evaluation of the effectiveness of different types of road signage.\n\nThere is a lack of studies on the differential effectiveness of network-wide, targeted or mixed approaches to speed enforcement on the road. There is also a lack of studies identifying the factors consistently associated with a reduction in injuries from road crashes.\n\nThe Group made 18 recommendations for research. These are listed in section 5.", 'Appendix E: Supporting documents': "Supporting documents are available online. These include the following:\n\nEvidence reviews:\n\n\n\nReview 1: 'Current practice and innovative approaches to prevent childhood unintentional injuries: An overview and synthesis of international comparative analyses and surveys of injury prevention policies, legislation and other activities'\n\nReview 2: 'A systematic review of risk factors for unintentional injuries among children and young people aged under 15 years'\n\nReview 3: 'An overview and synthesis of evidence relating to strategies and frameworks for planning, implementing, enforcing or promoting activities to prevent unintentional injury to children and young people on the road: legislation, regulation, standards and related strategies focusing on the design and modification of highways, roads or streets'\n\nReview 4: 'Strategic and regulatory frameworks for guiding, enforcing or promoting activities to prevent unintentional injury in children and young people in the home environment'\n\nReview 5: 'Strategies, policies and regulatory or legal frameworks and/or mass media campaigns to prevent unintentional injury to children during play and leisure in the external environment'.\n\nReview 6: 'Systematic review to provide an overview of published economic evaluations of relevant legislation, regulations, standards, and/or their enforcement and promotion by mass media'.\n\n\n\nEconomic analysis: 'Economic modelling of legislation/regulations and related national strategies to promote the wider use of: 20mph zones in residential areas, and thermostatic mixing valves (TMVs) in social housing for families'.\n\nExpert testimony:\n\n\n\nExpert testimony 1: 'Child road safety' (including 'Child casualties in road accidents: 2007. Road accidents factsheet number 5 ' [Department for Transport])\n\nExpert testimony 2: 'Preventing unintentional injuries among under-15s'\n\nExpert testimony 3: 'Inequities in child injuries'\n\nExpert testimony 4: 'Legislating for Health'\n\nExpert testimony 5: 'Cycle helmets – epidemiology and effectiveness'\n\nExpert testimony 6: 'Monitoring and surveillance issues – A&E pilot'.\n\n\n\nFieldwork report: 'Strategies to prevent unintentional injury among under-15s'.\n\nFor information on how NICE public health guidance is developed see:\n\nMethods for development of NICE public health guidance (second edition, 2009)'\n\nThe NICE public health guidance development process: An overview for stakeholders including public health practitioners, policy makers and the public (second edition, 2009).", 'About this guidance': 'NICE public health guidance makes recommendations on the promotion of good health and the prevention of ill health.\n\nThis guidance was developed using the NICE public health programme guidance process.\n\nTools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nThis is one of three pieces of NICE guidance published in November 2010 on how to prevent unintentional injuries among under-15s. A second publication covers the provision of home safety equipment and home risk assessments and a third covers unintentional injuries on the road.\n\nISBN: 978-1-4731-3613-7'}
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https://www.nice.org.uk/guidance/ph29
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This guideline covers strategies, regulation, enforcement, surveillance and workforce development in relation to preventing unintentional injuries in the home, on the road and during outdoor play and leisure.
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59e9bd0378c5329a947e0011a0f294718de65e4d
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nice
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Unintentional injuries in the home: interventions for under 15s
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Unintentional injuries in the home: interventions for under 15s
This guideline covers home safety assessments, supplying and installing safety equipment and providing education and advice. It aims to prevent unintentional injuries among all children and young people aged under 15 but, in particular, those living in disadvantaged circumstances.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
The evidence statements underpinning the recommendations are listed in appendix C.
See also the evidence reviews, supporting evidence statements and cost effectiveness modelling.
PHIAC considers that the recommended measures are cost effective. For the gaps in research, see appendix D.
# Context
The recommendations in this guidance should be implemented as part of a broader strategy to reduce unintentional injuries in the home. This would include the use of regulations and the provision of safety education to prevent such injuries. (Note that in November 2010, we published a NICE guideline on unintentional injuries: prevention strategies for under 15s.)
This guidance focuses on home safety assessments and the supply and installation of home safety equipment, either delivered separately or together. It also covers education and advice when delivered as part of these interventions.
Implementation of all the recommendations should ensure a systematic approach can be adopted. This involves prioritising households at greatest risk of unintentional injuries and establishing partnerships to ensure coordinated delivery and follow-up on home safety assessments and equipment interventions. In addition, the recommendations make the consideration of home safety issues a part of routine practice for all practitioners visiting children and young people at home.
# Definitions
NICE uses the term 'unintentional injuries' rather than 'accidents', since 'most injuries and their precipitating events are predictable and preventable' (Davis R, Pless B (2001) BMJ bans 'accidents'. Accidents are not unpredictable. BMJ 322: 1320–21). The term 'accident' implies an unpredictable and therefore, unavoidable event.
The process of systematically identifying potential hazards in the home, evaluating the risks and providing information or advice on how to reduce them is described here as a home safety assessment. Other terms commonly used to describe the same process include 'home risk assessment' and 'home safety check'. It may be carried out by a trained assessor or by parents and other householders, using an appropriate checklist (Home safety assessment tools are available from The Royal Society for the Prevention of Accidents and SafeHome.)
In this guidance, home safety equipment is any device used to prevent injury in the home. This includes door guards and cupboard locks, safety gates and barriers, smoke and carbon monoxide alarms, thermostatic mixing valves and window restrictors.
For the purposes of this guidance, 'home' refers to inside the dwelling itself. It does not include the garden or outbuildings.
# Whose health will benefit?
The recommendations aim to help children and young people aged under 15 years who are at greatest risk of an unintentional injury and their parents and carers. In particular, it is aimed at those living in disadvantaged circumstances.
# Recommendation 1 Prioritising households at greatest risk
## Who should take action?
Local safeguarding children boards.
Local authority children's services and their partnerships.
Local strategic partnerships.
Local authority health and wellbeing boards and partnerships (where they are not part of the local strategic partnership).
## What action should they take?
Determine the types of household where children and young people aged under 15 are at greatest risk of unintentional injury based on surveys, needs assessments and existing datasets (such as local council housing records).
Prioritise the households identified above for home safety assessments and the supply and installation of home safety equipment (see recommendations 2 and 3). 'Priority households' could include those with children aged under 5, families living in rented or overcrowded conditions or families living on a low income. It could also include those living in a property where there is a lack of appropriately installed safety equipment, or one where hazards have been identified through the Housing Health and Safety Rating System (HHSRS; this is a risk assessment procedure for residential properties).
Provide practitioners who visit children and young people at home with mechanisms (such as the Early Help Assessment) for sharing information about households that might need a home safety assessment. This includes health visitors, social workers and GPs.
Ensure practitioners adhere to good practice on maintaining the confidentiality and security of personal information. (For example, this includes using end-to-end encryption when sharing data with other agencies. See for example, the government's information sharing advice for safeguarding practitioners.)
# Recommendation 2 Working in partnership
## Who should take action?
Strategic planners and leads with responsibility for child health.
Fire and rescue services.
Housing associations.
Local authorities: leads for children's services, environmental health, accident prevention and home safety and housing.
Sure Start and children's centres.
## What action should they take?
Establish local partnerships with relevant statutory and voluntary organisations or support existing ones. Partners could include:
local community and parent groups
-rganisations employing health and social practitioners who visit children and young people in their homes (for example, health visitors)
childcare agencies
-thers with a remit to improve the health and wellbeing of children aged under 15
local umbrella organisations for private and social landlords
those involved in lifestyle and other health initiatives.
Use these partnerships to:
help collect information on specific households where children and young people aged under 15 may be at greatest risk of an unintentional injury (see recommendation 1). The collection and sharing of information should adhere to the standards referred to in recommendation 1
help determine and address barriers to creating a safe home environment. (For example, the cost of equipment, cultural norms, issues of trust or a lack of control over the home environment may all be barriers to installing safety equipment)
get the community involved (as outlined in the NICE guideline on community engagement). For example, local 'community champions' could be used to promote home safety interventions and help practitioners gain the trust of householders
carry out home safety assessments and supply and install home safety equipment, in line with recommendation 3 (Home safety assessment tools are available from The Royal Society for the Prevention of Accidents and SafeHome.).
# Recommendation 3 Coordinated delivery
## Who should take action?
Those who carry out home safety assessments and provide home safety equipment (see recommendation 2).
## What action should they take?
Offer home safety assessments to the households prioritised in recommendations 1 and 2 (Home safety assessment tools are available from The Royal Society for the Prevention of Accidents and SafeHome.). Where appropriate, supply and install suitable, high quality home safety equipment. Home safety equipment should adhere to the British 'Kite mark' standards or the equivalent European standard. Where resources are limited, it may be necessary to narrow down further the households being prioritised (for example, to those with children under the age of 5 years).
Ensure the assessment, supply and installation of equipment is tailored to meet the household's specific needs and circumstances. Factors to take into account include:
the developmental age of the children (in relation to any equipment installed)
whether or not a child or family member has a disability
cultural and religious beliefs
whether or not English is the first language
levels of literacy
the level of control people have over their home environment. (Many people may not have the authority to agree to an installation, for example, tenants of social and private landlords and those who are unable to make household or financial decisions)
the household's perception of, and degree of trust in, authority.
Ensure education, advice and information is given during a home safety assessment, and during the supply and installation of home safety equipment. This should emphasise the need to be vigilant about home safety and explain how to maintain and check home safety equipment. It should also explain why safety equipment has been installed – and the danger of disabling it. In addition, useful links and contacts should be provided in case of a home safety problem.
# Recommendation 4 Follow-up on home safety assessments and interventions
## Who should take action?
Those who carry out home safety assessments and provide home safety equipment (see recommendations 2 and 3).
## What action should they take?
Prevent duplication of effort by keeping a record of households that have been given safety advice or equipment. (It may be possible to use an existing local database.) Ensure the records are accessible to all those with a direct or indirect responsibility for preventing unintentional injuries in the home.
Adhere to the standards referred to in recommendation 1 in relation to the collection and sharing of information.
Use the records to identify when maintenance and follow-up are required, to feed into strategic planning and to prioritise future interventions (see recommendation 1).
Contact homes identified as being in need of an equipment maintenance check or follow-up. Offer to revisit them to see if the equipment is still appropriate and functional (and in case of a product recall or faults). Ascertain whether there are any new requirements (for example, due to changes in the building or the family). Reinforce home safety messages during these visits.
# Recommendation 5 Integrating home safety into other home visits
## Who should take action?
Practitioners who visit families and carers with children and young people aged under 15. This includes GPs, midwives, social workers and health visitors.
## What action should they take?
Recognise the importance of measures to prevent unintentional injuries in the home among children and young people aged under 15, particularly among those living in disadvantaged circumstances.
Provide child-focused home safety advice. If the family or carers agree, refer them to agencies that can undertake a home safety assessment and can supply and install home safety equipment.
Encourage parents, carers and others living with children and young people aged under 15 to conduct their own home safety assessment. They should use an appropriate tool, as outlined in recommendation 3.# Public health need and practice
Unintentional injury is a leading cause of death among children and young people aged 1–14 (Audit Commission and Healthcare Commission 2007). In England and Wales in 2008, 208 children and young people aged 0–14 died from such injuries (Office for National Statistics 2009).
In the UK, unintentional injury (in all environments) results in more than two million visits to accident and emergency (A&E) departments by children every year. Half of these injuries occur in the home (Audit Commission and Healthcare Commission 2007). In 2002, nearly 900,000 children and young people in the UK aged under 15 attended hospital following an unintentional injury in the home (Department of Trade and Industry 2002).
Children and young people who survive a serious unintentional injury can experience severe pain and may need lengthy treatment (including numerous stays in hospital). They could be permanently disabled or disfigured (Child Accident Prevention Trust 2008) and their injuries may have an impact on their social and psychological wellbeing.
# Types of injury
Children and young children are vulnerable to a range of unintentional injuries in the home including falls, burns and scalds, drowning, suffocation and poisoning (Child Accident Prevention Trust 2008).
In the UK between 2000 and 2002, falls were the major cause of unintentional injury in the home among those aged under 15, according to home accidents surveillance system (HASS) data (Department of Trade and Industry 2002). 'Drowning and submersion' and 'other accidental threats to breathing' led to the most deaths in the home among this group between 2002 and 2005 (Office for National Statistics 2009). On average, 1200 children a year under the age of 11 are injured – and 35 are killed – in fires in the home (Directgov 2008).
# Costs
Treating unintentional injuries among children and young people costs UK A&E departments approximately £146 million a year. Further treatment costs are significant, for example, it can cost £250,000 to treat one severe bath water scald (Child Accident Prevention Trust 2008). The indirect costs include enforced absence from school and the need for children and young people to be supervised during their recovery (which could involve family and carers taking time off from work).
# Risk factors
Epidemiological data indicate that the risk of an unintentional injury is greatest among households living in the most deprived circumstances. Children and young people from lower socioeconomic groups whose parents have never worked (or who are long-term unemployed) are 13 times more likely to die from such an injury than those whose parents are managers and professionals (Edwards et al. 2006).
The evidence also suggests that a range of interrelated factors can lead to a higher risk of injury. Apart from a low income and overcrowded housing conditions, they include a lack of safety equipment. Other factors include gender, age, culture, ethnicity and the household's level of control over their home environment. Although not necessarily the direct cause of injury, these factors can increase children and young people's risk of exposure to a potential hazard.
# Current policy and practice
Local strategic partnerships and local safeguarding children boards have a duty to promote children and young people's health, wellbeing and general welfare. In addition, local area agreements provide an opportunity for local authorities, in partnership with the NHS and other organisations, to focus on unintentional injuries in the home. Practice is variable, but some areas are taking innovative approaches to home safety.
In February 2009, the Department for Children, Schools and Families launched 'Safe at home: the national home safety equipment scheme' (2009). The 3-year, £18 m scheme is being developed and evaluated by the Royal Society for the Prevention of Accidents (RoSPA). Local organisations, working in partnership with RoSPA, will provide home safety advice and information and equipment to the most disadvantaged families in 141 areas of England with the highest accident rates.# Considerations
The Public Health Interventions Advisory Committee (PHIAC) took account of a number of factors and issues when developing the recommendations.
Both generic and targeted interventions are used to prevent injuries in the home. The former could include legislation – for example, to improve the way homes are constructed. The latter could include the provision of safety equipment. Both generic and targeted interventions aim to do three things, either independently or in combination: change attitudes and behaviour, alter the environment, and provide information or training (Lund and Aarǿ 2004).
PHIAC noted that forthcoming NICE guidance will cover strategic approaches to reducing unintentional injuries among the under-15s.
The technical efficacy of safety equipment has been demonstrated and, in most cases, has improved since the research studies included in the evidence reviews were undertaken.
The evidence did not cover all the home safety equipment available. For example, there were no evaluations of interventions involving the installation of carbon monoxide alarms.
There was limited evidence on residential care homes. While some elements of the recommendations may apply, residential care homes are already subject to a range of legislation. This includes The Care Homes Regulations 2001 (HM Government 2001) and 'Children's homes: national minimum standards, children's homes regulations' (DH 2002).
PHIAC considered it very unfortunate that many injury prevention schemes do not include an integrated and robust evaluation process. This limits the evidence available on their impact.
Children and young people learn by taking risks and challenging themselves when playing and in other activities. Many areas of the home – and activities that take place there – pose an inherent risk. Safety equipment and education help to keep children safe.
PHIAC acknowledged that interventions need to take into account a household's everyday circumstances and routine practices – and how receptive families are to safety messages.
PHIAC believes that it is important to raise awareness of safety issues.
Safety equipment has to be correctly used and maintained to be effective.
The cost-effectiveness modelling that underpins the recommendations is based on very limited data. It should not be regarded as a definitive analysis of cost-effectiveness. Rather, it explores the factors most likely to affect whether or not interventions to prevent unintentional injuries in the home represent good value for money. The analysis indicates that, from a public sector perspective, the cost effectiveness of such programmes is dependent on a number of factors (see cost effectiveness in appendix C).# Recommendations for research
PHIAC developed some provisional research recommendations, based on the evidence and expert advice from cooptees. These were passed to the NICE committee that developed related guidance on 'Strategies to prevent unintentional injuries among under-15s', for them to develop a comprehensive set of research recommendations covering all types of unintentional injuries.
More detail on the gaps in the evidence identified during development of the guidance on preventing unintentional injuries in the home among under-15s is provided in appendix D.# References
Audit Commission and Healthcare Commission (2007) Better safe than sorry: preventing unintentional injury to children. London: Audit Commission
Davis R, Pless B (2001) BMJ bans 'accident'. BMJ 322: 1320–1
Child Accident Prevention Trust (2008) Child Accident Prevention Trust factsheet: preventing bath water scalds using thermostatic mixing valves. London: Child Accident Prevention Trust
Department of Health (2002) Children's homes: national minimum standards, children's homes regulations. London: Department of Health
Department of Trade and Industry (2002) Home accidents surveillance system (HASS)
Directgov (2008) Fire safety for parents and child carers
Edwards P, Roberts I, Green J et al. (2006) Deaths from injury in children and employment status in family: analysis of trends in class specific death rates. BMJ 333: 119–21
HM Government (2001) The Care Homes Regulations 2001. London: HM Government
Lund J, Aarǿ LE (2004) Accident prevention. Presentation of a model placing emphasis on human, structural and cultural factors. Safety Science 42: 271–324
Office for National Statistics (2009) Mortality statistics: deaths registered in 2008. Review of the Registrar General on deaths in England and Wales# Appendix B: Summary of the methods used to develop this guidance
# Introduction
The reviews and cost effectiveness modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.
The minutes of the PHIAC meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations.
All supporting documents are listed in appendix E.
# Key questions
The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by PHIAC to help develop the recommendations. The overarching questions were:
Question 1: Which interventions involving the supply and/or installation of home safety equipment are effective and cost effective in preventing unintentional injuries among children and young people aged under 15 in the home?
Question 2: Are home-risk assessments effective and cost effective in preventing unintentional injuries among children and young people aged under 15?
Question 3: What are the barriers to, and facilitators of, interventions involving the supply and/or installation of home safety equipment and/or home-risk assessments?
These questions were made more specific for the reviews (see reviews for further details).
# Reviewing the evidence
Two evidence reviews were carried out: one on effectiveness and cost effectiveness and one on the barriers to, and facilitators of, the prevention of unintentional injury in children in the home.
## Identifying the evidence
The following databases were searched from 1990 up to March 2009, using a single strategy to identify relevant primary and qualitative research (no study design filters were applied):
Applied Social Science Index and Abstracts (ASSIA)
Bibliomap
Centre for Review and Dissemination databases
CINAHL (Cumulative Index of Nursing and Allied Health Literature)
Cochrane Library database of systematic reviews
Database of Abstracts of Reviews of Effects (DARE)
Database of Promoting Health Effectiveness Reviews (DoPHER)
EconLit
Evidence for Policy and Practice Information and Co-ordinating (EPPI) Centre databases
Health Management Information Consortium (HMIC)
ISI Web of Knowledge Social Science Citation Index (SSCI)
Science Citation Index Expanded (SCI-EXPANDED)
MEDLINE
National Health Service Economic Evaluations Database (NHSEED)
NHS Economic Evaluation Database (HTA)
PsycINFO
SafetyLit
Trials Register of Promoting Health Interventions (TRoPHI)
A follow-up targeted search of named programmes was conducted in MEDLINE and using the search engine Google.
The following websites were also searched:
Child Accident Prevention Trust
Children in Wales
Eurosafe
Injury Observatory for Britain & Ireland
Integris (EU Injuries programme for coordinating injury data)
International Society for Child and Adolescent Injury Prevention
Public Health Observatory website for the South West (lead on injuries)
The Royal Society for the Prevention of Accidents
Further details of the databases, search terms and strategies are included in the reviews.
## Selection criteria
Studies were included in the effectiveness and cost effectiveness review if they:
were published from 1990 to March 2009 in English
were conducted in member countries of the Organisation for Economic Cooperation and Development (OECD)
reported injury related outcomes (for example, a reduction in injuries from smoke inhalation, an increase in the number of smoke alarms installed and improved knowledge of how to prevent other injuries in the home).
Studies were excluded if they did not:
compare the injury-related outcome prior to or without the intervention report injury-related outcomes for children or young people aged under 15 (for examples, see above; however, studies that reported injury-related outcomes among, for example, those aged 5–18 years would be included if most of the data related to children aged 15 years or under.)
for the cost-effectiveness review only, assess the cost and related benefits or effectiveness of the intervention (or class of intervention).
## Quality appraisal
Included papers were assessed for methodological rigour and quality using the relevant NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.
++ All or most of the methodology checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are thought very unlikely to alter.
- Some of the methodology checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are thought unlikely to alter the conclusions.
– Few or no methodology checklist criteria have been fulfilled. The conclusions of the study are thought likely or very likely to alter.
## Summarising the evidence and making evidence statements
The review data was summarised in evidence tables (see full reviews).
The findings from the reviews were synthesised and used as the basis for evidence statements relating to each key question. The evidence statements were prepared by the public health collaborating centre (see appendix A). The statements reflect their judgement of the strength (quantity, type and quality) of evidence and its applicability to the populations and settings in the scope.
# Economic analysis
The economic analysis consisted of a review of economic evaluations (the cost effectiveness part of review 1) and a cost-effectiveness model (report 3).
## Cost effectiveness review (part of review 1)
As indicated above, a single search strategy was used to identify relevant economic evaluations from a wide range of databases (listed earlier).
## Cost-effectiveness modelling
Two economic models were constructed to incorporate data from the evidence reviews.
First, the intervention model was used to analyse the effectiveness of an intervention to increase the number of people using a particular safety feature (such as a smoke alarm or stair gate) in the home.
The second stage outcomes model used the levels of installed safety equipment in the population (derived from the first model) to predict the number of resulting injuries and fatalities over the lifetime of the population cohort. It involved a cost–utility analysis undertaken from the NHS and personal social services perspective.
A number of assumptions were made which could underestimate or overestimate the cost effectiveness of the interventions (see review modelling report for further details).
The results are reported in: Preventing unintentional injuries among under-15s in the home. Report 3: cost-effectiveness modelling of home-based interventions aimed at reducing unintentional injuries in children.
# Fieldwork
Fieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice.
It was conducted with practitioners and commissioners who are involved in preventing unintentional injuries among under-15s. They included: unintentional injury prevention specialists; practitioners working on local home-safety initiatives, including safety equipment distribution schemes; and practitioners with a broader remit for the welfare of children aged 0–15. The latter included: children's centre managers, health visitors, housing managers, public health practitioners, school nurses, social workers and others working in the NHS, local authorities, police and fire services, and voluntary sector organisations.
The fieldwork comprised nine focus groups carried out in different local authority areas and one in-depth interview. They were conducted by GHK (with Noble Denton) and involved a total of 65 participants.
The focus groups and in-depth interview were commissioned to ensure there was ample geographical coverage. The main issues arising are set out in appendix C fieldwork findings. See the full report, Preventing unintentional injuries in the home among under-15s: providing safety equipment and home-risk assessments: fieldwork report.
# How PHIAC formulated the recommendations
At its meeting in September 2009 PHIAC considered the evidence of effectiveness and cost effectiveness to determine:
whether there was sufficient evidence (in terms of quantity, quality and applicability) to form a judgement
whether, on balance, the evidence demonstrates that the intervention is effective, ineffective or equivocal
where there is an effect, the typical size of effect.
PHIAC developed draft recommendations through informal consensus, based on the following criteria.
Strength (quality and quantity) of evidence of effectiveness and its applicability to the populations/settings referred to in the scope.
Effect size and potential impact on the target population's health.
Impact on inequalities in health between different groups of the population.
Cost effectiveness (for the NHS and other public sector organisations).
Balance of risks and benefits.
Ease of implementation and any anticipated changes in practice.
Where possible, recommendations were linked to evidence statements (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).
The draft guidance, including the recommendations, was released for consultation in November 2009. At its meeting in January 2010, PHIAC amended the guidance in light of comments from stakeholders, experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in March 2010.# Appendix C: The evidence
This appendix lists evidence statements from two evidence reviews provided by public health collaborating centres (see appendix A) and links them to the relevant recommendations. (See appendix B for the key to quality assessments.) The evidence statements are presented here without references – these can be found in the full review (see appendix E for details). It also sets out a brief summary of findings from the economic analysis.
Evidence statement number E4d indicates that the linked statement is numbered 4d in review 1 'Preventing unintentional injuries among under-15s in the home. Systematic reviews of effectiveness and cost-effectiveness of home safety equipment and risk assessment schemes'.
Evidence statement number B1 indicates that the linked statement is numbered 1 in review 2 'Barriers to, and facilitators of the prevention of unintentional injury in children in the home: a systematic review of qualitative research.'
Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence) below.
Recommendation 1: economic modelling; IDE
Recommendation 2: evidence statements B4, B5, B6, B8, B9, B11, B12, B13, B14, B15; IDE
Recommendation 3: evidence statements E2a, E2b, E3b, E3c, E3d, E4b, E4c, E4d, E6b, E7b, E9b, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, B13, B14, B15; IDE
Recommendation 4: evidence statement B3; economic modelling, IDE
Recommendation 5: evidence statements E3e, E3f, E3h, E4b, B2, B9; IDE
# Evidence statements
Please note that the wording of some evidence statements has been altered slightly from those in the review team's report to make them more consistent with each other and NICE's standard house style.
## Evidence statement E2a
There is inconsistent evidence about impact on injury from one cluster RCT (++) and one controlled before-and-after study (CBA) (+). There is evidence from the better quality cluster RCT that the free supply and installation of smoke alarms had no significant effect on the incidence of fire-related hospitalisations and deaths (rate ratio 1.0 ). However, the CBA study suggests that the free supply and installation of smoke alarms decreased the incidence of fire-related injuries (within-group pre-post intervention comparison: 0.2 for the intervention group and 1.1 for the remainder of the city).
## Evidence statement E2b
There is inconsistent evidence about impact on rates of installation of home safety equipment from two cluster RCTs (one , one ) and one CBA (+). There is evidence from the better quality cluster RCT that the free supply and installation of smoke alarms had no significant effect on the installation or functioning of smoke alarms within households (Rate ratio 1.0 ). However, there is evidence from the other cluster RCT that the free supply and installation of smoke alarms had a significant effect on the installation and functioning of smoke alarms: odds ratio (OR) 4.82 (95% CI 3.97, 5.85). The CBA study reported that 51% of intervention households (identified as being without a smoke alarm prior to the intervention) had a correctly installed and functioning smoke alarm at 12 months follow-up.
## Evidence statement E3b
There is moderate evidence from three RCTs (one one and one ) that the free or discounted supply of smoke alarms in conjunction with safety education increases the rate of installation of these devices.
## Evidence statement E3c
There is weak evidence from two RCTs (one and one ) about interventions with free or discounted supply of home safety equipment in conjunction with safety education. Outcomes about three types of home safety equipment (buffers, electrical outlet covers and cupboard locks/latches) are reported, showing mixed evidence of effect. Outcomes about other types of home safety equipment (non-slip bathroom items, window locks, fire guards and stair gates) are presented in one report, with only fire guards reported as being more likely to be present post-intervention (based on self-report).
## Evidence statement E3d
There is weak evidence from one RCT (++) that the free or discounted supply of a range of safety equipment, in conjunction with safety education, increases the rate of installation of safety equipment as a whole (mean difference 21.1 ) (based on self-report).
## Evidence statement E3e
There is strong evidence from four RCTs (two , one and one ) that the free or discounted supply of a range of safety equipment, in conjunction with safety education, increases knowledgeabout the prevention of poisoning and scalds.
## Evidence statement E3f
There is inconsistent evidence from three RCTs (two and one ) about how a free or discounted supply of a range of safety equipment, in conjunction with safety education, affects knowledge about: the prevention of fires, falls and wounds.
## Evidence statement E3h
There is weak evidence from one RCT (+) that the free or discounted supply of a range of safety equipment, in conjunction with safety education, increases knowledge about the prevention of suffocation.
## Evidence statement E4b
There is weak evidence from one RCT (++) that free home safety equipment (or its delivery) and installation with safety education increases the use of smoke alarms at 12 months (OR 1.83 ) and 24 months (OR 1.67 ). The intervention did not have a statistically significant impact on reducing socioeconomic inequalities in the uptake and continued use (12 months post-intervention) of smoke alarms.
## Evidence statement E4c
There is weak evidence from one RCT (++) that showed mixed evidence of effect of the supply of free home safety equipment (or its delivery) and installation with safety education. Outcomes showed no impact on fire guards being fitted and always used after 12 or 24 months, and increased use of stair gates and window locks at 12 months, but not 24 months. The intervention had a statistically significant impact on reducing socioeconomic inequalities in the uptake and continued use (12 months post-intervention) of stair gates.
## Evidence statement E4d
There is weak evidence from one RCT (++) that free home safety equipment (or its delivery) and installation with safety education may increase the safe storage at 12 months of cleaning products and sharp objects, but these effects are no longer seen after 24 months for safe storage of sharp objects.
## Evidence statement E6b
There is inconsistent evidence from two RCTs (one and one ) and one CBA (+) about interventions with a home-risk assessment and free or discounted supply of home safety equipment that included a smoke alarm. Outcomes about the rates of installation of smoke alarms (all self-reported) show mixed evidence of effect(no effect, increased, increased).
## Evidence statement E7b
Three studies (one CBA and two before-and-after ) report on the continued presence and use of installed equipment after home-risk assessment and free or discounted supply and installation of home safety equipment. There is mixed evidence about the impact on continued working equipment. One study found that 60% of installed hot water tempering valves remained in situ after 6 to 9 months. One study found significant improvements in the numbers of households with working window guards and fire extinguishers post-intervention. Finally, two studies (one CBA and one BA ) showed significantly more smoke alarms installed and working post-intervention (p<0.0001; OR 0.30 ).
## Evidence statement E9b
There is inconsistent evidence from six robust studies (which use both observed outcome measures and a controlled study design) about the presence of functional smoke alarms. Four suggest that the intervention increased functioning presence (one RCT , one CBA , one RCT and one CBA ) and two suggest that no significant impact was seen on smoke alarms (both RCT ).
## Evidence statement B2
Three studies (three ) found that parents felt there was a lack of information or knowledge about existing policies or support. Examples included lack of knowledge of poison centre telephone number, and lack of 'direct information' on poisoning prevention.
A lack of communication about programmes to install smoke alarms limited uptake, especially for the most high-risk families (those in rented accommodation with a rapid turnover of tenants).
Timing of information was shown to be important. One study found that parents given information in hospital, at the time of a child's birth, did not retain this, while information provided subsequently in a community or physician setting was better retained.
## Evidence statement B3
Three studies (all ) found that partnerships and collaborations between different service providers facilitated the effectiveness of interventions to reduce unintentional injuries to children in low income communities.
Collaborations perceived as useful included multi-agency partnerships between different agencies, and between agencies and hard-to-reach groups. These collaborations aided the effectiveness of a UK smoke alarm installation programme and a partnership between health officials and low income mothers in home safety visits offering advice and provision of safety equipment
The importance of devising information and advice in ways that suit the target community (in terms of language, style, examples used) was noted in both of these papers dealing with low income populations with many ethnic minorities.
## Evidence statement B4
Nine studies (four , four and one ) found that a major barrier to implementing safety equipment and childproofing a home was living in a home one was not free to modify.
The studies found that mothers particularly found a lack of control over their home environment due to living in rented accommodation, and/or with extended family. In rented accommodation, landlords were reported as unresponsive to requests for installation or maintenance of safety equipment. In extended family homes, often in overcrowded situations, young parents often did not have a say in how the home was arranged. Two studies noted that high turnover of tenants in cheap rented accommodation limited the effectiveness of projects to organise effective installation and maintenance. In two studies, having landlords with the ability and eagerness to make repairs led to more effective interventions.
## Evidence statement B5
Four studies (two and two ) found that faulty or poor quality equipment was a barrier to interventions to reduce unintentional injuries to children in the home. For example, mothers resorted to taping over electric sockets when safety plugs were not provided or did not work.
The four studies made recommendations for different or better equipment. Studies recommended the provision of tamper-proof smoke alarms with 10- year batteries, alternatives of sprinkler systems for some populations, smoke alarms with longer lasting batteries, help for fitting alarms, or simpler systems for older residents, and more systematic provision of child-resistant containers.
Suspicion by those in vulnerable communities of strangers coming into their homes to assess or install property, and suspicion of 'free' offers, needs to be mitigated in successful interventions.
## Evidence statement B6
The two studies on smoke alarm installation (one , one ) both found that people balance immediate and longer term risks to health and wellbeing when they disable alarms. They were aware that it was less than ideal to disable smoke alarms, but weighed this against other factors, especially the inconvenience and stress of malfunctioning alarms.
## Evidence statement B7
Three studies (one and two ) based on evaluation of specific interventions all found that training in installation and equipment use/replacement was a facilitator to reducing the incidence of unintentional injuries to children in the home.
## Evidence statement B8
Cost emerged as a theme in five of the studies, always as a barrier to reducing accidents to children in the home, or to obtaining help if a child had been injured (two , two and one ). Three studies found that the perceived cost of installing safety devices or making repairs was a major barrier in the correct use of smoke alarms and in general for safety equipment. However, in one study the provision of free safety equipment, in this case a smoke alarm, led to the equipment being rejected due to suspicions precisely because it was free, which suggests that making equipment or installations totally free may not always be appropriate.
## Evidence statement B9
Four studies (one , two and one ) found that young or poorly educated mothers found it hard to anticipate the child's rate of development in terms of ability to climb, open containers or locks, or light fires. One study, in contrast, found that mothers were good at anticipating developmental milestones and adjusting the home environment in advance of changes, thereby reducing the rate of unintentional injuries in the home (+).
## Evidence statement B10
One study (++) found that exposure to a child poisoning incident, either in real life or in the media, increased awareness of that particular danger and was a motivator for implementing safety measures. This suggests that providing information on unintentional poisoning via media outlets might be an effective facilitator in raising awareness of risk.
## Evidence statement B11
One study (-) found that adolescent mothers found it hard to deal with issues of blame, oscillating between ideas of the accident-prone child who would have accidents whatever you did, and the negligent adult who was responsible for their child's accidents. The study recommends that care providers approach the topic of injury in a forthright manner when working with adolescent mothers, challenging the idea that injuries are unavoidable while not assigning blame to the mother for injury to the child. It also suggests that 'helping mothers identify risks to their specific child in their specific environment may be the most effective intervention'.
## Evidence statement B12
Five studies (two , two and one ) noted the large and constant amount of effort which mothers put into preventing unintentional injuries in the home as a major facilitator of reducing unintentional injuries in the home. Authors picked up on several main components of this maternal safeguarding work – commonsense safeguarding, constant vigilance and teaching children about safety.
While these maternal safeguarding activities do act as a short-term facilitator to accident reduction, it is important to note that they are time and energy- intensive and that, for this reason, need supplementing with other forms of unintentional injury prevention.
## Evidence statement B13
Three studies (two and one ) noted cultural practices which, while they may have been adequate safety measures in the parents' culture of origin, were risky in a new cultural context. There were two aspects to this theme; lack of experience of the particular risks of a host context, and lack of understanding by health officials about different child safety norms and expectations in immigrants' cultures.
Mexican mothers in one US study mostly came from rural and semi-rural backgrounds, so had less experience with urban hazards such as multi-storey buildings and hot water taps which could cause falls or scalds. Mexican mothers were also more likely to use Mexican products, which were more likely to come without safety warnings/packaging. Two US studies found significant cultural differences in experience and expectations which led to health visitors classing behaviour as risky because of a lack of understanding of immigrants' perception of safety and risk.
## Evidence Statement B14
Five studies (two , two and one ) found that a major barrier to child safety in the home was mothers' worry that asking about child injury in any context, including unintentional injury prevention, or taking an unintentionally hurt child to hospital, would result in the child being removed/seen as at risk, and they would be accused of abuse or neglect. All of these studies were in the US or Canada and focused on low-income mothers, and additionally, most were adolescent mothers or immigrant mothers.
## Evidence Statement B15
Two studies (one , one ) found that a major barrier to child safety in the home was mothers' lack of autonomy to make household or financial decisions. Policies/interventions might need to reconsider the often automatic targeting of mothers about safety equipment or behaviour, especially in populations where the fathers (or parents-in-law) traditionally make decisions about household purchases.
# Cost-effectiveness evidence
To supplement the cost-effectiveness review, two cost–utility analyses were carried out using the same model of the lifetime costs and effectiveness of relevant home safety interventions.
The first analysis compared the supply and installation of free smoke alarms versus no intervention. It found that a free smoke alarm scheme would probably be cost effective (incremental cost-effectiveness ratio £23,046). However, there were many uncertainties in this model and it should be noted that the empirical evidence is inconsistent.
The second analysis compared general home safety consultation and equipment provision versus no intervention. (This includes home safety consultation visits, provision of educational materials and advice, as well as the free supply and installation of a range of equipment.)
The sensitivity analyses demonstrate that, from a public sector perspective, cost–utility is likely to be highly dependent on:
the proportion of households that participate, the prevalence of existing safety devices in use and the proportion of households that correctly install or use any devices provided
how long the device is effective ('functional decay') and whether or not other changes take place in the household which affect its use
fixed or overhead costs of programmes relative to the number of households targeted
number of people in a household and their age
relative reduction in risk due to the device being properly fitted and used (or due to people adopting safer behaviour in the home).
# Fieldwork findings
Fieldwork aimed to test the relevance, usefulness and the feasibility of putting the recommendations into practice. PHIAC considered the findings when developing the final recommendations. For details, go to the fieldwork section in appendix B and Preventing unintentional injuries in the home among under-15s: providing safety equipment and home-risk assessments: fieldwork report.
Fieldwork participants who work with children and young people aged under 15 and their parents and carers were very positive about the recommendations and their potential to help prevent unintentional injuries among this group in the home.
However, they thought they represented an ideal scenario and that, currently, it was not feasible to implement some of the advice. Lack of resources was a key issue. In addition, they pointed out that children under 5 have different needs compared with older children – and that these differences should be acknowledged.
Participants wanted to see a greater emphasis on educational interventions that are delivered alongside the installation of home safety equipment. It was also important to overcome any possible stigma that particular households or communities might experience as a result of being prioritised for free safety kit.
Lack of clear lines of responsibility was deemed a key barrier to implementing the recommendations locally. Most participants felt this was due to the lack of national targets and indicators for reducing unintentional injuries among children in the home. Responsibility usually lay with local safeguarding children's boards in the focus group areas, but this was not always the case.# Appendix D: Gaps in the evidence
PHIAC identified a number of gaps in the evidence relating to the interventions under examination, based on an assessment of the evidence. These gaps are set out below.
. There is a lack of epidemiological data on unintentional injuries in the home among under-15s – the types, causes and severity of injuries (in particular, in relation to falls).
. There is limited, high quality evidence from the UK on the effectiveness of:
a range of home safety equipment, for example, carbon monoxide detectors and equipment incorporating new technologies (the latter include 10-year batteries and hard-wired smoke alarms)
different approaches to installing and maintaining home safety equipment and on the comparative effectiveness of combining different approaches (for example, education combined with the installation of safety equipment)
targeted approaches and the effects of interventions on different population groups, including deprived and high-risk households
making people aware of home safety issues to increase the use of safety equipment.
. There is a lack of cost-effectiveness studies and related data, such as the standard cost of home safety equipment and installation.
. There is limited evidence on the reasons why deprived and other high-risk households may be unreceptive to home safety interventions and on what encourages them to take them up.# Appendix E: Supporting documents
Supporting documents include:
Evidence reviews:
Review 1: 'Preventing unintentional injuries among under-15s in the home. Systematic reviews of effectiveness and cost-effectiveness of home safety equipment and risk assessment schemes'
Review 2: 'Barriers to, and facilitators of the prevention of unintentional injury in children in the home: a systematic review of qualitative research'.
Cost-effectiveness modelling: 'Preventing unintentional injuries among under-15s in the home. Report 3: cost-effectiveness modelling of home-based interventions aimed at reducing unintentional injuries in children'.
Fieldwork report: 'Preventing unintentional injuries in the home among under-15s: providing safety equipment and home-risk assessments: fieldwork report'
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe evidence statements underpinning the recommendations are listed in appendix C.\n\nSee also the evidence reviews, supporting evidence statements and cost effectiveness modelling.\n\nPHIAC considers that the recommended measures are cost effective. For the gaps in research, see appendix D.\n\n# Context\n\nThe recommendations in this guidance should be implemented as part of a broader strategy to reduce unintentional injuries in the home. This would include the use of regulations and the provision of safety education to prevent such injuries. (Note that in November 2010, we published a NICE guideline on unintentional injuries: prevention strategies for under 15s.)\n\nThis guidance focuses on home safety assessments and the supply and installation of home safety equipment, either delivered separately or together. It also covers education and advice when delivered as part of these interventions.\n\nImplementation of all the recommendations should ensure a systematic approach can be adopted. This involves prioritising households at greatest risk of unintentional injuries and establishing partnerships to ensure coordinated delivery and follow-up on home safety assessments and equipment interventions. In addition, the recommendations make the consideration of home safety issues a part of routine practice for all practitioners visiting children and young people at home.\n\n# Definitions\n\nNICE uses the term 'unintentional injuries' rather than 'accidents', since 'most injuries and their precipitating events are predictable and preventable' (Davis R, Pless B (2001) BMJ bans 'accidents'. Accidents are not unpredictable. BMJ 322: 1320–21). The term 'accident' implies an unpredictable and therefore, unavoidable event.\n\nThe process of systematically identifying potential hazards in the home, evaluating the risks and providing information or advice on how to reduce them is described here as a home safety assessment. Other terms commonly used to describe the same process include 'home risk assessment' and 'home safety check'. It may be carried out by a trained assessor or by parents and other householders, using an appropriate checklist (Home safety assessment tools are available from The Royal Society for the Prevention of Accidents and SafeHome.)\n\nIn this guidance, home safety equipment is any device used to prevent injury in the home. This includes door guards and cupboard locks, safety gates and barriers, smoke and carbon monoxide alarms, thermostatic mixing valves and window restrictors.\n\nFor the purposes of this guidance, 'home' refers to inside the dwelling itself. It does not include the garden or outbuildings.\n\n# Whose health will benefit?\n\nThe recommendations aim to help children and young people aged under 15 years who are at greatest risk of an unintentional injury and their parents and carers. In particular, it is aimed at those living in disadvantaged circumstances.\n\n# Recommendation 1 Prioritising households at greatest risk\n\n## Who should take action?\n\nLocal safeguarding children boards.\n\nLocal authority children's services and their partnerships.\n\nLocal strategic partnerships.\n\nLocal authority health and wellbeing boards and partnerships (where they are not part of the local strategic partnership).\n\n## What action should they take?\n\nDetermine the types of household where children and young people aged under 15 are at greatest risk of unintentional injury based on surveys, needs assessments and existing datasets (such as local council housing records).\n\nPrioritise the households identified above for home safety assessments and the supply and installation of home safety equipment (see recommendations 2 and 3). 'Priority households' could include those with children aged under 5, families living in rented or overcrowded conditions or families living on a low income. It could also include those living in a property where there is a lack of appropriately installed safety equipment, or one where hazards have been identified through the Housing Health and Safety Rating System (HHSRS; this is a risk assessment procedure for residential properties).\n\nProvide practitioners who visit children and young people at home with mechanisms (such as the Early Help Assessment) for sharing information about households that might need a home safety assessment. This includes health visitors, social workers and GPs.\n\nEnsure practitioners adhere to good practice on maintaining the confidentiality and security of personal information. (For example, this includes using end-to-end encryption when sharing data with other agencies. See for example, the government's information sharing advice for safeguarding practitioners.)\n\n# Recommendation 2 Working in partnership\n\n## Who should take action?\n\nStrategic planners and leads with responsibility for child health.\n\nFire and rescue services.\n\nHousing associations.\n\nLocal authorities: leads for children's services, environmental health, accident prevention and home safety and housing.\n\nSure Start and children's centres.\n\n## What action should they take?\n\nEstablish local partnerships with relevant statutory and voluntary organisations or support existing ones. Partners could include:\n\n\n\nlocal community and parent groups\n\norganisations employing health and social practitioners who visit children and young people in their homes (for example, health visitors)\n\nchildcare agencies\n\nothers with a remit to improve the health and wellbeing of children aged under 15\n\nlocal umbrella organisations for private and social landlords\n\nthose involved in lifestyle and other health initiatives.\n\n\n\nUse these partnerships to:\n\n\n\nhelp collect information on specific households where children and young people aged under 15 may be at greatest risk of an unintentional injury (see recommendation 1). The collection and sharing of information should adhere to the standards referred to in recommendation 1\n\nhelp determine and address barriers to creating a safe home environment. (For example, the cost of equipment, cultural norms, issues of trust or a lack of control over the home environment may all be barriers to installing safety equipment)\n\nget the community involved (as outlined in the NICE guideline on community engagement). For example, local 'community champions' could be used to promote home safety interventions and help practitioners gain the trust of householders\n\ncarry out home safety assessments and supply and install home safety equipment, in line with recommendation 3 (Home safety assessment tools are available from The Royal Society for the Prevention of Accidents and SafeHome.).\n\n\n\n# Recommendation 3 Coordinated delivery\n\n## Who should take action?\n\nThose who carry out home safety assessments and provide home safety equipment (see recommendation 2).\n\n## What action should they take?\n\nOffer home safety assessments to the households prioritised in recommendations 1 and 2 (Home safety assessment tools are available from The Royal Society for the Prevention of Accidents and SafeHome.). Where appropriate, supply and install suitable, high quality home safety equipment. Home safety equipment should adhere to the British 'Kite mark' standards or the equivalent European standard. Where resources are limited, it may be necessary to narrow down further the households being prioritised (for example, to those with children under the age of 5 years).\n\nEnsure the assessment, supply and installation of equipment is tailored to meet the household's specific needs and circumstances. Factors to take into account include:\n\n\n\nthe developmental age of the children (in relation to any equipment installed)\n\nwhether or not a child or family member has a disability\n\ncultural and religious beliefs\n\nwhether or not English is the first language\n\nlevels of literacy\n\nthe level of control people have over their home environment. (Many people may not have the authority to agree to an installation, for example, tenants of social and private landlords and those who are unable to make household or financial decisions)\n\nthe household's perception of, and degree of trust in, authority.\n\n\n\nEnsure education, advice and information is given during a home safety assessment, and during the supply and installation of home safety equipment. This should emphasise the need to be vigilant about home safety and explain how to maintain and check home safety equipment. It should also explain why safety equipment has been installed – and the danger of disabling it. In addition, useful links and contacts should be provided in case of a home safety problem.\n\n# Recommendation 4 Follow-up on home safety assessments and interventions\n\n## Who should take action?\n\nThose who carry out home safety assessments and provide home safety equipment (see recommendations 2 and 3).\n\n## What action should they take?\n\nPrevent duplication of effort by keeping a record of households that have been given safety advice or equipment. (It may be possible to use an existing local database.) Ensure the records are accessible to all those with a direct or indirect responsibility for preventing unintentional injuries in the home.\n\nAdhere to the standards referred to in recommendation 1 in relation to the collection and sharing of information.\n\nUse the records to identify when maintenance and follow-up are required, to feed into strategic planning and to prioritise future interventions (see recommendation 1).\n\nContact homes identified as being in need of an equipment maintenance check or follow-up. Offer to revisit them to see if the equipment is still appropriate and functional (and in case of a product recall or faults). Ascertain whether there are any new requirements (for example, due to changes in the building or the family). Reinforce home safety messages during these visits.\n\n# Recommendation 5 Integrating home safety into other home visits\n\n## Who should take action?\n\nPractitioners who visit families and carers with children and young people aged under 15. This includes GPs, midwives, social workers and health visitors.\n\n## What action should they take?\n\nRecognise the importance of measures to prevent unintentional injuries in the home among children and young people aged under 15, particularly among those living in disadvantaged circumstances.\n\nProvide child-focused home safety advice. If the family or carers agree, refer them to agencies that can undertake a home safety assessment and can supply and install home safety equipment.\n\nEncourage parents, carers and others living with children and young people aged under 15 to conduct their own home safety assessment. They should use an appropriate tool, as outlined in recommendation 3.", 'Public health need and practice': "Unintentional injury is a leading cause of death among children and young people aged 1–14 (Audit Commission and Healthcare Commission 2007). In England and Wales in 2008, 208 children and young people aged 0–14 died from such injuries (Office for National Statistics 2009).\n\nIn the UK, unintentional injury (in all environments) results in more than two million visits to accident and emergency (A&E) departments by children every year. Half of these injuries occur in the home (Audit Commission and Healthcare Commission 2007). In 2002, nearly 900,000 children and young people in the UK aged under 15 attended hospital following an unintentional injury in the home (Department of Trade and Industry 2002).\n\nChildren and young people who survive a serious unintentional injury can experience severe pain and may need lengthy treatment (including numerous stays in hospital). They could be permanently disabled or disfigured (Child Accident Prevention Trust 2008) and their injuries may have an impact on their social and psychological wellbeing.\n\n# Types of injury\n\nChildren and young children are vulnerable to a range of unintentional injuries in the home including falls, burns and scalds, drowning, suffocation and poisoning (Child Accident Prevention Trust 2008).\n\nIn the UK between 2000 and 2002, falls were the major cause of unintentional injury in the home among those aged under 15, according to home accidents surveillance system (HASS) data (Department of Trade and Industry 2002). 'Drowning and submersion' and 'other accidental threats to breathing' led to the most deaths in the home among this group between 2002 and 2005 (Office for National Statistics 2009). On average, 1200 children a year under the age of 11 are injured – and 35 are killed – in fires in the home (Directgov 2008).\n\n# Costs\n\nTreating unintentional injuries among children and young people costs UK A&E departments approximately £146 million a year. Further treatment costs are significant, for example, it can cost £250,000 to treat one severe bath water scald (Child Accident Prevention Trust 2008). The indirect costs include enforced absence from school and the need for children and young people to be supervised during their recovery (which could involve family and carers taking time off from work).\n\n# Risk factors\n\nEpidemiological data indicate that the risk of an unintentional injury is greatest among households living in the most deprived circumstances. Children and young people from lower socioeconomic groups whose parents have never worked (or who are long-term unemployed) are 13 times more likely to die from such an injury than those whose parents are managers and professionals (Edwards et al. 2006).\n\nThe evidence also suggests that a range of interrelated factors can lead to a higher risk of injury. Apart from a low income and overcrowded housing conditions, they include a lack of safety equipment. Other factors include gender, age, culture, ethnicity and the household's level of control over their home environment. Although not necessarily the direct cause of injury, these factors can increase children and young people's risk of exposure to a potential hazard.\n\n# Current policy and practice\n\nLocal strategic partnerships and local safeguarding children boards have a duty to promote children and young people's health, wellbeing and general welfare. In addition, local area agreements provide an opportunity for local authorities, in partnership with the NHS and other organisations, to focus on unintentional injuries in the home. Practice is variable, but some areas are taking innovative approaches to home safety.\n\nIn February 2009, the Department for Children, Schools and Families launched 'Safe at home: the national home safety equipment scheme' (2009). The 3-year, £18\xa0m scheme is being developed and evaluated by the Royal Society for the Prevention of Accidents (RoSPA). Local organisations, working in partnership with RoSPA, will provide home safety advice and information and equipment to the most disadvantaged families in 141 areas of England with the highest accident rates.", 'Considerations': "The Public Health Interventions Advisory Committee (PHIAC) took account of a number of factors and issues when developing the recommendations.\n\nBoth generic and targeted interventions are used to prevent injuries in the home. The former could include legislation – for example, to improve the way homes are constructed. The latter could include the provision of safety equipment. Both generic and targeted interventions aim to do three things, either independently or in combination: change attitudes and behaviour, alter the environment, and provide information or training (Lund and Aarǿ 2004).\n\nPHIAC noted that forthcoming NICE guidance will cover strategic approaches to reducing unintentional injuries among the under-15s.\n\nThe technical efficacy of safety equipment has been demonstrated and, in most cases, has improved since the research studies included in the evidence reviews were undertaken.\n\nThe evidence did not cover all the home safety equipment available. For example, there were no evaluations of interventions involving the installation of carbon monoxide alarms.\n\nThere was limited evidence on residential care homes. While some elements of the recommendations may apply, residential care homes are already subject to a range of legislation. This includes The Care Homes Regulations 2001 (HM Government 2001) and 'Children's homes: national minimum standards, children's homes regulations' (DH 2002).\n\nPHIAC considered it very unfortunate that many injury prevention schemes do not include an integrated and robust evaluation process. This limits the evidence available on their impact.\n\nChildren and young people learn by taking risks and challenging themselves when playing and in other activities. Many areas of the home – and activities that take place there – pose an inherent risk. Safety equipment and education help to keep children safe.\n\nPHIAC acknowledged that interventions need to take into account a household's everyday circumstances and routine practices – and how receptive families are to safety messages.\n\nPHIAC believes that it is important to raise awareness of safety issues.\n\nSafety equipment has to be correctly used and maintained to be effective.\n\nThe cost-effectiveness modelling that underpins the recommendations is based on very limited data. It should not be regarded as a definitive analysis of cost-effectiveness. Rather, it explores the factors most likely to affect whether or not interventions to prevent unintentional injuries in the home represent good value for money. The analysis indicates that, from a public sector perspective, the cost effectiveness of such programmes is dependent on a number of factors (see cost effectiveness in appendix C).", 'Recommendations for research': "PHIAC developed some provisional research recommendations, based on the evidence and expert advice from cooptees. These were passed to the NICE committee that developed related guidance on 'Strategies to prevent unintentional injuries among under-15s', for them to develop a comprehensive set of research recommendations covering all types of unintentional injuries.\n\nMore detail on the gaps in the evidence identified during development of the guidance on preventing unintentional injuries in the home among under-15s is provided in appendix D.", 'References': "Audit Commission and Healthcare Commission (2007) Better safe than sorry: preventing unintentional injury to children. London: Audit Commission\n\nDavis R, Pless B (2001) BMJ bans 'accident'. BMJ 322: 1320–1\n\nChild Accident Prevention Trust (2008) Child Accident Prevention Trust factsheet: preventing bath water scalds using thermostatic mixing valves. London: Child Accident Prevention Trust\n\nDepartment of Health (2002) Children's homes: national minimum standards, children's homes regulations. London: Department of Health\n\nDepartment of Trade and Industry (2002) Home accidents surveillance system (HASS)\n\nDirectgov (2008) Fire safety for parents and child carers [Accessed 20 January 2010]\n\nEdwards P, Roberts I, Green J et al. (2006) Deaths from injury in children and employment status in family: analysis of trends in class specific death rates. BMJ 333: 119–21\n\nHM Government (2001) The Care Homes Regulations 2001. London: HM Government\n\nLund J, Aarǿ LE (2004) Accident prevention. Presentation of a model placing emphasis on human, structural and cultural factors. Safety Science 42: 271–324\n\nOffice for National Statistics (2009) Mortality statistics: deaths registered in 2008. Review of the Registrar General on deaths in England and Wales", 'Appendix B: Summary of the methods used to develop this guidance': "# Introduction\n\nThe reviews and cost effectiveness modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the PHIAC meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in appendix E.\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by PHIAC to help develop the recommendations. The overarching questions were:\n\nQuestion 1: Which interventions involving the supply and/or installation of home safety equipment are effective and cost effective in preventing unintentional injuries among children and young people aged under 15 in the home?\n\nQuestion 2: Are home-risk assessments effective and cost effective in preventing unintentional injuries among children and young people aged under 15?\n\nQuestion 3: What are the barriers to, and facilitators of, interventions involving the supply and/or installation of home safety equipment and/or home-risk assessments?\n\nThese questions were made more specific for the reviews (see reviews for further details).\n\n# Reviewing the evidence\n\nTwo evidence reviews were carried out: one on effectiveness and cost effectiveness and one on the barriers to, and facilitators of, the prevention of unintentional injury in children in the home.\n\n## Identifying the evidence\n\nThe following databases were searched from 1990 up to March 2009, using a single strategy to identify relevant primary and qualitative research (no study design filters were applied):\n\nApplied Social Science Index and Abstracts (ASSIA)\n\nBibliomap\n\nCentre for Review and Dissemination databases\n\nCINAHL (Cumulative Index of Nursing and Allied Health Literature)\n\nCochrane Library database of systematic reviews\n\nDatabase of Abstracts of Reviews of Effects (DARE)\n\nDatabase of Promoting Health Effectiveness Reviews (DoPHER)\n\nEconLit\n\nEvidence for Policy and Practice Information and Co-ordinating (EPPI) Centre databases\n\nHealth Management Information Consortium (HMIC)\n\nISI Web of Knowledge Social Science Citation Index (SSCI)\n\nScience Citation Index Expanded (SCI-EXPANDED)\n\nMEDLINE\n\nNational Health Service Economic Evaluations Database (NHSEED)\n\nNHS Economic Evaluation Database (HTA)\n\nPsycINFO\n\nSafetyLit\n\nTrials Register of Promoting Health Interventions (TRoPHI)\n\nA follow-up targeted search of named programmes was conducted in MEDLINE and using the search engine Google.\n\nThe following websites were also searched:\n\nChild Accident Prevention Trust\n\nChildren in Wales\n\nEurosafe\n\nInjury Observatory for Britain & Ireland\n\nIntegris (EU Injuries programme for coordinating injury data)\n\nInternational Society for Child and Adolescent Injury Prevention\n\nPublic Health Observatory website for the South West (lead on injuries)\n\nThe Royal Society for the Prevention of Accidents\n\nFurther details of the databases, search terms and strategies are included in the reviews.\n\n## Selection criteria\n\nStudies were included in the effectiveness and cost effectiveness review if they:\n\nwere published from 1990 to March 2009 in English\n\nwere conducted in member countries of the Organisation for Economic Cooperation and Development (OECD)\n\nreported injury related outcomes (for example, a reduction in injuries from smoke inhalation, an increase in the number of smoke alarms installed and improved knowledge of how to prevent other injuries in the home).\n\nStudies were excluded if they did not:\n\ncompare the injury-related outcome prior to or without the intervention report injury-related outcomes for children or young people aged under 15 (for examples, see above; however, studies that reported injury-related outcomes among, for example, those aged 5–18 years would be included if most of the data related to children aged 15 years or under.)\n\nfor the cost-effectiveness review only, assess the cost and related benefits or effectiveness of the intervention (or class of intervention).\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the relevant NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.\n\n++ All or most of the methodology checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are thought very unlikely to alter.\n\n+ Some of the methodology checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are thought unlikely to alter the conclusions.\n\n– Few or no methodology checklist criteria have been fulfilled. The conclusions of the study are thought likely or very likely to alter.\n\n## Summarising the evidence and making evidence statements\n\nThe review data was summarised in evidence tables (see full reviews).\n\nThe findings from the reviews were synthesised and used as the basis for evidence statements relating to each key question. The evidence statements were prepared by the public health collaborating centre (see appendix A). The statements reflect their judgement of the strength (quantity, type and quality) of evidence and its applicability to the populations and settings in the scope.\n\n# Economic analysis\n\nThe economic analysis consisted of a review of economic evaluations (the cost effectiveness part of review 1) and a cost-effectiveness model (report 3).\n\n## Cost effectiveness review (part of review 1)\n\nAs indicated above, a single search strategy was used to identify relevant economic evaluations from a wide range of databases (listed earlier).\n\n## Cost-effectiveness modelling\n\nTwo economic models were constructed to incorporate data from the evidence reviews.\n\nFirst, the intervention model was used to analyse the effectiveness of an intervention to increase the number of people using a particular safety feature (such as a smoke alarm or stair gate) in the home.\n\nThe second stage outcomes model used the levels of installed safety equipment in the population (derived from the first model) to predict the number of resulting injuries and fatalities over the lifetime of the population cohort. It involved a cost–utility analysis undertaken from the NHS and personal social services perspective.\n\nA number of assumptions were made which could underestimate or overestimate the cost effectiveness of the interventions (see review modelling report for further details).\n\nThe results are reported in: Preventing unintentional injuries among under-15s in the home. Report 3: cost-effectiveness modelling of home-based interventions aimed at reducing unintentional injuries in children.\n\n# Fieldwork\n\nFieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice.\n\nIt was conducted with practitioners and commissioners who are involved in preventing unintentional injuries among under-15s. They included: unintentional injury prevention specialists; practitioners working on local home-safety initiatives, including safety equipment distribution schemes; and practitioners with a broader remit for the welfare of children aged 0–15. The latter included: children's centre managers, health visitors, housing managers, public health practitioners, school nurses, social workers and others working in the NHS, local authorities, police and fire services, and voluntary sector organisations.\n\nThe fieldwork comprised nine focus groups carried out in different local authority areas and one in-depth interview. They were conducted by GHK (with Noble Denton) and involved a total of 65 participants.\n\nThe focus groups and in-depth interview were commissioned to ensure there was ample geographical coverage. The main issues arising are set out in appendix C fieldwork findings. See the full report, Preventing unintentional injuries in the home among under-15s: providing safety equipment and home-risk assessments: fieldwork report.\n\n# How PHIAC formulated the recommendations\n\nAt its meeting in September 2009 PHIAC considered the evidence of effectiveness and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of quantity, quality and applicability) to form a judgement\n\nwhether, on balance, the evidence demonstrates that the intervention is effective, ineffective or equivocal\n\nwhere there is an effect, the typical size of effect.\n\nPHIAC developed draft recommendations through informal consensus, based on the following criteria.\n\nStrength (quality and quantity) of evidence of effectiveness and its applicability to the populations/settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of risks and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nWhere possible, recommendations were linked to evidence statements (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).\n\nThe draft guidance, including the recommendations, was released for consultation in November 2009. At its meeting in January 2010, PHIAC amended the guidance in light of comments from stakeholders, experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in March 2010.", 'Appendix C: The evidence': "This appendix lists evidence statements from two evidence reviews provided by public health collaborating centres (see appendix A) and links them to the relevant recommendations. (See appendix B for the key to quality assessments.) The evidence statements are presented here without references – these can be found in the full review (see appendix E for details). It also sets out a brief summary of findings from the economic analysis.\n\nEvidence statement number E4d indicates that the linked statement is numbered 4d in review 1 'Preventing unintentional injuries among under-15s in the home. Systematic reviews of effectiveness and cost-effectiveness of home safety equipment and risk assessment schemes'.\n\nEvidence statement number B1 indicates that the linked statement is numbered 1 in review 2 'Barriers to, and facilitators of the prevention of unintentional injury in children in the home: a systematic review of qualitative research.'\n\nWhere a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence) below.\n\nRecommendation 1: economic modelling; IDE\n\nRecommendation 2: evidence statements B4, B5, B6, B8, B9, B11, B12, B13, B14, B15; IDE\n\nRecommendation 3: evidence statements E2a, E2b, E3b, E3c, E3d, E4b, E4c, E4d, E6b, E7b, E9b, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, B13, B14, B15; IDE\n\nRecommendation 4: evidence statement B3; economic modelling, IDE\n\nRecommendation 5: evidence statements E3e, E3f, E3h, E4b, B2, B9; IDE\n\n# Evidence statements\n\nPlease note that the wording of some evidence statements has been altered slightly from those in the review team's report to make them more consistent with each other and NICE's standard house style.\n\n## Evidence statement E2a\n\nThere is inconsistent evidence about impact on injury from one cluster RCT (++) and one controlled before-and-after study (CBA) (+). There is evidence from the better quality cluster RCT that the free supply and installation of smoke alarms had no significant effect on the incidence of fire-related hospitalisations and deaths (rate ratio 1.0 [95% confidence interval {CI} 0.5, 2.0]). However, the CBA study suggests that the free supply and installation of smoke alarms decreased the incidence of fire-related injuries (within-group pre-post intervention comparison: 0.2 [95% CI 0.1, 0.4] for the intervention group and 1.1 [95% CI 0.7, 1.7] for the remainder of the city).\n\n## Evidence statement E2b\n\nThere is inconsistent evidence about impact on rates of installation of home safety equipment from two cluster RCTs (one [++], one [+]) and one CBA (+). There is evidence from the better quality cluster RCT that the free supply and installation of smoke alarms had no significant effect on the installation or functioning of smoke alarms within households (Rate ratio 1.0 [95% CI 0.4, 2.4]). However, there is evidence from the other cluster RCT that the free supply and installation of smoke alarms had a significant effect on the installation and functioning of smoke alarms: odds ratio (OR) 4.82 (95% CI 3.97, 5.85). The CBA study reported that 51% of intervention households (identified as being without a smoke alarm prior to the intervention) had a correctly installed and functioning smoke alarm at 12 months follow-up.\n\n## Evidence statement E3b\n\nThere is moderate evidence from three RCTs (one [++] one [+] and one [-]) that the free or discounted supply of smoke alarms in conjunction with safety education increases the rate of installation of these devices.\n\n## Evidence statement E3c\n\nThere is weak evidence from two RCTs (one [++] and one [+]) about interventions with free or discounted supply of home safety equipment in conjunction with safety education. Outcomes about three types of home safety equipment (buffers, electrical outlet covers and cupboard locks/latches) are reported, showing mixed evidence of effect. Outcomes about other types of home safety equipment (non-slip bathroom items, window locks, fire guards and stair gates) are presented in one report, with only fire guards reported as being more likely to be present post-intervention (based on self-report).\n\n## Evidence statement E3d\n\nThere is weak evidence from one RCT (++) that the free or discounted supply of a range of safety equipment, in conjunction with safety education, increases the rate of installation of safety equipment as a whole (mean difference [MD] 21.1 [95% CI 13.90, 28.30]) (based on self-report).\n\n## Evidence statement E3e\n\nThere is strong evidence from four RCTs (two [++], one [+] and one [-]) that the free or discounted supply of a range of safety equipment, in conjunction with safety education, increases knowledgeabout the prevention of poisoning and scalds.\n\n## Evidence statement E3f\n\nThere is inconsistent evidence from three RCTs (two [++] and one [+]) about how a free or discounted supply of a range of safety equipment, in conjunction with safety education, affects knowledge about: the prevention of fires, falls and wounds.\n\n## Evidence statement E3h\n\nThere is weak evidence from one RCT (+) that the free or discounted supply of a range of safety equipment, in conjunction with safety education, increases knowledge about the prevention of suffocation.\n\n## Evidence statement E4b\n\nThere is weak evidence from one RCT (++) that free home safety equipment (or its delivery) and installation with safety education increases the use of smoke alarms at 12 months (OR 1.83 [95% CI 1.33, 2.53]) and 24 months (OR 1.67 [95% CI 1.21, 2.32]). The intervention did not have a statistically significant impact on reducing socioeconomic inequalities in the uptake and continued use (12 months post-intervention) of smoke alarms.\n\n## Evidence statement E4c\n\nThere is weak evidence from one RCT (++) that showed mixed evidence of effect of the supply of free home safety equipment (or its delivery) and installation with safety education. Outcomes showed no impact on fire guards being fitted and always used after 12 or 24 months, and increased use of stair gates and window locks at 12 months, but not 24 months. The intervention had a statistically significant impact on reducing socioeconomic inequalities in the uptake and continued use (12 months post-intervention) of stair gates.\n\n## Evidence statement E4d\n\nThere is weak evidence from one RCT (++) that free home safety equipment (or its delivery) and installation with safety education may increase the safe storage at 12 months of cleaning products and sharp objects, but these effects are no longer seen after 24 months for safe storage of sharp objects.\n\n## Evidence statement E6b\n\nThere is inconsistent evidence from two RCTs (one [+] and one [++]) and one CBA (+) about interventions with a home-risk assessment and free or discounted supply of home safety equipment that included a smoke alarm. Outcomes about the rates of installation of smoke alarms (all self-reported) show mixed evidence of effect(no effect, increased, increased).\n\n## Evidence statement E7b\n\nThree studies (one CBA [+] and two before-and-after [BA] [{-}, {+}]) report on the continued presence and use of installed equipment after home-risk assessment and free or discounted supply and installation of home safety equipment. There is mixed evidence about the impact on continued working equipment. One study found that 60% of installed hot water tempering valves remained in situ after 6 to 9 months. One study found significant improvements in the numbers of households with working window guards and fire extinguishers post-intervention. Finally, two studies (one CBA [+] and one BA [+]) showed significantly more smoke alarms installed and working post-intervention (p<0.0001; OR 0.30 [95% CI 0.24, 0.38: showing less alarm absence in the intervention group]).\n\n## Evidence statement E9b\n\nThere is inconsistent evidence from six robust studies (which use both observed outcome measures and a controlled study design) about the presence of functional smoke alarms. Four suggest that the intervention increased functioning presence (one RCT [+], one CBA [+], one RCT [-] and one CBA [+]) and two suggest that no significant impact was seen on smoke alarms (both RCT [++]).\n\n## Evidence statement B2\n\nThree studies (three [-]) found that parents felt there was a lack of information or knowledge about existing policies or support. Examples included lack of knowledge of poison centre telephone number, and lack of 'direct information' on poisoning prevention.\n\nA lack of communication about programmes to install smoke alarms limited uptake, especially for the most high-risk families (those in rented accommodation with a rapid turnover of tenants).\n\nTiming of information was shown to be important. One study found that parents given information in hospital, at the time of a child's birth, did not retain this, while information provided subsequently in a community or physician setting was better retained.\n\n## Evidence statement B3\n\nThree studies (all [-]) found that partnerships and collaborations between different service providers facilitated the effectiveness of interventions to reduce unintentional injuries to children in low income communities.\n\nCollaborations perceived as useful included multi-agency partnerships between different agencies, and between agencies and hard-to-reach groups. These collaborations aided the effectiveness of a UK smoke alarm installation programme and a partnership between health officials and low income mothers in home safety visits offering advice and provision of safety equipment\n\nThe importance of devising information and advice in ways that suit the target community (in terms of language, style, examples used) was noted in both of these papers dealing with low income populations with many ethnic minorities.\n\n## Evidence statement B4\n\nNine studies (four [-], four [+] and one [++]) found that a major barrier to implementing safety equipment and childproofing a home was living in a home one was not free to modify.\n\nThe studies found that mothers particularly found a lack of control over their home environment due to living in rented accommodation, and/or with extended family. In rented accommodation, landlords were reported as unresponsive to requests for installation or maintenance of safety equipment. In extended family homes, often in overcrowded situations, young parents often did not have a say in how the home was arranged. Two studies noted that high turnover of tenants in cheap rented accommodation limited the effectiveness of projects to organise effective installation and maintenance. In two studies, having landlords with the ability and eagerness to make repairs led to more effective interventions.\n\n## Evidence statement B5\n\nFour studies (two [-] and two [+]) found that faulty or poor quality equipment was a barrier to interventions to reduce unintentional injuries to children in the home. For example, mothers resorted to taping over electric sockets when safety plugs were not provided or did not work.\n\nThe four studies made recommendations for different or better equipment. Studies recommended the provision of tamper-proof smoke alarms with 10- year batteries, alternatives of sprinkler systems for some populations, smoke alarms with longer lasting batteries, help for fitting alarms, or simpler systems for older residents, and more systematic provision of child-resistant containers.\n\nSuspicion by those in vulnerable communities of strangers coming into their homes to assess or install property, and suspicion of 'free' offers, needs to be mitigated in successful interventions.\n\n## Evidence statement B6\n\nThe two studies on smoke alarm installation (one [+], one [-]) both found that people balance immediate and longer term risks to health and wellbeing when they disable alarms. They were aware that it was less than ideal to disable smoke alarms, but weighed this against other factors, especially the inconvenience and stress of malfunctioning alarms.\n\n## Evidence statement B7\n\nThree studies (one [+] and two [-]) based on evaluation of specific interventions all found that training in installation and equipment use/replacement was a facilitator to reducing the incidence of unintentional injuries to children in the home.\n\n## Evidence statement B8\n\nCost emerged as a theme in five of the studies, always as a barrier to reducing accidents to children in the home, or to obtaining help if a child had been injured (two [-], two [+] and one [++]). Three studies found that the perceived cost of installing safety devices or making repairs was a major barrier in the correct use of smoke alarms and in general for safety equipment. However, in one study the provision of free safety equipment, in this case a smoke alarm, led to the equipment being rejected due to suspicions precisely because it was free, which suggests that making equipment or installations totally free may not always be appropriate.\n\n## Evidence statement B9\n\nFour studies (one [-], two [+] and one [++]) found that young or poorly educated mothers found it hard to anticipate the child's rate of development in terms of ability to climb, open containers or locks, or light fires. One study, in contrast, found that mothers were good at anticipating developmental milestones and adjusting the home environment in advance of changes, thereby reducing the rate of unintentional injuries in the home (+).\n\n## Evidence statement B10\n\nOne study (++) found that exposure to a child poisoning incident, either in real life or in the media, increased awareness of that particular danger and was a motivator for implementing safety measures. This suggests that providing information on unintentional poisoning via media outlets might be an effective facilitator in raising awareness of risk.\n\n## Evidence statement B11\n\nOne study (-) found that adolescent mothers found it hard to deal with issues of blame, oscillating between ideas of the accident-prone child who would have accidents whatever you did, and the negligent adult who was responsible for their child's accidents. The study recommends that care providers approach the topic of injury in a forthright manner when working with adolescent mothers, challenging the idea that injuries are unavoidable while not assigning blame to the mother for injury to the child. It also suggests that 'helping mothers identify risks to their specific child in their specific environment may be the most effective intervention'.\n\n## Evidence statement B12\n\nFive studies (two [-], two [+] and one [++]) noted the large and constant amount of effort which mothers put into preventing unintentional injuries in the home as a major facilitator of reducing unintentional injuries in the home. Authors picked up on several main components of this maternal safeguarding work – commonsense safeguarding, constant vigilance and teaching children about safety.\n\nWhile these maternal safeguarding activities do act as a short-term facilitator to accident reduction, it is important to note that they are time and energy- intensive and that, for this reason, need supplementing with other forms of unintentional injury prevention.\n\n## Evidence statement B13\n\nThree studies (two [+] and one [++]) noted cultural practices which, while they may have been adequate safety measures in the parents' culture of origin, were risky in a new cultural context. There were two aspects to this theme; lack of experience of the particular risks of a host context, and lack of understanding by health officials about different child safety norms and expectations in immigrants' cultures.\n\nMexican mothers in one US study mostly came from rural and semi-rural backgrounds, so had less experience with urban hazards such as multi-storey buildings and hot water taps which could cause falls or scalds. Mexican mothers were also more likely to use Mexican products, which were more likely to come without safety warnings/packaging. Two US studies found significant cultural differences in experience and expectations which led to health visitors classing behaviour as risky because of a lack of understanding of immigrants' perception of safety and risk.\n\n## Evidence Statement B14\n\nFive studies (two [-], two [+] and one [++]) found that a major barrier to child safety in the home was mothers' worry that asking about child injury in any context, including unintentional injury prevention, or taking an unintentionally hurt child to hospital, would result in the child being removed/seen as at risk, and they would be accused of abuse or neglect. All of these studies were in the US or Canada and focused on low-income mothers, and additionally, most were adolescent mothers or immigrant mothers.\n\n## Evidence Statement B15\n\nTwo studies (one [+], one [++]) found that a major barrier to child safety in the home was mothers' lack of autonomy to make household or financial decisions. Policies/interventions might need to reconsider the often automatic targeting of mothers about safety equipment or behaviour, especially in populations where the fathers (or parents-in-law) traditionally make decisions about household purchases.\n\n# Cost-effectiveness evidence\n\nTo supplement the cost-effectiveness review, two cost–utility analyses were carried out using the same model of the lifetime costs and effectiveness of relevant home safety interventions.\n\nThe first analysis compared the supply and installation of free smoke alarms versus no intervention. It found that a free smoke alarm scheme would probably be cost effective (incremental cost-effectiveness ratio [ICER] £23,046). However, there were many uncertainties in this model and it should be noted that the empirical evidence is inconsistent.\n\nThe second analysis compared general home safety consultation and equipment provision versus no intervention. (This includes home safety consultation visits, provision of educational materials and advice, as well as the free supply and installation of a range of equipment.)\n\nThe sensitivity analyses demonstrate that, from a public sector perspective, cost–utility is likely to be highly dependent on:\n\nthe proportion of households that participate, the prevalence of existing safety devices in use and the proportion of households that correctly install or use any devices provided\n\nhow long the device is effective ('functional decay') and whether or not other changes take place in the household which affect its use\n\nfixed or overhead costs of programmes relative to the number of households targeted\n\nnumber of people in a household and their age\n\nrelative reduction in risk due to the device being properly fitted and used (or due to people adopting safer behaviour in the home).\n\n# Fieldwork findings\n\nFieldwork aimed to test the relevance, usefulness and the feasibility of putting the recommendations into practice. PHIAC considered the findings when developing the final recommendations. For details, go to the fieldwork section in appendix B and Preventing unintentional injuries in the home among under-15s: providing safety equipment and home-risk assessments: fieldwork report.\n\nFieldwork participants who work with children and young people aged under 15 and their parents and carers were very positive about the recommendations and their potential to help prevent unintentional injuries among this group in the home.\n\nHowever, they thought they represented an ideal scenario and that, currently, it was not feasible to implement some of the advice. Lack of resources was a key issue. In addition, they pointed out that children under 5 have different needs compared with older children – and that these differences should be acknowledged.\n\nParticipants wanted to see a greater emphasis on educational interventions that are delivered alongside the installation of home safety equipment. It was also important to overcome any possible stigma that particular households or communities might experience as a result of being prioritised for free safety kit.\n\nLack of clear lines of responsibility was deemed a key barrier to implementing the recommendations locally. Most participants felt this was due to the lack of national targets and indicators for reducing unintentional injuries among children in the home. Responsibility usually lay with local safeguarding children's boards in the focus group areas, but this was not always the case.", 'Appendix D: Gaps in the evidence': 'PHIAC identified a number of gaps in the evidence relating to the interventions under examination, based on an assessment of the evidence. These gaps are set out below.\n\n. There is a lack of epidemiological data on unintentional injuries in the home among under-15s – the types, causes and severity of injuries (in particular, in relation to falls).\n\n. There is limited, high quality evidence from the UK on the effectiveness of:\n\na range of home safety equipment, for example, carbon monoxide detectors and equipment incorporating new technologies (the latter include 10-year batteries and hard-wired smoke alarms)\n\ndifferent approaches to installing and maintaining home safety equipment and on the comparative effectiveness of combining different approaches (for example, education combined with the installation of safety equipment)\n\ntargeted approaches and the effects of interventions on different population groups, including deprived and high-risk households\n\n\n\nmaking people aware of home safety issues to increase the use of safety equipment.\n\n\n\n. There is a lack of cost-effectiveness studies and related data, such as the standard cost of home safety equipment and installation.\n\n. There is limited evidence on the reasons why deprived and other high-risk households may be unreceptive to home safety interventions and on what encourages them to take them up.', 'Appendix E: Supporting documents': "Supporting documents include:\n\nEvidence reviews:\n\n\n\nReview 1: 'Preventing unintentional injuries among under-15s in the home. Systematic reviews of effectiveness and cost-effectiveness of home safety equipment and risk assessment schemes'\n\nReview 2: 'Barriers to, and facilitators of the prevention of unintentional injury in children in the home: a systematic review of qualitative research'.\n\n\n\nCost-effectiveness modelling: 'Preventing unintentional injuries among under-15s in the home. Report 3: cost-effectiveness modelling of home-based interventions aimed at reducing unintentional injuries in children'.\n\nFieldwork report: 'Preventing unintentional injuries in the home among under-15s: providing safety equipment and home-risk assessments: fieldwork report'"}
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https://www.nice.org.uk/guidance/ph30
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This guideline covers home safety assessments, supplying and installing safety equipment and providing education and advice. It aims to prevent unintentional injuries among all children and young people aged under 15 but, in particular, those living in disadvantaged circumstances.
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7628be93e5000bbf5af60055751857e270cc2662
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nice
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Unintentional injuries on the road: interventions for under 15s
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Unintentional injuries on the road: interventions for under 15s
This guideline covers road speed limits, 20 mph zones and engineering measures to reduce speed or make routes safer.
# Introduction
This is 1 of 3 pieces of NICE guidance published in November 2010 on how to prevent unintentional injuries among under-15s. A second publication covers strategies, regulation, enforcement, surveillance and workforce development and a third covers unintentional injuries in the home.
The Department of Health (DH) asked the National Institute for Health and Care Excellence (NICE) to produce public health guidance on preventing unintentional injuries to those aged under 15 on the road. This guidance focuses on road design and modification.
The guidance is for local highway authorities, local strategic partnerships, directors of public health, health professionals who have a responsibility for preventing or treating unintentional injuries affecting children and young people aged under 15, and school travel planners. It may also be of interest to road users, children, young people, their parents and carers and other members of the public.
This is 1 of 3 pieces of NICE guidance on how to prevent unintentional injuries among children and young people aged under 15. In particular, it is closely linked to guidance focused on strategies, regulation, enforcement, surveillance and workforce development. (This covers unintentional injuries on the road, in the home and in outdoor settings and was published in November 2010.) The other publication addresses unintentional injuries in the home.
The guidance complements, but does not replace, NICE guidance on promoting physical activity.
The Public Health Interventions Advisory Committee (PHIAC) developed these recommendations on the basis of reviews of the evidence, cost-effectiveness modelling, expert advice, stakeholder comments and fieldwork.
Members of PHIAC are listed in appendix A. The methods used to develop the guidance are summarised in appendix B. Supporting documents used to prepare this document are listed in appendix E.
See the full details of the evidence collated, including fieldwork data and stakeholder comments, along with a list of the stakeholders involved and NICE's supporting process and methods manuals.# Recommendations
The evidence statements underpinning the recommendations are listed in appendix C.
See also the evidence reviews, supporting evidence statements and cost-effectiveness modelling.
PHIAC considers that the recommended measures are cost effective. For the gaps in research, see appendix D.
# Context
The recommendations in this guidance should be implemented as part of a broader strategy that includes driver and public education and enforcement activities.
Note that in November 2010, we published a NICE guideline on unintentional injuries: prevention strategies for under 15s.
The recommendations in this guidance cover 20 miles per hour (mph) limits, 20 mph zones and engineering measures to reduce speed or make routes safer, reflecting the evidence identified and expert discussions. The absence of recommendations on any other measures is a result of a lack of evidence that met the inclusion criteria for the evidence reviews. It should not be taken as a judgement on whether or not any other measures are effective and cost effective.
# Definitions
This guidance uses the term 'unintentional injuries' rather than 'accidents', since 'most injuries and their precipitating events are predictable and preventable' (Davis R, Pless B (2001) BMJ bans 'accidents'. Accidents are not unpredictable. BMJ 322: 1320–21). The term 'accident' implies an unpredictable and therefore unavoidable event.
Engineering measures to reduce speed or make routes safer comprise physical features such as speed humps, chicanes or changes in traffic priority (that is, changes in the right for traffic to proceed). These may be used on single roads or across a larger area.
mph limits are imposed using signs at the start and end of roads covered by the limit and reminder signs at points in between (terminal and repeater signing).
mph zones are areas where engineering measures must be used to slow traffic.
# Whose health will benefit?
The recommendations aim to help children and young people aged under 15, although there may also be benefits for the wider population.
# Recommendation 1 Health advocacy and engagement
## Who should take action?
Directors of public health and other health professionals with responsibility for preventing or treating injuries.
Local strategic partnerships.
## What action should they take?
Ensure a senior public health position includes leading on, and responsibility for, the health sector's involvement in injury prevention and risk reduction.
Support and promote changes to the road environment as part of a broader strategy to prevent injuries and the risk of injuries.
Support coordinated working between health professionals and local highways authorities to promote changes to the road environment.
# Recommendation 2 Needs assessment and planning
## Who should take action?
Local highways authorities.
## What action should they take?
Work with other partners to introduce engineering measures to reduce speed as part of a broad strategy to prevent injuries and the risk of injuries (see recommendation 1).
These measures should be:
developed after considering data on risk of injury (such as traffic speed and volume) and injuries (including levels of casualties, their age, the groups involved and where they occur)
designed and constructed in line with current good practice guidelines and case studies (such as the Department for Transport's manual for streets 2), and determined by local context and the characteristics of the site (including physical limitations such as geological considerations)
designed taking into account all road users (not just car users), including vulnerable road users (such as pedestrians, cyclists and those with impaired mobility)
developed using effective processes of community engagement to seek the views of children, young people, their parents and carers (as outlined in the NICE guideline on community engagement) and with involvement of other interested parties such as the emergency services and local businesses
implemented based on local priorities for modifying the transport infrastructure
evaluated for their effect in terms of reducing the risk of injury and reducing the number of actual injuries
evaluated for any unintended consequences, such as the impact on the number of people walking or cycling or on injury rates in neighbouring streets.
# Recommendation 3 Measures to reduce speed
## Who should take action?
Local highways authorities.
Local strategic partnerships.
## What action should they take?
Introduce engineering measures to reduce speed in streets that are primarily residential or where pedestrian and cyclist movements are high. These measures could include:
speed reduction features (for example, traffic-calming measures on single streets, or 20 mph zones across wider areas)
changes to the speed limit with signing only (20 mph limits) where current average speeds are low enough, in line with Department for Transport guidelines.
Implement city or town-wide 20 mph limits and zones on appropriate roads. Use factors such as traffic volume, speed and function to determine which roads are appropriate.
Consider changes to speed limits and appropriate engineering measures on rural roads where the risk of injury is relatively high, in line with Department for Transport guidance.
Take account of the factors identified in recommendation 2 when introducing measures.
When introducing engineering measures to reduce speed, consider promoting smooth driving and speed reduction to minimise pollution (see the NICE guideline on air pollution: outdoor air quality and health).
# Recommendation 4 Popular routes
## Who should take action?
Directors of public health.
Local highways authorities.
Local strategic partnerships.
Public health professionals with an injury prevention remit.
School travel planners.
## What action should they take?
Consider opportunities to develop engineering measures to provide safer routes commonly used by children and young people, including to school and other destinations (such as parks, colleges and recreational sites). This should be done as part of the development of a broad package of measures to address travel, for instance when developing school travel plans.
Include school governors and head teachers in discussions about changes relating to school travel.# Public health need and practice
# Deaths and injuries from road collisions
The rate of deaths and serious injuries from road collisions has been declining over recent decades (by about 4% per year in all ages and 9% in children). However, unintentional injury is still a leading cause of death among children and young people aged 1 to 14 (Audit Commission and Healthcare Commission 2007) and nearly half (44%) of those deaths in England and Wales are transport-related (Office for National Statistics 2009).
In 2009, 65 young people aged under 15 were killed and 18,307 were injured on the roads in Great Britain, 2,267 of them seriously. Of those killed or seriously injured, 1,507 (65%) were pedestrians. Cyclists (381) and car passengers (380) made up the bulk of the remainder (that is, cyclists and car passengers each accounted for around 16% of the total; Department for Transport 2010a).
The most commonly used statistics on children injured in collisions come from 'Road casualties Great Britain'. This is based on STATS 19. However, 'Road casualties Great Britain' notes that: 'although STATS 19 is the most detailed and useful source of information on road casualties at national level, it is not a complete or perfect dataset' (Department for Transport 2009). It also notes that other estimates, based on the national travel survey, give a total number of casualties around 3 times the number recorded in STATS 19.
The number of people killed or seriously injured on the road increases with age. There is a noticeable increase between ages 10 and 11, which coincides with the move to secondary school and probably with increasingly unsupervised travel.
In 2008, 65% of children or young people killed or seriously injured were boys. This higher rate in boys is seen in all modes of transport (except for car passengers, where girls account for 54% of those killed or seriously injured).
Overall, population-based casualty rates for England are better than the European Union (EU) average. However, this rating masks poorer figures for pedestrians (Department for Transport 2008).
There are other people besides casualties whose health is affected in less apparent ways. People can be traumatised by near misses, or avoid activities or opportunities because of danger (real or perceived) on the roads. These opportunities include walking or cycling, meeting friends and family and other types of recreation, as well as the freedom to develop independence.
# Exposure to road danger
In recent decades, children's exposure to danger from various modes of road transport has changed considerably. By 2003, the average mileage travelled as a car occupant had increased by 70% compared with 1985. The average mileage walked had declined by 19%, and the average cycled had declined by 58% (Sonkin et al. 2006).
A Play England survey (2007) suggests that children now spend less time playing outside – 71% of adults played outside in the street or area close to their homes every day when they were children, compared with only 21% of children today.
Most traffic casualties among children and young people occur in urban rather than rural areas (2073 compared with 734 among those aged 0 to 15 years in 2008). In addition, the percentage of pedestrian casualties is higher in urban compared to rural settings (73% compared with 36% in 2008) (Department for Transport 2010b).
In urban settings, most casualties (74%) are on minor roads (Department for Transport 2010). Younger children (aged up to about 8) tend to be injured on streets close to their home. As they get older (around 11 and above) they tend to be injured further from home, and on busier roads, reflecting their increasing licence to travel independently. Boys tend to be given greater independence at an earlier age (Towner et al. 2005) and so this shift occurs at a younger age for boys.
# Inequalities
Among young people aged under 15, the likelihood of dying as a car occupant is 5.5 times higher if their parents are unemployed than if they have managerial or professional jobs. This ratio exceeds 20 among pedestrians and cyclists. Similarly, more than one quarter of child pedestrian injuries happen in the most deprived tenth of wards (Greyling et al. 2002).
The largest factor resulting in this difference in death rate is exposure to danger rather than behaviour (Edwards et al. 2006). People from lower socioeconomic groups are more likely, for example, to live in neighbourhoods with on-street parking, high-speed traffic and few or no off-street play areas.
National data, such as those reported in 'Road casualties Great Britain' (Department for Transport 2009), do not routinely feature information on the characteristics of the casualty other than age and sex. Information on ethnicity, for instance, has generally come from a small number of local studies which frequently focus on 1 ethnic group.
A report by the Department of the Environment, Transport and the Regions (2001) states that surveys suggest that there is a higher pedestrian casualty rate among children (age range not stated) from Asian backgrounds than non-Asian peers in the same area. Other groups may be similarly affected but have not been systematically studied.
# Factors influencing the rate and severity of road injuries
Factors before, around the time of and after a collision can all help determine whether someone is injured (and how badly) or killed in a road collision. These include: traffic speed, safety training and road surface; use of devices such as anti-lock brakes; use of seatbelts, airbags and other car design features; and the response of emergency services.
Approaches to preventing collisions (primary prevention) focus on altering the behaviour of road users (or the vehicle, if emergency action is required). The former, for example, might include educating people about road dangers or introducing engineering measures to restrict vehicle speed. The latter might include anti-lock brakes or anti-skid road surfaces (Racioppi et al. 2004). Approaches to reducing the severity of injury (secondary prevention) include car design and provision and the use of safety devices.
The logical place to start in considering road injuries is with primary prevention.
It's also worth bearing in mind that when someone feels very safe, this can alter their behaviour so that the actual risk becomes higher than might have been expected. (An example of this 'risk compensation' would be driving faster in a car with anti-lock brakes.).
# Road design
Road design has a key influence on speed (Department for Transport 2007). 'Excess and inappropriate' speed contributes to around 30% of fatal crashes in high-income countries (World Health Organization 2004).
Higher speeds reduce the time available for people to react and increase the severity of collisions. Vulnerable road users (cyclists and pedestrians) are at particular risk: pedestrians have a 90% chance of surviving car crashes at speeds below 30 kph but a less than 50% chance at speeds of 45 kph (Racioppi et al. 2004).# Considerations
The Public Health Interventions Advisory Committee (PHIAC) took account of a number of factors and issues when developing the recommendations.
PHIAC agreed that there is a moral imperative to protect children and young people, including on the roads. This includes addressing the behaviour of drivers through a variety of approaches.
Although engineering measures are important in preventing casualties, PHIAC discussed the importance of other factors. These included education, enforcement, and changing the percentage of journeys undertaken by car, public transport, on foot or by bicycle (modal shift). Engineering, education and enforcement activities are likely to be synergistic.
Methodological difficulties may make it hard to be clear about what an intervention has (or has not) achieved:
Engineering measures are not commonly assessed using trials.
The overall downward trend in injuries makes comparisons over time difficult.
The numbers of people killed or seriously injured are relatively small, so it is difficult for studies to be adequately powered to determine whether an intervention has been effective.
There is a lot of work to prevent injuries, both locally and nationally, which may add to the difficulty of identifying effective elements of interventions.
The diffuse nature of some interventions, often involving multiple components, makes comparisons between them difficult.
Interventions may be designed to achieve a range of outcomes.
Interventions are generally designed to reduce casualty rates for all road users rather than just children and young people.
Much of the evidence considered was from the UK and so was deemed applicable for England. However, PHIAC was aware that older UK publications might be less applicable, because changing political, cultural and economic backgrounds can alter the effectiveness of interventions. Nonetheless, it noted that the evidence consistently suggests that engineering measures to reduce traffic speed generally do reduce collisions and deaths or injuries among children and young people.
For inclusion in the reviews, evidence needed to provide data on injuries to children and young people. If data on speed was also provided, this was included. However, the literature relating to speed alone has not been considered in this work. Similarly, studies that did not provide an analysis of injuries to children and young people aged under 15 were not included.
PHIAC noted that pedestrians are much more likely to be killed in collisions at higher speeds.
For several types of intervention identified in the scope for this work, the reviews either found no evidence (for instance for woonerven – a Dutch term for a street where pedestrians and cyclists have priority over motorists, and motorised traffic is restricted to walking pace; and 'naked streets – roads cleared of markings, signage and pedestrian barriers) or found no impact on injuries (for instance for 'home zones' – where injury reduction is not the primary purpose). Therefore, these interventions do not appear in the recommendations.
Engineering measures may have other outcomes (both positive and negative) apart from helping to prevent injuries. These include noise, damage to buildings or vehicles (from vibration and the impact of vertical traffic-calming features) and air pollution (including CO2 emissions). Changes in behaviours influenced by engineering measures may also be related to health outcomes, for instance increasing levels of physical activity by supporting cycling and walking or encouraging greater social contact.
Changes to the physical environment can have unintended consequences that may disadvantage some groups. For example, changes that remove physical features (such as the distinction between pavement and road) might increase uncertainty on the part of motorists, and so promote a safer driving style. However, they might also make negotiating a street more difficult for people with a visual impairment.
PHIAC noted that the attitudes of communities and drivers to speed reduction measures are important. Drivers may be more accepting if they can see the point of speed restrictions (such as those near schools – although these areas may not, in fact, have significant injury rates).
Economic analysis in NICE guidance generally consists of an estimation of the cost per quality-adjusted life-year (QALY) gained. This enables a comparison with what is deemed to be value for money in the health service. However, when assessing road transport interventions other approaches may be more appropriate. In particular, the Department for Transport uses cost–benefit analysis taking a 'broad societal perspective' to assess value for money. Net present value (NPV) is used to determine the total monetary benefit of an intervention less its costs (compared with an alternative intervention) when discounted to its present value. A positive NPV occurs when the sum of the discounted benefits exceeds the sum of the discounted costs. As the costs fall on the transport sector, it is more appropriate to compare cost effectiveness with other transport interventions using a method followed by that sector (see the Department for Transport's transport analysis guidance). This is in line with Social value judgements: principles for the development of NICE guidance.
Enforcement strategies were not covered in the scope of this guidance. PHIAC noted that NICE's guideline on unintentional injuries: prevention strategies for under 15 was considering enforcement.# Recommendations for research
PHIAC developed some provisional research recommendations, based on the evidence and expert advice from co-optees. These were passed to the NICE committee that developed the related guidance on unintentional injuries: prevention strategies for under 15s. This has resulted in a comprehensive set of research recommendations covering all types of unintentional injuries.
More detail on the gaps in the evidence identified during development of the guidance on road design and modification is provided in appendix D.# References
Audit Commission and Healthcare Commission (2007) Better safe than sorry: preventing unintentional injury to children. London: Audit Commission
Davis R, Pless B (2001) BMJ bans 'accident'. BMJ 322: 1320–1
Department for Transport (2007) Child road safety strategy 2007. London: Department for Transport.
Department for Transport (2008) Road casualties Great Britain: 2007 annual report. London: The Stationery Office
Department for Transport (2010a) Road casualties Great Britain: 2009 annual report. London: The Stationery Office
Department for Transport (2010b) Child casualties in reported road accidents Great Britain: 2008 Road Accident Statistics Factsheet No. 5. London: Department for Transport
Department of the Environment, Transport and the Regions (2001) Road accident involvement of children from ethnic minorities: a literature review. London: Department of Environment, Transport and the Regions
Edwards P, Roberts I, Green J, et al. (2006) Deaths from injury in children and employment status in family: analysis of trends in class specific death rates. British Medical Journal 333: 119–21
Greyling T, Hallam K, Daniel G, et al. (2002) Streets ahead: safe and liveable streets for children. London: Institute for Public Policy Research
Office for National Statistics (2009) Mortality statistics: deaths registered in 2008. London: Office for National Statistics
Play England (2007) Playday 2007 – Our streets too! London: Play England
Racioppi F, Ericsson L, Tingvall C et al. (2004) Preventing road traffic injury: a public health perspective for Europe. Copenhagen: World Health Organization
Sonkin B, Edwards P, Roberts I et al. (2006) Walking, cycling and transport safety: an analysis of child road deaths. Journal of the Royal Society of Medicine 99: 402–5
Towner E, Dowswell T, Errington G et al. (2005) Injuries in children aged 0–14 years and inequalities. London: Health Development Agency
World Health Organization (2004) World report on road traffic injury prevention. Geneva: World Health Organization# Appendix B: Summary of the methods used to develop this guidance
# Introduction
The reviews and economic analysis include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.
The minutes of the PHIAC meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations.
All supporting documents are listed in appendix E.
# Key questions
The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by PHIAC to help develop the recommendations. The overarching questions were:
Question 1: What types of road design or modification to the road and street environment are effective and cost effective in reducing road injuries among children and young people aged under 15?
Question 2: What are the barriers and facilitators to implementing environmental modifications and road/street designs relating to the reduction of road injuries?
The subsidiary question was:
Question 3: What are the barriers and facilitators to implementing environmental modifications and designs relating to the reduction of vehicle speeds and road injuries?
These questions were made more specific for the reviews (see reviews for further details).
# Reviewing the evidence
One review of effectiveness and cost effectiveness was conducted, and 1 review of barriers and facilitators.
## Identifying the evidence
The following databases were searched for evaluations (prospective or retrospective) of relevant interventions that used comparative designs (randomised controlled trials , non-randomised controlled trials, before-and-after studies, or natural experiments); full economic evaluations and high quality costing studies conducted in the UK or countries of a similar level of economic development, patterns of transport use and urban environment; primary qualitative research involving the analysis of written or spoken evidence regarding attitudes towards, or experiences of, the relevant interventions, qualitative surveys of attitudes towards, or experiences of the relevant interventions:
Applied Social Science Index and Abstracts (ASSIA)
Bibliomap
Centre for Review and Dissemination
Database of Abstracts of Reviews of Effects (DARE)
Database of Promoting Health Effectiveness Reviews (DoPHER)
EPPI CENTRE databases
ERIC
Health Management Information Consortium (HMIC)
MEDLINE
MEDLINE In Process
National Health Service Economic Evaluations Database (NHSEED)
NHS Economic Evaluation Database (Health Technology Assessment)
PsycINFO
SafetyLit
Social Science Citation Index
Transport Research Information Service (TRIS)
Trials Register of Promoting Health Interventions TRoPHI
A follow up targeted search was done in TRIS and MEDLINE of specific named programmes and additional traffic-calming methods determined from the results of the original database searches.
## Quality appraisal
Included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.
++ All or most of the methodology checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are thought very unlikely to alter.
- Some of the methodology checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are thought unlikely to alter the conclusions.
– Few or no methodology checklist criteria have been fulfilled. The conclusions of the study are thought likely or very likely to alter.
## Summarising the evidence and making evidence statements
The review data was summarised in evidence tables (see full reviews).
The findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors/public health collaborating centres (see appendix A). The statements reflect their judgement of the strength (quantity, type and quality) of evidence and its applicability to the populations and settings in the scope.
# Economic analysis
The economic analysis consisted of a review of economic evaluations (the cost effectiveness part of review 1) and a cost-effectiveness modelling (report 3).
## Cost-effectiveness review (part of review 1)
A wide range of electronic databases was searched, including some that are specific to the areas of transport policy/research and safety policy/research. Papers or reports were sought that reported quantitative comparative evaluations of local or regional interventions to reduce injuries in children aged under 15 by road/street design or by modifying the road/street environment and highway design (for example, measures to reduce speed and 20 mph zones).
Studies were included if they were full economic evaluations of relevant types of intervention or scheme, and high quality costing studies conducted in the UK or countries of a similar level of economic development, patterns of transport use and urban environment.
Studies were excluded if they were cost-of-illness studies, or other studies that did not involve assessing the cost and related benefits/effectiveness of particular interventions (or class of intervention). Of 19 identified as potentially relevant 13 were included, all of which were cost–benefit analyses.
## Cost-effectiveness modelling
A number of assumptions were made that could underestimate or overestimate the cost effectiveness of the interventions (see modelling report for further details).
Economic modelling was undertaken to explore the cost effectiveness of mixed priority route schemes, mandatory 20 mph zones and advisory 20 mph limits. The results are presented as net present values as well as costs per quality adjusted life-year. (Net present value or NPV determines the total monetary benefit of an intervention less its costs - compared with an alternative intervention – when discounted to its present value. A positive NPV occurs when the sum of the discounted benefits exceeds the sum of the discounted costs.) They can be found in the cost-effectiveness modelling report of road and street design-based interventions aimed at reducing unintentional injuries in children.
# Fieldwork
Fieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with practitioners and commissioners who are involved in unintentional injury and transport services. They included those working in community and charitable organisations, local transport planning departments, directors of public health and NHS and government representatives.
The fieldwork comprised:
Six half-day workshops (2 each in Birmingham, London and Manchester) with practitioners including community and charitable organisations, local transport planning departments, directors of public health and NHS, government representatives.
Seven focus groups (in Hull, London, Manchester, Milton Keynes, Oxford, Portsmouth and Stockport) with transport planning departments in local authorities and within the private sector, including:
chartered civil engineers
members of the social inclusion team
road safety engineers
transport planners
road safety managers.
Telephone interviews with:
transport planners
a policy planner.
The studies were commissioned to ensure there was ample geographical coverage. The main issues arising from these studies are set out in fieldwork findings in appendix C. See the full report on prevention of unintentional road injury in under-15s: road design.
# How PHIAC formulated the recommendations
At its meeting in July 2009 PHIAC considered the evidence to determine:
whether there was sufficient evidence (in terms of strength and applicability) to form a judgement
where relevant, whether (on balance) the evidence demonstrates that an intervention or programme is effective or ineffective or whether the evidence is inconclusive
where relevant, the typical size of effect (where there is one)
whether the evidence is applicable to the target groups and contexts covered by the guidance.
PHIAC developed draft recommendations through informal consensus, based on the following criteria:
Strength (type, quality, quantity and consistency) of the evidence.
The applicability of the evidence to the populations/settings referred to in the scope.
Effect size and potential impact on the target population's health.
Impact on inequalities in health between different groups of the population.
Equality and diversity legislation.
Ethical issues and social value judgements.
Cost effectiveness (for the NHS and other public sector organisations).
Balance of harms and benefits.
Ease of implementation and any anticipated changes in practice.
PHIAC noted that effectiveness can vary according to context. For instance, the effectiveness of interventions on mixed priority routes varied with the initial casualty rate.
Where possible, recommendations were linked to evidence statements (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).
The draft guidance, including the recommendations, was released for consultation in November 2009. At its meeting in January 2010, PHIAC amended the guidance in light of comments from stakeholders, experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in March 2010.# Appendix C: The evidence
This appendix lists evidence statements from 2 evidence reviews, provided by external contractors (see appendix A) and links them to the relevant recommendations. (See appendix B for the key to quality assessments.) The evidence statements are presented here without references – these can be found in the full review (see appendix E for details). It also sets out a brief summary of findings from the economic analysis.
Evidence statement number B1a indicates that the linked statement is numbered 1a in the review 'Barriers to, and facilitators of, the prevention of unintentional injury in children on the road'.
Evidence statement number E1a indicates that the linked statement is numbered 1a in the review 'Systematic reviews of effectiveness and cost-effectiveness of road and street design-based interventions aimed at reducing unintentional injuries in children'.
Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence) below.
Recommendation 1: E1a–c, E2a–c, E3a–e
Recommendation 2: B2a–d, E10, E11; IDE
Recommendation 3: E1, E1a–c, E2, E2a–c, E3, E3a–e, E6b, E10, E11
Recommendation 4: E7, E7a, E7b, E9
# Evidence statements
Please note that the wording of some evidence statements has been altered slightly from those in the review team's report to make them more consistent with each other and NICE's standard house style.
## Evidence statement E1
Five UK based studies evaluated area-wide traffic-calming schemes. There were 1 controlled (+) and 3 uncontrolled (1 and 2 ) before and after studies, and 1 ecological study (+). Within these studies, casualties, injury collisions and speed outcomes were reported.
## Evidence statement E1a
There is moderate evidence from 2 uncontrolled before-and-after studies (both UK) that area-wide traffic-calming may reduce rates of killed or seriously injured children (both ). Both studies showed reductions in either killed and seriously injured child casualties or collisions in which a child pedestrian or cyclist is killed or seriously injured, but none of these was statistically significant.
## Evidence statement E1b
There is moderate evidence from 1 uncontrolled before-and-after study and 1 ecological study (both UK) that area-wide traffic calming may reduce child road casualty rates of any severity (both ). There is moderate evidence from 1 controlled and 2 uncontrolled before-and-after studies (all UK) that area-wide traffic calming may reduce child injury collision rates of any severity (1 and 2 ).
Of the 2 studies that reported child casualty rates, 1 ecological study showed a statistically significant reduction (rate ratio =0.777 for pedestrians in 1 of 2 cities studied, p=0.002 ), while the results in the other city, and the uncontrolled before-and-after study are consistent with a reduction, but do not reach significance (+).
The 2 studies that reported child injury collision rates (1 controlled and 2 uncontrolled before-and-after studies, all UK) also show reductions, but only 1 approaches statistical significance when compared with a control group (RaR=0.524; 95% confidence interval = 0.258, 1.062 for child cyclists; 1 and 2 ).
## Evidence statement E1c
There is weak evidence from 2 uncontrolled before-and-after studies that area-wide traffic calming may reduce traffic speeds (1 and 1 ).
With the possible exception of the much older study (1990), this evidence is judged as directly applicable to similar roads and/or communities in the UK.
## Evidence statement E2
Three UK-based studies evaluated single road traffic-calming schemes. These were all uncontrolled before-and-after studies (3 ). Within these studies, casualties, injury collisions and speed outcomes were reported.
## Evidence statement E2a
There is weak evidence from 2 UK-based uncontrolled before-and-after studies to show that single road traffic calming may reduce child road casualty rates. Only 1 of these studies showed a statistically significant reduction in child casualties from 12 to 0 (p<0.001 ). In the other study, numbers of casualties were too small (decreasing from 3 to 0) to be meaningful (+).
## Evidence statement E2b
There is weak evidence from 1 UK-based, uncontrolled before-and-after study that single road traffic calming may reduce child pedestrian injury collision rates (RaR 0.0381, p<0.001) while child cyclist injury collision rates were also reduced, but non-significantly (RaR=0.632, p=0.081 ).
## Evidence statement E2c
There is weak evidence from 2 uncontrolled before-and-after studies that single road traffic calming may reduce traffic speeds (both ). This evidence is judged as directly applicable to similar roads and/or communities in the UK, although the Chorlton evidence is dated.
## Evidence statement E3
Four UK-based studies evaluated 20 mph zones (mostly in urban areas). There were 1 controlled and 3 uncontrolled (all ) before-and-after studies, 2 of which was adjusted for background trends. There is some overlap between studies. Two of the studies are of 20 mph zones in London; 1 of which essentially updates the other. There are also small overlaps between these London-based studies and the England-wide study, and potentially between the England-wide study and the study based in Hull. Within these studies, casualties and speed outcomes were reported.
## Evidence statement E3a
There is moderate evidence from 2 uncontrolled before-and-after studies (1 adjusted for trends on background roads; both UK-based) that 20 mph zones reduce killed or seriously injured child casualty rates (RaR=0.242 to 0.859 depending on analysis and study, p<0.05 where recorded ). One controlled before-and-after study also showed a reduction in killed or seriously injured child casualty rates in the intervention group when compared with a control group; however, this reduction was not significant (+). It must be noted that this study also evaluated schemes in London and is essentially updated by this uncontrolled before-and-after study.
## Evidence statement E3b
There is weak evidence from 1 uncontrolled before-and-after study (London-based), which was adjusted for trends on background roads, that 20 mph zones may reduce child pedestrian killed and seriously injured casualty rates. However, this reduction was not significant once the results had been adjusted for changes in background trends on outside roads (+). One study also showed that 20 mph zones may reduce child pedestrian killed and seriously injured casualty rates (before and after data only reported for this outcome; RaR=0.394, p<0.001 ). As noted above, however, this study is essentially updated by the uncontrolled before-and-after 2008 study. The evidence should not therefore be 'counted' twice.
## Evidence statement E3c
There is weak evidence from 1 before-and-after study (controlled data only reported for this outcome) that 20 mph zones may reduce child cyclist killed or seriously injured casualty rates. This reduction approaches statistical significance (RaR=0.399, p=0.06 ).
## Evidence statement E3d
There is moderate evidence from 3 UK-based uncontrolled before-and-after studies (1 using adjusted analyses ) and 1 controlled before-and-after study of London schemes (+) that 20 mph zones may reduce child road casualty rates overall, and for child pedestrians and child pedal cyclists when analysed separately (road casualty rates overall RaR=0.331 to 0.716 depending on analysis and intervention, p<0.001 where recorded).
## Evidence statement E3e
There is weak evidence from 2 studies that 20 mph zones may reduce traffic speeds (both ). This evidence is judged as directly applicable to similar roads and/or communities in the UK, although some data is rather dated.
## Evidence statement E6b
There is weak evidence from 1 case-control study that living in an area with 0 to 5 streets with a speed limit of 30 kph may increase a child's risk of injury compared with a child living in an area with 15 or more streets with the same speed limit (OR=5.3, 95% CI=1.6, 17.6 ).
## Evidence statement E7
There is moderate evidence from 2 controlled before-and-after (injury data time-series) studies (both ) in the USA that Safe Routes to School (SRTS) programmes based predominantly on engineering measures may reduce the rates of crash-involved child pedestrians or cyclists, or the rate of child injury road collisions.
## Evidence statement E7a
In 125 SRTS project areas across California, and after assuming modest (10%) increases in rates of walking and cycling to school due to the programmes (such as increased exposure), a mean reduction of 7% in the all‑injury collision rate with child pedestrians and cyclists was estimated (14% for children aged 5 to 12) (+). However, the estimated impact on fatal or severe child injuries was less conclusive (ranging from a 52% increase to a 24% reduction, again depending on assumed changes in levels of walking/cycling to school).
## Evidence statement E7b
The evaluation of 53 projects in 3 unnamed US States (+) compared linear regression coefficients (giving 'T statistics') between the time-series trends of child injury data for the SRTS sites; these showed significantly greater reductions in crash-involved child pedestrians and cyclists at SRTS sites when compared with at least 2 of the 6 'control' time-series in all 3 US states (note, all of the 'T' values were negative, indicating that the reductions in crash outcomes in SRTS sites were always lower than in the comparison time-series.)
This evidence from evaluations of SRTS programmes in the US is judged as partially applicable to similar localities in the UK.
## Evidence statement E9
There is weak evidence from 1 controlled before-and-after study that combined traffic calming, safe routes to schools and education may reduce child road casualty rates when a before-and-after comparison was made (OR 0.722, p=0.007 ); however, compared with the control group the reduction was not significant. This Swedish evidence is judged as partially applicable to similar roads and/or communities in the UK.
## Evidence statement E10
There is moderate evidence from 3 cost–benefit analyses of a variety of area-wide traffic-calming schemes that show that, even in the short term (after 1 year), benefits are likely to exceed costs in most circumstances. However, there was considerable variation in first year rates of return. This evidence was judged to be partly applicable to the UK road setting.
## Evidence statement E11
There is moderate evidence from 1 cost–benefit analysis of advisory 20 mph speed limits that shows that, in the short term, benefits are likely to exceed costs. Similarly, there is moderate evidence from one cost–benefit analysis of mandatory 20 mph zones that shows that, in the medium to long term, benefits are likely to exceed costs. The evidence on 20 mph zones is judged as being directly applicable to other urban roads in England, whereas the applicability of the evidence on advisory speed limits in Scotland may have less applicability in England and Wales because of the different road regulations relating to 20 mph speed limits.
## Evidence statement B2a
Five studies, 4 UK and 1 US-based, discuss risk-taking behaviour among children and young people as a potential cause of collisions (2 and 3 ).
## Evidence statement B2b
Like adults, children and young people often engage in 'common' risk behaviours that are seen as part of everyday life, such as not always using crossings, crossing between parked cars or in traffic.
## Evidence statement B2c
One UK study reports that teenagers were more likely to take risks on the road than younger children (aged 8+).
## Evidence statement B2d
Three UK studies suggest that a minority of children and young people engage in 'extreme' risks – such as playing 'chicken' in the road or holding onto the back of buses, and that boys are more likely to do this, and to encourage such behaviour in each other. Such behaviours are regarded in a similar way to thrill-seeking sports.
# Cost-effectiveness evidence
The economic modelling suggests that setting advisory 20 mph limits is a highly cost-effective way of preventing unintentional injuries on the road (with a net present value of £64,209; net present value determines the total monetary benefit of an intervention less its costs – compared with an alternative intervention – when discounted to its present value; a positive net present value occurs when the sum of the discounted benefits exceeds the sum of the discounted costs). However, caution is needed in interpreting these results. First, because the studies modelled came from Scotland where the legal definition of what comprises an advisory 20 mph limit is different. Second, the areas where they were introduced were not necessarily comparable for example, in terms of previous collision rates, vehicle speeds and pedestrian usage.
Mandatory 20 mph zones were found to be much more cost effective in areas with previously high casualty rates (1.6 per year per km). The NPV was £90,625 in these areas, compared to a NPV of £25,480 when implemented in low casualty rate areas.
Deterministic sensitivity analyses identified a number of parameters that were important to all interventions: number of casualties in the comparator area, effectiveness of the intervention, the background reduction in casualties and the effective lifetime of the intervention all had an effect.
The modelling did not consider health benefits other than those due to casualties prevented. For instance, it did not consider the health benefits of increased physical activity or the reduction in air pollution due to a change in road use. It also did not consider the impact that road engineering measures to reduce speed can have on other factors such as congestion or noise. These would only be captured by cost–benefit analysis using a full societal perspective.
# Fieldwork findings
Fieldwork aimed to test the relevance, usefulness and the feasibility of putting the recommendations into practice. PHIAC considered the findings when developing the final recommendations. For details, go to the fieldwork section in appendix B.
Fieldwork participants who work in transport planning were fairly positive about the recommendations and their potential to help prevent unintentional injuries. Many participants stated that although the recommendations were 'nothing new' and were already being applied in general, engaging the health sector in this area was vitally important. They reported that the recommendations could have a positive impact if they helped to engage the health sector in preventing injuries among young people aged under 15.
Some stakeholders said that at partnership meetings (for example, local strategic partnerships) in their local areas the health aspect of the partnership was often missing, that is, the NHS representatives do not attend local injury prevention partnership meetings. Participants particularly noted NHS directors of public health as an important group to engage and ensure that they were active in work in this area. Others noted that stakeholders from education were also unable or unwilling to engage and that it would be an advantage if the recommendations could help engage education services in injury prevention.
The planning stakeholders consistently said in the workshops and focus groups that the recommendations do not add any content for planners. They said that the draft recommendations do not cross-reference to other supporting material, such as that from the Department for Transport. They also thought some of the content of the recommendations is not consistent with Department of Transport guidance and strategies (for example the road safety strategy). Delegates stated that a cohesive approach from government is important.
Overall, delegates said that the recommendations had a role to play in directing the NHS to plays its part in supporting local strategic partnerships and supplying data requirements.# Appendix D: Gaps in the evidence
PHIAC identified a number of gaps in the evidence relating to the interventions under examination, based on an assessment of the evidence. These gaps are set out below.
. There is a lack of evidence on the effectiveness and cost effectiveness of woonerven, home zones and quiet lanes on preventing unintentional injuries on the road for children and young people under 15.
. There is a lack of evidence as to whether there was any differential effect of environmental interventions on different populations in terms of age, gender, rural/urban/road type and level of disadvantage.
. There is a lack of UK evidence on the effectiveness and cost effectiveness of safe routes to school on preventing injuries on the road in children and young people under 15.
. There is a lack of UK evidence on the effectiveness and cost effectiveness of cycle routes on preventing injuries on the road in children and young people under 15.
. There is a lack of evidence on the attitudes of drivers/road users to environmental interventions that prevent unintentional injuries in children on the road.
. There is a lack of UK evidence as to the barriers and facilitators of implementing environmental interventions to prevent unintentional injuries in children on the road, for example, which factors enhance successful implementation of design-based interventions.# Appendix E: Supporting documents
Supporting documents include:
Reviews of effectiveness:
Review 1: 'Systematic reviews of effectiveness and cost-effectiveness of road and street design-based interventions aimed at reducing unintentional injuries in children'
Review 2: 'Barriers to, and facilitators of, the prevention of unintentional injury in children on the road'.
Cost-effectiveness modelling: 'Cost-effectiveness modelling of road and street design-based interventions aimed at reducing unintentional injuries in children'.
Fieldwork report: 'Prevention of unintentional road injury in under-15s: road design'.# Finding more information
To find NICE guidance on related topics, including guidance in development, see the NICE topic page on injuries, accidents and wounds.
For full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice.
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{'Introduction': "This is 1 of 3 pieces of NICE guidance published in November 2010 on how to prevent unintentional injuries among under-15s. A second publication covers strategies, regulation, enforcement, surveillance and workforce development and a third covers unintentional injuries in the home.\n\nThe Department of Health (DH) asked the National Institute for Health and Care Excellence (NICE) to produce public health guidance on preventing unintentional injuries to those aged under\xa015 on the road. This guidance focuses on road design and modification.\n\nThe guidance is for local highway authorities, local strategic partnerships, directors of public health, health professionals who have a responsibility for preventing or treating unintentional injuries affecting children and young people aged under\xa015, and school travel planners. It may also be of interest to road users, children, young people, their parents and carers and other members of the public.\n\nThis is 1 of 3 pieces of NICE guidance on how to prevent unintentional injuries among children and young people aged under\xa015. In particular, it is closely linked to guidance focused on strategies, regulation, enforcement, surveillance and workforce development. (This covers unintentional injuries on the road, in the home and in outdoor settings and was published in November 2010.) The other publication addresses unintentional injuries in the home.\n\nThe guidance complements, but does not replace, NICE guidance on promoting physical activity.\n\nThe Public Health Interventions Advisory Committee (PHIAC) developed these recommendations on the basis of reviews of the evidence, cost-effectiveness modelling, expert advice, stakeholder comments and fieldwork.\n\nMembers of PHIAC are listed in appendix\xa0A. The methods used to develop the guidance are summarised in appendix\xa0B. Supporting documents used to prepare this document are listed in appendix\xa0E.\n\nSee the full details of the evidence collated, including fieldwork data and stakeholder comments, along with a list of the stakeholders involved and NICE's supporting process and methods manuals.", 'Recommendations': "The evidence statements underpinning the recommendations are listed in appendix\xa0C.\n\nSee also the evidence reviews, supporting evidence statements and cost-effectiveness modelling.\n\nPHIAC considers that the recommended measures are cost effective. For the gaps in research, see appendix\xa0D.\n\n# Context\n\nThe recommendations in this guidance should be implemented as part of a broader strategy that includes driver and public education and enforcement activities.\n\nNote that in November 2010, we published a NICE guideline on unintentional injuries: prevention strategies for under\xa015s.\n\nThe recommendations in this guidance cover 20\xa0miles per hour (mph) limits, 20\xa0mph zones and engineering measures to reduce speed or make routes safer, reflecting the evidence identified and expert discussions. The absence of recommendations on any other measures is a result of a lack of evidence that met the inclusion criteria for the evidence reviews. It should not be taken as a judgement on whether or not any other measures are effective and cost effective.\n\n# Definitions\n\nThis guidance uses the term 'unintentional injuries' rather than 'accidents', since 'most injuries and their precipitating events are predictable and preventable' (Davis R, Pless B (2001) BMJ bans 'accidents'. Accidents are not unpredictable. BMJ 322: 1320–21). The term 'accident' implies an unpredictable and therefore unavoidable event.\n\nEngineering measures to reduce speed or make routes safer comprise physical features such as speed humps, chicanes or changes in traffic priority (that is, changes in the right for traffic to proceed). These may be used on single roads or across a larger area.\n\nmph limits are imposed using signs at the start and end of roads covered by the limit and reminder signs at points in between (terminal and repeater signing).\n\nmph zones are areas where engineering measures must be used to slow traffic.\n\n# Whose health will benefit?\n\nThe recommendations aim to help children and young people aged under\xa015, although there may also be benefits for the wider population.\n\n# Recommendation 1 Health advocacy and engagement\n\n## Who should take action?\n\nDirectors of public health and other health professionals with responsibility for preventing or treating injuries.\n\nLocal strategic partnerships.\n\n## What action should they take?\n\nEnsure a senior public health position includes leading on, and responsibility for, the health sector's involvement in injury prevention and risk reduction.\n\nSupport and promote changes to the road environment as part of a broader strategy to prevent injuries and the risk of injuries.\n\nSupport coordinated working between health professionals and local highways authorities to promote changes to the road environment.\n\n# Recommendation 2 Needs assessment and planning\n\n## Who should take action?\n\nLocal highways authorities.\n\n## What action should they take?\n\nWork with other partners to introduce engineering measures to reduce speed as part of a broad strategy to prevent injuries and the risk of injuries (see recommendation 1).\n\nThese measures should be:\n\ndeveloped after considering data on risk of injury (such as traffic speed and volume) and injuries (including levels of casualties, their age, the groups involved and where they occur)\n\ndesigned and constructed in line with current good practice guidelines and case studies (such as the Department for Transport's manual for streets 2), and determined by local context and the characteristics of the site (including physical limitations such as geological considerations)\n\ndesigned taking into account all road users (not just car users), including vulnerable road users (such as pedestrians, cyclists and those with impaired mobility)\n\ndeveloped using effective processes of community engagement to seek the views of children, young people, their parents and carers (as outlined in the NICE guideline on community engagement) and with involvement of other interested parties such as the emergency services and local businesses\n\nimplemented based on local priorities for modifying the transport infrastructure\n\nevaluated for their effect in terms of reducing the risk of injury and reducing the number of actual injuries\n\nevaluated for any unintended consequences, such as the impact on the number of people walking or cycling or on injury rates in neighbouring streets.\n\n# Recommendation 3 Measures to reduce speed\n\n## Who should take action?\n\nLocal highways authorities.\n\nLocal strategic partnerships.\n\n## What action should they take?\n\nIntroduce engineering measures to reduce speed in streets that are primarily residential or where pedestrian and cyclist movements are high. These measures could include:\n\n\n\nspeed reduction features (for example, traffic-calming measures on single streets, or 20 mph zones across wider areas)\n\nchanges to the speed limit with signing only (20 mph limits) where current average speeds are low enough, in line with Department for Transport guidelines.\n\n\n\nImplement city or town-wide 20 mph limits and zones on appropriate roads. Use factors such as traffic volume, speed and function to determine which roads are appropriate.\n\nConsider changes to speed limits and appropriate engineering measures on rural roads where the risk of injury is relatively high, in line with Department for Transport guidance.\n\nTake account of the factors identified in recommendation 2 when introducing measures.\n\nWhen introducing engineering measures to reduce speed, consider promoting smooth driving and speed reduction to minimise pollution (see the NICE guideline on air pollution: outdoor air quality and health).\n\n# Recommendation 4 Popular routes\n\n## Who should take action?\n\nDirectors of public health.\n\nLocal highways authorities.\n\nLocal strategic partnerships.\n\nPublic health professionals with an injury prevention remit.\n\nSchool travel planners.\n\n## What action should they take?\n\nConsider opportunities to develop engineering measures to provide safer routes commonly used by children and young people, including to school and other destinations (such as parks, colleges and recreational sites). This should be done as part of the development of a broad package of measures to address travel, for instance when developing school travel plans.\n\nInclude school governors and head teachers in discussions about changes relating to school travel.", 'Public health need and practice': "# Deaths and injuries from road collisions\n\nThe rate of deaths and serious injuries from road collisions has been declining over recent decades (by about 4% per year in all ages and 9% in children). However, unintentional injury is still a leading cause of death among children and young people aged 1\xa0to\xa014 (Audit Commission and Healthcare Commission 2007) and nearly half (44%) of those deaths in England and Wales are transport-related (Office for National Statistics 2009).\n\nIn 2009, 65 young people aged under\xa015 were killed and 18,307 were injured on the roads in Great Britain, 2,267 of them seriously. Of those killed or seriously injured, 1,507 (65%) were pedestrians. Cyclists (381) and car passengers (380) made up the bulk of the remainder (that is, cyclists and car passengers each accounted for around 16% of the total; Department for Transport 2010a).\n\nThe most commonly used statistics on children injured in collisions come from 'Road casualties Great Britain'. This is based on STATS 19. However, 'Road casualties Great Britain' notes that: 'although STATS 19 is the most detailed and useful source of information on road casualties at national level, it is not a complete or perfect dataset' (Department for Transport 2009). It also notes that other estimates, based on the national travel survey, give a total number of casualties around 3\xa0times the number recorded in STATS\xa019.\n\nThe number of people killed or seriously injured on the road increases with age. There is a noticeable increase between ages 10 and 11, which coincides with the move to secondary school and probably with increasingly unsupervised travel.\n\nIn 2008, 65% of children or young people killed or seriously injured were boys. This higher rate in boys is seen in all modes of transport (except for car passengers, where girls account for 54% of those killed or seriously injured).\n\nOverall, population-based casualty rates for England are better than the European Union (EU) average. However, this rating masks poorer figures for pedestrians (Department for Transport 2008).\n\nThere are other people besides casualties whose health is affected in less apparent ways. People can be traumatised by near misses, or avoid activities or opportunities because of danger (real or perceived) on the roads. These opportunities include walking or cycling, meeting friends and family and other types of recreation, as well as the freedom to develop independence.\n\n# Exposure to road danger\n\nIn recent decades, children's exposure to danger from various modes of road transport has changed considerably. By 2003, the average mileage travelled as a car occupant had increased by 70% compared with 1985. The average mileage walked had declined by 19%, and the average cycled had declined by 58% (Sonkin et al. 2006).\n\nA Play England survey (2007) suggests that children now spend less time playing outside – 71% of adults played outside in the street or area close to their homes every day when they were children, compared with only 21% of children today.\n\nMost traffic casualties among children and young people occur in urban rather than rural areas (2073 compared with 734 among those aged 0\xa0to\xa015 years in 2008). In addition, the percentage of pedestrian casualties is higher in urban compared to rural settings (73% compared with 36% in 2008) (Department for Transport 2010b).\n\nIn urban settings, most casualties (74%) are on minor roads (Department for Transport 2010). Younger children (aged up to about 8) tend to be injured on streets close to their home. As they get older (around 11 and above) they tend to be injured further from home, and on busier roads, reflecting their increasing licence to travel independently. Boys tend to be given greater independence at an earlier age (Towner et al. 2005) and so this shift occurs at a younger age for boys.\n\n# Inequalities\n\nAmong young people aged under\xa015, the likelihood of dying as a car occupant is 5.5\xa0times higher if their parents are unemployed than if they have managerial or professional jobs. This ratio exceeds 20 among pedestrians and cyclists. Similarly, more than one quarter of child pedestrian injuries happen in the most deprived tenth of wards (Greyling et al. 2002).\n\nThe largest factor resulting in this difference in death rate is exposure to danger rather than behaviour (Edwards et al. 2006). People from lower socioeconomic groups are more likely, for example, to live in neighbourhoods with on-street parking, high-speed traffic and few or no off-street play areas.\n\nNational data, such as those reported in 'Road casualties Great Britain' (Department for Transport 2009), do not routinely feature information on the characteristics of the casualty other than age and sex. Information on ethnicity, for instance, has generally come from a small number of local studies which frequently focus on 1\xa0ethnic group.\n\nA report by the Department of the Environment, Transport and the Regions (2001) states that surveys suggest that there is a higher pedestrian casualty rate among children (age range not stated) from Asian backgrounds than non-Asian peers in the same area. Other groups may be similarly affected but have not been systematically studied.\n\n# Factors influencing the rate and severity of road injuries\n\nFactors before, around the time of and after a collision can all help determine whether someone is injured (and how badly) or killed in a road collision. These include: traffic speed, safety training and road surface; use of devices such as anti-lock brakes; use of seatbelts, airbags and other car design features; and the response of emergency services.\n\nApproaches to preventing collisions (primary prevention) focus on altering the behaviour of road users (or the vehicle, if emergency action is required). The former, for example, might include educating people about road dangers or introducing engineering measures to restrict vehicle speed. The latter might include anti-lock brakes or anti-skid road surfaces (Racioppi et al. 2004). Approaches to reducing the severity of injury (secondary prevention) include car design and provision and the use of safety devices.\n\nThe logical place to start in considering road injuries is with primary prevention.\n\nIt's also worth bearing in mind that when someone feels very safe, this can alter their behaviour so that the actual risk becomes higher than might have been expected. (An example of this 'risk compensation' would be driving faster in a car with anti-lock brakes.).\n\n# Road design\n\nRoad design has a key influence on speed (Department for Transport 2007). 'Excess and inappropriate' speed contributes to around 30% of fatal crashes in high-income countries (World Health Organization 2004).\n\nHigher speeds reduce the time available for people to react and increase the severity of collisions. Vulnerable road users (cyclists and pedestrians) are at particular risk: pedestrians have a 90% chance of surviving car crashes at speeds below 30\xa0kph but a less than 50% chance at speeds of 45\xa0kph (Racioppi et al. 2004).", 'Considerations': "The Public Health Interventions Advisory Committee (PHIAC) took account of a number of factors and issues when developing the recommendations.\n\nPHIAC agreed that there is a moral imperative to protect children and young people, including on the roads. This includes addressing the behaviour of drivers through a variety of approaches.\n\nAlthough engineering measures are important in preventing casualties, PHIAC discussed the importance of other factors. These included education, enforcement, and changing the percentage of journeys undertaken by car, public transport, on foot or by bicycle (modal shift). Engineering, education and enforcement activities are likely to be synergistic.\n\nMethodological difficulties may make it hard to be clear about what an intervention has (or has not) achieved:\n\nEngineering measures are not commonly assessed using trials.\n\nThe overall downward trend in injuries makes comparisons over time difficult.\n\nThe numbers of people killed or seriously injured are relatively small, so it is difficult for studies to be adequately powered to determine whether an intervention has been effective.\n\nThere is a lot of work to prevent injuries, both locally and nationally, which may add to the difficulty of identifying effective elements of interventions.\n\nThe diffuse nature of some interventions, often involving multiple components, makes comparisons between them difficult.\n\nInterventions may be designed to achieve a range of outcomes.\n\nInterventions are generally designed to reduce casualty rates for all road users rather than just children and young people.\n\nMuch of the evidence considered was from the UK and so was deemed applicable for England. However, PHIAC was aware that older UK publications might be less applicable, because changing political, cultural and economic backgrounds can alter the effectiveness of interventions. Nonetheless, it noted that the evidence consistently suggests that engineering measures to reduce traffic speed generally do reduce collisions and deaths or injuries among children and young people.\n\nFor inclusion in the reviews, evidence needed to provide data on injuries to children and young people. If data on speed was also provided, this was included. However, the literature relating to speed alone has not been considered in this work. Similarly, studies that did not provide an analysis of injuries to children and young people aged under\xa015 were not included.\n\nPHIAC noted that pedestrians are much more likely to be killed in collisions at higher speeds.\n\nFor several types of intervention identified in the scope for this work, the reviews either found no evidence (for instance for woonerven – a Dutch term for a street where pedestrians and cyclists have priority over motorists, and motorised traffic is restricted to walking pace; and 'naked streets – roads cleared of markings, signage and pedestrian barriers) or found no impact on injuries (for instance for 'home zones' – where injury reduction is not the primary purpose). Therefore, these interventions do not appear in the recommendations.\n\nEngineering measures may have other outcomes (both positive and negative) apart from helping to prevent injuries. These include noise, damage to buildings or vehicles (from vibration and the impact of vertical traffic-calming features) and air pollution (including CO2 emissions). Changes in behaviours influenced by engineering measures may also be related to health outcomes, for instance increasing levels of physical activity by supporting cycling and walking or encouraging greater social contact.\n\nChanges to the physical environment can have unintended consequences that may disadvantage some groups. For example, changes that remove physical features (such as the distinction between pavement and road) might increase uncertainty on the part of motorists, and so promote a safer driving style. However, they might also make negotiating a street more difficult for people with a visual impairment.\n\nPHIAC noted that the attitudes of communities and drivers to speed reduction measures are important. Drivers may be more accepting if they can see the point of speed restrictions (such as those near schools – although these areas may not, in fact, have significant injury rates).\n\nEconomic analysis in NICE guidance generally consists of an estimation of the cost per quality-adjusted life-year (QALY) gained. This enables a comparison with what is deemed to be value for money in the health service. However, when assessing road transport interventions other approaches may be more appropriate. In particular, the Department for Transport uses cost–benefit analysis taking a 'broad societal perspective' to assess value for money. Net present value (NPV) is used to determine the total monetary benefit of an intervention less its costs (compared with an alternative intervention) when discounted to its present value. A positive NPV occurs when the sum of the discounted benefits exceeds the sum of the discounted costs. As the costs fall on the transport sector, it is more appropriate to compare cost effectiveness with other transport interventions using a method followed by that sector (see the Department for Transport's transport analysis guidance). This is in line with Social value judgements: principles for the development of NICE guidance.\n\nEnforcement strategies were not covered in the scope of this guidance. PHIAC noted that NICE's guideline on unintentional injuries: prevention strategies for under\xa015 was considering enforcement.", 'Recommendations for research': 'PHIAC developed some provisional research recommendations, based on the evidence and expert advice from co-optees. These were passed to the NICE committee that developed the related guidance on unintentional injuries: prevention strategies for under\xa015s. This has resulted in a comprehensive set of research recommendations covering all types of unintentional injuries.\n\nMore detail on the gaps in the evidence identified during development of the guidance on road design and modification is provided in appendix\xa0D.', 'References': "Audit Commission and Healthcare Commission (2007) Better safe than sorry: preventing unintentional injury to children. London: Audit Commission\n\nDavis R, Pless B (2001) BMJ bans 'accident'. BMJ 322: 1320–1\n\nDepartment for Transport (2007) Child road safety strategy 2007. London: Department for Transport.\n\nDepartment for Transport (2008) Road casualties Great Britain: 2007 annual report. London: The Stationery Office\n\nDepartment for Transport (2010a) Road casualties Great Britain: 2009 annual report. London: The Stationery Office\n\nDepartment for Transport (2010b) Child casualties in reported road accidents Great Britain: 2008 Road Accident Statistics Factsheet No. 5. London: Department for Transport\n\nDepartment of the Environment, Transport and the Regions (2001) Road accident involvement of children from ethnic minorities: a literature review. London: Department of Environment, Transport and the Regions\n\nEdwards P, Roberts I, Green J, et al. (2006) Deaths from injury in children and employment status in family: analysis of trends in class specific death rates. British Medical Journal 333: 119–21\n\nGreyling T, Hallam K, Daniel G, et al. (2002) Streets ahead: safe and liveable streets for children. London: Institute for Public Policy Research\n\nOffice for National Statistics (2009) Mortality statistics: deaths registered in 2008. London: Office for National Statistics\n\nPlay England (2007) Playday 2007 – Our streets too! London: Play England\n\nRacioppi F, Ericsson L, Tingvall C et al. (2004) Preventing road traffic injury: a public health perspective for Europe. Copenhagen: World Health Organization\n\nSonkin B, Edwards P, Roberts I et al. (2006) Walking, cycling and transport safety: an analysis of child road deaths. Journal of the Royal Society of Medicine 99: 402–5\n\nTowner E, Dowswell T, Errington G et al. (2005) Injuries in children aged 0–14 years and inequalities. London: Health Development Agency\n\nWorld Health Organization (2004) World report on road traffic injury prevention. Geneva: World Health Organization", 'Appendix B: Summary of the methods used to develop this guidance': "# Introduction\n\nThe reviews and economic analysis include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the PHIAC meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in appendix\xa0E.\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by PHIAC to help develop the recommendations. The overarching questions were:\n\nQuestion 1: What types of road design or modification to the road and street environment are effective and cost effective in reducing road injuries among children and young people aged under\xa015?\n\nQuestion 2: What are the barriers and facilitators to implementing environmental modifications and road/street designs relating to the reduction of road injuries?\n\nThe subsidiary question was:\n\nQuestion 3: What are the barriers and facilitators to implementing environmental modifications and designs relating to the reduction of vehicle speeds and road injuries?\n\nThese questions were made more specific for the reviews (see reviews for further details).\n\n# Reviewing the evidence\n\nOne review of effectiveness and cost effectiveness was conducted, and 1\xa0review of barriers and facilitators.\n\n## Identifying the evidence\n\nThe following databases were searched for evaluations (prospective or retrospective) of relevant interventions that used comparative designs (randomised controlled trials [RCTs], non-randomised controlled trials, before-and-after studies, or natural experiments); full economic evaluations and high quality costing studies conducted in the UK or countries of a similar level of economic development, patterns of transport use and urban environment; primary qualitative research involving the analysis of written or spoken evidence regarding attitudes towards, or experiences of, the relevant interventions, qualitative surveys of attitudes towards, or experiences of the relevant interventions:\n\nApplied Social Science Index and Abstracts (ASSIA)\n\nBibliomap\n\nCentre for Review and Dissemination\n\nDatabase of Abstracts of Reviews of Effects (DARE)\n\nDatabase of Promoting Health Effectiveness Reviews (DoPHER)\n\nEPPI CENTRE databases\n\nERIC\n\nHealth Management Information Consortium (HMIC)\n\nMEDLINE\n\nMEDLINE In Process\n\nNational Health Service Economic Evaluations Database (NHSEED)\n\nNHS Economic Evaluation Database (Health Technology Assessment)\n\nPsycINFO\n\nSafetyLit\n\nSocial Science Citation Index\n\nTransport Research Information Service (TRIS)\n\nTrials Register of Promoting Health Interventions TRoPHI\n\nA follow up targeted search was done in TRIS and MEDLINE of specific named programmes and additional traffic-calming methods determined from the results of the original database searches.\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix\xa0E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.\n\n++ All or most of the methodology checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are thought very unlikely to alter.\n\n+ Some of the methodology checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are thought unlikely to alter the conclusions.\n\n– Few or no methodology checklist criteria have been fulfilled. The conclusions of the study are thought likely or very likely to alter.\n\n## Summarising the evidence and making evidence statements\n\nThe review data was summarised in evidence tables (see full reviews).\n\nThe findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors/public health collaborating centres (see appendix\xa0A). The statements reflect their judgement of the strength (quantity, type and quality) of evidence and its applicability to the populations and settings in the scope.\n\n# Economic analysis\n\nThe economic analysis consisted of a review of economic evaluations (the cost effectiveness part of review 1) and a cost-effectiveness modelling (report\xa03).\n\n## Cost-effectiveness review (part of review 1)\n\nA wide range of electronic databases was searched, including some that are specific to the areas of transport policy/research and safety policy/research. Papers or reports were sought that reported quantitative comparative evaluations of local or regional interventions to reduce injuries in children aged under\xa015 by road/street design or by modifying the road/street environment and highway design (for example, measures to reduce speed and 20\xa0mph zones).\n\nStudies were included if they were full economic evaluations of relevant types of intervention or scheme, and high quality costing studies conducted in the UK or countries of a similar level of economic development, patterns of transport use and urban environment.\n\nStudies were excluded if they were cost-of-illness studies, or other studies that did not involve assessing the cost and related benefits/effectiveness of particular interventions (or class of intervention). Of 19 identified as potentially relevant 13 were included, all of which were cost–benefit analyses.\n\n## Cost-effectiveness modelling\n\nA number of assumptions were made that could underestimate or overestimate the cost effectiveness of the interventions (see modelling report for further details).\n\nEconomic modelling was undertaken to explore the cost effectiveness of mixed priority route schemes, mandatory 20\xa0mph zones and advisory 20\xa0mph limits. The results are presented as net present values as well as costs per quality adjusted life-year. (Net present value or NPV determines the total monetary benefit of an intervention less its costs - compared with an alternative intervention – when discounted to its present value. A positive NPV occurs when the sum of the discounted benefits exceeds the sum of the discounted costs.) They can be found in the cost-effectiveness modelling report of road and street design-based interventions aimed at reducing unintentional injuries in children.\n\n# Fieldwork\n\nFieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with practitioners and commissioners who are involved in unintentional injury and transport services. They included those working in community and charitable organisations, local transport planning departments, directors of public health and NHS and government representatives.\n\nThe fieldwork comprised:\n\nSix half-day workshops (2\xa0each in Birmingham, London and Manchester) with practitioners including community and charitable organisations, local transport planning departments, directors of public health and NHS, government representatives.\n\nSeven focus groups (in Hull, London, Manchester, Milton Keynes, Oxford, Portsmouth and Stockport) with transport planning departments in local authorities and within the private sector, including:\n\n\n\nchartered civil engineers\n\nmembers of the social inclusion team\n\nroad safety engineers\n\ntransport planners\n\nroad safety managers.\n\n\n\nTelephone interviews with:\n\n\n\ntransport planners\n\na policy planner.\n\n\n\nThe studies were commissioned to ensure there was ample geographical coverage. The main issues arising from these studies are set out in fieldwork findings in appendix\xa0C. See the full report on prevention of unintentional road injury in under-15s: road design.\n\n# How PHIAC formulated the recommendations\n\nAt its meeting in July 2009 PHIAC considered the evidence to determine:\n\nwhether there was sufficient evidence (in terms of strength and applicability) to form a judgement\n\nwhere relevant, whether (on balance) the evidence demonstrates that an intervention or programme is effective or ineffective or whether the evidence is inconclusive\n\nwhere relevant, the typical size of effect (where there is one)\n\nwhether the evidence is applicable to the target groups and contexts covered by the guidance.\n\nPHIAC developed draft recommendations through informal consensus, based on the following criteria:\n\nStrength (type, quality, quantity and consistency) of the evidence.\n\nThe applicability of the evidence to the populations/settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nEquality and diversity legislation.\n\nEthical issues and social value judgements.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of harms and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nPHIAC noted that effectiveness can vary according to context. For instance, the effectiveness of interventions on mixed priority routes varied with the initial casualty rate.\n\nWhere possible, recommendations were linked to evidence statements (see appendix\xa0C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).\n\nThe draft guidance, including the recommendations, was released for consultation in November 2009. At its meeting in January 2010, PHIAC amended the guidance in light of comments from stakeholders, experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in March 2010.", 'Appendix C: The evidence': "This appendix lists evidence statements from 2\xa0evidence reviews, provided by external contractors (see appendix\xa0A) and links them to the relevant recommendations. (See appendix\xa0B for the key to quality assessments.) The evidence statements are presented here without references – these can be found in the full review (see appendix\xa0E for details). It also sets out a brief summary of findings from the economic analysis.\n\nEvidence statement number B1a indicates that the linked statement is numbered 1a in the review 'Barriers to, and facilitators of, the prevention of unintentional injury in children on the road'.\n\nEvidence statement number E1a indicates that the linked statement is numbered 1a in the review 'Systematic reviews of effectiveness and cost-effectiveness of road and street design-based interventions aimed at reducing unintentional injuries in children'.\n\nWhere a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence) below.\n\nRecommendation 1: E1a–c, E2a–c, E3a–e\n\nRecommendation 2: B2a–d, E10, E11; IDE\n\nRecommendation 3: E1, E1a–c, E2, E2a–c, E3, E3a–e, E6b, E10, E11\n\nRecommendation 4: E7, E7a, E7b, E9\n\n# Evidence statements\n\nPlease note that the wording of some evidence statements has been altered slightly from those in the review team's report to make them more consistent with each other and NICE's standard house style.\n\n## Evidence statement E1\n\nFive UK based studies evaluated area-wide traffic-calming schemes. There were 1\xa0controlled (+) and 3\xa0uncontrolled (1 [−] and 2 [+]) before and after studies, and 1\xa0ecological study (+). Within these studies, casualties, injury collisions and speed outcomes were reported.\n\n## Evidence statement E1a\n\nThere is moderate evidence from 2\xa0uncontrolled before-and-after studies (both UK) that area-wide traffic-calming may reduce rates of killed or seriously injured children (both [+]). Both studies showed reductions in either killed and seriously injured child casualties or collisions in which a child pedestrian or cyclist is killed or seriously injured, but none of these was statistically significant.\n\n## Evidence statement E1b\n\nThere is moderate evidence from 1\xa0uncontrolled before-and-after study and 1\xa0ecological study (both UK) that area-wide traffic calming may reduce child road casualty rates of any severity (both [+]). There is moderate evidence from 1\xa0controlled and 2\xa0uncontrolled before-and-after studies (all UK) that area-wide traffic calming may reduce child injury collision rates of any severity (1\xa0[−] and 2\xa0[+]).\n\nOf the 2\xa0studies that reported child casualty rates, 1\xa0ecological study showed a statistically significant reduction (rate ratio [RaR]=0.777 for pedestrians in 1\xa0of\xa02\xa0cities studied, p=0.002 [+]), while the results in the other city, and the uncontrolled before-and-after study are consistent with a reduction, but do not reach significance (+).\n\nThe 2 studies that reported child injury collision rates (1\xa0controlled and 2\xa0uncontrolled before-and-after studies, all UK) also show reductions, but only 1\xa0approaches statistical significance when compared with a control group (RaR=0.524; 95% confidence interval [CI] = 0.258, 1.062 for child cyclists; 1\xa0[−] and 2\xa0[+]).\n\n## Evidence statement E1c\n\nThere is weak evidence from 2\xa0uncontrolled before-and-after studies that area-wide traffic calming may reduce traffic speeds (1\xa0[−] and 1\xa0[+]).\n\nWith the possible exception of the much older study (1990), this evidence is judged as directly applicable to similar roads and/or communities in the UK.\n\n## Evidence statement E2\n\nThree UK-based studies evaluated single road traffic-calming schemes. These were all uncontrolled before-and-after studies (3\xa0[+]). Within these studies, casualties, injury collisions and speed outcomes were reported.\n\n## Evidence statement E2a\n\nThere is weak evidence from 2\xa0UK-based uncontrolled before-and-after studies to show that single road traffic calming may reduce child road casualty rates. Only 1\xa0of these studies showed a statistically significant reduction in child casualties from 12 to\xa00 (p<0.001 [+]). In the other study, numbers of casualties were too small (decreasing from 3\xa0to\xa00) to be meaningful (+).\n\n## Evidence statement E2b\n\nThere is weak evidence from 1\xa0UK-based, uncontrolled before-and-after study that single road traffic calming may reduce child pedestrian injury collision rates (RaR 0.0381, p<0.001) while child cyclist injury collision rates were also reduced, but non-significantly (RaR=0.632, p=0.081 [+]).\n\n## Evidence statement E2c\n\nThere is weak evidence from 2\xa0uncontrolled before-and-after studies that single road traffic calming may reduce traffic speeds (both [+]). This evidence is judged as directly applicable to similar roads and/or communities in the UK, although the Chorlton evidence is dated.\n\n## Evidence statement E3\n\nFour UK-based studies evaluated 20 mph zones (mostly in urban areas). There were 1\xa0controlled and 3\xa0uncontrolled (all [+]) before-and-after studies, 2\xa0of which was adjusted for background trends. There is some overlap between studies. Two of the studies are of 20 mph zones in London; 1\xa0of which essentially updates the other. There are also small overlaps between these London-based studies and the England-wide study, and potentially between the England-wide study and the study based in Hull. Within these studies, casualties and speed outcomes were reported.\n\n## Evidence statement E3a\n\nThere is moderate evidence from 2\xa0uncontrolled before-and-after studies (1\xa0adjusted for trends on background roads; both UK-based) that 20 mph zones reduce killed or seriously injured child casualty rates (RaR=0.242 to 0.859 depending on analysis and study, p<0.05 where recorded [++]). One controlled before-and-after study also showed a reduction in killed or seriously injured child casualty rates in the intervention group when compared with a control group; however, this reduction was not significant (+). It must be noted that this study also evaluated schemes in London and is essentially updated by this uncontrolled before-and-after study.\n\n## Evidence statement E3b\n\nThere is weak evidence from 1\xa0uncontrolled before-and-after study (London-based), which was adjusted for trends on background roads, that 20 mph zones may reduce child pedestrian killed and seriously injured casualty rates. However, this reduction was not significant once the results had been adjusted for changes in background trends on outside roads (+). One study also showed that 20 mph zones may reduce child pedestrian killed and seriously injured casualty rates (before and after data only reported for this outcome; RaR=0.394, p<0.001 [+]). As noted above, however, this study is essentially updated by the uncontrolled before-and-after 2008 study. The evidence should not therefore be 'counted' twice.\n\n## Evidence statement E3c\n\nThere is weak evidence from 1\xa0before-and-after study (controlled data only reported for this outcome) that 20 mph zones may reduce child cyclist killed or seriously injured casualty rates. This reduction approaches statistical significance (RaR=0.399, p=0.06 [+]).\n\n## Evidence statement E3d\n\nThere is moderate evidence from 3\xa0UK-based uncontrolled before-and-after studies (1\xa0using adjusted analyses [+]) and 1\xa0controlled before-and-after study of London schemes (+) that 20 mph zones may reduce child road casualty rates overall, and for child pedestrians and child pedal cyclists when analysed separately (road casualty rates overall RaR=0.331 to 0.716 depending on analysis and intervention, p<0.001 where recorded).\n\n## Evidence statement E3e\n\nThere is weak evidence from 2\xa0studies that 20 mph zones may reduce traffic speeds (both [+]). This evidence is judged as directly applicable to similar roads and/or communities in the UK, although some data is rather dated.\n\n## Evidence statement E6b\n\nThere is weak evidence from 1\xa0case-control study that living in an area with 0\xa0to\xa05 streets with a speed limit of 30 kph may increase a child's risk of injury compared with a child living in an area with 15 or more streets with the same speed limit (OR=5.3, 95% CI=1.6, 17.6 [+]).\n\n## Evidence statement E7\n\nThere is moderate evidence from 2\xa0controlled before-and-after (injury data time-series) studies (both [+]) in the USA that Safe Routes to School (SRTS) programmes based predominantly on engineering measures may reduce the rates of crash-involved child pedestrians or cyclists, or the rate of child injury road collisions.\n\n## Evidence statement E7a\n\nIn 125 SRTS project areas across California, and after assuming modest (10%) increases in rates of walking and cycling to school due to the programmes (such as increased exposure), a mean reduction of 7% in the all‑injury collision rate with child pedestrians and cyclists was estimated (14% for children aged 5\xa0to\xa012) (+). However, the estimated impact on fatal or severe child injuries was less conclusive (ranging from a 52% increase to a 24% reduction, again depending on assumed changes in levels of walking/cycling to school).\n\n## Evidence statement E7b\n\nThe evaluation of 53 projects in 3\xa0unnamed US States (+) compared linear regression coefficients (giving 'T statistics') between the time-series trends of child injury data for the SRTS sites; these showed significantly greater reductions in crash-involved child pedestrians and cyclists at SRTS sites when compared with at least 2\xa0of the 6\xa0'control' time-series in all 3\xa0US states (note, all of the 'T' values were negative, indicating that the reductions in crash outcomes in SRTS sites were always lower [if not always statistically significantly lower] than in the comparison time-series.)\n\nThis evidence from evaluations of SRTS programmes in the US is judged as partially applicable to similar localities in the UK.\n\n## Evidence statement E9\n\nThere is weak evidence from 1\xa0controlled before-and-after study that combined traffic calming, safe routes to schools and education may reduce child road casualty rates when a before-and-after comparison was made (OR\xa00.722, p=0.007 [+]); however, compared with the control group the reduction was not significant. This Swedish evidence is judged as partially applicable to similar roads and/or communities in the UK.\n\n## Evidence statement E10\n\nThere is moderate evidence from 3\xa0cost–benefit analyses of a variety of area-wide traffic-calming schemes that show that, even in the short term (after 1 year), benefits are likely to exceed costs in most circumstances. However, there was considerable variation in first year rates of return. This evidence was judged to be partly applicable to the UK road setting.\n\n## Evidence statement E11\n\nThere is moderate evidence from 1\xa0cost–benefit analysis of advisory 20\xa0mph speed limits that shows that, in the short term, benefits are likely to exceed costs. Similarly, there is moderate evidence from one cost–benefit analysis of mandatory 20 mph zones that shows that, in the medium to long term, benefits are likely to exceed costs. The evidence on 20 mph zones is judged as being directly applicable to other urban roads in England, whereas the applicability of the evidence on advisory speed limits in Scotland may have less applicability in England and Wales because of the different road regulations relating to 20 mph speed limits.\n\n## Evidence statement B2a\n\nFive studies, 4\xa0UK and 1\xa0US-based, discuss risk-taking behaviour among children and young people as a potential cause of collisions (2\xa0[+] and 3\xa0[−]).\n\n## Evidence statement B2b\n\nLike adults, children and young people often engage in 'common' risk behaviours that are seen as part of everyday life, such as not always using crossings, crossing between parked cars or in traffic.\n\n## Evidence statement B2c\n\nOne UK study reports that teenagers were more likely to take risks on the road than younger children (aged 8+).\n\n## Evidence statement B2d\n\nThree UK studies suggest that a minority of children and young people engage in 'extreme' risks – such as playing 'chicken' in the road or holding onto the back of buses, and that boys are more likely to do this, and to encourage such behaviour in each other. Such behaviours are regarded in a similar way to thrill-seeking sports.\n\n# Cost-effectiveness evidence\n\nThe economic modelling suggests that setting advisory 20\xa0mph limits is a highly cost-effective way of preventing unintentional injuries on the road (with a net present value of £64,209; net present value determines the total monetary benefit of an intervention less its costs – compared with an alternative intervention – when discounted to its present value; a positive net present value occurs when the sum of the discounted benefits exceeds the sum of the discounted costs). However, caution is needed in interpreting these results. First, because the studies modelled came from Scotland where the legal definition of what comprises an advisory 20 mph limit is different. Second, the areas where they were introduced were not necessarily comparable for example, in terms of previous collision rates, vehicle speeds and pedestrian usage.\n\nMandatory 20 mph zones were found to be much more cost effective in areas with previously high casualty rates (1.6 per year per km). The NPV was £90,625 in these areas, compared to a NPV of £25,480 when implemented in low casualty rate areas.\n\nDeterministic sensitivity analyses identified a number of parameters that were important to all interventions: number of casualties in the comparator area, effectiveness of the intervention, the background reduction in casualties and the effective lifetime of the intervention all had an effect.\n\nThe modelling did not consider health benefits other than those due to casualties prevented. For instance, it did not consider the health benefits of increased physical activity or the reduction in air pollution due to a change in road use. It also did not consider the impact that road engineering measures to reduce speed can have on other factors such as congestion or noise. These would only be captured by cost–benefit analysis using a full societal perspective.\n\n# Fieldwork findings\n\nFieldwork aimed to test the relevance, usefulness and the feasibility of putting the recommendations into practice. PHIAC considered the findings when developing the final recommendations. For details, go to the fieldwork section in appendix\xa0B.\n\nFieldwork participants who work in transport planning were fairly positive about the recommendations and their potential to help prevent unintentional injuries. Many participants stated that although the recommendations were 'nothing new' and were already being applied in general, engaging the health sector in this area was vitally important. They reported that the recommendations could have a positive impact if they helped to engage the health sector in preventing injuries among young people aged under\xa015.\n\nSome stakeholders said that at partnership meetings (for example, local strategic partnerships) in their local areas the health aspect of the partnership was often missing, that is, the NHS representatives do not attend local injury prevention partnership meetings. Participants particularly noted NHS directors of public health as an important group to engage and ensure that they were active in work in this area. Others noted that stakeholders from education were also unable or unwilling to engage and that it would be an advantage if the recommendations could help engage education services in injury prevention.\n\nThe planning stakeholders consistently said in the workshops and focus groups that the recommendations do not add any content for planners. They said that the draft recommendations do not cross-reference to other supporting material, such as that from the Department for Transport. They also thought some of the content of the recommendations is not consistent with Department of Transport guidance and strategies (for example the road safety strategy). Delegates stated that a cohesive approach from government is important.\n\nOverall, delegates said that the recommendations had a role to play in directing the NHS to plays its part in supporting local strategic partnerships and supplying data requirements.", 'Appendix D: Gaps in the evidence': 'PHIAC identified a number of gaps in the evidence relating to the interventions under examination, based on an assessment of the evidence. These gaps are set out below.\n\n. There is a lack of evidence on the effectiveness and cost effectiveness of woonerven, home zones and quiet lanes on preventing unintentional injuries on the road for children and young people under\xa015.\n\n. There is a lack of evidence as to whether there was any differential effect of environmental interventions on different populations in terms of age, gender, rural/urban/road type and level of disadvantage.\n\n. There is a lack of UK evidence on the effectiveness and cost effectiveness of safe routes to school on preventing injuries on the road in children and young people under\xa015.\n\n. There is a lack of UK evidence on the effectiveness and cost effectiveness of cycle routes on preventing injuries on the road in children and young people under\xa015.\n\n. There is a lack of evidence on the attitudes of drivers/road users to environmental interventions that prevent unintentional injuries in children on the road.\n\n. There is a lack of UK evidence as to the barriers and facilitators of implementing environmental interventions to prevent unintentional injuries in children on the road, for example, which factors enhance successful implementation of design-based interventions.', 'Appendix E: Supporting documents': "Supporting documents include:\n\nReviews of effectiveness:\n\n\n\nReview 1: 'Systematic reviews of effectiveness and cost-effectiveness of road and street design-based interventions aimed at reducing unintentional injuries in children'\n\nReview 2: 'Barriers to, and facilitators of, the prevention of unintentional injury in children on the road'.\n\n\n\nCost-effectiveness modelling: 'Cost-effectiveness modelling of road and street design-based interventions aimed at reducing unintentional injuries in children'.\n\nFieldwork report: 'Prevention of unintentional road injury in under-15s: road design'.", 'Finding more information': "To find NICE guidance on related topics, including guidance in development, see the NICE topic page on injuries, accidents and wounds.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice."}
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https://www.nice.org.uk/guidance/ph31
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This guideline covers road speed limits, 20 mph zones and engineering measures to reduce speed or make routes safer.
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8d2a3b37828fe759f6c203b839d6891d223ef760
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nice
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Trastuzumab for the treatment of HER2-positive metastatic gastric cancer
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Trastuzumab for the treatment of HER2-positive metastatic gastric cancer
Evidence-based recommendations on trastuzumab (Herceptin) for treating HER2-positive metastatic gastric cancer in adults.
# Guidance
Trastuzumab, in combination with cisplatin and capecitabine or 5-fluorouracil, is recommended as an option for the treatment of people with human epidermal growth factor receptor 2 (HER2)-positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who:
have not received prior treatment for their metastatic disease and
have tumours expressing high levels of HER2 as defined by a positive immunohistochemistry score of 3 (IHC3 positive).
People who are currently receiving treatment with trastuzumab for HER2-positive metastatic gastric cancer who do not meet the criteria in 1.1 should have the option to continue treatment until they and their clinicians consider it appropriate to stop.# The technology
Trastuzumab (Herceptin, Roche Products) is a recombinant humanised IgG1 monoclonal antibody directed against HER2. Trastuzumab in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of patients with HER2-positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who have not received prior anticancer treatment for their metastatic disease. Trastuzumab is approved for use only in patients with metastatic gastric cancer whose tumours have HER2 overexpression as defined by immunohistochemistry (IHC)2 positive and a confirmatory fluorescence in situ hybridisation (FISH) positive result, or IHC3 positive, as determined by an accurate and validated assay. On 6 August 2010, the marketing authorisation for trastuzumab was revised to include silver in situ hybridisation (SISH) testing as another method for confirming HER2 overexpression. Because of the timing of the revision, SISH testing was not considered in this appraisal. For further details see the summary of product characteristics.
Trastuzumab is associated with cardiotoxicity. The summary of product characteristics states that all patients should have baseline cardiac assessment before starting treatment. Cardiac function should be further monitored during treatment (for example, every 12 weeks). The summary of product characteristics also states that caution should be taken in treating people with symptomatic heart failure, a history of hypertension, or documented coronary artery disease. For full details of side effects and contraindications, see the summary of product characteristics.
Trastuzumab is administered at an initial loading dose of 8 mg/kg body weight. The recommended maintenance dose at 3-weekly intervals is 6 mg/kg body weight, beginning 3 weeks after the loading dose. It is given as an intravenous infusion over 90 minutes. If the initial loading dose is well tolerated, the subsequent doses can be administered as 30-minute infusions. As long as treatment is tolerated, it can be given until disease progression.
The net price of a 150-mg vial of trastuzumab is £407.40 (excluding VAT; 'British national formulary' edition 59). For a patient weighing 62 kg, four vials are required for the first loading dose and three vials for each subsequent dose. Assuming that excess trastuzumab is wasted, the drug cost of eight infusions of trastuzumab (the median number of infusions in the regulatory trial) is £10,185. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of trastuzumab and a review of this submission by the Evidence Review Group (ERG; appendix B).
The manufacturer's decision problem compared trastuzumab plus cisplatin and either capecitabine or 5-fluorouracil with:
epirubicin plus cisplatin and either capecitabine or 5-fluorouracil and
epirubicin plus oxaliplatin and capecitabine. The choice of comparators was based on the results of a survey of commonly used treatments for gastric cancer in England and Wales. Outcomes were overall survival, progression-free survival, response rate, adverse effects of treatment and health-related quality of life. In the economic evaluation, the incremental cost per quality-adjusted life year (QALY) was presented. A lifetime horizon was used, and costs were considered from the NHS perspective.
# Clinical effectiveness
The manufacturer identified one phase III randomised controlled trial (ToGA) evaluating the efficacy of trastuzumab plus cisplatin and a fluoropyrimidine (that is, capecitabine or 5-fluorouracil) in people with inoperable locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. People in the trial had tumours with high levels of HER2 protein (see section 3.4), and had received no prior treatment for their advanced or metastatic disease.
The trial randomised 594 people to receive either chemotherapy (n = 296) or trastuzumab plus chemotherapy (n = 298). The chemotherapy group in the ToGA trial received intravenous cisplatin (80 mg/m2) on day one of each cycle with either oral capecitabine (1000 mg/m2) twice daily for 14 days, or an intravenous infusion of 5-fluorouracil (800 mg/m2) on days one to five of each of the six 3-weekly cycles. In addition to six 3-weekly cycles of chemotherapy, the treatment group received trastuzumab (8 mg/kg loading dose on day one, followed by 6 mg/kg intravenous infusion every 3 weeks) until disease progression. In both groups the choice of fluoropyrimidine was at the discretion of the investigator; 87% received capecitabine and 13% received 5-fluorouracil.
People whose tumours were classed as HER2 positive were included in the ToGA trial. IHC and FISH tests were done at the same time (parallel testing) according to the trial protocol. At the time of randomisation, tumours that were IHC3 positive, or those that tested FISH positive were defined as HER2 positive. Changes in the understanding of HER2 testing during the ToGA trial resulted in HER2 positive being defined as tumours that were IHC2 positive and FISH positive, or IHC3 positive. From the full population of 594 in the ToGA trial, 446 people (75%) had tumours that met this narrower definition. The European marketing authorisation was granted for this population (referred to as the EMA subgroup). Of this subgroup, 218 people received treatment with chemotherapy alone and 228 people received treatment with trastuzumab plus chemotherapy.
At baseline, characteristics in the ToGA trial were balanced between the treatment groups. These characteristics included sex, age, weight, region, and type of tumour (that is, intestinal, diffuse or mixed tumour types). A high proportion of people in the ToGA trial were male (76%) and 55% were from Asian countries. Almost all people had metastatic gastric cancer (97%), and accordingly the marketing authorisation was granted for the metastatic disease only.
The primary outcome in the ToGA trial was overall survival. The trial was terminated early in accordance with a revised stopping rule recommended by the Independent Data Monitoring Committee. At the time of the clinical cut-off, the median duration of survival follow-up was 18.6 months in the trastuzumab plus chemotherapy group and 17.1 months in the chemotherapy alone group. The hazard ratio for overall survival in the EMA subgroup was 0.65 (95% confidence interval 0.51 to 0.83) corresponding to a median survival for the trastuzumab plus chemotherapy group of 16 months compared with 11.8 months for the chemotherapy alone group (4.2-month improvement in survival). A median survival of 13.8 months was reported for the total trial population receiving trastuzumab plus chemotherapy compared with 11.1 months in the chemotherapy alone group (2.7-month improvement in survival).
The manufacturer reported the results for secondary outcomes including progression-free survival and overall response rate. For the EMA subgroup the hazard ratio for progression-free survival was 0.64 (95% CI 0.51 to 0.79), corresponding to a median progression-free survival for the trastuzumab plus chemotherapy group of 7.6 months compared with 5.5 months for the chemotherapy alone group (a 2.1-month improvement in progression-free survival). Results for overall response rate were reported for the total trial population only, and demonstrated a statistically significantly higher overall response rate in the trastuzumab plus chemotherapy group (47.3%) compared with the chemotherapy alone group (34.5%), odds ratio 1.70 (95% CI 1.22 to 2.38, p = 0.002).
Quality of life was assessed in the ToGA trial as a secondary objective using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 (global health status, functioning and symptoms) and QLQ-STO22 (containing 22 items associated with dysphagia, pain, reflux, eating restrictions, anxiety, dry mouth, body image and hair loss). Both treatment groups in the trial showed improvements in quality of life over the course of treatment. A statistical analysis of differences in quality of life between the treatment groups was not presented. Additionally, EQ-5D data were collected at baseline and every 3 weeks until disease progression.
In both groups, 68% of people had grade 3 or 4 adverse events. The most frequent were disorders of the blood and lymphatic system, gastrointestinal disorders, and metabolism and nutritional disorders. More people treated with trastuzumab plus chemotherapy had asymptomatic reductions in left ventricular ejection fraction; however, the difference in symptomatic cardiac events was not statistically significant.
# Cost effectiveness
The manufacturer developed a Markov economic model to assess the cost effectiveness of trastuzumab plus chemotherapy to treat people with HER2-positive metastatic gastric cancer. The model had three distinct health states: progression-free survival, disease progression and death. The model had a cycle length of 1 month and an 8-year time horizon (considered to be a lifetime horizon). Both costs and benefits were discounted at a rate of 3.5%. One-way sensitivity analyses were undertaken on utility values, survival analysis, unit costs and various resource use assumptions. Probabilistic sensitivity analysis was also undertaken to explore parameter uncertainty in the model.
The treatment regimens included in the manufacturer's economic evaluation were:
trastuzumab plus cisplatin and capecitabine
trastuzumab plus cisplatin and 5-fluorouracil
epirubicin plus cisplatin and capecitabine
epirubicin plus cisplatin and 5-fluorouracil
epirubicin plus oxaliplatin and capecitabine.
The clinical estimates (transition probabilities) in the model were derived from the overall survival and progression-free survival estimates from the trastuzumab plus chemotherapy group in the ToGA trial (EMA subgroup).
The manufacturer's literature search for comparator data did not find trials in which triple regimens including epirubicin were directly compared with triple regimens including trastuzumab. However, four studies were identified that evaluated one of the regimens of interest:
Tobe (1992) and Kim (2001), which compared epirubicin plus cisplatin and 5-fluorouracil with cisplatin and 5-fluorouracil
Yun (2010), which compared epirubicin plus cisplatin and capecitabine with cisplatin and capecitabine
REAL-2 (2008), which compared the non-inferiority of capecitabine with 5-fluorouracil in triple chemotherapy regimens including epirubicin. Additionally, a meta-analysis was identified (Wagner 2006) evaluating the efficacy of a triple regimen including an anthracycline (epirubicin) compared with a regimen that did not include an anthracycline. However, the results of this analysis were not used in the economic model because the largest trial assessed a comparison between epirubicin, cisplatin and 5-fluorouracil and cisplatin and 5-fluorouracil plus mitomycin (Ross 2002), and the other trials were presented in abstract form (Kim) or only included a small population with more severe disease (Tobe).
The manufacturer explored the possibility of conducting a network meta-analysis between the three comparator triple regimens used in UK clinical practice (that is, epirubicin plus cisplatin and capecitabine, epirubicin plus cisplatin and 5-fluorouracil, and epirubicin plus oxaliplatin and capecitabine) and the chemotherapy comparator group from the ToGA trial, to obtain the comparator effectiveness data for the model. However, the manufacturer concluded that the results of a network meta-analysis would not produce reliable or meaningful results because the only study to evaluate epirubicin plus cisplatin and capecitabine compared with cisplatin and capecitabine (Yun) did not report the primary outcome of the ToGA trial (overall survival). Additionally, the studies that compared cisplatin and 5-fluorouracil with epirubicin plus cisplatin and 5-fluorouracil (Tobe and Kim) did not have comparable patient populations. Therefore, the manufacturer presented a narrative summary of the results from the Yun, Tobe, Kim and REAL-2 trials.
For epirubicin plus cisplatin and capecitabine, the manufacturer concluded that the estimates of overall survival and progression-free survival could be assumed to be equivalent to those from the chemotherapy comparator group in the ToGA trial. This was because the Yun study showed no evidence of a significant difference (hazard ratio of progression-free survival for epirubicin plus cisplatin and capecitabine compared with cisplatin and capecitabine 0.96, 95% CI 0.58 to 1.57). The dose of cisplatin in the ToGA trial was also considered to be higher than it would be in UK clinical practice when added to a triple regimen including epirubicin, and that the two regimens could therefore be regarded as equivalent.
For epirubicin, cisplatin and 5-fluorouracil the manufacturer concluded that the estimates of progression-free survival could be assumed to be equivalent to those from the chemotherapy comparator group in the ToGA trial. The evidence to support this conclusion came from the study by Tobe (hazard ratio of overall survival for epirubicin plus cisplatin and 5-fluorouracil compared with cisplatin and 5-fluorouracil 0.57, 95% CI 0.27 to 1.2) and the study by Kim (hazard ratio of overall survival for epirubicin plus cisplatin and 5-fluorouracil compared with cisplatin and 5-fluorouracil 0.83, 95% CI 0.42 to 1.61). Additionally, the manufacturer used an overall survival benefit of capecitabine over 5-fluorouracil (hazard ratio 1.15) from a meta-analysis (Okines 2009).
For the third comparator regimen (epirubicin plus oxaliplatin and capecitabine), the manufacturer concluded that it could be considered equivalent to epirubicin plus cisplatin and capecitabine in effectiveness. This was based on the REAL-2 trial. The manufacturer stated that the results of this study indicated that oxaliplatin was as effective as cisplatin (hazard ratio of overall survival for oxaliplatin arms compared with cisplatin arms 0.92, 95% CI 0.80 to 1.10). Overall survival and progression-free survival estimates for epirubicin plus oxaliplatin and capecitabine were therefore considered equivalent to those for epirubicin plus cisplatin and capecitabine.
Health-related quality of life was estimated for progression-free survival and progressive disease health states. A utility value for the progression-free survival health state was calculated using results from the EQ-5D data collected at baseline and then every 3 weeks until progression in the ToGA trial. The manufacturer estimated a baseline utility value of 0.7292, which increased daily by 0.000142 during progression-free survival. For the progressive disease health state, an estimate from the literature was used because EQ-5D data were not collected after disease progression in the ToGA trial. The utility value of 0.577 for progressive disease was taken from 'Sunitinib for the treatment of gastrointestinal stromal tumours' (NICE technology appraisal guidance 179). Utility values associated with adverse events were not included in the model.
The model included costs for HER2 testing, drug acquisition, drug administration, monitoring during progression-free survival, treating adverse events, care costs in progression-free survival after chemotherapy treatment was stopped, and supportive care costs after progression of disease. The cost of HER2 testing was based on a sequential testing strategy in which only people who tested IHC2 positive received a FISH test. Total drug costs included an amount for wastage based on an assumption that 80% of centres using trastuzumab to treat gastric cancer would also use it to treat breast cancer and would share vials, thereby implying no wastage. Cardiac monitoring was assumed to be done using a multiple-gated acquisition scan or an echocardiogram and to take place once every cycle for people treated with epirubicin and once every 3 months for people treated with trastuzumab, in accordance with the summaries of product characteristics. The costs of grade 3 or 4 adverse events with an incidence of at least 5% in any of the treatment groups were included.
The model suggested that trastuzumab plus cisplatin and capecitabine compared with epirubicin plus cisplatin and capecitabine, and compared with epirubicin plus oxaliplatin and capecitabine, produced a mean gain of 4.8 months of life for both comparisons. Trastuzumab plus cisplatin and 5-fluorouracil compared with epirubicin plus cisplatin and 5-fluorouracil produced a mean gain of 4.3 months of life. In the manufacturer's incremental cost-effectiveness analysis of all five regimens, epirubicin plus cisplatin and 5-fluorouracil, and epirubicin plus oxaliplatin and capecitabine, were both less effective and more expensive than the other regimens (that is, they were dominated). Additionally, although the total cost of the trastuzumab plus cisplatin and 5-fluorouracil regimen was lower than that of trastuzumab plus cisplatin and capecitabine, it was also less effective and had a higher incremental cost-effectiveness ratio (ICER) than trastuzumab, cisplatin and capecitabine (that is, it was extendedly dominated). For the two remaining regimens, trastuzumab plus cisplatin and capecitabine had an additional cost of £13,064 and produced an additional 0.25 QALYs over epirubicin plus cisplatin and capecitabine. The ICER was £51,927 per QALY gained. The manufacturer examined other scenarios in a probabilistic sensitivity analysis. Distributions were applied to utility values, unit costs, monthly supportive care costs, adverse event probabilities, survival curves, parametric parameters, and progression-free survival monthly Kaplan-Maier estimates. This resulted in ICERs that ranged from £37,180 to £95,238 per QALY gained. The probability that trastuzumab plus cisplatin and capecitabine was cost effective at £30,000 was 0%.
The manufacturer also presented the results of pair-wise comparisons between trastuzumab plus cisplatin and 5-fluorouracil and epirubicin plus cisplatin and 5-fluorouracil, and between trastuzumab plus cisplatin and capecitabine and epirubicin plus oxaliplatin and capecitabine. The ICERs for these comparisons were £50,838 and £40,711 per QALY gained respectively.
# Evidence review group comments
The ERG stated that the manufacturer identified the only trial evaluating trastuzumab in the treatment of HER2-positive metastatic gastric cancer (the ToGA trial). This trial was a well-conducted phase III randomised controlled trial with appropriate validity assessment. The ERG considered that the ToGA trial demonstrated improved overall survival of people treated with trastuzumab when added to cisplatin plus either capecitabine or 5-fluorouracil. The economic model was considered appropriate for the decision problem and the general approach employed by the manufacturer to estimate lifetime cost effectiveness met the requirements of the NICE reference case.
The ERG identified some small errors in the manufacturer's model related to inconsistent assumptions about adverse events, distributions of survival data and resource use. Correcting these errors reduced the ICER from £51,927 per QALY gained to £49,005 per QALY gained. This ICER represented an additional cost of £12,332 and an additional 0.251 QALYs from treatment with trastuzumab plus cisplatin and capecitabine over epirubicin plus cisplatin and capecitabine.
The ERG highlighted the following main areas of concern in the manufacturer's submission:
The relevance of the trial data to a UK population.
The comparator data considered for network meta-analysis.
The relative effectiveness estimates of comparators in the model.
The utility values applied during progression-free survival.
The frequency of cardiac monitoring with trastuzumab and epirubicin.
The use of parallel and sequential HER2 testing strategies.
The ERG stated that the efficacy of standard triple regimens in people with HER2-positive gastric cancer was unknown. It was assumed that the HER2-positive population is equivalent to a mixed-HER2 population containing an unknown proportion of HER2-positive people. The ERG noted that the trial population in the ToGA trial was substantially younger than the UK population of people with gastric cancer, of whom only 17% die before the age of 65. The population of the ToGA trial also differed substantially from the UK clinical population, in that over 50% of people in the trial were from Asian countries.
The ERG considered that the most relevant comparators in the context of current clinical practice were epirubicin plus cisplatin and capecitabine, epirubicin plus cisplatin and 5-fluorouracil, epirubicin plus oxaliplatin and capecitabine, and epirubicin plus oxaliplatin and 5-fluorouracil. However, it stated that epirubicin plus oxaliplatin and capecitabine was likely to be used more often in routine clinical practice in England and Wales than the 6% suggested in the manufacturer's submission. Following clarification by the manufacturer, the ERG concluded that all relevant trials had been identified for inclusion in a possible network meta-analysis to establish a link between the triple regimens with the chemotherapy comparator group of the ToGA trial. The ERG considered that the manufacturer's decision not to attempt a network meta-analysis using these trials was justified, mainly because of differences in the trial populations.
The ERG stated that the manufacturer's assumption of no difference in effect between the chemotherapy comparator regimen in the ToGA trial and the comparator regimens in the economic evaluation largely rested on the critique of the meta-analysis by Wagner. This study found a benefit for triple regimens including an anthracycline over regimens that did not include an anthracycline. The ERG stated that the manufacturer's decision to exclude the meta-analysis on the basis that it contained a trial that had only been published in abstract form (Kim) and a trial with a small population of people with more severe disease (Tobe) was inconsistent with the decision to include these studies individually. As a result of dismissing the meta-analysis, the small phase II Kim, Tobe and Yun trials were used as evidence of no effect between double and triple regimens, and the ERG stated that these were underpowered to detect a statistically significant benefit of treatment. The ERG therefore considered that the manufacturer's assumption of no difference in effectiveness between the chemotherapy comparator group in the ToGA trial and triple regimens including epirubicin was not justified. The ERG noted that the balance of evidence suggested that there may be an advantage in adding epirubicin to a double regimen.
The ERG explored the effect on the ICER using the hazard ratio from the Yun study (0.96), which indicated a small benefit of adding epirubicin to a double regimen. When applied to progression-free survival only, the ICER increased from the revised base case of £49,005 per QALY gained to £49,754 per QALY gained. When applied to progression-free survival and overall survival, the ICER increased from £49,005 per QALY gained to £52,709 per QALY gained.
The ERG also explored the effect of the manufacturer's assumption of no difference between triple regimens including oxaliplatin and triple regimens including cisplatin. From the REAL-2 trial, a hazard ratio for overall survival and progression-free survival (0.87) was derived that suggested a benefit of oxaliplatin regimens over cisplatin regimens. As a result, the cisplatin regimen no longer dominated the oxaliplatin regimen in the incremental analysis, which increased the ICER for trastuzumab plus cisplatin and capecitabine. When applied to overall survival alone, the ICER increased from £49,005 per QALY gained to £50,745 per QALY gained. When applied to overall survival and progression-free survival, the ICER increased from £49,005 per QALY gained to £54,114 per QALY gained.
The ERG stated that the manufacturer's base-case approach was relatively optimistic because utility values were assumed to increase by 0.000142 for each day in progression-free survival. The ERG suggested that it would be more appropriate to apply a small decrease in utility values over time to reflect the change in utility over time for an equivalent group of people from UK general population norms for EQ-5D. The ERG calculated this utility decrement to be 0.003502 per year. The ERG explored the impact of applying this assumption to the corrected manufacturer's base case and reported an increase from £49,005 per QALY gained to £51,309 per QALY gained.
The ERG highlighted the manufacturer's base-case assumption that cardiac monitoring took place once every cycle with epirubicin and once every 3 months with trastuzumab. Although the summary of product characteristics for epirubicin recommends an echocardiogram before and after each treatment cycle, the ERG's clinical advisers considered that, in the UK, cardiac monitoring is not done this often. The ERG carried out an exploratory analysis assuming that cardiac monitoring was carried out at the same frequency for epirubicin as for trastuzumab. This resulted in the ICER increasing from the corrected base-case estimate of £49,005 per QALY gained to £50,816 per QALY gained.
The ERG raised a number of issues relating to HER2 testing in the manufacturer's base case. These included the potential costs of repeat tests needed because of test failures and that the effectiveness estimates in the model were derived from the ToGA trial, which used a parallel testing strategy rather than a sequential testing strategy. The ERG also noted the estimate that 17.8% of people with metastatic gastric cancer whose tumours are HER2-positive came from the full trial population; however, in the UK subgroup of people in the ToGA trial, this was 26%. To explore the impact of variations in the HER2-positive rate, the ERG undertook an exploratory analysis in which the HER2 rate was varied between 5% and 30%, indicating the lower and upper limits which it considered reasonable. The resulting ICERs from this analysis ranged from £52,866 per QALY gained for the lower assumption of 5% to £48,395 per QALY gained for the higher assumption of 30%.
To consider the combined potential impact of some of the uncertainties raised, the ERG undertook two alternative exploratory analyses in which the following key assumptions were considered to be equally plausible:
The hazard ratio of epirubicin plus oxaliplatin and capecitabine compared with epirubicin plus cisplatin and capecitabine was changed to 0.87.
The hazard ratio of epirubicin plus cisplatin and capecitabine compared with cisplatin and capecitabine was changed to 0.96 for progression-free survival and overall survival (indicating a survival benefit for epirubicin plus cisplatin and capecitabine compared with cisplatin and capecitabine alone).
Utility values during progression-free survival were changed to incorporate an expected decrease in utility in line with the general population over time.
The frequency of cardiac monitoring for epirubicin was changed to be the same as trastuzumab.The ERG presented the results of these exploratory analyses separately for sequential and parallel HER2 testing strategies. In both analyses, epirubicin plus cisplatin and capecitabine was no longer the dominant comparator regimen and the relevant comparator for trastuzumab plus cisplatin and capecitabine was epirubicin plus oxaliplatin and capecitabine. When trastuzumab plus cisplatin and capecitabine was compared with epirubicin plus oxaliplatin and capecitabine, the QALY gain was 0.149 at an incremental cost of £9987, giving an ICER of £66,982 per QALY gained using a sequential testing strategy. When a parallel testing strategy was assumed, the QALY gain was the same, however, the incremental costs increased to £10,681, giving an ICER of £71,637 per QALY gained.
Finally, the ERG undertook a separate exploratory analysis in which the hazard ratio was 0.77 (indicating a survival benefit) for epirubicin plus cisplatin and capecitabine, and epirubicin plus oxaliplatin and capecitabine, compared with cisplatin and capecitabine alone. This estimate of effectiveness was inferred from the Wagner meta-analysis in which a triple regimen including an anthracycline therapy had been compared with a regimen without an anthracycline. When applied to overall survival only, the QALY gain was approximately 0.13 at an incremental cost of £10,993, giving an ICER of £84,373 per QALY gained. When applied to overall survival and progression-free survival, the QALY gain was approximately 0.13 at an incremental cost of £11,226, giving an ICER of £99,797 per QALY gained.
# Additional data provided by the manufacturer
The manufacturer's response to the appraisal consultation document (ACD) included an alternative base-case analysis and a new economic analysis for a subgroup of people from the ToGA trial who were IHC3 positive.
The manufacturer's alternative base case incorporated three of the four parameter changes in the ERG's exploratory analysis (see section 3.33). These were:
a hazard ratio of 0.87 for epirubicin plus oxaliplatin and capecitabine compared with epirubicin plus cisplatin and capecitabine
a hazard ratio of 0.96 for overall survival for epirubicin plus cisplatin and capecitabine compared with cisplatin plus capecitabine
the same frequency of cardiac monitoring for epirubicin as trastuzumab. The decrement in utility values during progression-free survival in the ERG's exploratory analysis was not incorporated. The manufacturer included the estimate of increasing utility values during progression-free survival used in its original base-case analysis. The ICER for trastuzumab plus cisplatin and capecitabine in comparison with epirubicin plus oxaliplatin and capecitabine was £62,829 per QALY gained. The other treatments in the analysis were either dominated or extendedly dominated. A probabilistic sensitivity analysis for the same comparison produced an ICER with a mean value of £67,786 per QALY gained.
A new economic analysis based on a subgroup of people who tested IHC3 positive (that is, people with very high levels of HER2) was provided by the manufacturer. The analysis included 279 people, of whom 144 received treatment with trastuzumab plus cisplatin and either capecitabine or 5-fluorouracil, and 135 received treatment with cisplatin plus either capecitabine or 5-fluorouracil.
The clinical evidence submitted for the IHC3-positive subgroup included an analysis of overall survival. Analyses of progression-free survival and time to progression were provided as commercial-in-confidence. The hazard ratio of overall survival for the trastuzumab plus chemotherapy group compared with the chemotherapy alone group was 0.57 (95% CI 0.41 to 0.79), corresponding to a median survival for the trastuzumab plus chemotherapy group of 18 months compared with 12.4 months for the chemotherapy alone group (5.6-month improvement in survival). The manufacturer also provided an adjusted hazard ratio to account for an imbalance in baseline characteristics between the treatment groups in the IHC3-positive subgroup. The adjusted hazard ratio of overall survival for the trastuzumab plus chemotherapy group compared with the chemotherapy alone group was 0.51 (95% CI 0.36 to 0.72).
The manufacturer presented the results of an economic analysis for the IHC3-positive subgroup using the adjusted hazard ratio. The modelled mean overall survival for trastuzumab plus cisplatin and capecitabine was 7.4 months when compared with epirubicin plus cisplatin and capecitabine, and 6.2 months when compared with epirubicin plus oxaliplatin and capecitabine. The incremental analysis of all interventions resulted in an ICER of £42,969 per QALY gained for trastuzumab plus cisplatin and capecitabine compared with epirubicin plus cisplatin and capecitabine. This represented incremental costs of £16,654 and 0.388 incremental QALYs gained. All other treatment regimens were either dominated or extendedly dominated. A probabilistic sensitivity analysis produced a mean ICER of £43,970 per QALY gained.
# ERG comments on the manufacturer's additional data
The ERG commented that the manufacturer's alternative base-case analysis allowed the quality of life during progression-free survival to rise above that of the general population. It considered that this was not a plausible assumption. Therefore the ERG re-ran the analyses presented by the manufacturer using a ceiling utility value equal to general population utility value estimates. The results were presented separately for deterministic and probabilistic analyses. The incremental analysis of all interventions resulted in an ICER of £63,081 per QALY (deterministic) and £71,463 per QALY gained (probabilistic) for trastuzumab plus cisplatin and capecitabine compared with epirubicin plus oxaliplatin and capecitabine. All other regimens were either dominated or extendedly dominated.
The ICERs calculated by the ERG for the IHC3-positive subgroup were presented separately using the manufacturer's adjusted hazard ratio (stratified analysis, see section 3.39) and the unadjusted hazard ratio (unstratified analysis). The incremental analysis of all interventions using the stratified hazard ratio resulted in an ICER of £43,206 per QALY gained (deterministic) and £44,490 per QALY gained (probabilistic) for trastuzumab plus cisplatin and capecitabine compared with epirubicin plus cisplatin and capecitabine. When the unstratified hazard ratio was used, the optimal comparator treatment in the incremental analysis changed depending on whether a deterministic or probabilistic analysis was used. In the deterministic analysis, the ICER was £49,970 per QALY gained for trastuzumab plus cisplatin and capecitabine compared with epirubicin plus cisplatin and capecitabine. For the probabilistic analysis, the ICER was £51,934 per QALY gained for trastuzumab plus cisplatin and capecitabine compared with epirubicin plus oxaliplatin and capecitabine.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of trastuzumab when given in combination with cisplatin and either capecitabine or 5-fluorouracil, having considered evidence on the nature of metastatic gastric cancer and the value placed on the benefits of trastuzumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
# Clinical effectiveness
The Committee discussed current clinical practice in the UK. It noted comments from consultation that no treatment options for metastatic gastric cancer currently target HER2 overexpression, and that trastuzumab offers a new option for this patient group. The Committee heard from clinical specialists that current clinical practice in the UK is normally a triple regimen that includes an anthracycline, a platinum agent, and a fluoropyrimidine. It understood that epirubicin, cisplatin and capecitabine are the standard anthracycline, platinum agent and fluoropyrimidine therapies used. It also understood that oxaliplatin is sometimes used in place of cisplatin and that 5-fluorouracil is sometimes used in place of capecitabine. The Committee considered this in the context of the comparator regimen given in the ToGA trial, which was a double regimen including a platinum agent and a fluoropyrimidine, but not an anthracycline. The Committee discussed the fact that double regimens were not often used in UK clinical practice, and concluded that the comparator in the ToGA trial did not represent current practice in the UK.
The Committee considered whether the population in the ToGA trial could be considered representative of the population of people with HER2-positive metastatic gastric cancer in England in Wales. It noted that most of the people in the trial were from Asia. The Committee acknowledged subgroup analyses that appeared to confirm a similar overall survival benefit for the group of European people in the trial.
The Committee discussed the clinical effectiveness of the trastuzumab regimens presented in the ToGA trial. It noted that, compared with cisplatin plus either capecitabine or 5-fluorouracil, trastuzumab plus cisplatin and either capecitabine or 5-fluorouracil provided a 4.2-month gain in overall survival and a 2.1-month gain in progression-free survival. The Committee concluded that the ToGA trial demonstrated trastuzumab plus cisplatin and capecitabine or 5-fluorouracil offers clinical benefit.
The Committee discussed the likely clinical effectiveness of the current UK triple regimens, that is, when epirubicin is added to cisplatin and fluoropyrimidine. It heard from clinical specialists that adding epirubicin to cisplatin and a fluoropyrimidine provides sufficient additional benefit to be standard practice. However, clinical specialists underlined that this treatment regimen had not been subject to rigorous evaluation. The Committee discussed the evidence identified by the manufacturer and the ERG, recognising that none of the studies were completed in a HER2-positive population. The Committee acknowledged the lack of ideal evidence for this comparison. However, it considered, based on the evidence and the views of the clinical specialists, that epirubicin provided some additional benefit when added to a cisplatin and fluoropyrimidine combination.
The Committee discussed whether the results of the ToGA trial could be applied to the comparison between a trastuzumab plus chemotherapy regimen and an epirubicin plus chemotherapy regimen. It noted that the ToGA trial had used a higher dose of cisplatin than would be used as part of a triple regimen in UK clinical practice, and recognised the manufacturer's view that adding epirubicin to high-dose cisplatin would offer less benefit than adding it to lower-dose cisplatin. The Committee also noted comments from consultation that dose intensity was an important factor in chemotherapy and that reduced doses over a longer number of cycles could not be considered equivalent to higher doses over a shorter number of cycles. However, based on clinical specialist opinion, the Committee was not persuaded that the outcomes for the chemotherapy comparator group in the ToGA trial were representative of the outcomes of triple regimens in UK clinical practice. It did, however, accept that trastuzumab plus cisplatin and either capecitabine or 5-fluorouracil was likely to offer a survival benefit over treatment with epirubicin plus cisplatin and either capecitabine or 5-fluorouracil.
The Committee then discussed the range of possible estimates submitted for the clinical effectiveness of the triple regimens over the double regimens. It first considered the hazard ratio for progression-free survival of 0.96 for epirubicin plus cisplatin and capecitabine compared with cisplatin plus capecitabine from the Yun study. The Committee heard from the ERG that it had chosen to use this estimate in its revised base-case analysis because it was taken from a study that compared cisplatin plus capecitabine with epirubicin plus cisplatin and capecitabine. In the absence of any evidence specifically for the HER2-positive group, it considered that this study best represented the decision problem in the appraisal.
The Committee also considered the hazard ratio for overall survival of 0.77 (indicating a more favourable benefit of treatment with epirubicin) from the Wagner meta-analysis. It discussed concerns raised by the ERG that this study was not directly applicable to the estimates of effectiveness of the regimens including capecitabine, because two of the studies used 5-fluorouracil regimens and the third study compared two triple therapies. The Committee heard from clinical specialists that they considered that the meta-analysis may have overestimated the survival benefit of adding epirubicin to cisplatin and a fluoropyrimidine. It further noted comments from consultees that the quality of the studies in the meta-analysis was poor. The evidence from the largest study (Ross) was from an unplanned subgroup, which provided a greater estimate of the effect of epirubicin than the full population. The Committee further noted comments from consultees that the low doses of cisplatin in the studies did not reflect the higher dose used in the ToGA trial. The Committee concluded that the survival benefit of a triple regimen including epirubicin compared with that of a double regimen without epirubicin was unlikely to be represented by a hazard ratio of 0.77, and that the estimate would be closer to 0.96. However, this was associated with considerable uncertainty.
The Committee discussed the clinical effectiveness of trastuzumab for the IHC3-positive subgroup, who in clinical practice would not require a confirmatory FISH test. It noted the efficacy in the trial was greater for the subgroup than for the whole population. The Committee discussed the biological plausibility of greater benefit in the IHC3-positive subgroup and considered that greater effectiveness may be experienced with higher levels of HER2. The Committee concluded it was an appropriate subgroup and discussed the clinical evidence. It noted that the hazard ratio of overall survival for the trastuzumab plus chemotherapy group compared with the chemotherapy alone group was 0.57, corresponding to a median survival for the trastuzumab plus chemotherapy group of 18 months compared with 12.4 months for the chemotherapy alone group (a 5.6-month gain in survival). The Committee concluded that trastuzumab plus cisplatin and capecitabine or 5-fluorouracil is clinically effective in the IHC3-positive subgroup.
The Committee discussed the quality-of-life data from the ToGA trial. It noted that there were no differences in quality-of-life scores between the two treatment groups and no statistical analysis of these data. It heard from clinical specialists that treatment could bring about some improvement in quality of life, because gastric cancer has serious disease symptoms including pain, vomiting and anaemia, which chemotherapy can reduce. The clinical specialists considered that reduced symptoms outweighed the side effects of chemotherapy. The Committee was persuaded that because of the disease symptoms associated with gastric cancer it was plausible that quality of life could increase during progression-free survival.
The Committee discussed the adverse event data provided by the manufacturer. The Committee heard from clinical specialists that they considered that the adverse effects of trastuzumab are known and manageable in clinical practice because of its use in breast cancer. It further heard that epirubicin was associated with adverse effects and that providing trastuzumab as an alternative to epirubicin may have benefits. The Committee understood that trastuzumab is associated with cardiotoxicity, but noted that the incidence of cardiac failure in the trial was low and was similar in both treatment groups in the ToGA trial (two in the chemotherapy alone group and one in the trastuzumab plus chemotherapy group). It also noted commercial-in-confidence information relating to infusion-related reactions.
# Cost effectiveness
The Committee considered the base-case estimates of cost effectiveness in the manufacturer's model. It noted that after consultation on the ACD the manufacturer's alternative base-case ICER of £62,800 per QALY gained was approximately £11,000 per QALY gained higher than the original base-case ICER of £51,900 per QALY gained. It further noted that the alternative base case incorporated a number of assumptions considered equally plausible by the ERG in its report. The Committee discussed the analyses of cost effectiveness and specifically considered the following assumptions:
The most plausible estimate of comparator effectiveness.
The frequency of cardiac monitoring for people treated with epirubicin.
A parallel or sequential HER2 testing strategy.
The change in utility values during progression-free survival.
The assumption that 80% of centres would share vials of trastuzumab.
The Committee discussed the most plausible estimate of clinical effectiveness for the triple comparators. It recognised that, in the manufacturer's base-case analysis, a hazard ratio of 1.00 was used to estimate overall survival and progression-free survival of people treated with epirubicin plus cisplatin and capecitabine compared with cisplatin plus capecitabine. It noted that the ERG modified this to 0.96 in its exploratory analysis, and that this was incorporated into the manufacturer's alternative base case. It noted that when this parameter change was applied to both overall survival and progression-free survival, the ICER increased by less than £1000. The Committee also considered the estimate of the ICER using a hazard ratio of 0.77 (indicating a more favourable benefit of treatment with epirubicin) from the Wagner meta-analysis. The Committee noted that, although the effect of changing the hazard ratio to 0.96 had been relatively minor, the effect of changing the hazard ratio to 0.77 increased the ICER by up to £50,000 per QALY gained. The Committee concluded that it was appropriate to consider the ICERs that had used a hazard ratio of 0.96 (see section 4.8). However, it considered that there was considerable uncertainty in this estimate.
The Committee discussed the frequency of cardiac monitoring for people treated with epirubicin in the UK. It noted that the manufacturer's alternative base-case analysis assumed that people would have cardiac monitoring every 3 months whether they were treated with epirubicin or trastuzumab. This assumption was the same as that proposed by the ERG. The Committee heard from the clinical specialists that people on epirubicin treatment were not necessarily given cardiac monitoring this often in the UK. It heard that in current practice people were tested before starting epirubicin treatment and this was only repeated when treatment levels made it necessary or if cardiac toxicity was suspected during treatment. The Committee therefore concluded that an alternative scenario assuming equal monitoring may still slightly overestimate the cost of the comparator strategies. However, the Committee noted that the ICER was not very sensitive to this parameter. It therefore agreed to consider the ICERs that assumed equal frequency of cardiac monitoring for trastuzumab and epirubicin.
The Committee discussed sequential and parallel HER2 testing. It heard from the clinical specialists that people with gastric cancer are not routinely tested for their HER2 status. However, for people with breast cancer in the UK, testing is sequential and only people with a score of IHC2 have a confirmatory FISH test. The clinical specialists considered that there were no reasons to assume a different testing strategy for metastatic gastric cancer. The Committee therefore concluded that sequential testing would be appropriate in assessing HER2 status in people with metastatic gastric cancer.
The Committee discussed the manufacturer's assumption of a daily increase in utility during progression-free survival that was included in both the base-case and alternative base-case analyses. It was aware that this assumption was based on data only for people in the clinical trial surviving without progression without any adjustments. The Committee discussed the ERG's alternative assumption of a very slow decrease in utility calculated from those of a similar age group based on UK general population norms for EQ-5D. It recognised comments from the clinical specialists (see section 4.10) and noted that after consultation the ERG suggested that an increase in utility may be appropriate, but not above that of the general population. The Committee was persuaded that an increase in utility was plausible. However, it accepted the ERG comments that such increases should be capped so that they did not go above those of the general population of a comparable age.
The Committee noted the manufacturer's assumption that sharing vials between patients to minimise wastage would occur in 80% of centres. It considered that this might be an overestimate and that in some centres, particularly smaller centres, sharing vials may not be possible, and therefore there was likely to be large variation in vial sharing. The Committee concluded that there was not enough evidence to estimate the proportion of centres that would vial share in clinical practice, but that 80% could be an overestimate.
The Committee considered the manufacturer's alternative base-case ICER of £62,800 per QALY gained. It noted that this incorporated a hazard ratio for overall survival and progression-free survival of 0.96, but assumed that quality of life increased in progression-free survival. It further noted the results of the manufacturer's probabilistic sensitivity analysis around the alternative base case, in which the mean value of the ICER increased by approximately £5000. It concluded that the manufacturer's alternative base-case ICER was associated with considerable uncertainty and that the ICER would be greater than £62,800 per QALY gained.
The Committee discussed the results of the ERG's exploratory analyses, in which a cap on utility values during progression-free survival was applied (see section 3.40). It considered that this change to the assumptions was appropriate. The Committee agreed that the ICER for the population covered by the marketing authorisation in the manufacturer's base case probably lay between the ERG calculated deterministic ICER of £63,100 per QALY gained and the ERG calculated probabilistic ICER of £71,500 per QALY gained. The Committee concluded that the ICER for the population covered by the marketing authorisation was in excess of the range normally considered cost effective.
The Committee considered the manufacturer's estimate of the ICER based on the subgroup of people who tested IHC3 positive in ToGA. It noted that the assumptions in the alternative base case (about cardiac monitoring for epirubicin and trastuzumab, hazard ratios of comparator effectiveness and an increase in utility during progression-free survival) were applied. The Committee expressed the same concerns that the model allowed utility values during progression-free survival to increase more than those of the general population (see section 4.18). It further noted that the estimate of the ICER for the IHC3-positive subgroup was stratified for baseline imbalances in the characteristics of people in the treatment groups, and that the stratified hazard ratio was favourable to trastuzumab (see section 3.39). The Committee noted that the manufacturer's estimate of £43,000 per QALY gained for this population was based on a deterministic estimate (that is, a point estimate of the value of the ICER). The Committee concluded that the manufacturer's ICER for the IHC3-positive subgroup was probably an underestimate.
The Committee discussed the ERG's exploratory analyses for the IHC3-positive subgroup. It noted that these analyses imposed a cap on utility values during-progression free survival equal to general population utility estimates. Based on previous discussions (see section 4.16), it considered that this was a reasonable parameter change. The Committee noted that using probabilistic analysis increased the ICER by approximately £1500 per QALY gained compared with deterministic analysis. It further noted that the effect of stratification accounted for £6700 and £7400 per QALY gained for the deterministic and probabilistic analyses respectively. The Committee noted that the ERG's ICERs for the IHC3 subgroup (deterministic and probabilistic, stratified and unstratified) were between £43,200 and £52,000 per QALY gained. The comparator for three of these estimates was epirubicin plus cisplatin and capecitabine; the comparator in the highest estimate (probabilistic unstratified analysis) was epirubicin plus oxaliplatin and capecitabine. The Committee agreed that the most plausible estimate of cost effectiveness of trastuzumab plus cisplatin and capecitabine lay between £45,000 and £50,000 per QALY gained. The Committee concluded that the ICER for the population covered by the marketing authorisation was higher than would normally be considered cost effective.
The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference-case economic modelling are plausible, objective and robust.
The Committee considered the criteria that needed to be met to consider trastuzumab as a life-extending, end-of-life treatment. First, the Committee considered the life expectancy of people with HER2-positive metastatic gastric cancer. It understood that the ToGA trial reported a median 11.8 months overall survival for people receiving cisplatin plus either capecitabine or 5-fluorouracil. Therefore, the Committee was persuaded that trastuzumab plus cisplatin and either capecitabine or 5-fluorouracil met the criterion for short life expectancy.
The Committee then considered whether trastuzumab offers an extension to life of at least an additional 3 months. It noted that the median overall survival gain for the licensed population from the ToGA trial was 4.2 months for trastuzumab plus cisplatin and capecitabine or 5-fluorouracil compared with cisplatin and capecitabine or 5-fluorouracil alone. This produced a modelled mean overall survival gain of 4.8 months for people treated with trastuzumab plus cisplatin and capecitabine compared with people treated with epirubicin plus cisplatin and capecitabine. The Committee further noted that the median overall survival gain for the subgroup of people whose tumours were IHC3-positive in the ToGA trial was 5.6 months for trastuzumab plus cisplatin and capecitabine or 5-fluorouracil compared with cisplatin and capecitabine or 5-fluorouracil alone. This produced a modelled mean overall survival gain of 7.4 months for trastuzumab plus cisplatin and capecitabine compared with epirubicin plus cisplatin and capecitabine. The Committee considered that this was subject to uncertainty because of the absence of appropriate UK practice comparator data. However, on balance the Committee was persuaded that the addition of trastuzumab to chemotherapy would result in an extension to life of more than 3 months. The Committee therefore considered that trastuzumab plus cisplatin and capecitabine or 5-fluorouracil met the criterion for life extension.
The Committee considered the size of the patient population. Treatment with trastuzumab would be suitable for approximately 7000 people who have one of the diseases for which trastuzumab is licensed (that is, HER2-positive metastatic gastric cancer, HER2-positive early and locally advanced breast cancer and HER2-positive metastatic breast cancer). The Committee considered that 7000 was at the upper end of the population size for which it understood the supplementary advice to apply. However, the Committee concluded overall that applying the supplementary advice on end-of-life was appropriate.
The Committee discussed the cost effectiveness of trastuzumab plus cisplatin and capecitabine for the population covered by the marketing authorisation, taking into account the end-of-life criteria. It agreed that the most plausible estimate was between £63,100 per QALY gained (using the deterministic estimate from the ERG's alternative base-case analysis) and £71,500 per QALY gained (using the probabilistic estimate from the ERG's alternative base-case analysis). The Committee therefore considered that, even when taking the end-of-life considerations into account, the magnitude of weight required for the ICER to be in a range normally considered cost effective in the NHS was too high. The estimates exceed what can be considered a reasonable use of NHS resources. Therefore the Committee concluded that trastuzumab plus cisplatin and capecitabine or 5-fluorouracil could not be recommended as an appropriate use of NHS resources for the whole population covered by the marketing authorisation.
The Committee then discussed the cost effectiveness of trastuzumab plus cisplatin and capecitabine for the subgroup of people whose tumours are IHC3 positive, taking into account the end-of-life criteria. It agreed that the ICER was between £45,000 and £50,000 per QALY gained. The Committee considered that the magnitude of weight required for the ICER to be in a range normally considered cost effective in the NHS was acceptable. The Committee recognised that the ICER range was specifically for trastuzumab plus cisplatin and capecitabine, and not trastuzumab plus cisplatin and 5-fluorouracil. However, accepting the uncertainties around comparator effectiveness estimates for HER2-positive metastatic gastric cancer, the Committee considered it was appropriate to recommend 5-fluorouracil as an alternative to capecitabine for those people who required it. The Committee therefore concluded that trastuzumab plus cisplatin and capecitabine or 5-fluorouracil should be recommended as an option for the treatment of people with HER2-positive, metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who have not received prior treatment for their metastatic disease andwhose tumours express high levels of HER2, as defined by a positive immunohistochemistry score of 3 (IHC3 positive).
# Summary of the Appraisal Committee's key conclusions
TA208
Appraisal title: Trastuzumab for the treatment of HER2-positive metastatic gastric cancer
Section
Key conclusion
Trastuzumab, in combination with cisplatin and capecitabine or 5-fluorouracil, is recommended as an option for the treatment of people with HER2-positive, metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who:
have not received prior treatment for their metastatic disease and
have tumours expressing high levels of HER2 as defined by a positive immunohistochemistry score of 3 (IHC3 positive).
The Committee agreed that the ICER for this group was between £45,000 and £50,000 per QALY gained. It considered that it was appropriate to apply the end-of-life criteria. On this basis, the Committee was persuaded that the magnitude of weight required for the ICER to be in a range normally considered cost effective in the NHS was acceptable.
and 4.27
Current practice
Clinical need of patients including the availability of alternative treatments
Current NHS treatment for metastatic gastric cancer is a triple regimen of an anthracycline, a platinum agent and a fluoropyrimidine.
Chemotherapy is associated with overall survival of 11.8 months (based on the chemotherapy alone group in the ToGA trial) and reduces disease symptoms.
Treatment with anthracyclines such as epirubicin has side effects.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The Committee noted comments from consultation that no treatment options for metastatic gastric cancer currently target HER2 overexpression, and that trastuzumab offers a new option for this patient group.
What is the position of the treatment in the pathway of care for the condition?
The Committee did not discuss the position of the treatment in the pathway of care because the marketing authorisation for trastuzumab specifies metastatic disease that has not been previously treated.
N/A
Adverse effects
The Committee noted that the adverse effects of trastuzumab are known through its use in breast cancer treatment. It noted that trastuzumab is associated with cardiotoxicity, but that there was a similar incidence of cardiac events between the trastuzumab and comparator groups and that this was low.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee did not raise any issues about the quality of the evidence.
See 'Relevance to general clinical practice in the NHS' below.
N/A
Relevance to general clinical practice in the NHS
The Committee was persuaded that the population in the ToGA trial could be considered applicable to the UK population.
UK clinical practice is normally a triplet regimen that includes an anthracycline, a platinum agent and a fluoropyrimidine. The regimen given in the ToGA trial was a double regimen of a platinum agent and a fluoropyrimidine therapy. Double regimens are not often used in UK clinical practice. The Committee concluded that the comparator in the ToGA trial did not represent current practice in the UK.
Uncertainties generated by the evidence
The Committee heard from clinical specialists that adding epirubicin to cisplatin and a fluoropyrimidine provides sufficient additional benefit to be standard practice. However, this has not been subject to rigorous evaluation.
The Committee recognised that none of the studies for the comparators were completed in a HER2-positive population. The Committee acknowledged the lack of ideal evidence for this comparison. However, it considered, based on the evidence and the views of the clinical specialists, that epirubicin provided some additional benefit when added to a cisplatin and fluoropyrimidine combination.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The Committee considered that it is biologically plausible that people with very high levels of HER2 (IHC3 positive) may benefit from trastuzumab more than the whole population covered by the marketing authorisation.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee noted that trastuzumab plus cisplatin and capecitabine or 5-fluorouracil compared with cisplatin plus capecitabine or 5-fluorouracil gave a median gain in overall survival of 4.2 months for the full population and 5.6 months for the IHC3 subgroup. The evidence came from the ToGA trial.
and
Evidence for cost effectiveness
Availability and nature of evidence
Because the comparator in the ToGA trial was not the same as that used in clinical practice, the Committee considered whether the comparator in clinical practice offered similar benefit to that seen in the trial. It heard from clinical specialists that adding epirubicin to cisplatin and a fluoropyrimidine (as per clinical practice) provides sufficient additional benefit to be standard practice, but it has not been subject to rigorous evaluation.
The Committee concluded that it was appropriate to consider the ICERs that had used a hazard ratio of 0.96.
and
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee concluded that it was appropriate to consider the ICERs that had used a hazard ratio of 0.96. However, it considered that there was considerable uncertainty in this estimate.
Some uncertainty remained about the frequency of cardiac monitoring for epirubicin. However, the Committee noted that the ICER was not very sensitive to this parameter. It therefore agreed to consider the ICERs that assumed equal frequency of cardiac monitoring for trastuzumab and epirubicin.
The Committee concluded that there was not enough evidence to estimate the proportion of centres that would vial share in clinical practice.
Incorporation of health-related quality of life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee was persuaded that because of the disease symptoms associated with gastric cancer it was plausible that quality of life could increase during progression-free survival.
The Committee was persuaded that an increase in utility was plausible. However, it accepted the ERG comments that such increases should be capped so that they did not go above those of the general population of a comparable age.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee concluded that the most plausible estimates of cost effectiveness for the IHC3 positive subgroup were between £45,000 and £50,000 per QALY gained, and those for the full population covered by the marketing authorisation were between £63,100 and £71,500 per QALY gained.
and 4.19
What are the key drivers of cost effectiveness?
The Committee noted that, although the effect of changing the hazard ratio to 0.96 had been relatively minor, the effect of changing the hazard ratio to 0.77 increased the ICER by up to £50,000 per QALY gained.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee agreed that the ICER for the population covered by the marketing authorisation was between £63,100 and £71,500 per QALY gained (using the ERG exploratory analyses).
The Committee agreed that the ICER for the IHC3 subgroup was between £45,000 and £50,000 per QALY gained (using the ERG exploratory analyses).
Additional factors taken into account
Patient access schemes
(PPRS)
The manufacturer did not submit a patient access scheme.
N/A
End-of-life considerations
The Committee was persuaded that the criterion for short life expectancy was met.
On balance the Committee was persuaded that the addition of trastuzumab to chemotherapy would provide an extension to life of more than 3 months.
An estimated 7000 patients have one of the diseases for which trastuzumab is licensed (that is, HER2-positive metastatic gastric cancer, HER2-positive early and locally advanced breast cancer and HER2-positive metastatic breast cancer) and may be offered treatment with trastuzumab. The Committee considered that 7000 was at the upper end of the population size for which it understood the supplementary advice to apply. However, the Committee concluded overall that applying the supplementary advice on end-of-life was appropriate.
Using the estimates of the most plausible ICER, the Committee concluded that, for the total population covered by the marketing authorisation, the magnitude of weight that would need to be applied to the ICER was too high. However, the Committee concluded that, for the IHC3-positive subgroup, the magnitude of weight that would need to be applied to the ICER was in a range normally considered to be cost effective and was acceptable.
Equalities considerations, social value judgements
The Committee heard that the incidence of gastric cancer is increased in certain social classes but did not consider that the recommendations would lead to differential access to the technology according to social class.
N/A# Related NICE guidance
Capecitabine for the treatment of advanced gastric cancer.NICE technology appraisal guidance 191 (2010).# Review of guidance
The guidance on this technology will be considered for review in August 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveNovember 2010# Changes after publication
February 2014: implementation section updated to clarify that trastuzumab is recommended as an option for treating HER2-positive metastatic gastric cancer. Additional minor maintenance update also carried out.
March 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': 'Trastuzumab, in combination with cisplatin and capecitabine or 5-fluorouracil, is recommended as an option for the treatment of people with human epidermal growth factor receptor 2 (HER2)-positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who:\n\nhave not received prior treatment for their metastatic disease and\n\nhave tumours expressing high levels of HER2 as defined by a positive immunohistochemistry score of 3 (IHC3 positive).\n\nPeople who are currently receiving treatment with trastuzumab for HER2-positive metastatic gastric cancer who do not meet the criteria in 1.1 should have the option to continue treatment until they and their clinicians consider it appropriate to stop.', 'The technology ': "Trastuzumab (Herceptin, Roche Products) is a recombinant humanised IgG1 monoclonal antibody directed against HER2. Trastuzumab in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of patients with HER2-positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who have not received prior anticancer treatment for their metastatic disease. Trastuzumab is approved for use only in patients with metastatic gastric cancer whose tumours have HER2 overexpression as defined by immunohistochemistry (IHC)2 positive and a confirmatory fluorescence in situ hybridisation (FISH) positive result, or IHC3 positive, as determined by an accurate and validated assay. On 6 August 2010, the marketing authorisation for trastuzumab was revised to include silver in situ hybridisation (SISH) testing as another method for confirming HER2 overexpression. Because of the timing of the revision, SISH testing was not considered in this appraisal. For further details see the summary of product characteristics.\n\nTrastuzumab is associated with cardiotoxicity. The summary of product characteristics states that all patients should have baseline cardiac assessment before starting treatment. Cardiac function should be further monitored during treatment (for example, every 12\xa0weeks). The summary of product characteristics also states that caution should be taken in treating people with symptomatic heart failure, a history of hypertension, or documented coronary artery disease. For full details of side effects and contraindications, see the summary of product characteristics.\n\nTrastuzumab is administered at an initial loading dose of 8\xa0mg/kg body weight. The recommended maintenance dose at 3-weekly intervals is 6\xa0mg/kg body weight, beginning 3\xa0weeks after the loading dose. It is given as an intravenous infusion over 90\xa0minutes. If the initial loading dose is well tolerated, the subsequent doses can be administered as 30-minute infusions. As long as treatment is tolerated, it can be given until disease progression.\n\nThe net price of a 150-mg vial of trastuzumab is £407.40 (excluding VAT; 'British national formulary' [BNF] edition 59). For a patient weighing 62 kg, four vials are required for the first loading dose and three vials for each subsequent dose. Assuming that excess trastuzumab is wasted, the drug cost of eight infusions of trastuzumab (the median number of infusions in the regulatory trial) is £10,185. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of trastuzumab and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer's decision problem compared trastuzumab plus cisplatin and either capecitabine or 5-fluorouracil with:\n\nepirubicin plus cisplatin and either capecitabine or 5-fluorouracil and\n\nepirubicin plus oxaliplatin and capecitabine. The choice of comparators was based on the results of a survey of commonly used treatments for gastric cancer in England and Wales. Outcomes were overall survival, progression-free survival, response rate, adverse effects of treatment and health-related quality of life. In the economic evaluation, the incremental cost per quality-adjusted life year (QALY) was presented. A lifetime horizon was used, and costs were considered from the NHS perspective.\n\n# Clinical effectiveness\n\nThe manufacturer identified one phase III randomised controlled trial (ToGA) evaluating the efficacy of trastuzumab plus cisplatin and a fluoropyrimidine (that is, capecitabine or 5-fluorouracil) in people with inoperable locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. People in the trial had tumours with high levels of HER2 protein (see section\xa03.4), and had received no prior treatment for their advanced or metastatic disease.\n\nThe trial randomised 594 people to receive either chemotherapy (n\xa0=\xa0296) or trastuzumab plus chemotherapy (n\xa0=\xa0298). The chemotherapy group in the ToGA trial received intravenous cisplatin (80\xa0mg/m2) on day one of each cycle with either oral capecitabine (1000\xa0mg/m2) twice daily for 14\xa0days, or an intravenous infusion of 5-fluorouracil (800\xa0mg/m2) on days one to five of each of the six 3-weekly cycles. In addition to six 3-weekly cycles of chemotherapy, the treatment group received trastuzumab (8\xa0mg/kg loading dose on day one, followed by 6\xa0mg/kg intravenous infusion every 3\xa0weeks) until disease progression. In both groups the choice of fluoropyrimidine was at the discretion of the investigator; 87% received capecitabine and 13% received 5-fluorouracil.\n\nPeople whose tumours were classed as HER2 positive were included in the ToGA trial. IHC and FISH tests were done at the same time (parallel testing) according to the trial protocol. At the time of randomisation, tumours that were IHC3 positive, or those that tested FISH positive were defined as HER2 positive. Changes in the understanding of HER2 testing during the ToGA trial resulted in HER2 positive being defined as tumours that were IHC2 positive and FISH positive, or IHC3 positive. From the full population of 594 in the ToGA trial, 446 people (75%) had tumours that met this narrower definition. The European marketing authorisation was granted for this population (referred to as the EMA subgroup). Of this subgroup, 218 people received treatment with chemotherapy alone and 228 people received treatment with trastuzumab plus chemotherapy.\n\nAt baseline, characteristics in the ToGA trial were balanced between the treatment groups. These characteristics included sex, age, weight, region, and type of tumour (that is, intestinal, diffuse or mixed tumour types). A high proportion of people in the ToGA trial were male (76%) and 55% were from Asian countries. Almost all people had metastatic gastric cancer (97%), and accordingly the marketing authorisation was granted for the metastatic disease only.\n\nThe primary outcome in the ToGA trial was overall survival. The trial was terminated early in accordance with a revised stopping rule recommended by the Independent Data Monitoring Committee. At the time of the clinical cut-off, the median duration of survival follow-up was 18.6\xa0months in the trastuzumab plus chemotherapy group and 17.1\xa0months in the chemotherapy alone group. The hazard ratio for overall survival in the EMA subgroup was 0.65 (95% confidence interval [CI] 0.51 to 0.83) corresponding to a median survival for the trastuzumab plus chemotherapy group of 16\xa0months compared with 11.8\xa0months for the chemotherapy alone group (4.2-month improvement in survival). A median survival of 13.8\xa0months was reported for the total trial population receiving trastuzumab plus chemotherapy compared with 11.1\xa0months in the chemotherapy alone group (2.7-month improvement in survival).\n\nThe manufacturer reported the results for secondary outcomes including progression-free survival and overall response rate. For the EMA subgroup the hazard ratio for progression-free survival was 0.64 (95% CI 0.51 to 0.79), corresponding to a median progression-free survival for the trastuzumab plus chemotherapy group of 7.6\xa0months compared with 5.5\xa0months for the chemotherapy alone group (a 2.1-month improvement in progression-free survival). Results for overall response rate were reported for the total trial population only, and demonstrated a statistically significantly higher overall response rate in the trastuzumab plus chemotherapy group (47.3%) compared with the chemotherapy alone group (34.5%), odds ratio 1.70 (95% CI 1.22 to 2.38, p\xa0=\xa00.002).\n\nQuality of life was assessed in the ToGA trial as a secondary objective using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 (global health status, functioning and symptoms) and QLQ-STO22 (containing 22 items associated with dysphagia, pain, reflux, eating restrictions, anxiety, dry mouth, body image and hair loss). Both treatment groups in the trial showed improvements in quality of life over the course of treatment. A statistical analysis of differences in quality of life between the treatment groups was not presented. Additionally, EQ-5D data were collected at baseline and every 3\xa0weeks until disease progression.\n\nIn both groups, 68% of people had grade\xa03 or 4 adverse events. The most frequent were disorders of the blood and lymphatic system, gastrointestinal disorders, and metabolism and nutritional disorders. More people treated with trastuzumab plus chemotherapy had asymptomatic reductions in left ventricular ejection fraction; however, the difference in symptomatic cardiac events was not statistically significant.\n\n# Cost effectiveness\n\nThe manufacturer developed a Markov economic model to assess the cost effectiveness of trastuzumab plus chemotherapy to treat people with HER2-positive metastatic gastric cancer. The model had three distinct health states: progression-free survival, disease progression and death. The model had a cycle length of 1\xa0month and an 8-year time horizon (considered to be a lifetime horizon). Both costs and benefits were discounted at a rate of 3.5%. One-way sensitivity analyses were undertaken on utility values, survival analysis, unit costs and various resource use assumptions. Probabilistic sensitivity analysis was also undertaken to explore parameter uncertainty in the model.\n\nThe treatment regimens included in the manufacturer's economic evaluation were:\n\ntrastuzumab plus cisplatin and capecitabine\n\ntrastuzumab plus cisplatin and 5-fluorouracil\n\nepirubicin plus cisplatin and capecitabine\n\nepirubicin plus cisplatin and 5-fluorouracil\n\nepirubicin plus oxaliplatin and capecitabine.\n\nThe clinical estimates (transition probabilities) in the model were derived from the overall survival and progression-free survival estimates from the trastuzumab plus chemotherapy group in the ToGA trial (EMA subgroup).\n\nThe manufacturer's literature search for comparator data did not find trials in which triple regimens including epirubicin were directly compared with triple regimens including trastuzumab. However, four studies were identified that evaluated one of the regimens of interest:\n\nTobe (1992) and Kim (2001), which compared epirubicin plus cisplatin and 5-fluorouracil with cisplatin and 5-fluorouracil\n\nYun (2010), which compared epirubicin plus cisplatin and capecitabine with cisplatin and capecitabine\n\nREAL-2 (2008), which compared the non-inferiority of capecitabine with 5-fluorouracil in triple chemotherapy regimens including epirubicin. Additionally, a meta-analysis was identified (Wagner 2006) evaluating the efficacy of a triple regimen including an anthracycline (epirubicin) compared with a regimen that did not include an anthracycline. However, the results of this analysis were not used in the economic model because the largest trial assessed a comparison between epirubicin, cisplatin and 5-fluorouracil and cisplatin and 5-fluorouracil plus mitomycin (Ross 2002), and the other trials were presented in abstract form (Kim) or only included a small population with more severe disease (Tobe).\n\nThe manufacturer explored the possibility of conducting a network meta-analysis between the three comparator triple regimens used in UK clinical practice (that is, epirubicin plus cisplatin and capecitabine, epirubicin plus cisplatin and 5-fluorouracil, and epirubicin plus oxaliplatin and capecitabine) and the chemotherapy comparator group from the ToGA trial, to obtain the comparator effectiveness data for the model. However, the manufacturer concluded that the results of a network meta-analysis would not produce reliable or meaningful results because the only study to evaluate epirubicin plus cisplatin and capecitabine compared with cisplatin and capecitabine (Yun) did not report the primary outcome of the ToGA trial (overall survival). Additionally, the studies that compared cisplatin and 5-fluorouracil with epirubicin plus cisplatin and 5-fluorouracil (Tobe and Kim) did not have comparable patient populations. Therefore, the manufacturer presented a narrative summary of the results from the Yun, Tobe, Kim and REAL-2 trials.\n\nFor epirubicin plus cisplatin and capecitabine, the manufacturer concluded that the estimates of overall survival and progression-free survival could be assumed to be equivalent to those from the chemotherapy comparator group in the ToGA trial. This was because the Yun study showed no evidence of a significant difference (hazard ratio of progression-free survival for epirubicin plus cisplatin and capecitabine compared with cisplatin and capecitabine 0.96, 95% CI 0.58 to 1.57). The dose of cisplatin in the ToGA trial was also considered to be higher than it would be in UK clinical practice when added to a triple regimen including epirubicin, and that the two regimens could therefore be regarded as equivalent.\n\nFor epirubicin, cisplatin and 5-fluorouracil the manufacturer concluded that the estimates of progression-free survival could be assumed to be equivalent to those from the chemotherapy comparator group in the ToGA trial. The evidence to support this conclusion came from the study by Tobe (hazard ratio of overall survival for epirubicin plus cisplatin and 5-fluorouracil compared with cisplatin and 5-fluorouracil 0.57, 95% CI 0.27 to 1.2) and the study by Kim (hazard ratio of overall survival for epirubicin plus cisplatin and 5-fluorouracil compared with cisplatin and 5-fluorouracil 0.83, 95% CI 0.42 to 1.61). Additionally, the manufacturer used an overall survival benefit of capecitabine over 5-fluorouracil (hazard ratio 1.15) from a meta-analysis (Okines 2009).\n\nFor the third comparator regimen (epirubicin plus oxaliplatin and capecitabine), the manufacturer concluded that it could be considered equivalent to epirubicin plus cisplatin and capecitabine in effectiveness. This was based on the REAL-2 trial. The manufacturer stated that the results of this study indicated that oxaliplatin was as effective as cisplatin (hazard ratio of overall survival for oxaliplatin arms compared with cisplatin arms 0.92, 95% CI 0.80 to 1.10). Overall survival and progression-free survival estimates for epirubicin plus oxaliplatin and capecitabine were therefore considered equivalent to those for epirubicin plus cisplatin and capecitabine.\n\nHealth-related quality of life was estimated for progression-free survival and progressive disease health states. A utility value for the progression-free survival health state was calculated using results from the EQ-5D data collected at baseline and then every 3\xa0weeks until progression in the ToGA trial. The manufacturer estimated a baseline utility value of 0.7292, which increased daily by 0.000142 during progression-free survival. For the progressive disease health state, an estimate from the literature was used because EQ-5D data were not collected after disease progression in the ToGA trial. The utility value of 0.577 for progressive disease was taken from 'Sunitinib for the treatment of gastrointestinal stromal tumours' (NICE technology appraisal guidance 179). Utility values associated with adverse events were not included in the model.\n\nThe model included costs for HER2 testing, drug acquisition, drug administration, monitoring during progression-free survival, treating adverse events, care costs in progression-free survival after chemotherapy treatment was stopped, and supportive care costs after progression of disease. The cost of HER2 testing was based on a sequential testing strategy in which only people who tested IHC2 positive received a FISH test. Total drug costs included an amount for wastage based on an assumption that 80% of centres using trastuzumab to treat gastric cancer would also use it to treat breast cancer and would share vials, thereby implying no wastage. Cardiac monitoring was assumed to be done using a multiple-gated acquisition scan or an echocardiogram and to take place once every cycle for people treated with epirubicin and once every 3\xa0months for people treated with trastuzumab, in accordance with the summaries of product characteristics. The costs of grade 3 or 4 adverse events with an incidence of at least 5% in any of the treatment groups were included.\n\nThe model suggested that trastuzumab plus cisplatin and capecitabine compared with epirubicin plus cisplatin and capecitabine, and compared with epirubicin plus oxaliplatin and capecitabine, produced a mean gain of 4.8\xa0months of life for both comparisons. Trastuzumab plus cisplatin and 5-fluorouracil compared with epirubicin plus cisplatin and 5-fluorouracil produced a mean gain of 4.3\xa0months of life. In the manufacturer's incremental cost-effectiveness analysis of all five regimens, epirubicin plus cisplatin and 5-fluorouracil, and epirubicin plus oxaliplatin and capecitabine, were both less effective and more expensive than the other regimens (that is, they were dominated). Additionally, although the total cost of the trastuzumab plus cisplatin and 5-fluorouracil regimen was lower than that of trastuzumab plus cisplatin and capecitabine, it was also less effective and had a higher incremental cost-effectiveness ratio (ICER) than trastuzumab, cisplatin and capecitabine (that is, it was extendedly dominated). For the two remaining regimens, trastuzumab plus cisplatin and capecitabine had an additional cost of £13,064 and produced an additional 0.25 QALYs over epirubicin plus cisplatin and capecitabine. The ICER was £51,927 per QALY gained. The manufacturer examined other scenarios in a probabilistic sensitivity analysis. Distributions were applied to utility values, unit costs, monthly supportive care costs, adverse event probabilities, survival curves, parametric parameters, and progression-free survival monthly Kaplan-Maier estimates. This resulted in ICERs that ranged from £37,180 to £95,238 per QALY gained. The probability that trastuzumab plus cisplatin and capecitabine was cost effective at £30,000 was 0%.\n\nThe manufacturer also presented the results of pair-wise comparisons between trastuzumab plus cisplatin and 5-fluorouracil and epirubicin plus cisplatin and 5-fluorouracil, and between trastuzumab plus cisplatin and capecitabine and epirubicin plus oxaliplatin and capecitabine. The ICERs for these comparisons were £50,838 and £40,711 per QALY gained respectively.\n\n# Evidence review group comments\n\nThe ERG stated that the manufacturer identified the only trial evaluating trastuzumab in the treatment of HER2-positive metastatic gastric cancer (the ToGA trial). This trial was a well-conducted phase III randomised controlled trial with appropriate validity assessment. The ERG considered that the ToGA trial demonstrated improved overall survival of people treated with trastuzumab when added to cisplatin plus either capecitabine or 5-fluorouracil. The economic model was considered appropriate for the decision problem and the general approach employed by the manufacturer to estimate lifetime cost effectiveness met the requirements of the NICE reference case.\n\nThe ERG identified some small errors in the manufacturer's model related to inconsistent assumptions about adverse events, distributions of survival data and resource use. Correcting these errors reduced the ICER from £51,927 per QALY gained to £49,005 per QALY gained. This ICER represented an additional cost of £12,332 and an additional 0.251 QALYs from treatment with trastuzumab plus cisplatin and capecitabine over epirubicin plus cisplatin and capecitabine.\n\nThe ERG highlighted the following main areas of concern in the manufacturer's submission:\n\nThe relevance of the trial data to a UK population.\n\nThe comparator data considered for network meta-analysis.\n\nThe relative effectiveness estimates of comparators in the model.\n\nThe utility values applied during progression-free survival.\n\nThe frequency of cardiac monitoring with trastuzumab and epirubicin.\n\nThe use of parallel and sequential HER2 testing strategies.\n\nThe ERG stated that the efficacy of standard triple regimens in people with HER2-positive gastric cancer was unknown. It was assumed that the HER2-positive population is equivalent to a mixed-HER2 population containing an unknown proportion of HER2-positive people. The ERG noted that the trial population in the ToGA trial was substantially younger than the UK population of people with gastric cancer, of whom only 17% die before the age of 65. The population of the ToGA trial also differed substantially from the UK clinical population, in that over 50% of people in the trial were from Asian countries.\n\nThe ERG considered that the most relevant comparators in the context of current clinical practice were epirubicin plus cisplatin and capecitabine, epirubicin plus cisplatin and 5-fluorouracil, epirubicin plus oxaliplatin and capecitabine, and epirubicin plus oxaliplatin and 5-fluorouracil. However, it stated that epirubicin plus oxaliplatin and capecitabine was likely to be used more often in routine clinical practice in England and Wales than the 6% suggested in the manufacturer's submission. Following clarification by the manufacturer, the ERG concluded that all relevant trials had been identified for inclusion in a possible network meta-analysis to establish a link between the triple regimens with the chemotherapy comparator group of the ToGA trial. The ERG considered that the manufacturer's decision not to attempt a network meta-analysis using these trials was justified, mainly because of differences in the trial populations.\n\nThe ERG stated that the manufacturer's assumption of no difference in effect between the chemotherapy comparator regimen in the ToGA trial and the comparator regimens in the economic evaluation largely rested on the critique of the meta-analysis by Wagner. This study found a benefit for triple regimens including an anthracycline over regimens that did not include an anthracycline. The ERG stated that the manufacturer's decision to exclude the meta-analysis on the basis that it contained a trial that had only been published in abstract form (Kim) and a trial with a small population of people with more severe disease (Tobe) was inconsistent with the decision to include these studies individually. As a result of dismissing the meta-analysis, the small phase II Kim, Tobe and Yun trials were used as evidence of no effect between double and triple regimens, and the ERG stated that these were underpowered to detect a statistically significant benefit of treatment. The ERG therefore considered that the manufacturer's assumption of no difference in effectiveness between the chemotherapy comparator group in the ToGA trial and triple regimens including epirubicin was not justified. The ERG noted that the balance of evidence suggested that there may be an advantage in adding epirubicin to a double regimen.\n\nThe ERG explored the effect on the ICER using the hazard ratio from the Yun study (0.96), which indicated a small benefit of adding epirubicin to a double regimen. When applied to progression-free survival only, the ICER increased from the revised base case of £49,005 per QALY gained to £49,754 per QALY gained. When applied to progression-free survival and overall survival, the ICER increased from £49,005 per QALY gained to £52,709 per QALY gained.\n\nThe ERG also explored the effect of the manufacturer's assumption of no difference between triple regimens including oxaliplatin and triple regimens including cisplatin. From the REAL-2 trial, a hazard ratio for overall survival and progression-free survival (0.87) was derived that suggested a benefit of oxaliplatin regimens over cisplatin regimens. As a result, the cisplatin regimen no longer dominated the oxaliplatin regimen in the incremental analysis, which increased the ICER for trastuzumab plus cisplatin and capecitabine. When applied to overall survival alone, the ICER increased from £49,005 per QALY gained to £50,745 per QALY gained. When applied to overall survival and progression-free survival, the ICER increased from £49,005 per QALY gained to £54,114 per QALY gained.\n\nThe ERG stated that the manufacturer's base-case approach was relatively optimistic because utility values were assumed to increase by 0.000142 for each day in progression-free survival. The ERG suggested that it would be more appropriate to apply a small decrease in utility values over time to reflect the change in utility over time for an equivalent group of people from UK general population norms for EQ-5D. The ERG calculated this utility decrement to be 0.003502 per year. The ERG explored the impact of applying this assumption to the corrected manufacturer's base case and reported an increase from £49,005 per QALY gained to £51,309 per QALY gained.\n\nThe ERG highlighted the manufacturer's base-case assumption that cardiac monitoring took place once every cycle with epirubicin and once every 3\xa0months with trastuzumab. Although the summary of product characteristics for epirubicin recommends an echocardiogram before and after each treatment cycle, the ERG's clinical advisers considered that, in the UK, cardiac monitoring is not done this often. The ERG carried out an exploratory analysis assuming that cardiac monitoring was carried out at the same frequency for epirubicin as for trastuzumab. This resulted in the ICER increasing from the corrected base-case estimate of £49,005 per QALY gained to £50,816 per QALY gained.\n\nThe ERG raised a number of issues relating to HER2 testing in the manufacturer's base case. These included the potential costs of repeat tests needed because of test failures and that the effectiveness estimates in the model were derived from the ToGA trial, which used a parallel testing strategy rather than a sequential testing strategy. The ERG also noted the estimate that 17.8% of people with metastatic gastric cancer whose tumours are HER2-positive came from the full trial population; however, in the UK subgroup of people in the ToGA trial, this was 26%. To explore the impact of variations in the HER2-positive rate, the ERG undertook an exploratory analysis in which the HER2 rate was varied between 5% and 30%, indicating the lower and upper limits which it considered reasonable. The resulting ICERs from this analysis ranged from £52,866 per QALY gained for the lower assumption of 5% to £48,395 per QALY gained for the higher assumption of 30%.\n\nTo consider the combined potential impact of some of the uncertainties raised, the ERG undertook two alternative exploratory analyses in which the following key assumptions were considered to be equally plausible:\n\nThe hazard ratio of epirubicin plus oxaliplatin and capecitabine compared with epirubicin plus cisplatin and capecitabine was changed to 0.87.\n\nThe hazard ratio of epirubicin plus cisplatin and capecitabine compared with cisplatin and capecitabine was changed to 0.96 for progression-free survival and overall survival (indicating a survival benefit for epirubicin plus cisplatin and capecitabine compared with cisplatin and capecitabine alone).\n\nUtility values during progression-free survival were changed to incorporate an expected decrease in utility in line with the general population over time.\n\nThe frequency of cardiac monitoring for epirubicin was changed to be the same as trastuzumab.The ERG presented the results of these exploratory analyses separately for sequential and parallel HER2 testing strategies. In both analyses, epirubicin plus cisplatin and capecitabine was no longer the dominant comparator regimen and the relevant comparator for trastuzumab plus cisplatin and capecitabine was epirubicin plus oxaliplatin and capecitabine. When trastuzumab plus cisplatin and capecitabine was compared with epirubicin plus oxaliplatin and capecitabine, the QALY gain was 0.149 at an incremental cost of £9987, giving an ICER of £66,982 per QALY gained using a sequential testing strategy. When a parallel testing strategy was assumed, the QALY gain was the same, however, the incremental costs increased to £10,681, giving an ICER of £71,637 per QALY gained.\n\nFinally, the ERG undertook a separate exploratory analysis in which the hazard ratio was 0.77 (indicating a survival benefit) for epirubicin plus cisplatin and capecitabine, and epirubicin plus oxaliplatin and capecitabine, compared with cisplatin and capecitabine alone. This estimate of effectiveness was inferred from the Wagner meta-analysis in which a triple regimen including an anthracycline therapy had been compared with a regimen without an anthracycline. When applied to overall survival only, the QALY gain was approximately 0.13 at an incremental cost of £10,993, giving an ICER of £84,373 per QALY gained. When applied to overall survival and progression-free survival, the QALY gain was approximately 0.13 at an incremental cost of £11,226, giving an ICER of £99,797 per QALY gained.\n\n# Additional data provided by the manufacturer\n\nThe manufacturer's response to the appraisal consultation document (ACD) included an alternative base-case analysis and a new economic analysis for a subgroup of people from the ToGA trial who were IHC3 positive.\n\nThe manufacturer's alternative base case incorporated three of the four parameter changes in the ERG's exploratory analysis (see section 3.33). These were:\n\na hazard ratio of 0.87 for epirubicin plus oxaliplatin and capecitabine compared with epirubicin plus cisplatin and capecitabine\n\na hazard ratio of 0.96 for overall survival for epirubicin plus cisplatin and capecitabine compared with cisplatin plus capecitabine\n\nthe same frequency of cardiac monitoring for epirubicin as trastuzumab. The decrement in utility values during progression-free survival in the ERG's exploratory analysis was not incorporated. The manufacturer included the estimate of increasing utility values during progression-free survival used in its original base-case analysis. The ICER for trastuzumab plus cisplatin and capecitabine in comparison with epirubicin plus oxaliplatin and capecitabine was £62,829 per QALY gained. The other treatments in the analysis were either dominated or extendedly dominated. A probabilistic sensitivity analysis for the same comparison produced an ICER with a mean value of £67,786 per QALY gained.\n\nA new economic analysis based on a subgroup of people who tested IHC3 positive (that is, people with very high levels of HER2) was provided by the manufacturer. The analysis included 279 people, of whom 144 received treatment with trastuzumab plus cisplatin and either capecitabine or 5-fluorouracil, and 135 received treatment with cisplatin plus either capecitabine or 5-fluorouracil.\n\nThe clinical evidence submitted for the IHC3-positive subgroup included an analysis of overall survival. Analyses of progression-free survival and time to progression were provided as commercial-in-confidence. The hazard ratio of overall survival for the trastuzumab plus chemotherapy group compared with the chemotherapy alone group was 0.57 (95% CI 0.41 to 0.79), corresponding to a median survival for the trastuzumab plus chemotherapy group of 18\xa0months compared with 12.4\xa0months for the chemotherapy alone group (5.6-month improvement in survival). The manufacturer also provided an adjusted hazard ratio to account for an imbalance in baseline characteristics between the treatment groups in the IHC3-positive subgroup. The adjusted hazard ratio of overall survival for the trastuzumab plus chemotherapy group compared with the chemotherapy alone group was 0.51 (95% CI 0.36 to 0.72).\n\nThe manufacturer presented the results of an economic analysis for the IHC3-positive subgroup using the adjusted hazard ratio. The modelled mean overall survival for trastuzumab plus cisplatin and capecitabine was 7.4 months when compared with epirubicin plus cisplatin and capecitabine, and 6.2 months when compared with epirubicin plus oxaliplatin and capecitabine. The incremental analysis of all interventions resulted in an ICER of £42,969 per QALY gained for trastuzumab plus cisplatin and capecitabine compared with epirubicin plus cisplatin and capecitabine. This represented incremental costs of £16,654 and 0.388 incremental QALYs gained. All other treatment regimens were either dominated or extendedly dominated. A probabilistic sensitivity analysis produced a mean ICER of £43,970 per QALY gained.\n\n# ERG comments on the manufacturer's additional data\n\nThe ERG commented that the manufacturer's alternative base-case analysis allowed the quality of life during progression-free survival to rise above that of the general population. It considered that this was not a plausible assumption. Therefore the ERG re-ran the analyses presented by the manufacturer using a ceiling utility value equal to general population utility value estimates. The results were presented separately for deterministic and probabilistic analyses. The incremental analysis of all interventions resulted in an ICER of £63,081 per QALY (deterministic) and £71,463 per QALY gained (probabilistic) for trastuzumab plus cisplatin and capecitabine compared with epirubicin plus oxaliplatin and capecitabine. All other regimens were either dominated or extendedly dominated.\n\nThe ICERs calculated by the ERG for the IHC3-positive subgroup were presented separately using the manufacturer's adjusted hazard ratio (stratified analysis, see section 3.39) and the unadjusted hazard ratio (unstratified analysis). The incremental analysis of all interventions using the stratified hazard ratio resulted in an ICER of £43,206 per QALY gained (deterministic) and £44,490 per QALY gained (probabilistic) for trastuzumab plus cisplatin and capecitabine compared with epirubicin plus cisplatin and capecitabine. When the unstratified hazard ratio was used, the optimal comparator treatment in the incremental analysis changed depending on whether a deterministic or probabilistic analysis was used. In the deterministic analysis, the ICER was £49,970 per QALY gained for trastuzumab plus cisplatin and capecitabine compared with epirubicin plus cisplatin and capecitabine. For the probabilistic analysis, the ICER was £51,934 per QALY gained for trastuzumab plus cisplatin and capecitabine compared with epirubicin plus oxaliplatin and capecitabine.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of trastuzumab when given in combination with cisplatin and either capecitabine or 5-fluorouracil, having considered evidence on the nature of metastatic gastric cancer and the value placed on the benefits of trastuzumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee discussed current clinical practice in the UK. It noted comments from consultation that no treatment options for metastatic gastric cancer currently target HER2 overexpression, and that trastuzumab offers a new option for this patient group. The Committee heard from clinical specialists that current clinical practice in the UK is normally a triple regimen that includes an anthracycline, a platinum agent, and a fluoropyrimidine. It understood that epirubicin, cisplatin and capecitabine are the standard anthracycline, platinum agent and fluoropyrimidine therapies used. It also understood that oxaliplatin is sometimes used in place of cisplatin and that 5-fluorouracil is sometimes used in place of capecitabine. The Committee considered this in the context of the comparator regimen given in the ToGA trial, which was a double regimen including a platinum agent and a fluoropyrimidine, but not an anthracycline. The Committee discussed the fact that double regimens were not often used in UK clinical practice, and concluded that the comparator in the ToGA trial did not represent current practice in the UK.\n\nThe Committee considered whether the population in the ToGA trial could be considered representative of the population of people with HER2-positive metastatic gastric cancer in England in Wales. It noted that most of the people in the trial were from Asia. The Committee acknowledged subgroup analyses that appeared to confirm a similar overall survival benefit for the group of European people in the trial.\n\nThe Committee discussed the clinical effectiveness of the trastuzumab regimens presented in the ToGA trial. It noted that, compared with cisplatin plus either capecitabine or 5-fluorouracil, trastuzumab plus cisplatin and either capecitabine or 5-fluorouracil provided a 4.2-month gain in overall survival and a 2.1-month gain in progression-free survival. The Committee concluded that the ToGA trial demonstrated trastuzumab plus cisplatin and capecitabine or 5-fluorouracil offers clinical benefit.\n\nThe Committee discussed the likely clinical effectiveness of the current UK triple regimens, that is, when epirubicin is added to cisplatin and fluoropyrimidine. It heard from clinical specialists that adding epirubicin to cisplatin and a fluoropyrimidine provides sufficient additional benefit to be standard practice. However, clinical specialists underlined that this treatment regimen had not been subject to rigorous evaluation. The Committee discussed the evidence identified by the manufacturer and the ERG, recognising that none of the studies were completed in a HER2-positive population. The Committee acknowledged the lack of ideal evidence for this comparison. However, it considered, based on the evidence and the views of the clinical specialists, that epirubicin provided some additional benefit when added to a cisplatin and fluoropyrimidine combination.\n\nThe Committee discussed whether the results of the ToGA trial could be applied to the comparison between a trastuzumab plus chemotherapy regimen and an epirubicin plus chemotherapy regimen. It noted that the ToGA trial had used a higher dose of cisplatin than would be used as part of a triple regimen in UK clinical practice, and recognised the manufacturer's view that adding epirubicin to high-dose cisplatin would offer less benefit than adding it to lower-dose cisplatin. The Committee also noted comments from consultation that dose intensity was an important factor in chemotherapy and that reduced doses over a longer number of cycles could not be considered equivalent to higher doses over a shorter number of cycles. However, based on clinical specialist opinion, the Committee was not persuaded that the outcomes for the chemotherapy comparator group in the ToGA trial were representative of the outcomes of triple regimens in UK clinical practice. It did, however, accept that trastuzumab plus cisplatin and either capecitabine or 5-fluorouracil was likely to offer a survival benefit over treatment with epirubicin plus cisplatin and either capecitabine or 5-fluorouracil.\n\nThe Committee then discussed the range of possible estimates submitted for the clinical effectiveness of the triple regimens over the double regimens. It first considered the hazard ratio for progression-free survival of 0.96 for epirubicin plus cisplatin and capecitabine compared with cisplatin plus capecitabine from the Yun study. The Committee heard from the ERG that it had chosen to use this estimate in its revised base-case analysis because it was taken from a study that compared cisplatin plus capecitabine with epirubicin plus cisplatin and capecitabine. In the absence of any evidence specifically for the HER2-positive group, it considered that this study best represented the decision problem in the appraisal.\n\nThe Committee also considered the hazard ratio for overall survival of 0.77 (indicating a more favourable benefit of treatment with epirubicin) from the Wagner meta-analysis. It discussed concerns raised by the ERG that this study was not directly applicable to the estimates of effectiveness of the regimens including capecitabine, because two of the studies used 5-fluorouracil regimens and the third study compared two triple therapies. The Committee heard from clinical specialists that they considered that the meta-analysis may have overestimated the survival benefit of adding epirubicin to cisplatin and a fluoropyrimidine. It further noted comments from consultees that the quality of the studies in the meta-analysis was poor. The evidence from the largest study (Ross) was from an unplanned subgroup, which provided a greater estimate of the effect of epirubicin than the full population. The Committee further noted comments from consultees that the low doses of cisplatin in the studies did not reflect the higher dose used in the ToGA trial. The Committee concluded that the survival benefit of a triple regimen including epirubicin compared with that of a double regimen without epirubicin was unlikely to be represented by a hazard ratio of 0.77, and that the estimate would be closer to 0.96. However, this was associated with considerable uncertainty.\n\nThe Committee discussed the clinical effectiveness of trastuzumab for the IHC3-positive subgroup, who in clinical practice would not require a confirmatory FISH test. It noted the efficacy in the trial was greater for the subgroup than for the whole population. The Committee discussed the biological plausibility of greater benefit in the IHC3-positive subgroup and considered that greater effectiveness may be experienced with higher levels of HER2. The Committee concluded it was an appropriate subgroup and discussed the clinical evidence. It noted that the hazard ratio of overall survival for the trastuzumab plus chemotherapy group compared with the chemotherapy alone group was 0.57, corresponding to a median survival for the trastuzumab plus chemotherapy group of 18\xa0months compared with 12.4\xa0months for the chemotherapy alone group (a 5.6-month gain in survival). The Committee concluded that trastuzumab plus cisplatin and capecitabine or 5-fluorouracil is clinically effective in the IHC3-positive subgroup.\n\nThe Committee discussed the quality-of-life data from the ToGA trial. It noted that there were no differences in quality-of-life scores between the two treatment groups and no statistical analysis of these data. It heard from clinical specialists that treatment could bring about some improvement in quality of life, because gastric cancer has serious disease symptoms including pain, vomiting and anaemia, which chemotherapy can reduce. The clinical specialists considered that reduced symptoms outweighed the side effects of chemotherapy. The Committee was persuaded that because of the disease symptoms associated with gastric cancer it was plausible that quality of life could increase during progression-free survival.\n\nThe Committee discussed the adverse event data provided by the manufacturer. The Committee heard from clinical specialists that they considered that the adverse effects of trastuzumab are known and manageable in clinical practice because of its use in breast cancer. It further heard that epirubicin was associated with adverse effects and that providing trastuzumab as an alternative to epirubicin may have benefits. The Committee understood that trastuzumab is associated with cardiotoxicity, but noted that the incidence of cardiac failure in the trial was low and was similar in both treatment groups in the ToGA trial (two in the chemotherapy alone group and one in the trastuzumab plus chemotherapy group). It also noted commercial-in-confidence information relating to infusion-related reactions.\n\n# Cost effectiveness\n\nThe Committee considered the base-case estimates of cost effectiveness in the manufacturer's model. It noted that after consultation on the ACD the manufacturer's alternative base-case ICER of £62,800 per QALY gained was approximately £11,000 per QALY gained higher than the original base-case ICER of £51,900 per QALY gained. It further noted that the alternative base case incorporated a number of assumptions considered equally plausible by the ERG in its report. The Committee discussed the analyses of cost effectiveness and specifically considered the following assumptions:\n\nThe most plausible estimate of comparator effectiveness.\n\nThe frequency of cardiac monitoring for people treated with epirubicin.\n\nA parallel or sequential HER2 testing strategy.\n\nThe change in utility values during progression-free survival.\n\nThe assumption that 80% of centres would share vials of trastuzumab.\n\nThe Committee discussed the most plausible estimate of clinical effectiveness for the triple comparators. It recognised that, in the manufacturer's base-case analysis, a hazard ratio of 1.00 was used to estimate overall survival and progression-free survival of people treated with epirubicin plus cisplatin and capecitabine compared with cisplatin plus capecitabine. It noted that the ERG modified this to 0.96 in its exploratory analysis, and that this was incorporated into the manufacturer's alternative base case. It noted that when this parameter change was applied to both overall survival and progression-free survival, the ICER increased by less than £1000. The Committee also considered the estimate of the ICER using a hazard ratio of 0.77 (indicating a more favourable benefit of treatment with epirubicin) from the Wagner meta-analysis. The Committee noted that, although the effect of changing the hazard ratio to 0.96 had been relatively minor, the effect of changing the hazard ratio to 0.77 increased the ICER by up to £50,000 per QALY gained. The Committee concluded that it was appropriate to consider the ICERs that had used a hazard ratio of 0.96 (see section 4.8). However, it considered that there was considerable uncertainty in this estimate.\n\nThe Committee discussed the frequency of cardiac monitoring for people treated with epirubicin in the UK. It noted that the manufacturer's alternative base-case analysis assumed that people would have cardiac monitoring every 3\xa0months whether they were treated with epirubicin or trastuzumab. This assumption was the same as that proposed by the ERG. The Committee heard from the clinical specialists that people on epirubicin treatment were not necessarily given cardiac monitoring this often in the UK. It heard that in current practice people were tested before starting epirubicin treatment and this was only repeated when treatment levels made it necessary or if cardiac toxicity was suspected during treatment. The Committee therefore concluded that an alternative scenario assuming equal monitoring may still slightly overestimate the cost of the comparator strategies. However, the Committee noted that the ICER was not very sensitive to this parameter. It therefore agreed to consider the ICERs that assumed equal frequency of cardiac monitoring for trastuzumab and epirubicin.\n\nThe Committee discussed sequential and parallel HER2 testing. It heard from the clinical specialists that people with gastric cancer are not routinely tested for their HER2 status. However, for people with breast cancer in the UK, testing is sequential and only people with a score of IHC2 have a confirmatory FISH test. The clinical specialists considered that there were no reasons to assume a different testing strategy for metastatic gastric cancer. The Committee therefore concluded that sequential testing would be appropriate in assessing HER2 status in people with metastatic gastric cancer.\n\nThe Committee discussed the manufacturer's assumption of a daily increase in utility during progression-free survival that was included in both the base-case and alternative base-case analyses. It was aware that this assumption was based on data only for people in the clinical trial surviving without progression without any adjustments. The Committee discussed the ERG's alternative assumption of a very slow decrease in utility calculated from those of a similar age group based on UK general population norms for EQ-5D. It recognised comments from the clinical specialists (see section 4.10) and noted that after consultation the ERG suggested that an increase in utility may be appropriate, but not above that of the general population. The Committee was persuaded that an increase in utility was plausible. However, it accepted the ERG comments that such increases should be capped so that they did not go above those of the general population of a comparable age.\n\nThe Committee noted the manufacturer's assumption that sharing vials between patients to minimise wastage would occur in 80% of centres. It considered that this might be an overestimate and that in some centres, particularly smaller centres, sharing vials may not be possible, and therefore there was likely to be large variation in vial sharing. The Committee concluded that there was not enough evidence to estimate the proportion of centres that would vial share in clinical practice, but that 80% could be an overestimate.\n\nThe Committee considered the manufacturer's alternative base-case ICER of £62,800 per QALY gained. It noted that this incorporated a hazard ratio for overall survival and progression-free survival of 0.96, but assumed that quality of life increased in progression-free survival. It further noted the results of the manufacturer's probabilistic sensitivity analysis around the alternative base case, in which the mean value of the ICER increased by approximately £5000. It concluded that the manufacturer's alternative base-case ICER was associated with considerable uncertainty and that the ICER would be greater than £62,800 per QALY gained.\n\nThe Committee discussed the results of the ERG's exploratory analyses, in which a cap on utility values during progression-free survival was applied (see section 3.40). It considered that this change to the assumptions was appropriate. The Committee agreed that the ICER for the population covered by the marketing authorisation in the manufacturer's base case probably lay between the ERG calculated deterministic ICER of £63,100 per QALY gained and the ERG calculated probabilistic ICER of £71,500 per QALY gained. The Committee concluded that the ICER for the population covered by the marketing authorisation was in excess of the range normally considered cost effective.\n\nThe Committee considered the manufacturer's estimate of the ICER based on the subgroup of people who tested IHC3 positive in ToGA. It noted that the assumptions in the alternative base case (about cardiac monitoring for epirubicin and trastuzumab, hazard ratios of comparator effectiveness and an increase in utility during progression-free survival) were applied. The Committee expressed the same concerns that the model allowed utility values during progression-free survival to increase more than those of the general population (see section 4.18). It further noted that the estimate of the ICER for the IHC3-positive subgroup was stratified for baseline imbalances in the characteristics of people in the treatment groups, and that the stratified hazard ratio was favourable to trastuzumab (see section 3.39). The Committee noted that the manufacturer's estimate of £43,000 per QALY gained for this population was based on a deterministic estimate (that is, a point estimate of the value of the ICER). The Committee concluded that the manufacturer's ICER for the IHC3-positive subgroup was probably an underestimate.\n\nThe Committee discussed the ERG's exploratory analyses for the IHC3-positive subgroup. It noted that these analyses imposed a cap on utility values during-progression free survival equal to general population utility estimates. Based on previous discussions (see section 4.16), it considered that this was a reasonable parameter change. The Committee noted that using probabilistic analysis increased the ICER by approximately £1500 per QALY gained compared with deterministic analysis. It further noted that the effect of stratification accounted for £6700 and £7400 per QALY gained for the deterministic and probabilistic analyses respectively. The Committee noted that the ERG's ICERs for the IHC3 subgroup (deterministic and probabilistic, stratified and unstratified) were between £43,200 and £52,000 per QALY gained. The comparator for three of these estimates was epirubicin plus cisplatin and capecitabine; the comparator in the highest estimate (probabilistic unstratified analysis) was epirubicin plus oxaliplatin and capecitabine. The Committee agreed that the most plausible estimate of cost effectiveness of trastuzumab plus cisplatin and capecitabine lay between £45,000 and £50,000 per QALY gained. The Committee concluded that the ICER for the population covered by the marketing authorisation was higher than would normally be considered cost effective.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference-case economic modelling are plausible, objective and robust.\n\nThe Committee considered the criteria that needed to be met to consider trastuzumab as a life-extending, end-of-life treatment. First, the Committee considered the life expectancy of people with HER2-positive metastatic gastric cancer. It understood that the ToGA trial reported a median 11.8\xa0months overall survival for people receiving cisplatin plus either capecitabine or 5-fluorouracil. Therefore, the Committee was persuaded that trastuzumab plus cisplatin and either capecitabine or 5-fluorouracil met the criterion for short life expectancy.\n\nThe Committee then considered whether trastuzumab offers an extension to life of at least an additional 3 months. It noted that the median overall survival gain for the licensed population from the ToGA trial was 4.2\xa0months for trastuzumab plus cisplatin and capecitabine or 5-fluorouracil compared with cisplatin and capecitabine or 5-fluorouracil alone. This produced a modelled mean overall survival gain of 4.8\xa0months for people treated with trastuzumab plus cisplatin and capecitabine compared with people treated with epirubicin plus cisplatin and capecitabine. The Committee further noted that the median overall survival gain for the subgroup of people whose tumours were IHC3-positive in the ToGA trial was 5.6 months for trastuzumab plus cisplatin and capecitabine or 5-fluorouracil compared with cisplatin and capecitabine or 5-fluorouracil alone. This produced a modelled mean overall survival gain of 7.4\xa0months for trastuzumab plus cisplatin and capecitabine compared with epirubicin plus cisplatin and capecitabine. The Committee considered that this was subject to uncertainty because of the absence of appropriate UK practice comparator data. However, on balance the Committee was persuaded that the addition of trastuzumab to chemotherapy would result in an extension to life of more than 3\xa0months. The Committee therefore considered that trastuzumab plus cisplatin and capecitabine or 5-fluorouracil met the criterion for life extension.\n\nThe Committee considered the size of the patient population. Treatment with trastuzumab would be suitable for approximately 7000 people who have one of the diseases for which trastuzumab is licensed (that is, HER2-positive metastatic gastric cancer, HER2-positive early and locally advanced breast cancer and HER2-positive metastatic breast cancer). The Committee considered that 7000 was at the upper end of the population size for which it understood the supplementary advice to apply. However, the Committee concluded overall that applying the supplementary advice on end-of-life was appropriate.\n\nThe Committee discussed the cost effectiveness of trastuzumab plus cisplatin and capecitabine for the population covered by the marketing authorisation, taking into account the end-of-life criteria. It agreed that the most plausible estimate was between £63,100 per QALY gained (using the deterministic estimate from the ERG's alternative base-case analysis) and £71,500 per QALY gained (using the probabilistic estimate from the ERG's alternative base-case analysis). The Committee therefore considered that, even when taking the end-of-life considerations into account, the magnitude of weight required for the ICER to be in a range normally considered cost effective in the NHS was too high. The estimates exceed what can be considered a reasonable use of NHS resources. Therefore the Committee concluded that trastuzumab plus cisplatin and capecitabine or 5-fluorouracil could not be recommended as an appropriate use of NHS resources for the whole population covered by the marketing authorisation.\n\nThe Committee then discussed the cost effectiveness of trastuzumab plus cisplatin and capecitabine for the subgroup of people whose tumours are IHC3 positive, taking into account the end-of-life criteria. It agreed that the ICER was between £45,000 and £50,000 per QALY gained. The Committee considered that the magnitude of weight required for the ICER to be in a range normally considered cost effective in the NHS was acceptable. The Committee recognised that the ICER range was specifically for trastuzumab plus cisplatin and capecitabine, and not trastuzumab plus cisplatin and 5-fluorouracil. However, accepting the uncertainties around comparator effectiveness estimates for HER2-positive metastatic gastric cancer, the Committee considered it was appropriate to recommend 5-fluorouracil as an alternative to capecitabine for those people who required it. The Committee therefore concluded that trastuzumab plus cisplatin and capecitabine or 5-fluorouracil should be recommended as an option for the treatment of people with HER2-positive, metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who have not received prior treatment for their metastatic disease andwhose tumours express high levels of HER2, as defined by a positive immunohistochemistry score of 3 (IHC3 positive).\n\n# Summary of the Appraisal Committee's key conclusions\n\nTA208\n\n\n\nAppraisal title: Trastuzumab for the treatment of HER2-positive metastatic gastric cancer\n\nSection\n\nKey conclusion\n\nTrastuzumab, in combination with cisplatin and capecitabine or 5-fluorouracil, is recommended as an option for the treatment of people with HER2-positive, metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who:\n\nhave not received prior treatment for their metastatic disease and\n\nhave tumours expressing high levels of HER2 as defined by a positive immunohistochemistry score of 3 (IHC3 positive).\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee agreed that the ICER for this group was between £45,000 and £50,000 per QALY gained. It considered that it was appropriate to apply the end-of-life criteria. On this basis, the Committee was persuaded that the magnitude of weight required for the ICER to be in a range normally considered cost effective in the NHS was acceptable.\n\nand 4.27\n\n\n\nCurrent practice\n\nClinical need of patients including the availability of alternative treatments\n\n\n\nCurrent NHS treatment for metastatic gastric cancer is a triple regimen of an anthracycline, a platinum agent and a fluoropyrimidine.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nChemotherapy is associated with overall survival of 11.8\xa0months (based on the chemotherapy alone group in the ToGA trial) and reduces disease symptoms.\n\n\n\n\n\n\n\nTreatment with anthracyclines such as epirubicin has side effects.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\n\n\nThe Committee noted comments from consultation that no treatment options for metastatic gastric cancer currently target HER2 overexpression, and that trastuzumab offers a new option for this patient group.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\n\n\nThe Committee did not discuss the position of the treatment in the pathway of care because the marketing authorisation for trastuzumab specifies metastatic disease that has not been previously treated.\n\nN/A\n\nAdverse effects\n\n\n\nThe Committee noted that the adverse effects of trastuzumab are known through its use in breast cancer treatment. It noted that trastuzumab is associated with cardiotoxicity, but that there was a similar incidence of cardiac events between the trastuzumab and comparator groups and that this was low.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\n\n\nThe Committee did not raise any issues about the quality of the evidence.\n\n\n\nSee 'Relevance to general clinical practice in the NHS' below.\n\nN/A\n\nRelevance to general clinical practice in the NHS\n\n\n\nThe Committee was persuaded that the population in the ToGA trial could be considered applicable to the UK population.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nUK clinical practice is normally a triplet regimen that includes an anthracycline, a platinum agent and a fluoropyrimidine. The regimen given in the ToGA trial was a double regimen of a platinum agent and a fluoropyrimidine therapy. Double regimens are not often used in UK clinical practice. The Committee concluded that the comparator in the ToGA trial did not represent current practice in the UK.\n\n\n\nUncertainties generated by the evidence\n\n\n\nThe Committee heard from clinical specialists that adding epirubicin to cisplatin and a fluoropyrimidine provides sufficient additional benefit to be standard practice. However, this has not been subject to rigorous evaluation.\n\nThe Committee recognised that none of the studies for the comparators were completed in a HER2-positive population. The Committee acknowledged the lack of ideal evidence for this comparison. However, it considered, based on the evidence and the views of the clinical specialists, that epirubicin provided some additional benefit when added to a cisplatin and fluoropyrimidine combination.\n\n\n\n\n\n\n\n\n\n\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\n\n\nThe Committee considered that it is biologically plausible that people with very high levels of HER2 (IHC3 positive) may benefit from trastuzumab more than the whole population covered by the marketing authorisation.\n\n\n\n\n\n\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\n\n\nThe Committee noted that trastuzumab plus cisplatin and capecitabine or 5-fluorouracil compared with cisplatin plus capecitabine or 5-fluorouracil gave a median gain in overall survival of 4.2 months for the full population and 5.6 months for the IHC3 subgroup. The evidence came from the ToGA trial.\n\n\n\nand\n\n\n\n\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nBecause the comparator in the ToGA trial was not the same as that used in clinical practice, the Committee considered whether the comparator in clinical practice offered similar benefit to that seen in the trial. It heard from clinical specialists that adding epirubicin to cisplatin and a fluoropyrimidine (as per clinical practice) provides sufficient additional benefit to be standard practice, but it has not been subject to rigorous evaluation.\n\nThe Committee concluded that it was appropriate to consider the ICERs that had used a hazard ratio of 0.96.\n\n\n\nand\n\n\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee concluded that it was appropriate to consider the ICERs that had used a hazard ratio of 0.96. However, it considered that there was considerable uncertainty in this estimate.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nSome uncertainty remained about the frequency of cardiac monitoring for epirubicin. However, the Committee noted that the ICER was not very sensitive to this parameter. It therefore agreed to consider the ICERs that assumed equal frequency of cardiac monitoring for trastuzumab and epirubicin.\n\n\n\n\n\n\n\nThe Committee concluded that there was not enough evidence to estimate the proportion of centres that would vial share in clinical practice.\n\n\n\nIncorporation of health-related quality of life benefits and utility values\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\n\n\nThe Committee was persuaded that because of the disease symptoms associated with gastric cancer it was plausible that quality of life could increase during progression-free survival.\n\nThe Committee was persuaded that an increase in utility was plausible. However, it accepted the ERG comments that such increases should be capped so that they did not go above those of the general population of a comparable age.\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee concluded that the most plausible estimates of cost effectiveness for the IHC3 positive subgroup were between £45,000 and £50,000 per QALY gained, and those for the full population covered by the marketing authorisation were between £63,100 and £71,500 per QALY gained.\n\nand 4.19\n\nWhat are the key drivers of cost effectiveness?\n\n\n\nThe Committee noted that, although the effect of changing the hazard ratio to 0.96 had been relatively minor, the effect of changing the hazard ratio to 0.77 increased the ICER by up to £50,000 per QALY gained.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nThe Committee agreed that the ICER for the population covered by the marketing authorisation was between £63,100 and £71,500 per QALY gained (using the ERG exploratory analyses).\n\n\n\n\n\n\n\n\n\n\n\nThe Committee agreed that the ICER for the IHC3 subgroup was between £45,000 and £50,000 per QALY gained (using the ERG exploratory analyses).\n\n\n\nAdditional factors taken into account\n\nPatient access schemes\n\n(PPRS)\n\nThe manufacturer did not submit a patient access scheme.\n\nN/A\n\nEnd-of-life considerations\n\n\n\nThe Committee was persuaded that the criterion for short life expectancy was met.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nOn balance the Committee was persuaded that the addition of trastuzumab to chemotherapy would provide an extension to life of more than 3\xa0months.\n\n\n\n\n\n\n\nAn estimated 7000 patients have one of the diseases for which trastuzumab is licensed (that is, HER2-positive metastatic gastric cancer, HER2-positive early and locally advanced breast cancer and HER2-positive metastatic breast cancer) and may be offered treatment with trastuzumab. The Committee considered that 7000 was at the upper end of the population size for which it understood the supplementary advice to apply. However, the Committee concluded overall that applying the supplementary advice on end-of-life was appropriate.\n\n\n\n\n\n\n\nUsing the estimates of the most plausible ICER, the Committee concluded that, for the total population covered by the marketing authorisation, the magnitude of weight that would need to be applied to the ICER was too high. However, the Committee concluded that, for the IHC3-positive subgroup, the magnitude of weight that would need to be applied to the ICER was in a range normally considered to be cost effective and was acceptable.\n\n4.27\n\nEqualities considerations, social value judgements\n\n\n\nThe Committee heard that the incidence of gastric cancer is increased in certain social classes but did not consider that the recommendations would lead to differential access to the technology according to social class.\n\nN/A", 'Related NICE guidance': 'Capecitabine for the treatment of advanced gastric cancer.NICE technology appraisal guidance 191 (2010).', 'Review of guidance': 'The guidance on this technology will be considered for review in August 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveNovember 2010', 'Changes after publication': 'February 2014: implementation section updated to clarify that trastuzumab is recommended as an option for treating HER2-positive metastatic gastric cancer. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}
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https://www.nice.org.uk/guidance/ta208
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Evidence-based recommendations on trastuzumab (Herceptin) for treating HER2-positive metastatic gastric cancer in adults.
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99f910d18d5ad1f22379dd0071606450d30b240f
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Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours
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Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours
Evidence-based recommendations on imatinib for treating unresectable or metastatic gastrointestinal stromal tumours in adults.
# Guidance
This guidance should be read in conjunction with NICE technology appraisal guidance 86 (TA86) 'Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours'.
This guidance updates recommendation 1.5 of TA86. All other recommendations in TA86 still stand.
Imatinib at 600 or 800 mg/day is not recommended for people with unresectable and/or metastatic gastrointestinal stromal tumours whose disease has progressed after treatment with 400 mg/day imatinib.
People who are currently receiving 600 or 800 mg/day imatinib for unresectable and/or metastatic gastrointestinal stromal tumours should have the option to continue therapy until they and their clinicians consider it appropriate to stop.# Clinical need and practice
Gastrointestinal stromal tumours (GISTs) are rare tumours of the gastrointestinal tract. Although GISTs can occur along the length of the gastrointestinal tract from the oesophagus to the anus, the majority (60–70%) arise in the stomach. Most GISTs are associated with overexpression of the tyrosine kinase receptor KIT (CD117), which is thought to promote tumour growth or to inhibit tumour cell death through a signal transduction pathway involving stem cell factor.
Approximately one third of people with GISTs are asymptomatic during the early stages of the disease. Signs and symptoms can include abdominal discomfort or pain, a feeling of abdominal fullness and the presence of a palpable mass. People have more severe symptoms when tumours metastasise or when they become large, rupture and bleed or obstruct the gastrointestinal tract. In metastatic disease, systemic symptoms such as fever, night sweats and weight loss are common.
Approximately 900 people are newly diagnosed with GISTs in the UK each year. Although GISTs can occur at any age, the usual age of presentation is between 50 and 70 years. Diagnosis of GIST is confirmed by clinical presentation and tissue biopsy to determine the histological characteristics of the tumour, including expression of the KIT (CD117) protein. Approximately 4% of GISTs have characteristic clinical and morphological features, but do not express the KIT (CD117) protein.
The size, growth rate and location of the tumour often influence prognosis. Without treatment GISTs progress and will eventually metastasise. Prognosis depends on whether the tumour can be resected, which is the primary treatment for GISTs. Only 50% of GISTs are resectable at presentation. Conventional cytotoxic chemotherapy and radiotherapy are ineffective in treating advanced or metastatic GISTs. Similarly, surgery to treat advanced or metastatic GISTs is not recommended unless there is an immediate clinical need, such as to remove an obstructing tumour.# The technology
Imatinib (Glivec, Novartis Pharmaceuticals UK) is a signal-transduction inhibitor that selectively inhibits tyrosine kinases, including the KIT (CD117) receptor that is expressed in GISTs. Imatinib binds to activated KIT (CD117) receptors and blocks the cell-signalling pathway to inhibit uncontrolled cell proliferation. Imatinib has a UK marketing authorisation for the treatment of adults with KIT (CD117)-positive unresectable and/or metastatic malignant GISTs.
The most commonly reported adverse events in trials of imatinib were oedema, fatigue, myalgia, muscle cramps, rash, abdominal pain, vomiting, diarrhoea and nausea. For full details of adverse effects and contraindications, see the summary of product characteristics.
Imatinib is administered orally. The summary of product characteristics recommends 400 mg/day imatinib for the treatment of unresectable and/or metastatic GISTs. It states that there are limited data on the effect of increasing the dose of imatinib from 400 mg/day to 600 or 800 mg/day in people whose disease has progressed at the lower imatinib dose.
Imatinib is available in strengths of 100 mg (60-tablet pack) and 400 mg (30-tablet pack) at a cost of £802.04 and £1604.08 per pack respectively (excluding VAT; 'British national formulary' edition 59). The annual acquisition costs for treatment with imatinib are approximately £19,500 (400 mg/day), £29,300 (600 mg/day) and £39,100 (800 mg/day). Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
# Clinical effectiveness
The Assessment Group considered the clinical effectiveness of increased doses of imatinib (600 or 800 mg/day) compared with sunitinib or best supportive care for the treatment of people with unresectable and/or metastatic GISTs whose disease had progressed on 400 mg/day imatinib. Studies reporting the clinical effectiveness of comparator treatments (sunitinib plus best supportive care or best supportive care alone) were also identified.
The Assessment Group did not identify any randomised controlled trials or non-randomised studies comparing the effectiveness of increased doses of imatinib (600 or 800 mg/day) with sunitinib or best supportive care. However, it identified six papers and ten abstracts reporting four separate clinical trials and one non-randomised retrospective cohort study that included a treatment arm of 400 mg/day imatinib and reported data separately for people who initially received 400 mg/day imatinib, then received an increased dose of imatinib when disease progressed ('crossover groups'). The outcomes for people who took increased doses of imatinib informed this appraisal.
The EORTC-ISG-AGITG randomised controlled trial (Zalcberg et al. 2005; Debiec-Rychter et al. 2006) compared 800 mg/day imatinib with 400 mg/day imatinib in people with advanced GISTs (473 people from total trial population of 946 participants). When disease progressed in people randomised to 400 mg/day imatinib the dose was increased to 800 mg/day imatinib (n = 133 out of 473 people). Interim response data were reported for 97 people from this trial (Zalcberg et al. 2004). The S0033 randomised controlled trial (Blanke et al. 2008a) also compared 800 mg/day imatinib with 400 mg/day imatinib in people with advanced GISTs (345 people from total trial population of 746 participants). One hundred and seventeen people originally randomised to 400 mg/day who received an increased dose of 800 mg/day imatinib after disease progression were assessed for response. Interim response data (Rankin et al. 2004) were reported for 68 people. The B2222 randomised controlled trial (Blanke et al. 2008) compared 400 mg/day imatinib (n = 73) with 600 mg/day imatinib (n = 74) in people with advanced GISTs. People with disease progression on 400 mg/day imatinib, but who could tolerate a higher imatinib dose, received an increased dose of 600 mg/day. Forty-three people originally randomised to 400 mg/day imatinib and 13 people originally randomised to 600 mg/day imatinib received increased doses of imatinib. A retrospective cohort study (n = 24) (Park et al. 2009) reported data for people with metastatic or unresectable GISTs. People in this study received an initial dose of 400 mg/day imatinib that was increased to 600 or 800 mg/day imatinib on disease progression.
The Assessment Group identified seven abstracts that provided interim results for an ongoing, non-comparative open-label trial on the effectiveness of sunitinib in people whose condition had failed to respond to treatment with different doses of imatinib (including doses up to 400 mg/day). An abstract by Seddon et al. (2008) (n = 1117) was considered by the Assessment Group to be the primary source for this trial. The Assessment Group also used data from Reichardt et al. (2008) to obtain overall survival rates for sunitinib and data from Prior et al. (2009) and Demetri et al. (2006) to obtain response rates for sunitinib.
Overall, 28.1% (EORTC-ISG-AGITG), 34.2% (S0033) and 58.9% (B2222) of people initially randomised to receive 400 mg/day imatinib had disease progression and received either 600 or 800 mg/day imatinib. All the people in the retrospective cohort study received an increased dose of imatinib. In the sunitinib study (Seddon et al. 2008), 31.4% of people received sunitinib after disease progression on 400 mg/day imatinib.
## Overall response
The results for people treated with an increased dose of 600 mg/day imatinib after disease progression on 400 mg/day imatinib were reported in the B2222 trial and the retrospective cohort study. In the B2222 trial, the median length of follow-up was 63 months (maximum 71 months) from randomisation. After disease progression, 11 out of 43 people (25.6%) who increased to 600 mg/day imatinib either had a partial response or had stable disease. The Assessment Group noted that some of the people who received increased doses may have had an initial response to 400 mg/day imatinib before disease progression. In the retrospective cohort study the median length of follow-up was 8 months (range 1.4–22.3 months). Of the 12 people who received 600 mg/day imatinib, 5 (41.7%) either had a partial response or had stable disease after treatment.
The results for people treated with an increased dose of 800 mg/day imatinib after disease progression on 400 mg/day imatinib were reported in the S0033 trial, the EORTC-ISG-AGITG trial, and the retrospective cohort study. Of the subgroups who received increased doses in the S0033 and EORTC-ISG-AGITG trials (117/345 and 133/473 people respectively), 3 people in each trial had a partial response to treatment, while 33 and 36 people respectively achieved stable disease as a best response. Out of a total of 250 people in the two studies combined, 75 (30%) met the criteria for a response to treatment after an increase in the dose of imatinib from 400 to 800 mg/day. The retrospective cohort study reported that 4 of the 12 people (33.3%) who received an increased dose of imatinib (800 mg/day) after disease progression either had a partial response or had stable disease.
The manufacturer of imatinib reported confidential data from a meta-analysis of the S0033 and EORTC-ISG-AGITG trials in their submission, which reported the response to treatment in people who received increased doses of imatinib. However, the Assessment Group did not review these data because of differences in the numbers of people who achieved stable disease or had a partial response after increased doses of imatinib compared with the results from the same studies available as published articles.
Interim data for the EORTC-ISG-AGITG trial reported that, of 97 people whose disease had progressed on 400 mg/day imatinib, 2 (2.1%) showed a partial response, 30 (30.9%) had stable disease, and 65 (67.0%) still had progressive disease after an increase in the dose of imatinib from 400 to 800 mg/day. Interim data from the S0033 trial showed that, of 68 people whose disease had progressed on 400 mg/day imatinib, 5 (7.4%) had a partial response and 20 (29.4%) had stable disease after an increase in the dose of imatinib from 400 to 800 mg/day.
In addition, a secondary analysis of the EORTC-ISG-AGITG trial (Debiec-Rychter et al. 2006) suggested (without stating the number of people involved) that response to treatment after increasing the dose of imatinib from 400 to 800 mg/day was significantly more likely to occur in people with wild-type GISTs compared with the KIT exon 11 mutation (p = 0.0012). Response after increasing the dose of imatinib was also significantly more likely to occur in people with the KIT exon 9 mutation compared with the exon 11 mutation (p = 0.0017). The Assessment Group noted that it was outside the remit of this appraisal to consider outcomes for patients receiving escalated doses other than after disease progression on an initial dose of 400 mg/day imatinib. In the Debiec-Rychter et al. study, the dose of imatinib was increased to 800 mg/day shortly after starting on 400 mg/day imatinib, not necessarily after disease progression. Because of the lack of data available from the study, it was not possible for the Assessment Group to analyse the impact of increased doses of imatinib after disease progression on 400 mg/day imatinib for people with specific KIT exon mutations.
Response rates to treatment with 400 mg/day imatinib followed by 50 mg/day sunitinib on disease progression were not reported in the studies identified by the Assessment Group. The Assessment Group instead calculated a weighted average response rate from two studies (Demetri et al. 2002; Prior et al. 2009), but noted that there were differences between the patient groups in these two studies. The Prior et al. study did not report the dose of imatinib that people received before starting on sunitinib. In Demetri et al., people were randomised to receive sunitinib or placebo after treatment failure with a median dose of 800 mg/day imatinib (300–1600 mg/day). Across these two studies 266 of a total of 382 people had a response to treatment, and a simple weighted mean was used to derive the pooled response rate (69.6%). This response rate was assumed to be unaffected by prior treatment received. The Assessment Group determined that there was no statistically significant difference in the response rates between these two studies.
## Overall survival
The S0033 study reported the overall survival for people who were randomised to an initial dose of 400 mg/day imatinib which was increased to 800 mg/day after disease progression. The median follow-up for the study was 4.5 years (follow-up calculated from start of increased dose following disease progression at 400 mg/day imatinib), during which time 76 of 118 people (64.4%) had died. The median overall survival was 19 months (95% confidence interval 13 to 23 months) from the point at which the dose of imatinib was increased. Interim data for the S0033 trial were also provided by Rankin et al. (2004), who reported that median overall survival after the increase in dose of imatinib was 19 months.
Two abstracts with different follow-up periods for the same study reported overall survival data for people receiving 50 mg/day sunitinib after disease progression or for people who could not tolerate imatinib at a dose of up to 400 mg/day. Reichardt et al. (2008) analysed data after a median of 24 weeks, at which point 231 of 339 people (68.1%) were still alive. Seddon et al. (2008) analysed data after a median of 51 weeks (range 0.1–159 weeks) and 193 of 351 people (55.0%) were still alive. The Assessment Group used data on the proportion of people still alive (Reichardt et al.) and the median follow-up (Seddon et al.) in its analysis.
## Progression-free survival
Progression-free survival data were not published for the B2222 trial for people receiving an initial dose of 400 mg/day imatinib which was increased to 600 mg/day after disease progression.
The S0033 and the EORTC-ISG-AGITG trials reported data on progression-free survival for people randomised to an initial dose of 400 mg/day imatinib, which was increased to 800 mg/day after disease progression. For the S0033 trial, at a median follow-up of 54 months from randomisation, the disease had progressed in 99 of 118 people (83.9%) who received 800 mg/day imatinib. Median progression-free survival was estimated to be 5 months (95% CI 2 to 10 months). Using interim data from this trial for 68 people (Rankin et al. 2004), the authors estimated a median progression-free survival after crossover of 4 months. For the EORTC-ISG-AGITG trial, at a median follow-up of 25 months (maximum follow-up 35 months), the disease had progressed in 108 of 133 people (81.2%) who received 800 mg/day imatinib. Median progression-free survival was 2.7 months.
The sunitinib trial (Seddon et al. 2008) reported no data on disease progression in people randomised to an initial dose of imatinib of up to 400 mg/day, followed by 50 mg/day sunitinib after disease progression.
## Time to treatment failure
The retrospective cohort study reported data on the duration of response and time to treatment failure. Of the 12 people who received an increased dose of 600 mg/day imatinib after disease progression on 400 mg/day, 1 person died of a cause unrelated to both disease and treatment, while disease progressed in the remaining 11 people after a median of 1.7 months (range 0.7–24.9 months).
Data from the EORTC-ISG-AGITG trial showed that of the people who had a partial response or had stable disease after receiving an increased dose of imatinib (from 400 to 800 mg/day) after disease progression, the median duration of stable disease was 153 days (range 37–574 days).
The sunitinib trial (Seddon et al. 2008) did not provide the specific median duration of treatment with sunitinib for people who initially received up to 400 mg/day imatinib, followed by 50 mg/day sunitinib after disease progression. However, the median duration of treatment for the whole cohort was reported as 126 days (range 1–618 days) and did not differ significantly between people based on the dose of imatinib they received before sunitinib treatment.
## Health-related quality of life
None of the included studies reported data on health-related quality of life.
## Adverse events
Adverse events were not reported for people receiving an increased dose of 600 mg/day imatinib after disease progression on 400 mg/day imatinib.
No information on adverse events in people receiving an increased dose of 800 mg/day imatinib after disease progression on 400 mg/day was given by Zalcberg et al. (EORTC-ISG-AGITG trial). The authors reported that the majority of people who stopped taking imatinib (88.4%) did so because of disease progression. The Assessment Group suggested that this indicates 11.6% (11 of 97) stopped treatment because of adverse events. Interim data from this study showed that 31% of people (absolute number not given) needed to reduce the dose from 800 mg/day imatinib to a dose that was not reported.
Interim data for the S0033 trial reported by Dileo et al. (2005) showed that of the 77 people who had increased their dose of imatinib from 400 to 800 mg/day, 18 (23.4%) had at least one delay in dose, and 14 (18%) had at least one dose reduction because of oedema or rash. No information was given on the reduced dose given.
No adverse event data were available for people in the sunitinib trial (Seddon et al. 2008).
# Cost effectiveness
The Assessment Group carried out a systematic review of the literature. Seven studies that assessed both the costs and cost effectiveness of imatinib or alternative treatments for GISTs were identified.
Three studies compared imatinib (at 400 mg/day or at increased doses) with best supportive care (Wilson et al. 2005; Mabasa et al. 2008; Huse et al. 2007). Two studies included sunitinib, increased doses of imatinib, and best supportive care or palliative care as comparators (Contreras-Hernandez et al. 2008; Teich et al. 2009). Because the results of the Teich et al. study were available in abstract form only, its definition of best supportive care was not available. Studies by Chabot et al. (2008) and Paz-Ares et al. (2008) compared treatment with sunitinib and best supportive care for people with GISTs that were resistant to or intolerant of imatinib.
The study by Wilson et al. (2005) used a modified version of the model submitted by the manufacturer in 'Imatinib for the treatment of unresectable and/or metastatic gastrointestinal tumours' (NICE technology appraisal guidance 86). This appraisal evaluated the cost effectiveness of increased doses of imatinib (to 600 mg/day) after disease progression on 400 mg/day in people with unresectable and/or metastatic GISTs from a UK NHS perspective. The estimates for the incremental cost per quality-adjusted life year (QALY) gained compared with best supportive care ranged from £51,515 to £98,889 at 2 years, and from £27,331 to £44,236 at 5 years.
The study by Contreras-Hernandez et al. (2008) suggested that 800 mg/day imatinib would deliver cost savings compared with best supportive care when best supportive care includes treatment with imatinib at a dose lower than 800 mg/day. Over a 5-year treatment horizon, Contreras-Hernandez et al. (2008) found that the mean life years gained was 1.40 for people receiving sunitinib, 1.31 for people receiving imatinib 800 mg/day and 1.08 for people receiving best supportive care. The study also suggested that receiving 800 mg/day imatinib incurred the highest mean treatment costs, indicating that 800 mg/day imatinib is dominated by sunitinib. Teich et al. (2009) found that 800 mg/day imatinib was less effective than sunitinib (0.02 life years gained and 0.47 progression-free life years gained) and less costly over 6 years, also indicating that 800 mg/day imatinib is dominated by sunitinib.
## Manufacturer's submission
The manufacturer did not submit a cost-effectiveness analysis of imatinib for this appraisal. The manufacturer stated that major limitations with the available clinical data prevented it from developing a sufficiently robust health economics model.
## Assessment Group economic assessment
The Assessment Group developed a Markov model to compare alternative treatments for people with KIT (CD117)-positive unresectable and/or metastatic GISTs whose disease had progressed on imatinib 400 mg/day or whose treatment with imatinib had failed because of resistance or intolerance. The Assessment Group specifically addressed the cost effectiveness of imatinib at doses of 600 or 800 mg/day compared with best supportive care or sunitinib.
The model looked at the costs and outcomes for GIST treatments. A time horizon of 10 years and a cycle length of 1 month were used to reflect the natural history of the disease. The costs and outcomes were discounted at 3.5% in accordance with the NICE reference case.
The Assessment Group considered a range of treatment pathways for people whose disease had progressed on 400 mg/day imatinib. Based on advice from its clinical advisers, the Assessment Group decided on seven clinically plausible pathways on which to base the model:
Pathway 1: people receive best supportive care plus 400 mg/day imatinib
Pathway 2: people receive 600 mg/day imatinib, and on disease progression, they receive 800 mg/day imatinib. On further disease progression people then receive 50 mg/day sunitinib, followed by, on further disease progression, best supportive care plus 400 mg/day imatinib.
Pathway 3: people receive 600 mg/day imatinib, and on disease progression, they receive 50 mg/day sunitinib. After further disease progression on sunitinib, people receive best supportive care plus 400 mg/day imatinib.
Pathway 4: people receive 600 mg/day imatinib, and on disease progression, they receive best supportive care plus 400 mg/day imatinib.
Pathway 5: people receive 800 mg/day imatinib, and on disease progression, they receive 50 mg/day sunitinib. After disease progression on sunitinib, people receive best supportive care plus 400 mg/day imatinib.
Pathway 6: people receive 800 mg/day imatinib, and on disease progression, they receive best supportive care plus 400 mg/day imatinib.
Pathway 7: people receive 50 mg/day sunitinib, and on disease progression, they receive best supportive care plus 400 mg/day imatinib.The Assessment Group determined clinical effectiveness using results from the systematic review and other evidence. No data were available to estimate the effectiveness of any of the treatment pathways compared with each other.
In the model the Assessment Group combined the estimates of effectiveness with data on health state utility to provide estimates of QALYs for the different treatment pathways. The Assessment Group obtained data on survival for best supportive care (which includes treatment with 400 mg/day imatinib for all patients) from two studies (McGrath et al. 1987; Pierie et al. 2001). Pooled weighted estimates from these studies suggested that 87.9% (51 of 58) of people died during the observation period of 60 months. Data on survival for people receiving 600 mg/day imatinib were obtained from the B2222 trial. Forty-five per cent (5 of 11) of people whose dose of imatinib was increased from 400 mg/day to 600 mg/day died during the trial period of 60 months. Data on survival for 800 mg/day imatinib came from the S0033 trial, and indicated that 64.4% (76 of 118) of people died in this group during a median follow-up period of 4.5 years. The data on survival for people receiving sunitinib came from Seddon et al. (2008) and showed that 55.0% (193 of 351) of people receiving sunitinib were still alive after a median survival period of 11.8 months. The Assessment Group derived a monthly mortality rate from these survival rates and assumed exponential rates. The Assessment Group also assumed that the monthly mortality rate for people receiving sunitinib did not depend on whether they had received previous treatment.
The Assessment Group took response rates for 600 mg/day imatinib from the B2222 trial. The trial reported that 25.5% (11 of 43) of people receiving 600 mg/day imatinib had a response to treatment and remained stable during a median follow-up of 63 months. Data from the S0033 and EORTC-ISG-AGITG trials provided the response rate to 800 mg/day imatinib. The trials reported that 30% (75 of 250) of people receiving 800 mg/day imatinib showed a partial response or remained stable after a median follow-up of 54 months. For response rates to sunitinib, the Assessment Group took data from two studies (Demetri et al. 2002; Prior et al. 2009). A simple weighted mean was used to derive a pooled response rate of 70% (266 of 382) at a median follow-up period of 3.6 months, which did not take into account previous treatment. The Assessment Group converted data reflecting no response for each treatment into monthly transition probabilities by assuming an exponential rate.
The costs of 400 mg/day, 600 mg/day and 800 mg/day imatinib and 50 mg/day sunitinib in the Assessment Group's model were calculated from costs listed in BNF 58. Because sunitinib treatment is given for 4 weeks followed by no treatment for 2 weeks, the Assessment Group calculated the costs per year, and a proportional rate per month. The Assessment Group assumed that the cost for people receiving best supportive care was equivalent to the cost of 400 mg/day imatinib (which all people on best supportive care also received).
The Assessment Group based resource costs for 600 mg/day and 800 mg/day imatinib on those reported by Wilson et al. (2005). The resource costs included GP visits and outpatient visits, including tests, computed tomography scans and the costs of managing adverse events. For sunitinib and best supportive care, the Assessment Group based resource costs on the manufacturer's submission for 'Sunitinib for the treatment of gastrointestinal stromal tumours' (NICE technology appraisal guidance 179). The Assessment Group adjusted the costs from 2008 to 2009 prices using the Hospital and Community Health Services Index.
The Assessment Group derived health state utility values from the EQ-5D and Chabot et al. (2008) in the absence of data from the available clinical studies. The utility value for progression-free survival for people whose disease responded to imatinib, regardless of dose, was assumed to be 0.935. The utility value for people receiving best supportive care was assumed to be 0.577 (Chabot et al. 2008). In the absence of alternative data, the utility value for people whose disease responded to sunitinib was assumed to be the same as that for imatinib, that is, 0.935.
The base-case results show that pathway 4 (600 mg/day imatinib followed by, on disease progression, best supportive care plus 400 mg/day imatinib) has an incremental cost-effectiveness ratio (ICER) of £27,304 per QALY gained compared with pathway 7 (50 mg/day sunitinib then best supportive care plus 400 mg/day imatinib). For pathway 2 (600 mg/day imatinib, increasing to 800 mg/day imatinib, then 50 mg/day sunitinib followed by best supportive care plus 400 mg/day imatinib) the ICER was £45,850 per QALY gained (compared with the next least costly option, pathway 4). For pathway 3 (600 mg/day imatinib, then 50 mg/day sunitinib followed by best supportive care plus 400 mg/day imatinib) the ICER was £71,723 per QALY gained (compared with the next more costly option, pathway 4). Both pathway 5 (800 mg/day imatinib, then 50 mg/day sunitinib, followed by best supportive care plus 400 mg/day imatinib) and pathway 6 (800 mg/day imatinib, then best supportive care plus 400 mg/day imatinib) were dominated by pathway 4 (that is, they were more costly and less effective). The estimated survival benefit of 800 mg/day imatinib compared with best supportive care was 4.2 months.
The Assessment Group also performed sensitivity analyses to account for uncertainties in the model. The parameters varied included structure and methodological assumptions around distribution, transition probabilities of survival and response to treatment with 600 mg/day imatinib, utility values, and the costs of imatinib and sunitinib.
# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of increased doses of imatinib after disease progression on 400 mg/day imatinib, having considered evidence on the nature of unresectable and/or metastatic GISTs and the value placed on the benefits of imatinib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee discussed current clinical practice for the treatment of people with unresectable and/or metastatic GISTs. The Committee heard from the clinical specialists that, despite the recommendations in NICE technology appraisal guidance 86 (recommendation 1.4 states that an increase in the dose of imatinib is not recommended for people receiving imatinib who develop progressive disease after initially responding), people frequently receive 800 mg/day imatinib when their disease progresses on 400 mg/day imatinib if they have tolerated previous imatinib treatment. The clinical specialists reported that 600 mg/day imatinib is rarely prescribed after disease progression on 400 mg/day. The Committee was aware that NICE technology appraisal guidance 179 recommends that patients have the option to receive treatment with sunitinib after disease progression on 400 mg/day imatinib. However, the clinical specialists explained to the Committee that clinicians often consider increasing the dose of imatinib before offering treatment with sunitinib because imatinib is considered to have a more favourable adverse event profile, even at higher doses, than sunitinib. They also noted that if a person's disease progresses on 400mg/day imatinib, it is common practice (in approximately 50% of people) to continue treatment with 400 mg/day imatinib in addition to best supportive care if the person tolerates imatinib, however this is inconsistent with NICE technology appraisal guidance 86 which does not recommend continued treatment with imatinib after disease progression (recommendation 1.3). The Committee heard from patient experts that the limited data available suggest that imatinib at higher doses may be effective in prolonging survival and improving quality of life. Clinical specialists and patient experts also highlighted the importance of providing hope to people with metastatic GISTs by offering them additional treatment options after disease progression on 400 mg/day imatinib. Despite the lack of clinical trial evidence to demonstrate the effectiveness of increased doses of imatinib treatment after disease progression on 400 mg/day imatinib, the Committee acknowledged that there is a perception among both patient experts and clinical specialists that treatment with 800 mg/day imatinib after disease progression on 400 mg/day imatinib may offer some benefit.
## Clinical effectiveness
The Committee considered the evidence provided by the Assessment Group and the manufacturer on the clinical effectiveness of 600 and 800 mg/day imatinib after disease progression on 400 mg/day imatinib. The Committee heard from the Assessment Group that no randomised controlled trials were identified on the effectiveness of an increased dose of imatinib after disease progression on 400 mg/day imatinib compared with sunitinib or best supportive care – the two comparator treatments identified in the scope for this appraisal. Uncontrolled observational data were available evaluating the effectiveness of increased doses of imatinib in people with unresectable and/or metastatic GISTs who had not received previous imatinib treatment. However, the Committee was concerned that the populations in these studies differed from the population covered by this appraisal (that is, people whose disease has progressed on 400 mg/day imatinib), and that the studies did not explore the comparisons defined in the scope. The Committee also noted that the populations in the studies varied substantially and that combining results may introduce more uncertainty. The Committee noted that this appraisal is a part review of NICE technology appraisal guidance 86, published in 2004, which was intended to only address whether increased doses of 600 or 800 mg/day imatinib could be recommended after disease progression on 400 mg/day imatinib. The Committee noted that consultees had requested the review based on the belief that a large amount of clinical evidence about imatinib had been published since 2004. The Committee further noted that during the scoping process for this review consultees and commentators for this appraisal were given another opportunity to comment on the appropriateness of this review. The Committee was reminded that, at the time of the review proposal, the manufacturer of imatinib was seeking to extend the marketing authorisation for 800 mg/day imatinib for unresectable and/or metastatic GISTs and that the manufacturer supported the review going ahead. However, in their submission and during the Committee meeting, the manufacturer stated that no new evidence had emerged since 2004 on the effectiveness of increased doses of imatinib after disease progression on 400 mg/day imatinib. The Committee heard from the patient experts that they were disappointed that the available studies did not provide clear evidence about the effectiveness of higher doses of imatinib. The Committee agreed with the manufacturer and the Assessment Group that there is a lack of robust data available to demonstrate the effectiveness of increased doses of imatinib after disease progression on 400 mg/day imatinib, and that the available evidence is associated with uncertainty and potential bias.
The Committee noted that the majority of available data related to people who received an increased dose of 800 mg/day imatinib after disease progression on 400 mg/day imatinib. Only one phase II study (B2222) described the experience of 43 people who received an increased dose of 600 mg/day imatinib. The Committee heard that data from the Gastrointestinal Stromal Tumor Meta-Analysis Group (metaGIST) was published in March 2010. However, these data were not included in the Assessment Group's economic analyses because the population was randomised to higher doses of imatinib at baseline and had not received treatment with 400 mg/day imatinib first. Therefore, the population in the metaGIST study was different from the population for this appraisal. The Committee discussed the possible biases in the evidence for increased doses of imatinib from the uncontrolled observational data. The Committee recognised that if people with a better prognosis preferentially received increased doses of imatinib, then any improvement in outcome might not be because of the use of higher doses. For example, the Committee was aware that in the B2222 study, people with disease progression on 400 mg/day imatinib, received a higher dose of imatinib if they were described as having a good performance status (such as ECOG status <2). The Committee heard from the manufacturer that there are no ongoing trials that address the decision problem in this appraisal. The Committee heard from the clinical specialists that a trial comparing high-dose imatinib with sunitinib had been stopped after it failed to recruit a sufficient number of people. The Committee concluded that the Assessment Group had made a good effort to include all available data relevant to this appraisal in its report but was concerned about the lack of data and the nature of the evidence available.
After receiving comments from consultees and commentators on the appraisal consultation document, the Committee considered the UK guideline for the management of GISTs that was published in May 2009. The Committee noted that the guideline contains the same evidence that was identified for this appraisal by the Assessment Group and the manufacturer, and that the development of the guideline had been sponsored by the manufacturer of imatinib. The Committee was aware that the guideline did not consider the cost effectiveness of any treatments and therefore the recommendations in this appraisal would likely be different from the guideline.
The Committee considered the effectiveness of imatinib in slowing disease progression in unresectable and/or metastatic GISTs. The Committee heard from the clinical specialists that comparable measures of disease progression had been used in the different clinical trials. The Committee heard that the three studies in which the dose of imatinib was increased from 400 mg/day to 800 mg/day showed that approximately one third of people had either a partial response or had stable disease after receiving the increased dose. The Committee concluded that imatinib treatment at higher doses may offer some benefit to people whose disease progresses on 400 mg/day imatinib; however, because of the biases inherent to the clinical-effectiveness evidence available, it was aware that this conclusion was uncertain.
The Committee heard from the patient experts that measuring plasma concentrations of imatinib could be a major advantage, because it might allow an individualised approach to the dosing of imatinib. However, the clinical specialists noted that this does not happen in routine UK clinical practice, and the Committee noted that no data had been presented to demonstrate an association between plasma concentrations and outcomes. The Committee concluded that while measuring plasma concentrations of imatinib might potentially be of benefit in the future, it could not base any recommendations on this because of the current lack of evidence and because it was not done in routine clinical practice.
The Committee discussed whether benefits from increased doses of imatinib might be greater in certain subgroups of people. The Committee heard from the clinical specialists that there is some evidence suggesting that GISTs with certain mutations in the KIT gene are likely to be more or less sensitive to imatinib treatment. The clinical specialists suggested that the presence of an exon 9 mutation may be associated with a better outcome in people whose dose is increased to 800 mg/day imatinib. In addition, the clinical specialists explained that, although outside the current marketing authorisation, clinicians might choose to begin treatment with 800 mg/day imatinib without having tried lower doses in people with confirmed exon 9 mutations. However, they explained that the clinical evidence supporting this practice is based on the experience of a small number of people. The Committee also noted that data from a meta-analysis (metaGIST), in which people with exon 9 mutations started treatment on 800 mg/day imatinib, showed that there was no statistically significant difference in overall survival between people with exon 9 mutations treated with 400 mg/day imatinib compared with 800 mg/day imatinib. Furthermore, in light of the limited data available, the Committee noted that any economic analyses for this subgroup would not be considered more robust than for the entire population. The Committee also understood that mutational analysis in people with progressive disease had a limited role, if any, in clinical decision-making about increasing imatinib doses. Therefore, the Committee concluded that there was not sufficient evidence to justify a separate recommendation for the use of 600 or 800 mg/day imatinib for people with exon 9 mutations whose disease had progressed on imatinib 400 mg/day.
The Committee considered the data reported by the Assessment Group for the comparator treatment, sunitinib. The Committee noted that this evidence was mainly from an 'expanded access programme', in which regulators allow investigational drugs to be used to treat people with serious or immediately life-threatening diseases who cannot participate in clinical trials and who have no alternative therapy. The Committee was aware that people in this study were treated with sunitinib after receiving higher (600 or 800 mg/day) rather than lower (400 mg/day) doses of imatinib and did not necessarily reflect the population of interest in this appraisal – that is, people whose disease progresses on 400 mg/day imatinib.
## Cost effectiveness
The Committee discussed the cost effectiveness of imatinib 600 and 800 mg/day after disease progression on 400 mg/day imatinib. The Committee noted the Assessment Group's view that it had great difficulty undertaking an assessment of cost effectiveness in the absence of robust comparative clinical evidence for increased doses of imatinib after disease progression on 400 mg/day imatinib. The Committee also noted that the manufacturer stated that they would not submit an economic model because of the lack of robust data comparing increased doses of imatinib with sunitinib and best supportive care.
The Committee then considered the monthly mortality rates used in the Assessment Group's economic evaluation and noted that they were key drivers of the outcomes in the model. The Committee noted that a higher monthly mortality rate for people receiving sunitinib treatment was used in the Assessment Group's model than for people receiving best supportive care, which the Committee considered was implausible. The Committee heard from the Assessment Group that the limited evidence available reported that the mortality rate for 600 mg/day imatinib was lower than the rate for 800 mg/day imatinib, and that treatment with 800 mg/day imatinib generated fewer life years and fewer QALYs than treatment with 600 mg/day imatinib. The Committee considered these data implausible and agreed that this difference was unlikely to reflect the true effect of 600 and 800 mg/day imatinib, but that this highlighted the limitations in the clinical evidence for the two doses. The Committee also noted that the monthly mortality rate applied for best supportive care appeared to be very low, despite these data being pooled from two studies that had been carried out before imatinib was introduced into clinical practice. The Committee also considered that when the studies were carried out, advanced diagnostic methods for GISTs did not exist, and that people may have had other tumours (for example, leiomyosarcoma) which were associated with a different mortality rate than for GISTs. The Committee was also aware that best supportive care was likely to have improved since the studies were carried out, leading to better outcomes, including lower mortality rates. The Committee concluded that, taking into account the limitations of the data used to derive the monthly mortality rates, the results presented by the Assessment Group may not reflect the true value of cost effectiveness of high doses of imatinib after disease progression on 400 mg/day imatinib and therefore should be interpreted with caution.
The Committee discussed the options for collecting data to establish outcomes in people receiving increased doses of imatinib or one of the comparator treatments defined in the scope. The Committee noted that despite the research recommendation in NICE technology appraisal guidance 86 (published in 2004) suggesting that a national register for people receiving imatinib treatment for GISTs be maintained, such a register had not been established. The Committee heard from the manufacturer that a national register for people with GISTs is currently being set up, with pilot testing expected to begin by the end of 2010. The Committee heard from the clinical specialists that a small register has also been set up in Scotland to collect long-term treatment outcomes for people with GISTs, and that observational data from specialist cancer centres in the USA may also be available. The Committee welcomed the initiative of the manufacturer to establish a register for people with GISTs and suggested that it is important that the register collects data on outcomes specific to unresectable and metastatic GISTs.
The Committee discussed the health-related quality of life of people with unresectable and/or metastatic GISTs. It noted that the Assessment Group did not identify any data to use in its economic model that specifically measured the quality of life of people with GISTs who received imatinib treatment. The Committee heard from patient experts that the health measures defined in the NICE reference case, such as the EQ-5D, might not capture the benefits that people gain from imatinib treatment. The Committee considered the utility value used in the Assessment Group's economic model for imatinib and sunitinib (0.935). The Committee considered that this value was implausibly high and noted that this value had been derived from three out of nine clinicians who had responded to a questionnaire. The Committee also noted that this utility value was higher than the value used in NICE technology appraisal guidance 179 on sunitinib for the treatment of GISTs after disease progression on imatinib treatment. Although the Assessment Group carried out some sensitivity analyses that varied the utility value, the Committee was not convinced that the most plausible value had been used and considered that this added further uncertainty to the model. The Committee also considered that using a more appropriate utility value would probably increase the ICER because the difference between the utility values for active treatment and the comparator would be smaller. Therefore, the Committee concluded that collecting utility data is important for any future informed decision-making for this population.
The Committee considered comments from consultees and commentators on the appraisal consultation document. The Committee heard that recommendations in NICE technology appraisal guidance 86 for stopping imatinib 400 mg/day were not supported by clinical specialists. The Committee heard that consultees noted that the lack of clinical evidence for this appraisal was directly attributable to the rarity of GISTs. The Committee acknowledged that, although the rarity of GISTs did contribute to the lack of evidence, more could have been done to describe the clinical experience that exists. The consultees and commentators repeated the Committee's concerns that a disease register had not been established since the publication of NICE technology appraisal guidance 86. The Committee also noted that the Assessment Group had highlighted issues contributing to the uncertainty about the clinical and cost effectiveness of imatinib at increased doses after disease progression on 400 mg/day. These issues include differing study populations, a lack of clinical evidence, and particularly sparse data on the clinical pathway of treatment with sunitinib after disease progression on 400 mg/day imatinib. The Committee appreciated the point made by consultees and commentators that, as this appraisal affected only a small group of people, giving clinicians the discretion to prescribe imatinib at doses higher than 400 mg/day would have little overall financial impact on the NHS. However, the Committee emphasised that (in line with NICE's 'Guide to the methods of technology appraisal') the potential budget impact of the adoption of a new technology does not determine its decision.
The Committee explored whether it was possible to estimate a most plausible ICER. The Committee noted that the lowest ICER calculated by the Assessment Group was £27,300 per QALY gained for 600 mg/day imatinib after disease progression on 400 mg/day imatinib compared with sunitinib. However, in light of the inconsistencies in the model inputs and in the results, it recognised that this value was associated with considerable uncertainty, and should be interpreted with caution. The Committee discussed whether making any changes to the major assumptions made by the Assessment Group or further modelling might reduce the uncertainty in the estimates of cost effectiveness for high doses of imatinib. The Committee noted that any further modelling would need estimates of disease progression and mortality rates to be plausible as well as comparable across different treatment arms. The Committee agreed that all of the following changes in the assumptions would be likely to increase the ICER associated with imatinib treatment at increased doses:
Decreasing the utility value for imatinib and sunitinib from 0.935 to a more plausible value.
Assuming that only 50%, rather than 100%, of people receive 400 mg/day imatinib in addition to best supportive care after progression of disease at higher doses of imatinib, which is in line with current clinical practice.
Assuming that no one receives 400 mg/day imatinib in addition to best supportive care after progression of disease at higher doses of imatinib, which is in line with current NICE recommendations.
Using more up-to-date estimates of the effectiveness of best supportive care, which is assumed to be more effective now than when the data used in the modelling were collected.
Accounting for utility values for additional adverse events associated with higher doses of imatinib.
Using a more realistic effectiveness estimate for sunitinib treatment – this would be likely to increase the ICER for imatinib compared with sunitinib.Because these assumptions would increase rather than decrease the ICERs for increased doses of imatinib, the Committee concluded that it was highly likely that the ICERs for 600 or 800 mg/day imatinib after disease progression on 400 mg/day imatinib, compared with best supportive care or with sunitinib were above £30,000 per QALY gained.
Because of the lack of robust clinical effectiveness evidence available, the Committee explored if there were any other approaches for exploring a most plausible ICER. The Committee acknowledged that when imatinib was first appraised in 2004 (NICE technology appraisal guidance 86), the results of the model from the Decision Support Unit (DSU) suggested that 400 mg/day imatinib had an ICER of approximately £32,000 per QALY gained compared with best supportive care. In addition, the ICER for 600 mg/day imatinib after disease progression on 400 mg/day compared with best supportive care was estimated to be £39,000 per QALY gained. The Committee noted that at the time these results were considered to be uncertain and that since then no clinical evidence has been published that would improve the robustness of the modelling results or reduce the uncertainty of the cost effectiveness of imatinib at increased doses. The Committee also considered that, given that the acquisition cost of 600 and 800 mg/day imatinib is obviously much higher than the cost of 400 mg/day imatinib, higher doses would need to be substantively more effective to be considered cost effective. The Committee concluded that the available evidence does not suggest that higher doses of imatinib lead to a substantive increase in effectiveness for the treatment of unresectable and/or metastatic GISTs after disease progression on 400 mg/day imatinib and that using this approach corroborates the conclusion that the most plausible ICER for 600 or 800 mg/day imatinib compared with best supportive care or with sunitinib was above £30,000 per QALY gained.
The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations. In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case of the economic modelling are plausible, objective and robust.
The Committee was aware that the number of people newly diagnosed with GISTs in England and Wales ranges from approximately 200 to 2000 per year. It noted that imatinib has a marketing authorisation for a number of other indications in addition to the treatment of unresectable and/or metastatic GISTs. The Committee noted that for people with unresectable GISTs, prognosis is poor, with survival generally less than 2 years without further treatment. The Committee noted that in the economic model the survival benefit following treatment with imatinib 800 mg/day compared with best supportive care was 4.2 months. However, the Committee agreed that the evidence for this life extension could not be considered sufficiently robust, considering the uncertainty about the assumptions in the economic model, and the lack of comparative clinical effectiveness data. In addition, the Committee noted that the results of the meta-analysis (metaGIST) showed no overall survival benefit for people receiving 800 mg/day imatinib compared with people receiving 400 mg/day imatinib in people with exon 9 mutations. The Committee therefore concluded that increased doses of imatinib after disease progression on 400 mg/day imatinib did not meet the criteria for being a life-extending, end-of-life treatment.
The Committee considered whether its recommendation was associated with any potential issues related to equality, and noted comments made during consultation on the appraisal consultation document that not recommending 600 or 800mg/day of imatinib following disease progression with 400mg/day imatinib unfairly discriminates against people with rare diseases. The Committee also noted the respective consultees' acknowledgement that having a rare disease does not constitute one of the protected characteristics in the current equalities legislation or the Equality Act. However, the Committee was aware that it has general Public Law obligations of fairness and reasonableness in respect of the impact of its guidance on patients. The Committee was also aware that the Human Rights Act and article 14 of the European Convention on Human Rights (ECHR) can protect groups of people other than those covered by the UK equalities legislation. As regards article 14 ECHR, the Committee noted that it was not clear that patients affected by this appraisal or those with an exon 9 mutation would be regarded as a 'group' protected by article 14, nor that any of the substantive ECHR articles was engaged. In relation to both the ECHR obligations and public law requirements, the Committee considered that its recommendation did not unfairly disadvantage any groups within the remit of this appraisal. The Committee noted that its role was to appraise clinical and cost effectiveness and that in relation to each technology it is required to consider the robustness or otherwise of the available evidence. The Committee took into account the lack of robust clinical evidence for a survival benefit of higher doses of imatinib, specifically for the subgroup of people that have been reported to respond better, that is people with an exon 9 mutation. The Committee was also aware that an alternative treatment option is available for this group of people because NICE technology appraisal guidance 179 recommends that patients have the option to receive treatment with sunitinib after disease progression on 400 mg/day imatinib. The Committee was satisfied that its recommendation was consistent with NICE's legislative obligations under the equalities legislation and the requirement for fairness.
In summary, the Committee agreed that clinical opinion suggests that increased doses of imatinib after disease progression on 400 mg/day imatinib may offer benefit to some people. However, since the previous appraisal of imatinib (NICE technology appraisal guidance 86), there are no new good-quality data on the clinical effectiveness of increasing the dose of imatinib. The Committee concluded that the current available clinical and cost-effectiveness evidence does not justify a positive recommendation for the use of imatinib at increased doses of 600 mg/day and 800 mg/day as an appropriate use of NHS resources for the treatment of people with unresectable and/or metastatic GISTs whose disease has progressed on 400 mg/day imatinib.
# Summary of the Appraisal Committee's key conclusions
TA 209 (MTA): Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours (part review of technology appraisal guidance 86)
FAD section
Key conclusion
Imatinib at 600 or 800 mg/day is not recommended for people with unresectable and/or metastatic gastrointestinal stromal tumours whose disease has progressed after treatment with 400 mg/day imatinib.
The Appraisal Committee considered that there was an absence of new good-quality evidence since the previous appraisal of imatinib (NICE technology appraisal guidance 86) was published, and that the data available, including a most plausible ICER above £30,000 per QALY gained, do not justify a positive recommendation for the use of imatinib at increased doses of 600 mg/day and 800 mg/day after progression at 400mg/day, as an appropriate use of NHS resources.
Current practice
Clinical need of patients including the availability of alternative treatments
Clinical specialists and patient experts highlighted the importance of providing hope to people with metastatic GISTs by offering them additional treatment options after disease progression on 400 mg/day imatinib.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits and how it might improve the way that current need is met (is this a 'step-change' in the management of the condition?)
Despite the lack of clinical trial evidence to demonstrate the effectiveness of increased doses of imatinib treatment after disease progression on 400 mg/day imatinib, the Committee acknowledged that there is a perception among both patient experts and clinical specialists that treatment with 800 mg/day imatinib after disease progression on 400 mg/day imatinib may offer some benefit.
What is the position of the treatment in the pathway of care for the condition?
The Committee heard from the clinical specialists that, despite the recommendations in NICE technology appraisal guidance 86 (recommendation 1.4 states that an increase in the dose of imatinib is not recommended for people receiving imatinib who develop progressive disease after initially responding), people frequently receive 800 mg/day imatinib when their disease progresses on 400 mg/day imatinib if they have tolerated previous imatinib treatment. The clinical specialists noted that if a person's disease progresses on higher doses of imatinib, it is common practice (in approximately 50% of people) to continue treatment with 400 mg/day imatinib in addition to best supportive care if the person tolerates imatinib, however this is inconsistent with TA86 which does not recommend continued treatment with imatinib after disease progression (recommendation 1.3).
Adverse effects
The clinical specialists explained to the Committee that clinicians often consider increasing the dose of imatinib before offering treatment with sunitinib because imatinib is considered to have a more favourable adverse event profile, even at higher doses, than sunitinib.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
No randomised controlled trials were identified on the effectiveness of an increased dose of imatinib after disease progression on 400 mg/day imatinib compared with sunitinib or best supportive care – the two comparator treatments identified in the scope to this appraisal.
The Committee agreed with the manufacturer and the Assessment Group that there is a lack of robust data available to demonstrate the effectiveness of increased doses of imatinib after disease progression on 400 mg/day imatinib, and that the available evidence is associated with uncertainty and potential bias.
The Committee noted that the majority of available data related to people who received an increased dose of 800 mg/day imatinib after disease progression on 400 mg/day imatinib. The Committee heard from the manufacturer that there are no ongoing trials that address the decision problem in this appraisal.
Relevance to general clinical practice in the NHS
The Committee heard from the clinical specialists that people frequently receive 800 mg/day imatinib when their disease progresses on 400 mg/day imatinib if they have tolerated previous imatinib treatment. The clinical specialists reported that 600 mg/day imatinib is rarely prescribed after disease progression on 400 mg/day.
The Committee heard from the patient experts that measuring plasma concentrations of imatinib could offer a major advantage, because it might allow an individualised approach to the dosing of imatinib. The Committee concluded that while measuring plasma concentrations of imatinib might potentially be of benefit in the future, it could not base any recommendations on this because of the current lack of evidence and because it was not done in routine clinical practice.
Uncertainties generated by the evidence
See 'Availability, nature and quality of evidence' above
The Committee considered the data reported by the Assessment Group for the comparator treatment, sunitinib. The Committee was aware that people in this study were treated with sunitinib after receiving higher (600 or 800 mg/day) rather than lower (400 mg/day) doses of imatinib and did not necessarily reflect the population of interest in this appraisal – that is, people whose disease progresses on 400 mg/day imatinib.
The Committee also noted that the Assessment Group had highlighted issues contributing to the uncertainty about the clinical and cost effectiveness of imatinib at increased doses after disease progression on 400 mg/day. These issues include differing study populations, a lack of clinical evidence, and particularly sparse data on the clinical pathway of treatment with sunitinib after disease progression on 400 mg/day imatinib.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness
The Committee discussed whether benefits from increased doses of imatinib might be greater in certain subgroups of people. The Committee heard from the clinical specialists that there is some evidence suggesting that GISTs with certain mutations in the KIT gene are likely to be more or less sensitive to imatinib treatment. The clinical specialists suggested that the presence of an exon 9 mutation may be associated with a better outcome in people whose dose is increased to 800 mg/day imatinib. However, they explained that the clinical evidence supporting this practice is based on the experience of a small number of people. The Committee also noted that data from a meta-analysis (metaGIST), in which people with exon 9 mutations started treatment on 800 mg/day imatinib, showed that there was no statistically significant difference in overall survival between people with exon 9 mutations treated with 400 mg/day imatinib compared with 800 mg/day imatinib. The Committee also understood that mutational analysis in people with progressive disease had a limited role, if any, in clinical decision-making about increasing imatinib doses.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee heard that the three studies in which the dose of imatinib was increased from 400 to 800 mg/day showed that approximately one third of people had either a partial response or had stable disease after receiving the increased dose. The Committee concluded that imatinib treatment at higher doses may offer some benefit to people whose disease progresses on 400 mg/day imatinib; however, because of the biases inherent to the clinical-effectiveness evidence available, it was aware that this conclusion was uncertain.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee noted the Assessment Group's view that it had great difficulty undertaking an assessment of cost effectiveness in the absence of robust comparative clinical evidence for increased doses of imatinib after disease progression on 400 mg/day imatinib. The Committee also noted that the manufacturer stated that they would not submit an economic model because of the lack of robust data comparing increased doses of imatinib with sunitinib and best supportive care.
Uncertainties around and plausibility of assumptions and inputs in the economic model
Key uncertainties in the clinical effectiveness evidence followed through to the economic analysis. A key uncertainty in the economic analysis was the monthly mortality rates assumed for sunitinib, best supportive care and for increased doses of imatinib. The Committee concluded that, taking into account the limitations of the data used to derive the monthly mortality rates, the results presented by the Assessment Group may not reflect the true value of cost effectiveness of high doses of imatinib after disease progression on 400 mg/day imatinib and therefore should be interpreted with caution.
The Committee discussed whether making any changes to the major assumptions made by the Assessment Group or further modelling might reduce the uncertainty in the estimates of cost-effectiveness for high doses of imatinib. The Committee noted that any further modelling would need estimates of disease progression and mortality rates to be plausible as well as comparable across different treatment arms. The Committee noted that these changes would be likely to increase the ICER (that is, worsen the cost-effectiveness) associated with imatinib at increased doses.
Incorporation of health-related quality of life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the quality-adjusted life year (QALY) calculation? How have these been separately evaluated and what is the impact (if any) on the judgement of the most plausible incremental cost-effectiveness ratio) ICER?
The Assessment Group did not identify any data to use in its economic model that specifically measured the quality of life of people with GISTs who received imatinib treatment.
The Committee considered the utility value used in the Assessment Group's economic model for imatinib and sunitinib (0.935). The Committee considered that this value was implausibly high and noted that this value had been derived from three out of nine clinicians who had responded to a questionnaire. The Committee also noted that this utility value was higher than the value used in NICE technology appraisal guidance 179 on sunitinib for the treatment of GISTs after disease progression on imatinib treatment. Although the Assessment Group carried out some sensitivity analyses that varied the utility value, the Committee was not convinced that the most plausible value had been used and considered that this added further uncertainty to the model.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee noted that data from the metaGIST study, in which people with exon 9 mutations started treatment on 800 mg/day imatinib, showed that there was no statistically significant difference in overall survival between people with exon 9 mutations treated with 400 mg/day imatinib compared with 800 mg/day imatinib. Furthermore, in light of the limited data available, the Committee noted that any economic analysis for this subgroup would not be considered more robust than for the entire population. Therefore, the Committee concluded that there was not sufficient evidence to justify a separate recommendation for the use of 600 or 800 mg/day imatinib for people with exon 9 mutations whose disease had progressed on imatinib 400 mg/day.
What are the key drivers of cost effectiveness?
The Committee considered the monthly mortality rates used in the Assessment Group's economic model and noted that they were key drivers of the outcomes in the model.
Most likely cost-effectiveness estimate (given as an ICER)
The Committee noted that the lowest ICER calculated by the Assessment Group was £27,300 per QALY gained for 600 mg/day imatinib after disease progression on 400 mg/day imatinib compared with sunitinib. However, in light of the inconsistencies in the model inputs and in the results, it recognised that this value was associated with considerable uncertainty, and should be interpreted with caution. The Committee discussed whether making any changes to the major assumptions made by the Assessment Group or further modelling might reduce the uncertainty in the estimates of cost effectiveness for high doses of imatinib. Because changes to the assumptions would worsen rather than improve the cost effectiveness of increased doses of imatinib, the Committee concluded that it was highly likely that the ICERs for 600 or 800 mg/day imatinib after disease progression on 400 mg/day imatinib compared with best supportive care or with sunitinib was above £30,000 per QALY gained.
The Committee acknowledged that when imatinib was first appraised in 2004 (TA86) the results of the model from the Decision Support Unit (DSU) suggested that the ICER for 600 mg/day imatinib after disease progression on 400 mg/day compared with best supportive care was £39,000 per QALY gained. The Committee noted that at the time these results were considered to be uncertain and since then no clinical evidence has been published that would improve the robustness of the modelling results or reduce the uncertainty of the cost effectiveness of imatinib at increased doses. It concluded that using this approach corroborates the conclusion that the most plausible ICER for 600 or 800 mg/day imatinib compared with best supportive care or with sunitinib was above £30,000 per QALY gained.
Additional factors taken into account
Patient access schemes (Pharmaceutical Price Regulation Programme)
Not applicable.
End-of-life considerations
The Committee concluded that increased doses of imatinib after disease progression on 400 mg/day imatinib did not meet the criteria for being a life-extending, end-of-life treatment.
Equalities considerations, Social Value Judgement
During ACD consultation, comments were made that not recommending 600 or 800mg/day imatinib following disease progression with 400mg/day imatinib unfairly discriminates against people with rare diseases. The respective consultees acknowledged that having a rare disease does not constitute one of the protected characteristics in the current equalities legislation or the Equality Act. However, the Committee took also into account general Public Law obligations of fairness and reasonableness and the Human Rights Act and article 14 of the European Convention on Human Rights (ECHR) The Committee noted that it was not clear that patients affected by this appraisal or those with an exon 9 mutation would be regarded as a 'group' protected by article 14, nor that any of the substantive ECHR articles was engaged. In relation to both the ECHR obligations and public law requirements, the Committee considered that its recommendation did not unfairly disadvantage any groups within the remit of this appraisal. The Committee took into account the lack of robust clinical evidence for a survival benefit of higher doses of imatinib, specifically for the subgroup of people that have been reported to respond better, that is people with an exon 9 mutation. The Committee was also aware that an alternative treatment option is available for this group of people because NICE technology appraisal guidance 179 recommends that patients have the option to receive treatment with sunitinib after disease progression on 400 mg/day imatinib. The Committee was satisfied that its recommendation was consistent with NICE's legislative obligations under the equalities legislation and the requirement for fairness.
# Recommendations for further research
The Committee concluded that there were substantial gaps in the evidence and that research into the following areas should be considered:
A national register should be maintained for all people with GISTs being treated with imatinib, sunitinib and best supportive care (to support future appraisals of treatments for this patient group). Details should include patient characteristics, dose and duration of treatment, tumour response rates and survival, both with and after discontinuation of treatment.
The use of mutational analysis to predict individual response to imatinib treatment and long-term outcomes.
The use of plasma level measurement to individualise imatinib treatment and to optimise long-term outcomes.# Related NICE guidance
Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours.NICE technology appraisal guidance 86 (2004).
Sunitinib for the treatment of gastrointestinal stromal tumours. NICE technology appraisal guidance 179 (2009).# Review of guidance
The guidance on this technology will be considered for review in August 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew DillonChief ExecutiveNovember 2010# Changes after publication
September 2013: correction to show that recommendation 1.5 in TA 86 had been updated, rather than recommendation 1.4.
March 2012: minor maintenance.# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE multiple technology appraisal process.
This guidance updates recommendation 1.5 of NICE technology appraisal guidance 86 (TA86) 'Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours'. All other recommendations in TA86 still stand.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.
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{'Guidance': "This guidance should be read in conjunction with NICE technology appraisal guidance 86 (TA86) 'Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours'.\n\nThis guidance updates recommendation 1.5 of TA86. All other recommendations in TA86 still stand.\n\nImatinib at 600\xa0or 800\xa0mg/day is not recommended for people with unresectable and/or metastatic gastrointestinal stromal tumours whose disease has progressed after treatment with 400\xa0mg/day imatinib.\n\nPeople who are currently receiving 600\xa0or 800\xa0mg/day imatinib for unresectable and/or metastatic gastrointestinal stromal tumours should have the option to continue therapy until they and their clinicians consider it appropriate to stop.", 'Clinical need and practice': 'Gastrointestinal stromal tumours (GISTs) are rare tumours of the gastrointestinal tract. Although GISTs can occur along the length of the gastrointestinal tract from the oesophagus to the anus, the majority (60–70%) arise in the stomach. Most GISTs are associated with overexpression of the tyrosine kinase receptor KIT (CD117), which is thought to promote tumour growth or to inhibit tumour cell death through a signal transduction pathway involving stem cell factor.\n\nApproximately one third of people with GISTs are asymptomatic during the early stages of the disease. Signs and symptoms can include abdominal discomfort or pain, a feeling of abdominal fullness and the presence of a palpable mass. People have more severe symptoms when tumours metastasise or when they become large, rupture and bleed or obstruct the gastrointestinal tract. In metastatic disease, systemic symptoms such as fever, night sweats and weight loss are common.\n\nApproximately 900 people are newly diagnosed with GISTs in the UK each year. Although GISTs can occur at any age, the usual age of presentation is between 50 and 70\xa0years. Diagnosis of GIST is confirmed by clinical presentation and tissue biopsy to determine the histological characteristics of the tumour, including expression of the KIT (CD117) protein. Approximately 4% of GISTs have characteristic clinical and morphological features, but do not express the KIT (CD117) protein.\n\nThe size, growth rate and location of the tumour often influence prognosis. Without treatment GISTs progress and will eventually metastasise. Prognosis depends on whether the tumour can be resected, which is the primary treatment for GISTs. Only 50% of GISTs are resectable at presentation. Conventional cytotoxic chemotherapy and radiotherapy are ineffective in treating advanced or metastatic GISTs. Similarly, surgery to treat advanced or metastatic GISTs is not recommended unless there is an immediate clinical need, such as to remove an obstructing tumour.', 'The technology ': "Imatinib (Glivec, Novartis Pharmaceuticals UK) is a signal-transduction inhibitor that selectively inhibits tyrosine kinases, including the KIT (CD117) receptor that is expressed in GISTs. Imatinib binds to activated KIT (CD117) receptors and blocks the cell-signalling pathway to inhibit uncontrolled cell proliferation. Imatinib has a UK marketing authorisation for the treatment of adults with KIT (CD117)-positive unresectable and/or metastatic malignant GISTs.\n\nThe most commonly reported adverse events in trials of imatinib were oedema, fatigue, myalgia, muscle cramps, rash, abdominal pain, vomiting, diarrhoea and nausea. For full details of adverse effects and contraindications, see the summary of product characteristics.\n\nImatinib is administered orally. The summary of product characteristics recommends 400\xa0mg/day imatinib for the treatment of unresectable and/or metastatic GISTs. It states that there are limited data on the effect of increasing the dose of imatinib from 400\xa0mg/day to 600 or 800\xa0mg/day in people whose disease has progressed at the lower imatinib dose.\n\nImatinib is available in strengths of 100\xa0mg (60-tablet pack) and 400\xa0mg (30-tablet pack) at a cost of £802.04 and £1604.08 per pack respectively (excluding VAT; 'British national formulary' [BNF] edition 59). The annual acquisition costs for treatment with imatinib are approximately £19,500 (400\xa0mg/day), £29,300 (600\xa0mg/day) and £39,100 (800\xa0mg/day). Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nThe Assessment Group considered the clinical effectiveness of increased doses of imatinib (600 or 800\xa0mg/day) compared with sunitinib or best supportive care for the treatment of people with unresectable and/or metastatic GISTs whose disease had progressed on 400\xa0mg/day imatinib. Studies reporting the clinical effectiveness of comparator treatments (sunitinib plus best supportive care or best supportive care alone) were also identified.\n\nThe Assessment Group did not identify any randomised controlled trials or non-randomised studies comparing the effectiveness of increased doses of imatinib (600 or 800\xa0mg/day) with sunitinib or best supportive care. However, it identified six papers and ten abstracts reporting four separate clinical trials and one non-randomised retrospective cohort study that included a treatment arm of 400\xa0mg/day imatinib and reported data separately for people who initially received 400\xa0mg/day imatinib, then received an increased dose of imatinib when disease progressed ('crossover groups'). The outcomes for people who took increased doses of imatinib informed this appraisal.\n\nThe EORTC-ISG-AGITG randomised controlled trial (Zalcberg et al. 2005; Debiec-Rychter et al. 2006) compared 800\xa0mg/day imatinib with 400\xa0mg/day imatinib in people with advanced GISTs (473 people from total trial population of 946 participants). When disease progressed in people randomised to 400\xa0mg/day imatinib the dose was increased to 800\xa0mg/day imatinib (n\xa0=\xa0133 out of 473 people). Interim response data were reported for 97 people from this trial (Zalcberg et al. 2004). The S0033 randomised controlled trial (Blanke et al. 2008a) also compared 800\xa0mg/day imatinib with 400\xa0mg/day imatinib in people with advanced GISTs (345 people from total trial population of 746 participants). One hundred and seventeen people originally randomised to 400\xa0mg/day who received an increased dose of 800\xa0mg/day imatinib after disease progression were assessed for response. Interim response data (Rankin et al. 2004) were reported for 68 people. The B2222 randomised controlled trial (Blanke et al. 2008) compared 400\xa0mg/day imatinib (n\xa0=\xa073) with 600\xa0mg/day imatinib (n\xa0=\xa074) in people with advanced GISTs. People with disease progression on 400\xa0mg/day imatinib, but who could tolerate a higher imatinib dose, received an increased dose of 600\xa0mg/day. Forty-three people originally randomised to 400\xa0mg/day imatinib and 13 people originally randomised to 600\xa0mg/day imatinib received increased doses of imatinib. A retrospective cohort study (n\xa0=\xa024) (Park et al. 2009) reported data for people with metastatic or unresectable GISTs. People in this study received an initial dose of 400\xa0mg/day imatinib that was increased to 600\xa0or 800\xa0mg/day imatinib on disease progression.\n\nThe Assessment Group identified seven abstracts that provided interim results for an ongoing, non-comparative open-label trial on the effectiveness of sunitinib in people whose condition had failed to respond to treatment with different doses of imatinib (including doses up to 400\xa0mg/day). An abstract by Seddon et al. (2008) (n\xa0=\xa01117) was considered by the Assessment Group to be the primary source for this trial. The Assessment Group also used data from Reichardt et al. (2008) to obtain overall survival rates for sunitinib and data from Prior et al. (2009) and Demetri et al. (2006) to obtain response rates for sunitinib.\n\nOverall, 28.1% (EORTC-ISG-AGITG), 34.2% (S0033) and 58.9% (B2222) of people initially randomised to receive 400\xa0mg/day imatinib had disease progression and received either 600 or 800\xa0mg/day imatinib. All the people in the retrospective cohort study received an increased dose of imatinib. In the sunitinib study (Seddon et al. 2008), 31.4% of people received sunitinib after disease progression on 400\xa0mg/day imatinib.\n\n## Overall response\n\nThe results for people treated with an increased dose of 600\xa0mg/day imatinib after disease progression on 400\xa0mg/day imatinib were reported in the B2222 trial and the retrospective cohort study. In the B2222 trial, the median length of follow-up was 63\xa0months (maximum 71\xa0months) from randomisation. After disease progression, 11 out of 43 people (25.6%) who increased to 600\xa0mg/day imatinib either had a partial response or had stable disease. The Assessment Group noted that some of the people who received increased doses may have had an initial response to 400\xa0mg/day imatinib before disease progression. In the retrospective cohort study the median length of follow-up was 8\xa0months (range 1.4–22.3\xa0months). Of the 12 people who received 600\xa0mg/day imatinib, 5 (41.7%) either had a partial response or had stable disease after treatment.\n\nThe results for people treated with an increased dose of 800\xa0mg/day imatinib after disease progression on 400\xa0mg/day imatinib were reported in the S0033 trial, the EORTC-ISG-AGITG trial, and the retrospective cohort study. Of the subgroups who received increased doses in the S0033 and EORTC-ISG-AGITG trials (117/345 and 133/473 people respectively), 3 people in each trial had a partial response to treatment, while 33 and 36 people respectively achieved stable disease as a best response. Out of a total of 250 people in the two studies combined, 75 (30%) met the criteria for a response to treatment after an increase in the dose of imatinib from 400 to 800\xa0mg/day. The retrospective cohort study reported that 4 of the 12 people (33.3%) who received an increased dose of imatinib (800\xa0mg/day) after disease progression either had a partial response or had stable disease.\n\nThe manufacturer of imatinib reported confidential data from a meta-analysis of the S0033 and EORTC-ISG-AGITG trials in their submission, which reported the response to treatment in people who received increased doses of imatinib. However, the Assessment Group did not review these data because of differences in the numbers of people who achieved stable disease or had a partial response after increased doses of imatinib compared with the results from the same studies available as published articles.\n\nInterim data for the EORTC-ISG-AGITG trial reported that, of 97 people whose disease had progressed on 400 mg/day imatinib, 2 (2.1%) showed a partial response, 30 (30.9%) had stable disease, and 65 (67.0%) still had progressive disease after an increase in the dose of imatinib from 400 to 800\xa0mg/day. Interim data from the S0033 trial showed that, of 68 people whose disease had progressed on 400 mg/day imatinib, 5 (7.4%) had a partial response and 20 (29.4%) had stable disease after an increase in the dose of imatinib from 400 to 800\xa0mg/day.\n\nIn addition, a secondary analysis of the EORTC-ISG-AGITG trial (Debiec-Rychter et al. 2006) suggested (without stating the number of people involved) that response to treatment after increasing the dose of imatinib from 400 to 800\xa0mg/day was significantly more likely to occur in people with wild-type GISTs compared with the KIT exon 11 mutation (p\xa0=\xa00.0012). Response after increasing the dose of imatinib was also significantly more likely to occur in people with the KIT exon 9 mutation compared with the exon 11 mutation (p\xa0=\xa00.0017). The Assessment Group noted that it was outside the remit of this appraisal to consider outcomes for patients receiving escalated doses other than after disease progression on an initial dose of 400 mg/day imatinib. In the Debiec-Rychter et al. study, the dose of imatinib was increased to 800 mg/day shortly after starting on 400 mg/day imatinib, not necessarily after disease progression. Because of the lack of data available from the study, it was not possible for the Assessment Group to analyse the impact of increased doses of imatinib after disease progression on 400 mg/day imatinib for people with specific KIT exon mutations.\n\nResponse rates to treatment with 400\xa0mg/day imatinib followed by 50\xa0mg/day sunitinib on disease progression were not reported in the studies identified by the Assessment Group. The Assessment Group instead calculated a weighted average response rate from two studies (Demetri et al. 2002; Prior et al. 2009), but noted that there were differences between the patient groups in these two studies. The Prior et al. study did not report the dose of imatinib that people received before starting on sunitinib. In Demetri et al., people were randomised to receive sunitinib or placebo after treatment failure with a median dose of 800\xa0mg/day imatinib (300–1600\xa0mg/day). Across these two studies 266 of a total of 382 people had a response to treatment, and a simple weighted mean was used to derive the pooled response rate (69.6%). This response rate was assumed to be unaffected by prior treatment received. The Assessment Group determined that there was no statistically significant difference in the response rates between these two studies.\n\n## Overall survival\n\nThe S0033 study reported the overall survival for people who were randomised to an initial dose of 400\xa0mg/day imatinib which was increased to 800\xa0mg/day after disease progression. The median follow-up for the study was 4.5 years (follow-up calculated from start of increased dose following disease progression at 400 mg/day imatinib), during which time 76 of 118 people (64.4%) had died. The median overall survival was 19\xa0months (95% confidence interval [CI] 13 to 23\xa0months) from the point at which the dose of imatinib was increased. Interim data for the S0033 trial were also provided by Rankin et al. (2004), who reported that median overall survival after the increase in dose of imatinib was 19\xa0months.\n\nTwo abstracts with different follow-up periods for the same study reported overall survival data for people receiving 50\xa0mg/day sunitinib after disease progression or for people who could not tolerate imatinib at a dose of up to 400\xa0mg/day. Reichardt et al. (2008) analysed data after a median of 24\xa0weeks, at which point 231 of 339 people (68.1%) were still alive. Seddon et al. (2008) analysed data after a median of 51\xa0weeks (range 0.1–159\xa0weeks) and 193 of 351 people (55.0%) were still alive. The Assessment Group used data on the proportion of people still alive (Reichardt et al.) and the median follow-up (Seddon et al.) in its analysis.\n\n## Progression-free survival\n\nProgression-free survival data were not published for the B2222 trial for people receiving an initial dose of 400\xa0mg/day imatinib which was increased to 600\xa0mg/day after disease progression.\n\nThe S0033 and the EORTC-ISG-AGITG trials reported data on progression-free survival for people randomised to an initial dose of 400\xa0mg/day imatinib, which was increased to 800\xa0mg/day after disease progression. For the S0033 trial, at a median follow-up of 54\xa0months from randomisation, the disease had progressed in 99 of 118 people (83.9%) who received 800\xa0mg/day imatinib. Median progression-free survival was estimated to be 5\xa0months (95% CI 2 to 10\xa0months). Using interim data from this trial for 68 people (Rankin et al. 2004), the authors estimated a median progression-free survival after crossover of 4\xa0months. For the EORTC-ISG-AGITG trial, at a median follow-up of 25\xa0months (maximum follow-up 35\xa0months), the disease had progressed in 108 of 133 people (81.2%) who received 800\xa0mg/day imatinib. Median progression-free survival was 2.7\xa0months.\n\nThe sunitinib trial (Seddon et al. 2008) reported no data on disease progression in people randomised to an initial dose of imatinib of up to 400\xa0mg/day, followed by 50\xa0mg/day sunitinib after disease progression.\n\n## Time to treatment failure\n\nThe retrospective cohort study reported data on the duration of response and time to treatment failure. Of the 12 people who received an increased dose of 600\xa0mg/day imatinib after disease progression on 400\xa0mg/day, 1 person died of a cause unrelated to both disease and treatment, while disease progressed in the remaining 11 people after a median of 1.7\xa0months (range 0.7–24.9\xa0months).\n\nData from the EORTC-ISG-AGITG trial showed that of the people who had a partial response or had stable disease after receiving an increased dose of imatinib (from 400\xa0to 800\xa0mg/day) after disease progression, the median duration of stable disease was 153\xa0days (range 37–574\xa0days).\n\nThe sunitinib trial (Seddon et al. 2008) did not provide the specific median duration of treatment with sunitinib for people who initially received up to 400\xa0mg/day imatinib, followed by 50\xa0mg/day sunitinib after disease progression. However, the median duration of treatment for the whole cohort was reported as 126\xa0days (range 1–618\xa0days) and did not differ significantly between people based on the dose of imatinib they received before sunitinib treatment.\n\n## Health-related quality of life\n\nNone of the included studies reported data on health-related quality of life.\n\n## Adverse events\n\nAdverse events were not reported for people receiving an increased dose of 600\xa0mg/day imatinib after disease progression on 400 mg/day imatinib.\n\nNo information on adverse events in people receiving an increased dose of 800\xa0mg/day imatinib after disease progression on 400\xa0mg/day was given by Zalcberg et al. (EORTC-ISG-AGITG trial). The authors reported that the majority of people who stopped taking imatinib (88.4%) did so because of disease progression. The Assessment Group suggested that this indicates 11.6% (11 of 97) stopped treatment because of adverse events. Interim data from this study showed that 31% of people (absolute number not given) needed to reduce the dose from 800\xa0mg/day imatinib to a dose that was not reported.\n\nInterim data for the S0033 trial reported by Dileo et al. (2005) showed that of the 77 people who had increased their dose of imatinib from 400 to 800\xa0mg/day, 18 (23.4%) had at least one delay in dose, and 14 (18%) had at least one dose reduction because of oedema or rash. No information was given on the reduced dose given.\n\nNo adverse event data were available for people in the sunitinib trial (Seddon et al. 2008).\n\n# Cost effectiveness\n\nThe Assessment Group carried out a systematic review of the literature. Seven studies that assessed both the costs and cost effectiveness of imatinib or alternative treatments for GISTs were identified.\n\nThree studies compared imatinib (at 400\xa0mg/day or at increased doses) with best supportive care (Wilson et al. 2005; Mabasa et al. 2008; Huse et al. 2007). Two studies included sunitinib, increased doses of imatinib, and best supportive care or palliative care as comparators (Contreras-Hernandez et al. 2008; Teich et al. 2009). Because the results of the Teich et al. study were available in abstract form only, its definition of best supportive care was not available. Studies by Chabot et al. (2008) and Paz-Ares et al. (2008) compared treatment with sunitinib and best supportive care for people with GISTs that were resistant to or intolerant of imatinib.\n\nThe study by Wilson et al. (2005) used a modified version of the model submitted by the manufacturer in 'Imatinib for the treatment of unresectable and/or metastatic gastrointestinal tumours' (NICE technology appraisal guidance 86). This appraisal evaluated the cost effectiveness of increased doses of imatinib (to 600\xa0mg/day) after disease progression on 400\xa0mg/day in people with unresectable and/or metastatic GISTs from a UK NHS perspective. The estimates for the incremental cost per quality-adjusted life year (QALY) gained compared with best supportive care ranged from £51,515 to £98,889 at 2\xa0years, and from £27,331 to £44,236 at 5\xa0years.\n\nThe study by Contreras-Hernandez et al. (2008) suggested that 800\xa0mg/day imatinib would deliver cost savings compared with best supportive care when best supportive care includes treatment with imatinib at a dose lower than 800\xa0mg/day. Over a 5-year treatment horizon, Contreras-Hernandez et al. (2008) found that the mean life years gained was 1.40 for people receiving sunitinib, 1.31 for people receiving imatinib 800\xa0mg/day and 1.08 for people receiving best supportive care. The study also suggested that receiving 800\xa0mg/day imatinib incurred the highest mean treatment costs, indicating that 800 mg/day imatinib is dominated by sunitinib. Teich et al. (2009) found that 800 mg/day imatinib was less effective than sunitinib (0.02 life years gained and 0.47 progression-free life years gained) and less costly over 6\xa0years, also indicating that 800 mg/day imatinib is dominated by sunitinib.\n\n## Manufacturer's submission\n\nThe manufacturer did not submit a cost-effectiveness analysis of imatinib for this appraisal. The manufacturer stated that major limitations with the available clinical data prevented it from developing a sufficiently robust health economics model.\n\n## Assessment Group economic assessment\n\nThe Assessment Group developed a Markov model to compare alternative treatments for people with KIT (CD117)-positive unresectable and/or metastatic GISTs whose disease had progressed on imatinib 400\xa0mg/day or whose treatment with imatinib had failed because of resistance or intolerance. The Assessment Group specifically addressed the cost effectiveness of imatinib at doses of 600 or 800\xa0mg/day compared with best supportive care or sunitinib.\n\nThe model looked at the costs and outcomes for GIST treatments. A time horizon of 10\xa0years and a cycle length of 1\xa0month were used to reflect the natural history of the disease. The costs and outcomes were discounted at 3.5% in accordance with the NICE reference case.\n\nThe Assessment Group considered a range of treatment pathways for people whose disease had progressed on 400\xa0mg/day imatinib. Based on advice from its clinical advisers, the Assessment Group decided on seven clinically plausible pathways on which to base the model:\n\nPathway 1: people receive best supportive care plus 400\xa0mg/day imatinib\n\nPathway 2: people receive 600\xa0mg/day imatinib, and on disease progression, they receive 800 mg/day imatinib. On further disease progression people then receive 50 mg/day sunitinib, followed by, on further disease progression, best supportive care plus 400 mg/day imatinib.\n\nPathway 3: people receive 600 mg/day imatinib, and on disease progression, they receive 50 mg/day sunitinib. After further disease progression on sunitinib, people receive best supportive care plus 400 mg/day imatinib.\n\nPathway 4: people receive 600 mg/day imatinib, and on disease progression, they receive best supportive care plus 400\xa0mg/day imatinib.\n\nPathway 5: people receive 800 mg/day imatinib, and on disease progression, they receive 50 mg/day sunitinib. After disease progression on sunitinib, people receive best supportive care plus 400 mg/day imatinib.\n\nPathway 6: people receive 800 mg/day imatinib, and on disease progression, they receive best supportive care plus 400\xa0mg/day imatinib.\n\nPathway 7: people receive 50 mg/day sunitinib, and on disease progression, they receive best supportive care plus 400\xa0mg/day imatinib.The Assessment Group determined clinical effectiveness using results from the systematic review and other evidence. No data were available to estimate the effectiveness of any of the treatment pathways compared with each other.\n\nIn the model the Assessment Group combined the estimates of effectiveness with data on health state utility to provide estimates of QALYs for the different treatment pathways. The Assessment Group obtained data on survival for best supportive care (which includes treatment with 400\xa0mg/day imatinib for all patients) from two studies (McGrath et al. 1987; Pierie et al. 2001). Pooled weighted estimates from these studies suggested that 87.9% (51 of 58) of people died during the observation period of 60\xa0months. Data on survival for people receiving 600 mg/day imatinib were obtained from the B2222 trial. Forty-five per cent (5 of 11) of people whose dose of imatinib was increased from 400\xa0mg/day to 600\xa0mg/day died during the trial period of 60\xa0months. Data on survival for 800\xa0mg/day imatinib came from the S0033 trial, and indicated that 64.4% (76 of 118) of people died in this group during a median follow-up period of 4.5\xa0years. The data on survival for people receiving sunitinib came from Seddon et al. (2008) and showed that 55.0% (193 of 351) of people receiving sunitinib were still alive after a median survival period of 11.8\xa0months. The Assessment Group derived a monthly mortality rate from these survival rates and assumed exponential rates. The Assessment Group also assumed that the monthly mortality rate for people receiving sunitinib did not depend on whether they had received previous treatment.\n\nThe Assessment Group took response rates for 600\xa0mg/day imatinib from the B2222 trial. The trial reported that 25.5% (11 of 43) of people receiving 600\xa0mg/day imatinib had a response to treatment and remained stable during a median follow-up of 63\xa0months. Data from the S0033 and EORTC-ISG-AGITG trials provided the response rate to 800\xa0mg/day imatinib. The trials reported that 30% (75 of 250) of people receiving 800\xa0mg/day imatinib showed a partial response or remained stable after a median follow-up of 54\xa0months. For response rates to sunitinib, the Assessment Group took data from two studies (Demetri et al. 2002; Prior et al. 2009). A simple weighted mean was used to derive a pooled response rate of 70% (266 of 382) at a median follow-up period of 3.6\xa0months, which did not take into account previous treatment. The Assessment Group converted data reflecting no response for each treatment into monthly transition probabilities by assuming an exponential rate.\n\nThe costs of 400\xa0mg/day, 600\xa0mg/day and 800\xa0mg/day imatinib and 50\xa0mg/day sunitinib in the Assessment Group's model were calculated from costs listed in BNF 58. Because sunitinib treatment is given for 4\xa0weeks followed by no treatment for 2\xa0weeks, the Assessment Group calculated the costs per year, and a proportional rate per month. The Assessment Group assumed that the cost for people receiving best supportive care was equivalent to the cost of 400\xa0mg/day imatinib (which all people on best supportive care also received).\n\nThe Assessment Group based resource costs for 600\xa0mg/day and 800\xa0mg/day imatinib on those reported by Wilson et al. (2005). The resource costs included GP visits and outpatient visits, including tests, computed tomography scans and the costs of managing adverse events. For sunitinib and best supportive care, the Assessment Group based resource costs on the manufacturer's submission for 'Sunitinib for the treatment of gastrointestinal stromal tumours' (NICE technology appraisal guidance 179). The Assessment Group adjusted the costs from 2008 to 2009 prices using the Hospital and Community Health Services Index.\n\nThe Assessment Group derived health state utility values from the EQ-5D and Chabot et al. (2008) in the absence of data from the available clinical studies. The utility value for progression-free survival for people whose disease responded to imatinib, regardless of dose, was assumed to be 0.935. The utility value for people receiving best supportive care was assumed to be 0.577 (Chabot et al. 2008). In the absence of alternative data, the utility value for people whose disease responded to sunitinib was assumed to be the same as that for imatinib, that is, 0.935.\n\nThe base-case results show that pathway 4 (600\xa0mg/day imatinib followed by, on disease progression, best supportive care plus 400\xa0mg/day imatinib) has an incremental cost-effectiveness ratio (ICER) of £27,304 per QALY gained compared with pathway 7 (50\xa0mg/day sunitinib then best supportive care plus 400\xa0mg/day imatinib). For pathway 2 (600\xa0mg/day imatinib, increasing to 800\xa0mg/day imatinib, then 50\xa0mg/day sunitinib followed by best supportive care plus 400\xa0mg/day imatinib) the ICER was £45,850 per QALY gained (compared with the next least costly option, pathway 4). For pathway 3 (600\xa0mg/day imatinib, then 50\xa0mg/day sunitinib followed by best supportive care plus 400\xa0mg/day imatinib) the ICER was £71,723 per QALY gained (compared with the next more costly option, pathway 4). Both pathway 5 (800\xa0mg/day imatinib, then 50\xa0mg/day sunitinib, followed by best supportive care plus 400\xa0mg/day imatinib) and pathway 6 (800\xa0mg/day imatinib, then best supportive care plus 400\xa0mg/day imatinib) were dominated by pathway 4 (that is, they were more costly and less effective). The estimated survival benefit of 800\xa0mg/day imatinib compared with best supportive care was 4.2\xa0months.\n\nThe Assessment Group also performed sensitivity analyses to account for uncertainties in the model. The parameters varied included structure and methodological assumptions around distribution, transition probabilities of survival and response to treatment with 600\xa0mg/day imatinib, utility values, and the costs of imatinib and sunitinib.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of increased doses of imatinib after disease progression on 400\xa0mg/day imatinib, having considered evidence on the nature of unresectable and/or metastatic GISTs and the value placed on the benefits of imatinib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed current clinical practice for the treatment of people with unresectable and/or metastatic GISTs. The Committee heard from the clinical specialists that, despite the recommendations in NICE technology appraisal guidance 86 (recommendation 1.4 states that an increase in the dose of imatinib is not recommended for people receiving imatinib who develop progressive disease after initially responding), people frequently receive 800\xa0mg/day imatinib when their disease progresses on 400\xa0mg/day imatinib if they have tolerated previous imatinib treatment. The clinical specialists reported that 600\xa0mg/day imatinib is rarely prescribed after disease progression on 400\xa0mg/day. The Committee was aware that NICE technology appraisal guidance 179 recommends that patients have the option to receive treatment with sunitinib after disease progression on 400\xa0mg/day imatinib. However, the clinical specialists explained to the Committee that clinicians often consider increasing the dose of imatinib before offering treatment with sunitinib because imatinib is considered to have a more favourable adverse event profile, even at higher doses, than sunitinib. They also noted that if a person's disease progresses on 400mg/day imatinib, it is common practice (in approximately 50% of people) to continue treatment with 400\xa0mg/day imatinib in addition to best supportive care if the person tolerates imatinib, however this is inconsistent with NICE technology appraisal guidance 86 which does not recommend continued treatment with imatinib after disease progression (recommendation 1.3). The Committee heard from patient experts that the limited data available suggest that imatinib at higher doses may be effective in prolonging survival and improving quality of life. Clinical specialists and patient experts also highlighted the importance of providing hope to people with metastatic GISTs by offering them additional treatment options after disease progression on 400\xa0mg/day imatinib. Despite the lack of clinical trial evidence to demonstrate the effectiveness of increased doses of imatinib treatment after disease progression on 400 mg/day imatinib, the Committee acknowledged that there is a perception among both patient experts and clinical specialists that treatment with 800\xa0mg/day imatinib after disease progression on 400\xa0mg/day imatinib may offer some benefit.\n\n## Clinical effectiveness\n\nThe Committee considered the evidence provided by the Assessment Group and the manufacturer on the clinical effectiveness of 600 and 800\xa0mg/day imatinib after disease progression on 400\xa0mg/day imatinib. The Committee heard from the Assessment Group that no randomised controlled trials were identified on the effectiveness of an increased dose of imatinib after disease progression on 400 mg/day imatinib compared with sunitinib or best supportive care – the two comparator treatments identified in the scope for this appraisal. Uncontrolled observational data were available evaluating the effectiveness of increased doses of imatinib in people with unresectable and/or metastatic GISTs who had not received previous imatinib treatment. However, the Committee was concerned that the populations in these studies differed from the population covered by this appraisal (that is, people whose disease has progressed on 400\xa0mg/day imatinib), and that the studies did not explore the comparisons defined in the scope. The Committee also noted that the populations in the studies varied substantially and that combining results may introduce more uncertainty. The Committee noted that this appraisal is a part review of NICE technology appraisal guidance 86, published in 2004, which was intended to only address whether increased doses of 600 or 800 mg/day imatinib could be recommended after disease progression on 400\xa0mg/day imatinib. The Committee noted that consultees had requested the review based on the belief that a large amount of clinical evidence about imatinib had been published since 2004. The Committee further noted that during the scoping process for this review consultees and commentators for this appraisal were given another opportunity to comment on the appropriateness of this review. The Committee was reminded that, at the time of the review proposal, the manufacturer of imatinib was seeking to extend the marketing authorisation for 800\xa0mg/day imatinib for unresectable and/or metastatic GISTs and that the manufacturer supported the review going ahead. However, in their submission and during the Committee meeting, the manufacturer stated that no new evidence had emerged since 2004 on the effectiveness of increased doses of imatinib after disease progression on 400\xa0mg/day imatinib. The Committee heard from the patient experts that they were disappointed that the available studies did not provide clear evidence about the effectiveness of higher doses of imatinib. The Committee agreed with the manufacturer and the Assessment Group that there is a lack of robust data available to demonstrate the effectiveness of increased doses of imatinib after disease progression on 400\xa0mg/day imatinib, and that the available evidence is associated with uncertainty and potential bias.\n\nThe Committee noted that the majority of available data related to people who received an increased dose of 800\xa0mg/day imatinib after disease progression on 400\xa0mg/day imatinib. Only one phase II study (B2222) described the experience of 43 people who received an increased dose of 600\xa0mg/day imatinib. The Committee heard that data from the Gastrointestinal Stromal Tumor Meta-Analysis Group (metaGIST) was published in March 2010. However, these data were not included in the Assessment Group's economic analyses because the population was randomised to higher doses of imatinib at baseline and had not received treatment with 400\xa0mg/day imatinib first. Therefore, the population in the metaGIST study was different from the population for this appraisal. The Committee discussed the possible biases in the evidence for increased doses of imatinib from the uncontrolled observational data. The Committee recognised that if people with a better prognosis preferentially received increased doses of imatinib, then any improvement in outcome might not be because of the use of higher doses. For example, the Committee was aware that in the B2222 study, people with disease progression on 400\xa0mg/day imatinib, received a higher dose of imatinib if they were described as having a good performance status (such as ECOG status <2). The Committee heard from the manufacturer that there are no ongoing trials that address the decision problem in this appraisal. The Committee heard from the clinical specialists that a trial comparing high-dose imatinib with sunitinib had been stopped after it failed to recruit a sufficient number of people. The Committee concluded that the Assessment Group had made a good effort to include all available data relevant to this appraisal in its report but was concerned about the lack of data and the nature of the evidence available.\n\nAfter receiving comments from consultees and commentators on the appraisal consultation document, the Committee considered the UK guideline for the management of GISTs that was published in May 2009. The Committee noted that the guideline contains the same evidence that was identified for this appraisal by the Assessment Group and the manufacturer, and that the development of the guideline had been sponsored by the manufacturer of imatinib. The Committee was aware that the guideline did not consider the cost effectiveness of any treatments and therefore the recommendations in this appraisal would likely be different from the guideline.\n\nThe Committee considered the effectiveness of imatinib in slowing disease progression in unresectable and/or metastatic GISTs. The Committee heard from the clinical specialists that comparable measures of disease progression had been used in the different clinical trials. The Committee heard that the three studies in which the dose of imatinib was increased from 400\xa0mg/day to 800\xa0mg/day showed that approximately one third of people had either a partial response or had stable disease after receiving the increased dose. The Committee concluded that imatinib treatment at higher doses may offer some benefit to people whose disease progresses on 400\xa0mg/day imatinib; however, because of the biases inherent to the clinical-effectiveness evidence available, it was aware that this conclusion was uncertain.\n\nThe Committee heard from the patient experts that measuring plasma concentrations of imatinib could be a major advantage, because it might allow an individualised approach to the dosing of imatinib. However, the clinical specialists noted that this does not happen in routine UK clinical practice, and the Committee noted that no data had been presented to demonstrate an association between plasma concentrations and outcomes. The Committee concluded that while measuring plasma concentrations of imatinib might potentially be of benefit in the future, it could not base any recommendations on this because of the current lack of evidence and because it was not done in routine clinical practice.\n\nThe Committee discussed whether benefits from increased doses of imatinib might be greater in certain subgroups of people. The Committee heard from the clinical specialists that there is some evidence suggesting that GISTs with certain mutations in the KIT gene are likely to be more or less sensitive to imatinib treatment. The clinical specialists suggested that the presence of an exon 9 mutation may be associated with a better outcome in people whose dose is increased to 800\xa0mg/day imatinib. In addition, the clinical specialists explained that, although outside the current marketing authorisation, clinicians might choose to begin treatment with 800\xa0mg/day imatinib without having tried lower doses in people with confirmed exon 9 mutations. However, they explained that the clinical evidence supporting this practice is based on the experience of a small number of people. The Committee also noted that data from a meta-analysis (metaGIST), in which people with exon 9 mutations started treatment on 800\xa0mg/day imatinib, showed that there was no statistically significant difference in overall survival between people with exon 9 mutations treated with 400\xa0mg/day imatinib compared with 800\xa0mg/day imatinib. Furthermore, in light of the limited data available, the Committee noted that any economic analyses for this subgroup would not be considered more robust than for the entire population. The Committee also understood that mutational analysis in people with progressive disease had a limited role, if any, in clinical decision-making about increasing imatinib doses. Therefore, the Committee concluded that there was not sufficient evidence to justify a separate recommendation for the use of 600 or 800\xa0mg/day imatinib for people with exon 9 mutations whose disease had progressed on imatinib 400\xa0mg/day.\n\nThe Committee considered the data reported by the Assessment Group for the comparator treatment, sunitinib. The Committee noted that this evidence was mainly from an 'expanded access programme', in which regulators allow investigational drugs to be used to treat people with serious or immediately life-threatening diseases who cannot participate in clinical trials and who have no alternative therapy. The Committee was aware that people in this study were treated with sunitinib after receiving higher (600 or 800\xa0mg/day) rather than lower (400\xa0mg/day) doses of imatinib and did not necessarily reflect the population of interest in this appraisal – that is, people whose disease progresses on 400\xa0mg/day imatinib.\n\n## Cost effectiveness\n\nThe Committee discussed the cost effectiveness of imatinib 600\xa0and 800\xa0mg/day after disease progression on 400\xa0mg/day imatinib. The Committee noted the Assessment Group's view that it had great difficulty undertaking an assessment of cost effectiveness in the absence of robust comparative clinical evidence for increased doses of imatinib after disease progression on 400 mg/day imatinib. The Committee also noted that the manufacturer stated that they would not submit an economic model because of the lack of robust data comparing increased doses of imatinib with sunitinib and best supportive care.\n\nThe Committee then considered the monthly mortality rates used in the Assessment Group's economic evaluation and noted that they were key drivers of the outcomes in the model. The Committee noted that a higher monthly mortality rate for people receiving sunitinib treatment was used in the Assessment Group's model than for people receiving best supportive care, which the Committee considered was implausible. The Committee heard from the Assessment Group that the limited evidence available reported that the mortality rate for 600\xa0mg/day imatinib was lower than the rate for 800\xa0mg/day imatinib, and that treatment with 800\xa0mg/day imatinib generated fewer life years and fewer QALYs than treatment with 600\xa0mg/day imatinib. The Committee considered these data implausible and agreed that this difference was unlikely to reflect the true effect of 600 and 800\xa0mg/day imatinib, but that this highlighted the limitations in the clinical evidence for the two doses. The Committee also noted that the monthly mortality rate applied for best supportive care appeared to be very low, despite these data being pooled from two studies that had been carried out before imatinib was introduced into clinical practice. The Committee also considered that when the studies were carried out, advanced diagnostic methods for GISTs did not exist, and that people may have had other tumours (for example, leiomyosarcoma) which were associated with a different mortality rate than for GISTs. The Committee was also aware that best supportive care was likely to have improved since the studies were carried out, leading to better outcomes, including lower mortality rates. The Committee concluded that, taking into account the limitations of the data used to derive the monthly mortality rates, the results presented by the Assessment Group may not reflect the true value of cost effectiveness of high doses of imatinib after disease progression on 400 mg/day imatinib and therefore should be interpreted with caution.\n\nThe Committee discussed the options for collecting data to establish outcomes in people receiving increased doses of imatinib or one of the comparator treatments defined in the scope. The Committee noted that despite the research recommendation in NICE technology appraisal guidance 86 (published in 2004) suggesting that a national register for people receiving imatinib treatment for GISTs be maintained, such a register had not been established. The Committee heard from the manufacturer that a national register for people with GISTs is currently being set up, with pilot testing expected to begin by the end of 2010. The Committee heard from the clinical specialists that a small register has also been set up in Scotland to collect long-term treatment outcomes for people with GISTs, and that observational data from specialist cancer centres in the USA may also be available. The Committee welcomed the initiative of the manufacturer to establish a register for people with GISTs and suggested that it is important that the register collects data on outcomes specific to unresectable and metastatic GISTs.\n\nThe Committee discussed the health-related quality of life of people with unresectable and/or metastatic GISTs. It noted that the Assessment Group did not identify any data to use in its economic model that specifically measured the quality of life of people with GISTs who received imatinib treatment. The Committee heard from patient experts that the health measures defined in the NICE reference case, such as the EQ-5D, might not capture the benefits that people gain from imatinib treatment. The Committee considered the utility value used in the Assessment Group's economic model for imatinib and sunitinib (0.935). The Committee considered that this value was implausibly high and noted that this value had been derived from three out of nine clinicians who had responded to a questionnaire. The Committee also noted that this utility value was higher than the value used in NICE technology appraisal guidance 179 on sunitinib for the treatment of GISTs after disease progression on imatinib treatment. Although the Assessment Group carried out some sensitivity analyses that varied the utility value, the Committee was not convinced that the most plausible value had been used and considered that this added further uncertainty to the model. The Committee also considered that using a more appropriate utility value would probably increase the ICER because the difference between the utility values for active treatment and the comparator would be smaller. Therefore, the Committee concluded that collecting utility data is important for any future informed decision-making for this population.\n\nThe Committee considered comments from consultees and commentators on the appraisal consultation document. The Committee heard that recommendations in NICE technology appraisal guidance 86 for stopping imatinib 400\xa0mg/day were not supported by clinical specialists. The Committee heard that consultees noted that the lack of clinical evidence for this appraisal was directly attributable to the rarity of GISTs. The Committee acknowledged that, although the rarity of GISTs did contribute to the lack of evidence, more could have been done to describe the clinical experience that exists. The consultees and commentators repeated the Committee's concerns that a disease register had not been established since the publication of NICE technology appraisal guidance 86. The Committee also noted that the Assessment Group had highlighted issues contributing to the uncertainty about the clinical and cost effectiveness of imatinib at increased doses after disease progression on 400\xa0mg/day. These issues include differing study populations, a lack of clinical evidence, and particularly sparse data on the clinical pathway of treatment with sunitinib after disease progression on 400\xa0mg/day imatinib. The Committee appreciated the point made by consultees and commentators that, as this appraisal affected only a small group of people, giving clinicians the discretion to prescribe imatinib at doses higher than 400\xa0mg/day would have little overall financial impact on the NHS. However, the Committee emphasised that (in line with NICE's 'Guide to the methods of technology appraisal') the potential budget impact of the adoption of a new technology does not determine its decision.\n\nThe Committee explored whether it was possible to estimate a most plausible ICER. The Committee noted that the lowest ICER calculated by the Assessment Group was £27,300 per QALY gained for 600\xa0mg/day imatinib after disease progression on 400 mg/day imatinib compared with sunitinib. However, in light of the inconsistencies in the model inputs and in the results, it recognised that this value was associated with considerable uncertainty, and should be interpreted with caution. The Committee discussed whether making any changes to the major assumptions made by the Assessment Group or further modelling might reduce the uncertainty in the estimates of cost effectiveness for high doses of imatinib. The Committee noted that any further modelling would need estimates of disease progression and mortality rates to be plausible as well as comparable across different treatment arms. The Committee agreed that all of the following changes in the assumptions would be likely to increase the ICER associated with imatinib treatment at increased doses:\n\nDecreasing the utility value for imatinib and sunitinib from 0.935 to a more plausible value.\n\nAssuming that only 50%, rather than 100%, of people receive 400\xa0mg/day imatinib in addition to best supportive care after progression of disease at higher doses of imatinib, which is in line with current clinical practice.\n\nAssuming that no one receives 400\xa0mg/day imatinib in addition to best supportive care after progression of disease at higher doses of imatinib, which is in line with current NICE recommendations.\n\nUsing more up-to-date estimates of the effectiveness of best supportive care, which is assumed to be more effective now than when the data used in the modelling were collected.\n\nAccounting for utility values for additional adverse events associated with higher doses of imatinib.\n\nUsing a more realistic effectiveness estimate for sunitinib treatment – this would be likely to increase the ICER for imatinib compared with sunitinib.Because these assumptions would increase rather than decrease the ICERs for increased doses of imatinib, the Committee concluded that it was highly likely that the ICERs for 600\xa0or 800\xa0mg/day imatinib after disease progression on 400 mg/day imatinib, compared with best supportive care or with sunitinib were above £30,000 per QALY gained.\n\nBecause of the lack of robust clinical effectiveness evidence available, the Committee explored if there were any other approaches for exploring a most plausible ICER. The Committee acknowledged that when imatinib was first appraised in 2004 (NICE technology appraisal guidance 86), the results of the model from the Decision Support Unit (DSU) suggested that 400\xa0mg/day imatinib had an ICER of approximately £32,000 per QALY gained compared with best supportive care. In addition, the ICER for 600\xa0mg/day imatinib after disease progression on 400 mg/day compared with best supportive care was estimated to be £39,000 per QALY gained. The Committee noted that at the time these results were considered to be uncertain and that since then no clinical evidence has been published that would improve the robustness of the modelling results or reduce the uncertainty of the cost effectiveness of imatinib at increased doses. The Committee also considered that, given that the acquisition cost of 600\xa0and 800 mg/day imatinib is obviously much higher than the cost of 400\xa0mg/day imatinib, higher doses would need to be substantively more effective to be considered cost effective. The Committee concluded that the available evidence does not suggest that higher doses of imatinib lead to a substantive increase in effectiveness for the treatment of unresectable and/or metastatic GISTs after disease progression on 400 mg/day imatinib and that using this approach corroborates the conclusion that the most plausible ICER for 600\xa0or 800\xa0mg/day imatinib compared with best supportive care or with sunitinib was above £30,000 per QALY gained.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations. In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe Committee was aware that the number of people newly diagnosed with GISTs in England and Wales ranges from approximately 200 to 2000 per year. It noted that imatinib has a marketing authorisation for a number of other indications in addition to the treatment of unresectable and/or metastatic GISTs. The Committee noted that for people with unresectable GISTs, prognosis is poor, with survival generally less than 2 years without further treatment. The Committee noted that in the economic model the survival benefit following treatment with imatinib 800\xa0mg/day compared with best supportive care was 4.2 months. However, the Committee agreed that the evidence for this life extension could not be considered sufficiently robust, considering the uncertainty about the assumptions in the economic model, and the lack of comparative clinical effectiveness data. In addition, the Committee noted that the results of the meta-analysis (metaGIST) showed no overall survival benefit for people receiving 800 mg/day imatinib compared with people receiving 400 mg/day imatinib in people with exon 9 mutations. The Committee therefore concluded that increased doses of imatinib after disease progression on 400\xa0mg/day imatinib did not meet the criteria for being a life-extending, end-of-life treatment.\n\nThe Committee considered whether its recommendation was associated with any potential issues related to equality, and noted comments made during consultation on the appraisal consultation document that not recommending 600 or 800mg/day of imatinib following disease progression with 400mg/day imatinib unfairly discriminates against people with rare diseases. The Committee also noted the respective consultees' acknowledgement that having a rare disease does not constitute one of the protected characteristics in the current equalities legislation or the Equality Act. However, the Committee was aware that it has general Public Law obligations of fairness and reasonableness in respect of the impact of its guidance on patients. The Committee was also aware that the Human Rights Act and article 14 of the European Convention on Human Rights (ECHR) can protect groups of people other than those covered by the UK equalities legislation. As regards article 14 ECHR, the Committee noted that it was not clear that patients affected by this appraisal or those with an exon 9 mutation would be regarded as a 'group' protected by article 14, nor that any of the substantive ECHR articles was engaged. In relation to both the ECHR obligations and public law requirements, the Committee considered that its recommendation did not unfairly disadvantage any groups within the remit of this appraisal. The Committee noted that its role was to appraise clinical and cost effectiveness and that in relation to each technology it is required to consider the robustness or otherwise of the available evidence. The Committee took into account the lack of robust clinical evidence for a survival benefit of higher doses of imatinib, specifically for the subgroup of people that have been reported to respond better, that is people with an exon 9 mutation. The Committee was also aware that an alternative treatment option is available for this group of people because NICE technology appraisal guidance 179 recommends that patients have the option to receive treatment with sunitinib after disease progression on 400 mg/day imatinib. The Committee was satisfied that its recommendation was consistent with NICE's legislative obligations under the equalities legislation and the requirement for fairness.\n\nIn summary, the Committee agreed that clinical opinion suggests that increased doses of imatinib after disease progression on 400\xa0mg/day imatinib may offer benefit to some people. However, since the previous appraisal of imatinib (NICE technology appraisal guidance 86), there are no new good-quality data on the clinical effectiveness of increasing the dose of imatinib. The Committee concluded that the current available clinical and cost-effectiveness evidence does not justify a positive recommendation for the use of imatinib at increased doses of 600\xa0mg/day and 800\xa0mg/day as an appropriate use of NHS resources for the treatment of people with unresectable and/or metastatic GISTs whose disease has progressed on 400\xa0mg/day imatinib.\n\n# Summary of the Appraisal Committee's key conclusions\n\nTA 209 (MTA): Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours (part review of technology appraisal guidance 86)\n\n\n\nFAD section\n\nKey conclusion\n\n\n\nImatinib at 600 or 800\xa0mg/day is not recommended for people with unresectable and/or metastatic gastrointestinal stromal tumours whose disease has progressed after treatment with 400\xa0mg/day imatinib.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Appraisal Committee considered that there was an absence of new good-quality evidence since the previous appraisal of imatinib (NICE technology appraisal guidance 86) was published, and that the data available, including a most plausible ICER above £30,000 per QALY gained, do not justify a positive recommendation for the use of imatinib at increased doses of 600 mg/day and 800 mg/day after progression at 400mg/day, as an appropriate use of NHS resources.\n\n\n\nCurrent practice\n\nClinical need of patients including the availability of alternative treatments\n\nClinical specialists and patient experts highlighted the importance of providing hope to people with metastatic GISTs by offering them additional treatment options after disease progression on 400\xa0mg/day imatinib.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits and how it might improve the way that current need is met (is this a 'step-change' in the management of the condition?)\n\nDespite the lack of clinical trial evidence to demonstrate the effectiveness of increased doses of imatinib treatment after disease progression on 400 mg/day imatinib, the Committee acknowledged that there is a perception among both patient experts and clinical specialists that treatment with 800\xa0mg/day imatinib after disease progression on 400\xa0mg/day imatinib may offer some benefit.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee heard from the clinical specialists that, despite the recommendations in NICE technology appraisal guidance 86 (recommendation 1.4 states that an increase in the dose of imatinib is not recommended for people receiving imatinib who develop progressive disease after initially responding), people frequently receive 800\xa0mg/day imatinib when their disease progresses on 400\xa0mg/day imatinib if they have tolerated previous imatinib treatment. The clinical specialists noted that if a person's disease progresses on higher doses of imatinib, it is common practice (in approximately 50% of people) to continue treatment with 400\xa0mg/day imatinib in addition to best supportive care if the person tolerates imatinib, however this is inconsistent with TA86 which does not recommend continued treatment with imatinib after disease progression (recommendation 1.3).\n\n\n\nAdverse effects\n\nThe clinical specialists explained to the Committee that clinicians often consider increasing the dose of imatinib before offering treatment with sunitinib because imatinib is considered to have a more favourable adverse event profile, even at higher doses, than sunitinib.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nNo randomised controlled trials were identified on the effectiveness of an increased dose of imatinib after disease progression on 400 mg/day imatinib compared with sunitinib or best supportive care – the two comparator treatments identified in the scope to this appraisal.\n\n\n\n\n\n\n\n\n\n\n\nThe Committee agreed with the manufacturer and the Assessment Group that there is a lack of robust data available to demonstrate the effectiveness of increased doses of imatinib after disease progression on 400 mg/day imatinib, and that the available evidence is associated with uncertainty and potential bias.\n\n\n\n\n\n\n\nThe Committee noted that the majority of available data related to people who received an increased dose of 800\xa0mg/day imatinib after disease progression on 400\xa0mg/day imatinib. The Committee heard from the manufacturer that there are no ongoing trials that address the decision problem in this appraisal.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee heard from the clinical specialists that people frequently receive 800\xa0mg/day imatinib when their disease progresses on 400\xa0mg/day imatinib if they have tolerated previous imatinib treatment. The clinical specialists reported that 600\xa0mg/day imatinib is rarely prescribed after disease progression on 400\xa0mg/day.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee heard from the patient experts that measuring plasma concentrations of imatinib could offer a major advantage, because it might allow an individualised approach to the dosing of imatinib. The Committee concluded that while measuring plasma concentrations of imatinib might potentially be of benefit in the future, it could not base any recommendations on this because of the current lack of evidence and because it was not done in routine clinical practice.\n\n\n\n\n\nUncertainties generated by the evidence\n\nSee 'Availability, nature and quality of evidence' above\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee considered the data reported by the Assessment Group for the comparator treatment, sunitinib. The Committee was aware that people in this study were treated with sunitinib after receiving higher (600 or 800\xa0mg/day) rather than lower (400\xa0mg/day) doses of imatinib and did not necessarily reflect the population of interest in this appraisal – that is, people whose disease progresses on 400\xa0mg/day imatinib.\n\n\n\n\n\n\n\nThe Committee also noted that the Assessment Group had highlighted issues contributing to the uncertainty about the clinical and cost effectiveness of imatinib at increased doses after disease progression on 400\xa0mg/day. These issues include differing study populations, a lack of clinical evidence, and particularly sparse data on the clinical pathway of treatment with sunitinib after disease progression on 400\xa0mg/day imatinib.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness\n\nThe Committee discussed whether benefits from increased doses of imatinib might be greater in certain subgroups of people. The Committee heard from the clinical specialists that there is some evidence suggesting that GISTs with certain mutations in the KIT gene are likely to be more or less sensitive to imatinib treatment. The clinical specialists suggested that the presence of an exon 9 mutation may be associated with a better outcome in people whose dose is increased to 800\xa0mg/day imatinib. However, they explained that the clinical evidence supporting this practice is based on the experience of a small number of people. The Committee also noted that data from a meta-analysis (metaGIST), in which people with exon 9 mutations started treatment on 800\xa0mg/day imatinib, showed that there was no statistically significant difference in overall survival between people with exon 9 mutations treated with 400\xa0mg/day imatinib compared with 800\xa0mg/day imatinib. The Committee also understood that mutational analysis in people with progressive disease had a limited role, if any, in clinical decision-making about increasing imatinib doses.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee heard that the three studies in which the dose of imatinib was increased from 400 to 800\xa0mg/day showed that approximately one third of people had either a partial response or had stable disease after receiving the increased dose. The Committee concluded that imatinib treatment at higher doses may offer some benefit to people whose disease progresses on 400\xa0mg/day imatinib; however, because of the biases inherent to the clinical-effectiveness evidence available, it was aware that this conclusion was uncertain.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee noted the Assessment Group's view that it had great difficulty undertaking an assessment of cost effectiveness in the absence of robust comparative clinical evidence for increased doses of imatinib after disease progression on 400 mg/day imatinib. The Committee also noted that the manufacturer stated that they would not submit an economic model because of the lack of robust data comparing increased doses of imatinib with sunitinib and best supportive care.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nKey uncertainties in the clinical effectiveness evidence followed through to the economic analysis. A key uncertainty in the economic analysis was the monthly mortality rates assumed for sunitinib, best supportive care and for increased doses of imatinib. The Committee concluded that, taking into account the limitations of the data used to derive the monthly mortality rates, the results presented by the Assessment Group may not reflect the true value of cost effectiveness of high doses of imatinib after disease progression on 400 mg/day imatinib and therefore should be interpreted with caution.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee discussed whether making any changes to the major assumptions made by the Assessment Group or further modelling might reduce the uncertainty in the estimates of cost-effectiveness for high doses of imatinib. The Committee noted that any further modelling would need estimates of disease progression and mortality rates to be plausible as well as comparable across different treatment arms. The Committee noted that these changes would be likely to increase the ICER (that is, worsen the cost-effectiveness) associated with imatinib at increased doses.\n\n\n\n\n\n\n\nIncorporation of health-related quality of life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the quality-adjusted life year (QALY) calculation? How have these been separately evaluated and what is the impact (if any) on the judgement of the most plausible incremental cost-effectiveness ratio) ICER?\n\nThe Assessment Group did not identify any data to use in its economic model that specifically measured the quality of life of people with GISTs who received imatinib treatment.\n\n\n\nThe Committee considered the utility value used in the Assessment Group's economic model for imatinib and sunitinib (0.935). The Committee considered that this value was implausibly high and noted that this value had been derived from three out of nine clinicians who had responded to a questionnaire. The Committee also noted that this utility value was higher than the value used in NICE technology appraisal guidance 179 on sunitinib for the treatment of GISTs after disease progression on imatinib treatment. Although the Assessment Group carried out some sensitivity analyses that varied the utility value, the Committee was not convinced that the most plausible value had been used and considered that this added further uncertainty to the model.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee noted that data from the metaGIST study, in which people with exon 9 mutations started treatment on 800 mg/day imatinib, showed that there was no statistically significant difference in overall survival between people with exon 9 mutations treated with 400 mg/day imatinib compared with 800 mg/day imatinib. Furthermore, in light of the limited data available, the Committee noted that any economic analysis for this subgroup would not be considered more robust than for the entire population. Therefore, the Committee concluded that there was not sufficient evidence to justify a separate recommendation for the use of 600 or 800\xa0mg/day imatinib for people with exon 9 mutations whose disease had progressed on imatinib 400\xa0mg/day.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee considered the monthly mortality rates used in the Assessment Group's economic model and noted that they were key drivers of the outcomes in the model.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee noted that the lowest ICER calculated by the Assessment Group was £27,300 per QALY gained for 600\xa0mg/day imatinib after disease progression on 400 mg/day imatinib compared with sunitinib. However, in light of the inconsistencies in the model inputs and in the results, it recognised that this value was associated with considerable uncertainty, and should be interpreted with caution. The Committee discussed whether making any changes to the major assumptions made by the Assessment Group or further modelling might reduce the uncertainty in the estimates of cost effectiveness for high doses of imatinib. Because changes to the assumptions would worsen rather than improve the cost effectiveness of increased doses of imatinib, the Committee concluded that it was highly likely that the ICERs for 600 or 800 mg/day imatinib after disease progression on 400 mg/day imatinib compared with best supportive care or with sunitinib was above £30,000 per QALY gained.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee acknowledged that when imatinib was first appraised in 2004 (TA86) the results of the model from the Decision Support Unit (DSU) suggested that the ICER for 600 mg/day imatinib after disease progression on 400 mg/day compared with best supportive care was £39,000 per QALY gained. The Committee noted that at the time these results were considered to be uncertain and since then no clinical evidence has been published that would improve the robustness of the modelling results or reduce the uncertainty of the cost effectiveness of imatinib at increased doses. It concluded that using this approach corroborates the conclusion that the most plausible ICER for 600 or 800 mg/day imatinib compared with best supportive care or with sunitinib was above £30,000 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (Pharmaceutical Price Regulation Programme)\n\nNot applicable.\n\n-\n\nEnd-of-life considerations\n\nThe Committee concluded that increased doses of imatinib after disease progression on 400 mg/day imatinib did not meet the criteria for being a life-extending, end-of-life treatment.\n\n, 4.3.18\n\nEqualities considerations, Social Value Judgement\n\nDuring ACD consultation, comments were made that not recommending 600 or 800mg/day imatinib following disease progression with 400mg/day imatinib unfairly discriminates against people with rare diseases. The respective consultees acknowledged that having a rare disease does not constitute one of the protected characteristics in the current equalities legislation or the Equality Act. However, the Committee took also into account general Public Law obligations of fairness and reasonableness and the Human Rights Act and article 14 of the European Convention on Human Rights (ECHR) The Committee noted that it was not clear that patients affected by this appraisal or those with an exon 9 mutation would be regarded as a 'group' protected by article 14, nor that any of the substantive ECHR articles was engaged. In relation to both the ECHR obligations and public law requirements, the Committee considered that its recommendation did not unfairly disadvantage any groups within the remit of this appraisal. The Committee took into account the lack of robust clinical evidence for a survival benefit of higher doses of imatinib, specifically for the subgroup of people that have been reported to respond better, that is people with an exon 9 mutation. The Committee was also aware that an alternative treatment option is available for this group of people because NICE technology appraisal guidance 179 recommends that patients have the option to receive treatment with sunitinib after disease progression on 400 mg/day imatinib. The Committee was satisfied that its recommendation was consistent with NICE's legislative obligations under the equalities legislation and the requirement for fairness.\n\n", 'Recommendations for further research ': 'The Committee concluded that there were substantial gaps in the evidence and that research into the following areas should be considered:\n\nA national register should be maintained for all people with GISTs being treated with imatinib, sunitinib and best supportive care (to support future appraisals of treatments for this patient group). Details should include patient characteristics, dose and duration of treatment, tumour response rates and survival, both with and after discontinuation of treatment.\n\nThe use of mutational analysis to predict individual response to imatinib treatment and long-term outcomes.\n\nThe use of plasma level measurement to individualise imatinib treatment and to optimise long-term outcomes.', 'Related NICE guidance': 'Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours.NICE technology appraisal guidance 86 (2004).\n\nSunitinib for the treatment of gastrointestinal stromal tumours. NICE technology appraisal guidance 179 (2009).', 'Review of guidance': 'The guidance on this technology will be considered for review in August 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveNovember 2010', 'Changes after publication': 'September 2013: correction to show that recommendation 1.5 in TA 86 had been updated, rather than recommendation 1.4.\n\nMarch 2012: minor maintenance.', 'About this guidance': "NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nThis guidance updates recommendation 1.5 of NICE technology appraisal guidance 86 (TA86) 'Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours'. All other recommendations in TA86 still stand.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE."}
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https://www.nice.org.uk/guidance/ta209
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Evidence-based recommendations on imatinib for treating unresectable or metastatic gastrointestinal stromal tumours in adults.
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